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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.)

A 6-year-old intact female domestic dwarf rabbit (Oryctolagus cuniculus) was referred because of a chronic obstructive rhinitis not resolving despite antibiotic treatments. Computed tomography examination revealed 2 sub-obstructive structures of mineral density in the right nasal cavity and nasopharynx. Neoplasia and rhinolithiasis were the main differential diagnoses. A dorsal rhinostomy was performed and 1 mineralized lesion was removed. Infrared spectrophotometric and histological examinations of the lesion and nasal mucosa were consistent with a 100% calcium carbonate rhinolith with bacterial colonization and chronic lymphocytic rhinitis. Clinical signs improved during the first 4 wk following surgery. However, despite inhaled anti-inflammatory treatment, the rabbit's condition deteriorated when the rhinostomy site closed, and she died 7 wk after surgery. Rhinolith and lymphocytic rhinitis should be considered as differential diagnoses for upper respiratory tract signs in rabbits resistant to antimicrobial treatment. Key clinical message: Rhinolithiasis and chronic lymphocytic rhinitis should be included in the differential diagnoses of rabbits presenting with chronic obstructive upper respiratory tract signs characterized by purulent nasal discharge and failure of treatment despite adequate antimicrobial therapy, especially with unilateral signs. Computed tomography and rhinoscopy with biopsies are suggested to explore those possibilities., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)

Background: Epithelial-mesenchymal transition (EMT) plays a crucial role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). However, the involvement of small extracellular vesicles (sEVs) in EMT and their contributions to CRSwNP has not been extensively investigated., Methods: SEVs were isolated from nasal mucosa through ultracentrifugation. MicroRNA sequencing and reverse-transcription quantitative polymerase chain reaction were employed to analyze the differential expression of microRNAs carried by sEVs. Human nasal epithelial cells (hNECs) were used to assess the EMT-inducing effect of sEVs/microRNAs. EMT-associated markers were detected by western blotting and immunofluorescence. Dual-luciferase reporter assay was performed to determine the target gene of miR-375-3p. MicroRNA mimic, lentiviral, and plasmid transduction were used for functional experiments., Results: In line with the greater EMT status in eosinophilic CRSwNP (ENP), sEVs derived from ENP (ENP-sEVs) could induce EMT in hNECs. MiR-375-3p was elevated in ENP-sEVs compared to that in control and nonENP. MiR-375-3p carried by ENP-sEVs facilitated EMT by directly targeting KH domain containing RNA binding (QKI) at seed sequences of 913-919, 1025-1033, and 2438-2444 in 3’-untranslated region. Inhibition of QKI by miR-375-3p overexpression promoted EMT, which could be reversed by restoration of QKI. Furthermore, the abundance of miR-375-3p in sEVs was closely correlated with the clinical symptom score and disease severity., Conclusions: MiR-375-3p-enriched sEVs facilitated EMT by suppressing QKI in hNECs. The association of miR-375-3p with disease severity underscores its potential as both a diagnostic marker and a therapeutic target for the innovative management of CRSwNP.

Objectives: Prior studies evaluating the role of sinonasal anatomic variants with recurrent acute rhinosinusitis (RARS) are limited by inconsistent results. The goal of this study is to evaluate the association between sinonasal anatomic variants and RARS., Methods: A 1:2 retrospective case-control study was conducted using patients presenting to the rhinology clinic from August 2020 to January 2023. A total of 60 patients with RARS were compared to 120 control patients. RARS was diagnosed based on the International Consensus Statement on Allergy and Rhinology criteria of four or more independent episodes of acute rhinosinusitis per year with at least one episode documented by objective findings, with complete resolution of the infection in-between episodes. Sinonasal anatomic variants included nasal septal deviation (NSD), concha bullosa (CB), infraorbital (Haller) cells, nasal septal spur in the middle meatus, and frontal sinus cells (supra-agger, supra-agger frontal, and suprabullar frontal cells)., Results: Age was similar in RARS and control patients (47.4 ± 16.5 vs. 49.3 ± 14.5, p = 0.432). Both the RARS group and control group were more likely to be female (78.3% vs. 77.5%, p = 0.899). There was no significant association between NSD and RARS compared to the control group (OR = 0.97, p = 0.916), and no significant association between any of the anatomic variants and RARS [infraorbital cells (OR = 0.64, p = 0.167), CB (OR = 0.84, p = 0.596), spur in the middle meatus (OR = 1.28, p = 0.514), supra-agger (OR = 0.88, p = 0.708), supra-agger frontal cells (OR = 0.97, p = 0.939), or suprabullar frontal cells (OR = 1.13, p = 0.766)]., Conclusion: Our findings suggest no association between nasal septal deviation or any of the anatomic variants studied and RARS., Level of Evidence: 3 Laryngoscope, 134:3489-3492, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Chronic rhinosinusitis (CRS) is a highly prevalent airway disease worldwide. Whereas eosinophilic CRS with nasal polyps (eCRSwNP) represents its most severe phenotype, pathogenic mechanisms remain poorly understood despite a wide spectrum of in vitro and in vivo experimental models. A mouse model of experimental ovalbumin (OVA)-induced airway allergy with coadministration of Staphylococcus aureus enterotoxin B (SEB) has been widely used to study eosinophilic eCRSwNP. This study revisits the features of this model and its suitability for studying eCRS., Methodology: We implemented the most used eCRSwNP mouse model based on OVA+SEB intranasal challenges. Readouts including inflammatory features by (immuno)histology of the sinonasal epithelium (NP formation, eosinophils, epithelial and basement membrane thickness, fibrosis, goblet cells, Charcot-Leyden crystals (CLC)-like, tight junctions) and IgE production by enzyme-linked immunosorbent assay (ELISA), were compared to features of the corresponding human disease., Results: The OVA+SEB model induced eosinophilic inflammation of upper and lower airways, with epithelial and basement membrane thickening, goblet cell hyperplasia and subepithelial fibrosis in the sinuses, along increased IgE production. Except local IgE in nasal lavage (NL), which was only increased in OVA+SEB group, all other features did not differ between OVA and OVA+SEB groups. Macro- or microscopic NP were not detected., Conclusions: With the notable exception of local IgE production, the addition of SEB did not induce additional inflammatory or structural change in the sinuses from mice exposed to and challenged with OVA. This model might represent a model for severe upper airway allergy rather than a specific model of human eCRSwNP.

Objective: To investigate the effect of nasal mucosa-derived ectodermal mesenchymal stem cells (NM-EMSCs) on the inflammatory state of rats with chronic rhinosinusitis (CRS) and the underlying therapeutic mechanism., Methods: NM-EMSCs were isolated and extracted to construct a rat model of CRS. Fifteen Sprague‒Dawley (SD) rats were randomly divided into three groups: CK + NS group rats were injected locally with saline in the nasal mucosa; CRS + NS group rats were injected locally with saline in the nasal mucosa; and CRS + EMSCs group rats were injected locally with NM-EMSCs in the nasal mucosa. One rat from the CRS + EMSCs group was randomly euthanized at 2, 4, and 6 days after injection, and the nasal mucosa tissues were collected for HE staining, Masson's trichrome staining, and periodic acid-Schiff staining., Results: NM-EMSCs specifically expressing CD73, CD105, and CD90 were successfully isolated from the nasal mucosa of rats and were able to differentiate into adipocytes, osteoblasts, and chondrocytes. After saline and NM-EMSC injection, compared with those in the blank control CK + NS group, the nasal mucosa in the CRS + NS and CRS + EMSC groups exhibited obvious thickening, a large amount of inflammatory cell infiltration, and increased collagen and mucin distribution. Four days post-NM-EMSC injection, the thickening of the nasal mucosa in the CRS group was gradually alleviated, the inflammatory cell infiltration gradually decreased, and the distribution of collagen and mucin and the collagen-positive area gradually decreased. Moreover, only a small number of inflammatory cells were visible, and the distribution of mucins was limited to 6 days post-NM-EMSC injection., Conclusion: NM-EMSCs effectively attenuated inflammation in the nasal mucosa of CRS model rats., (© 2024 The Author(s). Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Background: Endoscopic sinus surgery (ESS) could significantly improve olfactory function among patients with chronic rhinosinusitis (CRS). This study aimed to perform a meta-analysis to evaluate the effect of ESS on the olfactory bulb volume (OBV) among patients with CRS., Methods: A systemic search of PubMed, Medline, Embase, Web of Science, and other databases was conducted to identify studies assessing OBV changes in patients with CRS after ESS utilizing magnetic resonance imaging., Results: A total of four studies with 168 participants were included. Comparing the changes in OBV of patients with CRS before and after surgery within 3-6 months, the ESS significantly improved the overall OBV ( P  = 0.005, I 2  = 66%), with the left OBV increased by 5.57mm 3 ( P  = 0.84, I 2  = 0%), and the right OBV increased by 8.63mm 3 ( P  = 0.09, I 2  = 53%). A difference in OBV persists between healthy controls and patients with CRS 3-6 months after ESS. The overall OBV of patients with CRS after ESS was significantly smaller than controls (mean difference = -3.84, P  = 0.04), with a mean difference of 4.13mm 3 on the left side ( P  = 0.72, I 2  = 0%), and a mean difference of 3.22mm 3 on the right side ( P  = 0.0001, I 2  = 89%)., Conclusions: ESS significantly increases the OBV among patients with CRS., 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.

The olfactory epithelium (OE) is directly exposed to environmental agents entering the nasal cavity, leaving OSNs prone to injury and degeneration. The causes of olfactory dysfunction are diverse and include head trauma, neurodegenerative diseases, and aging, but the main causes are chronic rhinosinusitis (CRS) and viral infections. In CRS and viral infections, reduced airflow due to local inflammation, inflammatory cytokine production, release of degranulated proteins from eosinophils, and cell injury lead to decreased olfactory function. It is well known that injury-induced loss of mature OSNs in the adult OE causes massive regeneration of new OSNs within a few months through the proliferation and differentiation of progenitor basal cells that are subsequently incorporated into olfactory neural circuits. Although normal olfactory function returns after injury in most cases, prolonged olfactory impairment and lack of improvement in olfactory function in some cases poses a major clinical problem. Persistent inflammation or severe injury in the OE results in morphological changes in the OE and respiratory epithelium and decreases the number of mature OSNs, resulting in irreversible loss of olfactory function. In this review, we discuss the histological structure and distribution of the human OE, and the pathogenesis of olfactory dysfunction associated with CRS and viral infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kikuta, Nagayama and Hasegawa-Ishii.)

Background: Elevated body mass index (BMI) has been recognized as an important contributor to corticosteroid insensitivity in chronic rhinosinusitis with nasal polyps (CRSwNP). We aimed to delineate the effects of elevated BMI on immunological endotype and recurrence in CRSwNP individuals., Methodology: A total of 325 patients with CRSwNP undergoing FESS were recruited and stratified by BMI. H&E staining was employed for histological evaluation. Characteristics of inflammatory patterns were identified by immunohistochemical staining. The predictive factors for recurrence were determined and evaluated by multivariable logistic regression analysis and the receiver operating characteristic (ROC) curves across all subjects and by weight group., Results: In all patients with CRSwNP, 26.15% subjects were classified as overweight/obese group across BMI categories and exhibited a higher symptom burden. The upregulated eosinophil/neutrophil-dominant cellular endotype and amplified type 2/ type 3 coexisting inflammation was present in overweight/obese compared to underweight/normal weight controls. Additionally, a higher recurrent proportion was shown in overweight/obese patients than that in underweight/normal weight cohorts. Multivariable logistic regression analysis identified BMI as an independent predictor for recurrence. The predictive capacity of each conventional parameter (tissue eosinophil and CLCs count, and blood eosinophil percentage) alone or in combination was poor in overweight/obese subjects., Conclusions: Overweight/obese CRSwNP stands for a unique phenotype and endotype. Conventional parameters predicting recurrence are compromised in overweight/obese CRSwNP, and there is an urgent need for novel biomarkers that predict recurrence for these patients.

Background: SERPINB2, a biomarker of Type-2 (T2) inflammatory processes, has been described in the context of asthma. Chronic rhinosinusitis with nasal polyps (CRSwNP) is also correlated with T2 inflammation and elevated 15LO1 induced by IL-4/13 in nasal epithelial cells. The aim of this study was to evaluate the expression and location of SERPINB2 in nasal epithelial cells (NECs) and determine whether SERPINB2 regulates 15LO1 and downstream T2 markers in NECs via STAT6 signalling., Methods: SERPINB2 gene expression in bulk and single-cell RNAseq database was analysed by bioinformatics analysis. SERPINB2, 15LO1 and other T2 markers were evaluated from CRSwNP and HCs NECs. The colocalization of SERPINB2 and 15LO1 was evaluated by immunofluorescence. Fresh NECs were cultured at an air-liquid interface with or without IL-13, SERPINB2 Dicer-substrate short interfering RNAs (DsiRNAs) transfection, exogenous SERPINB2, 15-HETE recombinant protein and pSTAT6 inhibitors. 15LO1, 15-HETE and downstream T2 markers were analysed by qRT-PCR, western blot and ELISA., Results: SERPINB2 expression was increased in eosinophilic nasal polyps compared with that in noneosinophilic nasal polyps and control tissues and positively correlated with 15LO1 and other downstream T2 markers. SERPINB2 was predominantly expressed by epithelial cells in NP tissue and was colocalized with 15LO1. In primary NECs in vitro, SERPINB2 expression was induced by IL-13. Knockdown or overexpression SERPINB2 decreased or enhanced expression of 15LO1 and 15-HETE in NECs, respectively, in a STAT6-dependent manner. SERPINB2 siRNA also inhibited the expression of the 15LO1 downstream genes, such as CCL26, POSTN and NOS2. STAT6 inhibition similarly decreased SERPINB2-induced 15LO1., Conclusions: SERPINB2 is increased in NP epithelial cells of eosinophilic CRSwNP (eCRSwNP) and contributes to T2 inflammation via STAT6 signalling. SERPINB2 could be considered a novel therapeutic target for eCRSwNP., (© 2024 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Background: Functional endoscopic sinus surgery is a principal option for treating chronic rhinosinusitis with nasal polyps (CRSwNP) after medication failures. Unfortunately, some patients still have unsatisfactory postoperative recovery. The type of inflammatory cell infiltration in nasal polyp tissue has been reported available for recurrence prediction. As it is invasive and time-consuming, this technique is hard to promote clinically under the existing technical conditions. And during the course of clinical treatment, we have noted that differences in the postoperative recurrence rate of patients present among different traditional Chinese medicine syndrome types., Methods and Analysis: This is a non-randomized, single-center, and prospective cohort study started in Chengdu Sichuan Province, People's Republic of China, in January 2021. A total of 200 participants will be recruited from patients who are diagnosed with CRSwNP and prepared for functional endoscopic sinus surgery. We collect preoperative data which includes general information, medical history, TCM syndromes, visual analogue scale (VAS) of subjective symptoms, Lund-Kennedy endoscopic score, and Lund-Mackay score of computed tomography (CT) scanning of sinuses. We acquire the VAS score and Lund-Kennedy score of subjective symptoms through multiple planned follow-up after surgery. After 1 year of follow-up, the recurrence rate will be calculated, and the curative effect will be assessed. Meanwhile, the patients' pathological sections will be sorted out, and inflammatory cell infiltration will be analyzed. Statistical analysis will be carried out to evaluate the correlation among CRSwNP recurrence and TCM syndrome types and tissue inflammatory cell infiltration types. Then we will establish a predictive model for CRSwNP recurrence. Analyses of survey data include descriptive and inferential statistical approaches., Discussion: This is the first prospective cohort study on investigating the correlation of CRSwNP recurrence with TCM syndrome types and tissue inflammatory cell infiltration types. Through this study, we hope to discover a new and simple, effective, and noninvasive way to predict the recurrence rate rapidly after CRSwNP and provide reference for the intervention timing of traditional Chinese medicine application, thereby achieving customized diagnosis and treatment, minimizing risks of surgical events, and delaying postoperative recurrence of CRSwNP., Systematic Review Registration: PROSPERO ChiCTR2100041646., (© 2024. The Author(s).)

Chronic rhinosinusitis (CRS) is a complex syndrome with various inflammatory mechanisms resulting in different patterns of inflammation that correlate with the clinical phenotypes of CRS. Our aim was to use detected IL-1, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12, Ki 67, HBD-2, HBD-3, and LL-37 to classify specific inflammatory endotypes in chronic rhinosinusitis with the tissue of nasal polyps (CRSwNP). Samples from 35 individuals with primary and recurrent CRSwNP were taken during surgery. The tissues were stained for the previously mentioned biomarkers immunohistochemically. A hierarchical cluster analysis was performed. The clinical parameters were compared between clusters. Five clusters had significantly different biomarkers between groups. There were no significant differences in the clinical parameters, except for the Lund-Mackay score, which was significantly higher in cluster 4 compared to that of cluster 1 ( p = 0.024). Five endotypes of (CRSwNP) are characterized by different combinations of type 1, type 2, and type 3 tissue inflammation patterns. In the Latvian population, endotypes associated with neutrophilic inflammation or a combination of neutrophilic inflammation and type 2 inflammation are predominant. Increased proliferation marker Ki 67 values are not associated with more severe inflammation in the tissue samples of chronic rhinosinusitis with nasal polyps.

Significant advancements have been achieved in understanding the roles of different immune cells, as well as cytokines and chemokines, in the pathogenesis of eosinophilic airway conditions. This review examines the pathogenesis of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), marked by complex immune dysregulation, with major contributions from type 2 inflammation and dysfunctional airway epithelium. The presence of eosinophils and the role of T-cell subsets, particularly an imbalance between Treg and Th17 cells, are crucial to the disease's pathogenesis. The review also investigates the pathogenesis of eosinophilic asthma, a unique asthma subtype. It is characterized by inflammation and high eosinophil levels, with eosinophils playing a pivotal role in triggering type 2 inflammation. The immune response involves Th2 cells, eosinophils, and IgE, among others, all activated by genetic and environmental factors. The intricate interplay among these elements, chemokines, and innate lymphoid cells results in airway inflammation and hyper-responsiveness, contributing to the pathogenesis of eosinophilic asthma. Another scope of this review is the pathogenesis of Eosinophilic Granulomatosis with Polyangiitis (EGPA); a complex inflammatory disease that commonly affects the respiratory tract and small to medium-sized blood vessels. It is characterized by elevated eosinophil levels in blood and tissues. The pathogenesis involves the activation of adaptive immune responses by antigens leading to T and B cell activation and eosinophil stimulation, which causes tissue and vessel damage. On the other hand, Allergic Bronchopulmonary Aspergillosis (ABPA) is a hypersensitive response that occurs when the airways become colonized by aspergillus fungus, with the pathogenesis involving activation of Th2 immune responses, production of IgE antibodies, and eosinophilic action leading to bronchial inflammation and subsequent lung damage. This analysis scrutinizes how an imbalanced immune system contributes to these eosinophilic diseases. The understanding derived from this assessment can steer researchers toward designing new potential therapeutic targets for efficient control of these disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 AlBloushi and Al-Ahmad.)

Chronic rhinosinusitis (CRS) is heterogeneous and contains diverse pathogenesis including type 1, type 2, and/or type 3 inflammation. For severe type 2 CRS especially CRS with nasal polyps (CRSwNP), biologics that target inflammatory molecules have recently been applied along with further changes in the treatment algorithm for CRS. Currently, a completed phase 3 clinical trial for biologics for severe CRSwNP with inadequate response to surgery and/or intranasal corticosteroids, including omalizumab (anti-IgE), mepolizumab (anti-IL-5), benralizumab (anti-IL-5Rα), and dupilumab (anti-IL-4Rα), have all shown efficacy. Similar phase 3 clinical trials for tezepelumab (anti-TSLP) and etokimab (anti-IL-33) are now underway and completed, respectively. Further studies need to evaluate how to optimally and cost-effectively use biologics for CRS and determine if any biomarkers are indicative of which biologics should be administered. A definition of complete and/or clinical remission of CRS is also needed to determine when to reduce or discontinue biologics. In addition, more precise basic research on CRS, such as endotyping and genotyping, will need to be undertaken in order to determine novel targets for biologics., Competing Interests: Declaration of Competing Interest MO received honoraria from Sanofi. The authors have no funding source relevant to this manuscript., (Copyright © 2023. Published by Elsevier B.V.)

According to the concept of "united airway diseases", the airway is a single organ in which upper and lower airway diseases are commonly comorbid. A range of inflammatory factors have been found to play an important role in the chain reaction of upper and lower airway diseases. However, the amount of research on this concept remains limited. The underlying mechanism of the relationship between typical diseases of the united airway, such as asthma, allergic rhinitis, and chronic sinusitis, also needs to be further explored. This review highlights the interaction between upper and lower respiratory diseases gathered from epidemiological, histoembryology, neural mechanistic, microbiological, and clinical studies, revealing the relationship between the upper and lower respiratory tracts., 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 Ltd. All rights reserved.)

Chronic rhinosinusitis (CRS) is an inflammatory condition of the sinonasal mucosa. Despite being a common health issue, the exact cause of CRS is yet to be understood. However, research suggests that Staphylococcus aureus , particularly in its biofilm form, is associated with the disease. This study aimed to investigate the impact of long-term exposure to secreted factors of Staphylococcus aureus biofilm (SABSFs), harvested from clinical isolates of non-CRS carrier and CRS patients, on the nasal mucosa in a rat model. Animals were randomised (n = 5/group) to receive daily intranasal instillations of 40 μL (200 μg/μL) SABSFs for 28 days or vehicle control. The sinonasal samples were analysed through histopathology and transcriptome profiling. The results showed that all three intervention groups displayed significant lymphocytic infiltration ( p ≤ 0.05). However, only the SABSFs collected from the CRSwNP patient caused significant mucosal damage, mast cell infiltration, and goblet cell hyperplasia compared to the control. The transcriptomics results indicated that SABSFs significantly enriched multiple inflammatory pathways and showed distinct transcriptional expression differences between the control group and the SABSFs collected from CRS patients ( p ≤ 0.05). Additionally, the SABSF challenges induced the expression of IgA and IgG but not IgE. This in vivo study indicates that long-term exposure to SABSFs leads to an inflammatory response in the nasal mucosa with increased severity for S. aureus isolated from a CRSwNP patient. Moreover, exposure to SABSFs does not induce local production of IgE.

Background: Neutrophil extracellular traps (NETs) are observed in chronic rhinosinusitis (CRS), although their role remains unclear., Objectives: This study aimed to investigate the influence of NETs on the CRS epithelium., Methods: Forty-five sinonasal biopsy specimens were immunofluorescence-stained to identify NETs and p63 + basal stem cells. Investigators treated human nasal epithelial cells with NETs and studied them with immunofluorescence staining, Western blotting, and quantitative real-time PCR. NET inhibitors were administered to a murine neutrophilic nasal polyp model., Results: NETs existed in tissues in patients with CRS with nasal polyps, especially in noneosinophilic nasal polyp tissues. p63 + basal cell expression had a positive correlation with the release of NETs. NETs induced the expansion of Ki-67 + p63 + cells. We found that ΔNp63, an isoform of p63, was mainly expressed in the nasal epithelium and controlled by NETs. Treatment with deoxyribonuclease (DNase) I or Sivelestat (NET inhibitors) prevented the overexpression of ΔNp63+ epithelial stem cells and reduced polyp formation., Conclusions: These results reveal that NETs are implicated in CRS pathogenesis via basal cell hyperplasia. This study suggests a novel possibility of treating CRS by targeting NETs., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Platelet-activating factor (PAF) is a phospholipid-derived inflammatory mediator that triggers various inflammatory conditions, including eosinophil activation and recruitment. This study aimed to evaluate the expressions of PAF-metabolism-associated genes, namely genes coding the enzymes involved in PAF synthesis (LPCAT1, LPCAT2, LPCAT3, and LPCAT4), PAF degradation (PAFAH1B2, PAFAH1B3, and PAFAH2), and the gene for the PAF receptor (PTAFR) in subtypes of CRSwNP classified by clinical- or hierarchal-analysis-based classifications. Transcriptomic analysis using bulk RNA barcoding and sequencing (BRB-seq) was performed with CRSwNP, including eosinophilic CRS (ECRS) ( n = 9), nonECRS (n = 8), ECRS with aspirin-exacerbated respiratory disease (Asp) ( n = 3), and controls with a normal uncinate process mucosa ( n = 6). PTAFR was only upregulated in ECRS and nonECRS. In the hierarchical cluster analysis with clusters 1 and 2 reflecting patients with low-to-moderate and high levels of type 2 inflammation, respectively, cluster 1 exhibited a significant downregulation of LPCAT2 and an upregulation of PTAFR expression, while cluster 2 showed an upregulation of LPCAT1, PAFAH1B2, and PTAFR and downregulation of PAFAH2 expression. Understanding this strong PAF-associated pathophysiology in the severe type 2 inflammation group could provide valuable insights into the treatment and management of CRSwNP.

Purpose of Review: To highlight the current evidence that supports the view that eosinophils may not drive disease in chronic rhinosinusitis with nasal polyps (CRSwNP) and the emerging evidence for B cells as an important player in this disease., Recent Findings: Eosinophil depletion studies in CRSwNP do not fully support a critical role for eosinophils in CRSwNP. Almost complete eosinophil depletion with dexpramipexole had no impact on polyp size reduction or clinical improvement. Anti-interleukin (IL)-5 and IL-5Rα inhibition were more effective though with less clinical impact when compared to anti-immunoglobulin E (IgE) or IL-4Rα inhibition strategies. As IL-5Rα is also expressed on CRSwNP derived IgE+ and IgG4+ plasma cells to the same extent as eosinophils, improvements in CRSwNP with IL-5 inhibition may suggest a role for B cells over eosinophils in CRSwNP. We review both eosinophils and B cells in the context of CRSwNP and highlight the current evidence that supports an emerging role for B cells., Summary: Despite many aspects of immunopathology in CRSwNP explainable by B cell dysfunction, B cells have so far been ignored in CRSwNP. Further work is needed, as targeting B cells may offer an exciting new therapeutic option in the future., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: The aim of the present review was to highlight the interactions between rhinitis, rhinosinusitis and asthma in children and to discuss the most relevant scientific progresses in the pathophysiology and treatment of these combined conditions., Recent Findings: Advances in understanding the mechanisms underlying the relationship between upper and lower airways have provided valuable insights into the role of eosinophils in the pathophysiology of inflammatory events and have further delineated the concept of united airway disease. Studies addressed to evaluate the burden of sinonasal system on asthma outcomes showed a parallel severity of upper and lower airway diseases. Histopathology of sinonasal tissue in patients with chronic rhinosinusitis is different in adults and children. Targeted administration of biological agents represents an effective treatment in patients with severe uncontrolled asthma, but specific trials are awaited in children with chronic sinonasal disease., Summary: Allergic rhinitis and rhinosinusitis are important comorbidities in patients with asthma. Improved knowledge of pathogenic mechanisms of inflammation and remodelling in the sinonasal system and the lung has led to new therapeutic approaches in patients with united airway disease and opened interesting perspectives for personalized drug therapies., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Excessive epithelial-to-mesenchymal transition (EMT) of nasal epithelial cells (NECs) play a prominent role in chronic rhinosinusitis with nasal polyps (CRSwNP) pathogenesis. Long intergenic non-coding RNA 01094 (LINC01094) was previously reported to be overexpressed in CRSwNP, while the regulatory mechanism by which LINC01094 regulates CRSwNP progression remains unclear. Our study aimed to investigate the role of LINC01094 in CRSwNP development., Methods: hNEC were isolated from tissues of controls and CRSwNP patients and stimulated with interleukin (IL)-13. 3-(4, 5-Dimethylthiazolyl2)-2, 5-diphenyltetrazolium bromide (MTT) assay was employed to analyze hNEC viability. Flow cytometry was employed to analyze pyroptosis. Immunofluorescence was employed to analyze Snail nuclear translocation. The interactions between LINC01094, fused in sarcoma (FUS) and high mobility group box-1 (HMGB1) were analyzed by RNA immunoprecipitation (RIP) and RNA pull-down assays., Results: LINC01094 and EMT-related proteins were markedly upregulated in nasal polyp tissues of CRSwNP. LINC01094 knockdown inhibited IL-13-induced hNEC EMT and pyroptosis. LINC01094 promoted HMGB1 expression in CRSwNP by binding with FUS. HMGB1 promoted Snail nuclear import in GSK-B phosphorylation-dependent manner., Conclusion: LINC01094 facilitated hNEC EMT and pyroptosis in CRSwNP by activating the HMGB1/GSK-B Snail axis, which suggested that LINC01094 might serve as a biomarker and therapeutic target in CRSwNP.

Introduction: Immunoglobulin G4-related disease (IgG4-RD) is a systemic inflammatory disease characterized by elevated serum IgG4, tissue infiltration of IgG4-positive cells, and fibrosis. Although a number of IgG4-RD patients show sinonasal involvement, there is little known about sinonasal inflammation associated with IgG4-RD. This study aimed to describe the clinicopathological features of sinonasal inflammation associated with IgG4-RD and to compare with other inflammatory diseases, such as eosinophilic chronic rhinosinusitis (ECRS) and granulomatosis with polyangiitis (GPA)., Methods: A retrospective analysis of clinicopathological features of patients with sinonasal lesions and high serum IgG4 was performed. Patient data were reviewed to determine whether they fulfilled the diagnostic criteria for other inflammatory diseases., Results: Six of 7 patients were diagnosed with IgG4-RD, while 1 patient was diagnosed with GPA. In the 6 patients with IgG4-RD, intranasal findings showed nasal polyps in 3 patients (50%) and nasal crusting in the 3 patients (50%). Computed tomography showed ethmoid sinus involvement in 5 patients (83%). Five of the 6 patients (83%) were diagnosed with IgG4-RD based on nasal biopsy, whereas 1 patient (17%) was diagnosed based on lacrimal gland biopsy. Four patients fulfilled the Japanese epidemiological survey of refractory ECRS (JESREC) criteria. However, none of the patients showed eosinophil infiltration. Although the patient with GPA showed high levels of serum IgG4 and tissue infiltration of IgG4-positive cells in the nasal biopsy, the patient showed common clinical features of GPA., Conclusion: Patients with sinonasal inflammation associated with IgG4-RD had similar clinical characteristics with ECRS and GPA. Histopathological findings of the nasal biopsy from clinically diagnosed GPA was consistent with that of IgG4-RD. Sinonasal inflammation associated with IgG4-RD should be diagnosed based not only on tissue infiltration of IgG4-positive cells but in conjunction with clinical findings such as local nasal characteristics, involvement of other organs, and serum antineutrophil cytoplasmic antibody levels. IgG4-RD should be ruled out in patients with eosinophilia without histopathological eosinophil infiltration., (© 2024 S. Karger AG, Basel.)

Background: Frontal sinus surgery remained a challenge of restenosis or obliteration of the drainage pathway caused by the scarring and neo-osteogenesis after mucosal stripping and bone drill-out. The pedicled or free nasal mucosal flap is typically used to repair the exposed bone surface to avoid or reduce recurrence., Objective: This study aimed to explore the histopathological mechanism of mucosal flaps repairing bare bone after mucosal resection and bone drill-out in the rabbit model., Methods: Thirty New Zealand white rabbits were used. Sixteen rabbits were selected as the experimental group, and Staphylococcus aureus was used to establish the CRS model (CRS group). Fourteen healthy rabbits were allocated to the control group (NCRS group). Each group was divided into two subgroups with or without mucosal flap repair (CRS-FLAP, CRS-NFLAP, NCRS-FLAP, and NCRS-NFLAP, respectively). The bony anterior and lateral walls of the maxillary sinus of each rabbit were abraded by the drill. The bare bone was then covered with a flap in FLAP subgroups. Bone remodeling and mucosal morphological changes were observed and compared by histopathological hematoxylin and eosin and Masson staining., Results: In the CRS-NFLAP subgroup, the regenerated epithelium lacked typical structure, accompanied by numerous inflammatory cell infiltration and collagen deposition. Conversely, the inflammatory reaction was mild in the CRS-FLAP subgroup, and there was less collagen deposition. The restored mucosal structure was like the normal mucosa. The epithelium in the NCRS-NFLAP subgroup was partially exfoliated, with few cilia, goblet cells, and glandular structures. Compared with the NCRS-NFLAP subgroup, the CRS-NFLAP subgroup showed significant bone remodeling with enhanced activity of osteoblast and osteoclast cells., Conclusions: Pedicled mucosal flap repair could significantly reduce local mucosal and bone remodeling in a rabbit model of CRS., 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.

Key Points: CRSwNP patients had decreased nNO and increased SNOT-22, endoscopy, and CT scores. CRSwNP patients exhibited decreased nNO despite elevated iNOS and eNOS mRNA expression. The mechanism behind lowered nNO in CRSwNP may not be related to NOS expression., (© 2023 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Chronic rhinosinusitis (CRS) is an inflammation of the nasal and paranasal sinus mucosa, and eosinophilic CRS (eCRS) is a subtype characterized by significant eosinophil infiltration and immune response by T-helper-2 cells. The pathogenesis of eCRS is heterogeneous and involves various environmental and host factors. Proteases from external sources, such as mites, fungi, and bacteria, have been implicated in inducing type 2 inflammatory reactions. The balance between these proteases and endogenous protease inhibitors (EPIs) is considered important, and their imbalance can potentially lead to type 2 inflammatory reactions, such as eCRS. In this review, we discuss various mechanisms by which exogenous proteases influence eCRS and highlight the emerging role of endogenous protease inhibitors in eCRS pathogenesis.

Background: Eosinophils are associated with olfactory dysfunction in chronic rhinosinusitis (CRS) and eosinophil-derived neurotoxin (EDN) is a sensitive marker of intense eosinophil activation. This study aimed to analyze olfactory cleft mucus and olfactory mucosa EDN levels and their association with olfactory dysfunction in CRS., Methods: We prospectively recruited 150 patients with CRS electing endoscopic sinus surgery and 25 healthy controls. Both superior turbinate biopsy specimens and olfactory cleft mucus were collected to analyze EDN levels. Sniffin' Sticks test scores, olfactory cleft computed tomography (CT) scores, and olfactory cleft endoscopy scale (OCES) were obtained. Multivariable logistic regression analysis was applied to analyze the predictability of EDN levels for olfactory dysfunction in CRS., Results: Chronic rhinosinusitis with olfactory dysfunction presented significantly higher olfactory mucosa (p = 0.016) and olfactory cleft mucus (p < 0.001) EDN levels than CRS without olfactory dysfunction. Mucus EDN levels were positively correlated with blood eosinophils (r = 0.625, p = 0.002), olfactory cleft CT scores (r = 0.738, p < 0.001), and OCES (r = 0.605, p = 0.004) in CRS. Furthermore, mucus EDN levels were significantly negatively correlated with threshold, discrimination, and identification (TDI) (r = -0.688), olfactory threshold (r = -0.606), olfactory discrimination (r = -0.608), and olfactory identification (r = -0.697) scores. After adjusting for patient demographics and comorbidities, mucus EDN levels were significantly associated with olfactory dysfunction in CRS (odds ratio = 2.162; p = 0.027). Mucus EDN levels showed a significantly better performance for predicting olfactory dysfunction than blood eosinophil counts (area under the curve, 0.873 vs. 0.764, p = 0.024)., Conclusion: Olfactory cleft mucus EDN level may be a better biomarker for predicting olfactory dysfunction in CRS than blood eosinophil counts., (© 2023 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Background: Chronic rhinosinusitis (CRS) is a common chronic inflammatory disease and is subdivided into eosinophilic and noneosinophilic forms. There are few reports investigating the nasal microbiome and its pathological functions in patients with CRS., Objective: We sought to analyze factors contributing to variations of the nasal microbiome in CRS, and on the basis of these factors, to elucidate whether the bacterial metabolites were related to the pathogenesis., Methods: Nasal swabs were collected, and the V3 to V4 variable region of the 16S ribosomal RNA gene was amplified and sequenced. Factors contributing to variations of the nasal microbiome in patients with CRS were compared. The most influential factor was whether CRS was eosinophilic, and we compared α- and β-diversity, bacterial species, and predictive bacterial functions between the 2 patient groups. In addition, the metabolites of the key bacteria were extracted, and we evaluated the predicted bacterial functions in airway epithelial cells., Results: In total, 110 patients with CRS and 33 control subjects were enrolled. On the basis of the factors of variation, it was found that patients with eosinophilic CRS (n = 65) had different microbiomes with weighted UniFrac β-diversity and lower α-diversity compared with those with noneosinophilic CRS (n = 45). A higher abundance of Fusobacterium nucleatum and an increased LPS pathway were observed in patients with noneosinophilic CRS compared with those with eosinophilic CRS. In airway epithelial cells, LPS derived from F nucleatum suppressed the expression levels of ALOX15 induced by T H 2 cytokines., Conclusions: The differences in the nasal microbiome may play a key role in the pathophysiology of CRS., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The immune modulation in the epithelium is a protective feature of the epithelial function in the mucosal airways. Dysfunction of the epithelium can lead to chronic allergic airway inflammatory diseases, such as chronic rhinosinusitis with nasal polyps (CRSwNP), allergic rhinitis (AR), and allergic asthma. Chitinase-3-like-1 (CHI3L1) is a key modulator in the epithelium against irritants, pathogens, and allergens and is involved in cancers, autoimmune diseases, neurological disorders, and other chronic diseases. Induction of epithelial cell-derived CHI3L1 is also confirmed to be implicated in the pathogenesis of Th2-related airway diseases like CRSwNP, AR, and allergic asthma, triggering a cascade of subsequent inflammatory reactions leading to the disease development. The techniques that block the biological function of CHI3L1 include small interfering RNA, neutralizing antibodies, and microRNAs and these methods proved to be successful in preclinical and clinical investigation in cancers, autoimmune diseases, asthma, and chronic obstructive pulmonary disease. Therefore, treatment with CHI3L1-blocking methods could open up therapeutic options for allergic airway diseases. This review article discusses the role of epithelial cell-derived CHI3L1 in the development of CRSwNP, AR, and allergic asthma and examines the use of CHI3L1 as a potential therapeutic agent for allergic airway diseases., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous and common upper airway disease divided into various inflammatory endotypes. Recent epidemiological findings showed a T helper 2 (Th2)-skewed dominance in CRSwNP patients. Histone modification alterations can regulate transcriptional and translational expression, resulting in abnormal pathogenic changes and the occurrence of diseases. Trimethylation of histone H3 lysine 4 (H3K4me3) is considered an activator of gene expression through modulation of accessibility for transcription, which is closely related to CRSwNP. H3K4me3 levels in the human nasal epithelium may change under Th2-biased inflammatory conditions, resulting in exaggerated local nasal Th2 responses via the regulation of naïve CD4 + T-cell differentiation. Here, we revealed that the level of SET and MYND domain-containing protein 3 (SMYD3)-mediated H3K4me3 was increased in NPs from Th2 CRSwNP patients compared with those from healthy controls. We demonstrated that SMYD3-mediated H3K4me3 is increased in human nasal epithelial cells under Th2-biased inflammatory conditions via S-adenosyl-L-methionine (SAM) production and further found that the H3K4me3 high status of insulin-like growth factor 2 (IGF2) produced in primary human nasal epithelial cells could promote naïve CD4 + T-cell differentiation into Th2 cells. Moreover, we found that SAM production was dependent on the c-Myc/methionine adenosyltransferase 2A (MAT2A) axis in the nasal epithelium. Understanding histone modifications in the nasal epithelium has immense potential utility in the development of novel classes of therapeutics targeting Th2 polarization in Th2 CRSwNP. Video Abstract., (© 2023. The Author(s).)

Chronic rhinosinusitis (CRS) is a persistent inflammation of the sinus mucosa. Recalcitrant CRS patients are unresponsive to medical and surgical interventions and often present with nasal polyps, tissue eosinophilia, and Staphylococcus aureus dominant mucosal biofilms. However, S. aureus sinonasal mucosal colonisation occurs in the absence of inflammation, questioning the role of S. aureus in CRS pathogenesis. Here, we aimed to investigate the relationship between S. aureus biofilm metabolic activity and virulence genes, innate immune cells, and disease severity in CRS. Biospecimens, including sinonasal tissue and nasal swabs, and clinical datasets, including disease severity scores, were obtained from CRS patients and non-CRS controls. S. aureus isolates were grown into biofilms in vitro, characterised, and sequenced. The patients' innate immune response was evaluated using flow cytometry. S. aureus was isolated in 6/19 (31.58%) controls and 23/53 (43.40%) CRS patients of 72 recruited patients. We found increased S. aureus biofilm metabolic activity in relation to increased eosinophil cell frequencies and disease severity in recalcitrant CRS cases. Mast cell frequencies were higher in tissue samples of patients carrying S. aureus harbouring lukF.PV, sea, and fnbB genes. Patients with S. aureus harbouring lukF.PV and sdrE genes had more severe disease. This offers insights into the pathophysiology of CRS and could lead to the development of more targeted therapies., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: RNA sequencing (transcriptomics) is used to study biological pathways. However, the yield of data depends on comparing well-characterized cohorts. We compared tissue eosinophilia versus nasal polyp (NP) status as the metric to characterize transcriptomic mechanisms at play in eosinophilic and non-eosinophilic chronic rhinosinusitis (CRS) versus controls., Methods: RNA sequencing was conducted on sinonasal tissue samples of CRS and controls. Analyses were conducted based on polyp status [with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP)] as well as tissue eosinophil levels per high power field (eos/hpf)[non-eosinophilic (<10 eos/hpf, neCRS) or eosinophilic (≥10 eos/hpf, eCRS)]. The yield of differentially expressed genes (DEGs) and biological pathways through Ingenuity Pathway Analysis (IPA) were compared., Results: CRS tissue differed from controls by 736 statistically significant DEGs. Both NP status and tissue eosinophilia were effective in differentiating CRS from controls and into two distinct subgroups. Statistically significant DEGs identified when comparing CRS by NP status were 60, whereas 110 DEGs were identified using eosinophil cutoff ≥10 and <10 eos/hpf. Additionally, heatmaps showed greater homogeneity within each CRS subgroup when analyzed by tissue eosinophilia versus NP status. On IPA, the IL-17 signaling pathway was significantly different only by tissue eosinophilia status, not NP status, being higher in CRS <10 eos/hpf., Conclusion: Tissue eosinophilia is superior to an analysis by NP status for the study of CRS transcriptome by RNA sequencing in identifying DEGs. Classification of CRS samples by eosinophil counts agnostic of NP status may offer advantageous insights into CRS pathogenetic mechanisms., Level of Evidence: 3 Laryngoscope, 133:2480-2489, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Key Points: An integrated proteomics and metabolomics were used to investigate the pathogenesis of CRSwNP. Amino acid metabolism and mitochondrial dysfunction play key roles in the pathogenesis of CRSwNP., (© 2023 ARS-AAOA, LLC.)

The ability of human tissue to reorganize and restore its existing structure underlies tissue homeostasis in the healthy airways, but in disease can persist without normal resolution, leading to an altered airway structure. Eosinophils play a cardinal role in airway remodeling both in health and disease, driving epithelial homeostasis and extracellular matrix turnover. Physiological consequences associated with eosinophil-driven remodeling include impaired lung function and reduced bronchodilator reversibility in asthma, and obstructed airflow in chronic rhinosinusitis with nasal polyps. Given the contribution of airway remodeling to the development and persistence of symptoms in airways disease, targeting remodeling is an important therapeutic consideration. Indeed, there is early evidence that eosinophil attenuation may reduce remodeling and disease progression in asthma. This review provides an overview of tissue remodeling in both health and airway disease with a particular focus on eosinophilic asthma and chronic rhinosinusitis with nasal polyps, as well as the role of eosinophils in these processes and the implications for therapeutic interventions. Areas for future research are also noted, to help improve our understanding of the homeostatic and pathological roles of eosinophils in tissue remodeling, which should aid the development of targeted and effective treatments for eosinophilic diseases of the airways., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Fractional exhaled nitric oxide (FeNO) is useful in the management of asthma and predicting the efficacy of standard corticosteroids and biologics. However, the diagnostic value of FeNO in asthmatic chronic rhinosinusitis with nasal polyps (CRSwNP) remains unclear., Objective: We assessed FeNO levels in patients with CRSwNP and evaluated the diagnostic value of FeNO for screening type 2 CRSwNP (T2-CRSwNP) with asthma., Methods: We enrolled 94 patients who were diagnosed with CRSwNP and underwent functional endoscopic sinus surgery. FeNO levels, the blood eosinophil percentage, total IgE, spirometry tests (FEV1/FVC), Lund-Mackay CT score, and percentage of patients with comorbid asthma were compared among CRSwNP subgroups. Spearman rank correlation test was used to assess the degree of association between variables. ROC curve analysis was conducted to evaluate the diagnostic capability to differentiate T2-CRSwNP based on clinical and histological classifications., Results: FeNO levels and the blood eosinophil percentage were significantly higher in patients with T2-CRSwNP(h) based on histological data ( P  < .05). FeNO was correlated with the blood eosinophil percentage ( r  = 0.420, P  < .001) and FEV1/FVC ( r  = -0.324, P  = .001). A FeNO level of 27 ppb had a good ability to discriminate patients with asthmatic T2-CRSwNP(h) (AUC = 0.848; 95% CI = 0.7602-0.9361; sensitivity = 90.9%; specificity = 63.9%). The optimal cutoff values for FeNO and the blood eosinophil percentage for diagnosing asthmatic T2-CRSwNP(h) were 68 ppb and 5.6% (sensitivity = 95.5%; specificity = 86.1%; AUC = 0.931; 95% CI = 0.8832-0.9791). In the diagnosis of severe T2-CRSwNP(c) based on clinical data, a FeNO level of 36 ppb showed the highest AUC (0.816; 95% CI = 0.7173-0.914; sensitivity = 72.7%; specificity = 79.2%)., Conclusion: FeNO is a useful marker for screening asthmatic T2-CRSwNP even prior to biopsy or asthma evaluation and may assist in selecting a proper treatment.

Background: Adult and elderly patients with chronic rhinosinusitis (CRS) undergo similar therapeutic management. Few studies have undertaken sinonasal tissue-level comparisons of these groups. This study examines histopathological differences between adults (>18, <65 years) and the elderly (≥65 years) with CRS, with the goal of optimizing medical management., Methods: In a retrospective cohort analysis, demographic factors, comorbidities, and a structured histopathological report of 13 variables were compared across adult and elderly patients with CRS who underwent functional endoscopic sinus surgery. These cohorts of adult and elderly patients included patients with and without nasal polyps (NP)., Results: Three hundred adult (158 aCRSsNP, 142 aCRSwNP) and 77 elderly (38 eCRSsNP, 39 eCRSwNP) patients were analyzed. Mean age of the adult cohort was 44.4 ± 12.4 years, while that of the elderly cohort was 71.9 ± 5.9 years ( P   <   .001 ). Significantly more adults compared to elderly individuals demonstrated a positive atopic status (79.7% vs 64.0%, P   =   .004 ). Elderly patients exhibited higher rates of comorbid diabetes mellitus than adult patients (21.6% vs 10.3%, P   =   .009 ). Adults exhibited more tissue eosinophilia (43.4% vs 28.6%, P   =   .012 ) and presence of eosinophil aggregates (25.0% vs 14.3%, P   =   .029 ) compared to elderly patients, regardless of NP status. Conversely, the elderly demonstrated significantly more fungal elements (11.7% vs 3.0%, P   =   .004 ), and trended toward increased overall inflammation (63.6% vs 55.3%, P   =   .118 ) and tissue neutrophilia (35.1% vs 27.3%, P   =   .117 ), compared to adults., Conclusion: Sinonasal tissue of adult and elderly patients with CRS demonstrates clear histopathological differences. Patient comorbidities, in addition to histopathological characterizations, may provide further context for management optimization., Level of Evidence: 2., Short Summary: Sinonasal tissue samples from adult and elderly patients with CRS demonstrate clear histopathological differences. These patient populations also exhibit unique comorbidities. These distinctions have the potential to inform and optimize management of this condition.

Rhinosinusitis is a commonly encountered disease. Imaging is not typically required in acute uncomplicated rhinosinusitis; however, it is integral in the evaluation of patients who present with prolonged or atypical symptoms or when acute intracranial complications or alternate diagnoses are suspected. Knowledge of the paranasal sinus anatomy is important to understand patterns of sinonasal opacification. Bacterial, viral, and fungal pathogens are responsible culprits and, with duration of symptoms, serve to categorize infectious sinonasal disease. Several systemic inflammatory and vasculitic processes have a predilection for the sinonasal region. Imaging, along with laboratory and histopathologic analysis, assist in arriving at these diagnoses., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Structured histopathology profiling is recommended when reporting chronic rhinosinusitis with nasal polyp (CRSwNP) tissue. The objective of this study is to identify features in structured histopathology that predict outcome after functional endoscopic sinus surgery (FESS) in a cohort of CRSwNP patients from Singapore., Methods: Latent class analysis was performed on structured histopathology reports of 126 CRSwNP patients who had undergone FESS. Outcome measures were polyp recurrence, need for systemic corticosteroids, revision surgery or biologics, and disease control at 2 years post-FESS., Results: Three classes were identified. Class 1 was characterised by mild, predominantly lymphoplasmacytic inflammation. Class 2 comprised of 100 eosinophils/HPF, hyperplastic seromucinous glands, mucosal ulceration and mucin containing eosinophil aggregates and Charcot-Leyden crystals. Classes 2 and 3 were significantly associated with uncontrolled disease at 2 years post-FESS. Class 3 was additionally associated with the need for systemic corticosteroids., Conclusions: Eosinophil count, degree of inflammation, predominant inflammatory type, hyperplastic seromucinous glands, mucosal ulceration and mucin containing eosinophil aggregates and Charcot-Leyden crystals predicted need for systemic corticosteroids and uncontrolled disease at 2 years post-FESS. The presence of &gt;100 eosinophils/HPF should be reported, as this subset of tissue eosinophilia was associated with less favourable outcomes after FESS.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by chronic eosinophilic inflammation and new bone formation (NBF). These processes may be associated with each other in the pathogenesis and influence the severity and prognosis of the disease. However, it is still unclear how eosinophilic inflammation is involved in the NBF., Methodology: Sinus bone cells were isolated from ethmoid bone tissues of patients with CRSwNP and controls. Transforming growth factor beta 1 (TGFβ1) and alkaline phosphatase (ALP) expression in sinus bone cells was determined using quantitative RT-PCR, immunoblotting, and immunohistochemistry. The co-localization of TGFβ1 with eosinophils was assessed by immunofluorescence staining. Sinus bone cells were co-cultured with eosinophils (Eol-1 cell line), which were differentiated with butyrate, to measure the osteoblast differentiation activity of sinus bone cells., Results: TGFβ1 expression was increased in sinus bone tissues and correlated with CT scores in CRSwNP. TGFβ1 was also increased in the submucosa of CRSwNP and co-localized predominantly with eosinophils compared with neutrophils Differentiated Eol-1 cells-derived TGFβ1 increased ALP expression in sinus bone cells. Treatment with a TGFβ inhibitor attenuated TGFβ1-induced ALP expression and staining in sinus bone cells of CRSwNP, leading to loss of bone formation., Conclusions: Eosinophil-derived TGFβ1 was enriched in the submucosa of CRSwNP, which induced ALP expression in sinus bone cells and NBF. Therefore, eosinophil-derived TGFβ1 may mediate aberrant bone remodeling in CRSwNP.

Purpose: Nitric oxide (NO) is an important messenger molecule widely present in the human body. However, the role of nasal NO (nNO) in eosinophilic chronic rhinosinusitis with nasal polyps (Eos CRSwNP) remain unclear. This study aimed to investigate the diagnostic value and underlying mechanism of nNO in Eos CRSwNP., Methods: The medical records of 84 non-Eos CRSwNP patients, 55 Eos CRSwNP patients, and 37 control subjects were retrospectively reviewed. The diagnostic value of nNO for Eos CRSwNP was assessed. The expression of inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and tight junctions (TJs) components claudin-1, occludin, and ZO-1 was detected in the nasal polyps. Primary human nasal epithelial cells (HNECs) were co-treated with eNOS inhibitor (L-NAME) or Akt inhibitor (MK-2206), interleukin (IL)-13, and dexamethasone (Dex). The level of NO and the expression of TJs and Akt/eNOS pathways were examined., Results: The nNO levels of the CRSwNP group were significantly lower than those of the control group. Compared with the non-Eos CRSwNP group, the Eos CRSwNP group showed higher nNO level. The combination of nNO level, eosinophilic percentage, and posterior ethmoid score had a better predictive value for Eos CRSwNP (AUC = 0.855). The expression of iNOS, eNOS, and p-eNOS was higher in the CRSwNP groups than in the control group, and p-eNOS expression was higher in the Eos CRSwNP group than in the non-Eos CRSwNP group. The expression of TJs was lower in the Eos CRSwNP group than in the non-Eos CRSwNP and control group. IL-13 decreased TJ expression in HNECs, while Dex promoted Akt and eNOS phosphorylation, NO production and TJ expression. Furthermore, these effects of Dex were inhibited by L-NAME and MK-2206 in HNECs., Conclusion: nNO may have a high diagnostic value in Eos CRSwNP, and Akt/eNOS pathway may promote the generation of NO to protect TJs. NO may have a potentially important role in the diagnosis and treatment of Eos CRSwNP., Competing Interests: Conflicts of Interest All authors confirmed that there was no conflict of interest in the study., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This study aimed to establish a convenient and accurate chronic rhinosinusitis evaluation platform CRSAI 1.0 according to four phenotypes of nasal polyps., Research Design and Methods: Tissue sections of a training ( n  = 54) and test cohort ( n  = 13) were sourced from the Tongren Hospital, and those for a validation cohort ( n  = 55) from external hospitals. Redundant tissues were automatically removed by the semantic segmentation algorithm of Unet++ with Efficientnet-B4 as backbone. After independent analysis by two pathologists, four types of inflammatory cells were detected and used to train the CRSAI 1.0. Dataset from Tongren Hospital were used for training and testing, and validation tests used the multicentre dataset., Results: The mean average precision (mAP) in the training and test cohorts for tissue eosinophil%, neutrophil%, lymphocyte%, and plasma cell% was 0.924, 0.743, 0.854, 0.911 and 0.94, 0.74, 0.839, and 0.881, respectively. The mAP in the validation dataset was consistent with that of the test cohort. The four phenotypes of nasal polyps varied significantly according to the occurrence of asthma or recurrence., Conclusions: CRSAI 1.0 can accurately identify various types of inflammatory cells in CRSwNP from multicentre data, which could enable rapid diagnosis and personalized treatment.

Introduction: Central compartment atopic disease (CCAD) is a newly recognized variant subtype of chronic rhinosinusitis (CRS). Although CCAD has been reported to be correlated with allergy, there is still a considerable gap in our knowledge regarding CCAD., Areas Covered: We have conducted a thorough analysis of the literature on CCAD. This review provides current understanding and therapeutic strategies of CCAD. In this article, we will review the clinical presentations and parameters, allergy-related etiology, endotypes, and recommended management of CCAD., Expert Opinion: CCAD is considered as an aeroallergen-driven type 2/eosinophilic inflammatory pattern. Although CCAD can be diagnosed by endoscopy and radiology, as well as allergen test, pathogenesis and management strategies leave much to be desired, and further studies are needed.

Introduction: Chronic rhinosinusitis (CRS) comprises several heterogenous groups, now classified based on endotype more often than on phenotype. A number of studies aimed at finding a useful biomarker for type 2 CRS suggest that periostin is a promising surrogate., Areas Covered: A comprehensive overview of the clinical significance of tissue periostin expression and serum periostin in CRS patients is provided. The effects of comorbid asthma on serum periostin and samples other than serum in which periostin can be detected in CRS patients are also discussed. Moreover, the functional roles of periostin in CRS pathogenesis are summarized., Expert Opinion: The position of periostin as a signature biomarker of type 2 CRS has been well established, enabling us to classify CRS patients by endotyping. Serum periostin is useful not only for endotyping CRS patients, but also for estimating disease severity, comorbidity, prognosis, and response to treatment, and in particular, predicting recurrence after surgery. However, it remains to be addressed how we apply serum periostin to using biologics for CRS patients. Further studies aimed at showing periostin to be a therapeutic target for CRS are awaited.

Objective: To compare culture results between eosinophilic chronic rhinosinusitis (CRS) with nasal polyps (ECRSwNP) and noneosinophilic CRS with nasal polyps (nECRSwNP)., Study Design: Retrospective study., Setting: Tertiary medical center., Methods: We retrospectively analyzed a cohort of CRSwNP patients undergoing primary functional endoscopic sinus surgery. Prior to surgery, swab samples for bacterial culture were collected from their middle meatus using cotton tips. After surgery, postoperative specimens were histologically examined for tissue eosinophilia. A tissue eosinophil density of >10 cells at high power magnification was used to discriminate between ECRSwNP and nECRSwNP., Results: A total of 295 patients were studied with polyps present on 471 sides of the nasal cavity. Among them, 236 sides were ECRSwNP, and the remaining 235 sides were nECRSwNP. Bacterial growth was found in 94 ECRSwNP sides, and in 88 nECRSwNP sides. Culture rates were similar between ECRSwNP and nECRSwNP sides (p = .595). However, Gram-negative aerobes were found in 25 of 236 ECRSwNP sides, and in 42 of 235 nECRSwNP sides. The Gram-negative culture rate was significantly higher in nECRSwNP than in ECRSwNP sides (p = .024)., Conclusion: The bacteriology of CRS was different between ECRSwNP and nECRSwNP. The Gram-negative aerobes were present more in nECRSwNP than in ECRSwNP., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Chronic rhinosinusitis with nasal polyps (CRSwNP) has long been considered a benign, chronic inflammatory, and hyperplastic disease. Recent studies have shown that autoimmune-related mechanisms are involved in the pathology of nasal polyps. Activated plasma cells, eosinophils, basophils, innate type 2 lymphocytes, mast cells, and proinflammatory cytokine in polyp tissue indicate the mobilization of innate and adaptive immune pathways during polyp formation. The discovery of a series of autoantibodies further supports the autoimmune nature of nasal polyps. Local homeostasis dysregulation, infection, and chronic inflammation may trigger autoimmunity through several mechanisms, including autoantigens overproduction, microbial translocation, molecular mimicry, superantigens, activation or inhibition of receptors, bystander activation, dysregulation of Toll-Like Receptors (TLRs), epitope spreading, autoantigens complementarity. In this paper, we elaborated on the microbiome-mediated mechanism, abnormal host immunity, and genetic changes to update the role of autoimmunity in the pathogenesis of chronic rhinosinusitis with nasal polyps.

Background: Epithelial remodeling is a histopathologic feature of chronic inflammatory airway diseases including chronic rhinosinusitis (CRS). Cell-type shifts and their relationship to CRS endotypes and severity are incompletely described., Objective: We sought to understand the relationship of epithelial cell remodeling to inflammatory endotypes and disease outcomes in CRS., Methods: Using cell-type transcriptional signatures derived from epithelial single-cell sequencing, we analyzed bulk RNA-sequencing data from sinus epithelial brushings obtained from patients with CRS with and without nasal polyps in comparison to healthy controls., Results: The airway epithelium in nasal polyposis displayed increased tuft cell transcripts and decreased ciliated cell transcripts along with an IL-13 activation signature. In contrast, CRS without polyps showed an IL-17 activation signature. IL-13 activation scores were associated with increased tuft cell, goblet cell, and mast cell scores and decreased ciliated cell scores. Furthermore, the IL-13 score was strongly associated with a previously reported activated ("polyp") tuft cell score and a prostaglandin E2 activation signature. The Lund-Mackay score, a computed tomographic metric of sinus opacification, correlated positively with activated tuft cell, mast cell, prostaglandin E2, and IL-13 signatures and negatively with ciliated cell transcriptional signatures., Conclusions: These results demonstrate that cell-type alterations and prostaglandin E2 stimulation are key components of IL-13-induced epithelial remodeling in nasal polyposis, whereas IL-17 signaling is more prominent in CRS without polyps, and that clinical severity correlates with the degree of IL-13-driven epithelial remodeling., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chronic rhinosinusitis (CRS) is a complex inflammatory disease of the sinonasal tract. To understand this disease entity and develop targeted treatments, a reproducible animal model is paramount., Aims/objectives: To optimize a murine model of eosinophilic CRS by establishing benchmark histological markers and validate its fidelity in evaluating intranasal treatments., Material and Methods: Forty-five Balb/c mice were included in the 7-week protocol. Experimental animals (n = 20) were induced a CRS disease state upon receiving intraperitoneal sensitization with ovalbumin (OVA), followed by intranasal OVA with Aspergillus oryzae protease. Analysis of complete blood count with differential, peripheral blood smear, and histological markers from the nasal cavity mucosa were performed. CRS mice were additionally treated with intranasal saline (n = 5) or mometasone (n = 10) and compared with control groups of untreated CRS (n = 5) and healthy (n = 5) mice after week 7., Results: Histological analysis of experimental animal nasal mucosa revealed significantly higher levels of eosinophilic tissue infiltration/degranulation, hyaline droplets, Charcot-Leyden crystals, and respiratory epithelial thickness compared to healthy controls. Treatment with mometasone significantly reversed the histopathological changes observed in CRS mice., Conclusion and Significance: This murine model induced substantial local eosinophilic inflammation within sinonasal mucosa, that was reversible with mometasone. This model may be used to evaluate the efficacy of therapeutics designed to target CRS., (© 2023. The Author(s).)

Eosinophils play a key role in airway inflammation in many diseases, such as allergic and non-allergic asthma, chronic rhinosinusitis with nasal polyps, and chronic obstructive pulmonary disease. In these chronic disabling conditions, eosinophils contribute to tissue damage, repair, remodeling, and disease persistence through the production a variety of mediators. With the introduction of biological drugs for the treatment of these respiratory diseases, the classification of patients based on clinical characteristics (phenotype) and pathobiological mechanisms (endotype) has become mandatory. This need is particularly evident in severe asthma, where, despite the great scientific efforts to understand the immunological pathways underlying clinical phenotypes, the identification of specific biomarkers defining endotypes or predicting pharmacological response remains unsatisfied. In addition, a significant heterogeneity also exists among patients with other airway diseases. In this review, we describe some of the immunological differences in eosinophilic airway inflammation associated with severe asthma and other airway diseases and how these factors might influence the clinical presentation, with the aim of clarifying when eosinophils play a key pathogenic role and, therefore, represent the preferred therapeutic target.

Background: Fibroblasts and others mesenchymal cells have recently been identified as critical cells triggering tissue-specific inflammatory responses. Persistent activation of fibroblasts inflammatory program has been suggested as an underlying cause of chronic inflammation in a wide range of tissues and pathologies. Nevertheless, the role of fibroblasts in the emergence of chronic inflammation in the upper airway has not been previously addressed. We aimed to elucidate whether fibroblasts could have a role in the inflammatory response in chronic rhinosinusitis with nasal polyps (CRSwNP)., Methodology: We performed whole-transcriptome microarray in fibroblast cultured from CRSwNP samples and confirmed our results by qRT-PCR. We selected patients without other associated diseases in upper airway. To investigate shifts in transcriptional profile we used fibroblasts from nasal polyps and uncinate mucosae from patient with CRSwNP, and fibroblasts from uncinate mucosae from healthy subjects as controls., Results: This study exposes activation of a pro-inflammatory and pro-fibrotic transcriptional program in nasal polyps and CRSwNP fibroblasts when compared to controls. Our Gene-set Enrichment Analysis (GSEA) pointed to common up-regulation of several pro-inflammatory pathways in patients-derived fibroblasts, along with higher mRNA expression levels of cytokines, growth factors and extracellular matrix components., Conclusions: Our work reveals a potential new source of inflammatory signaling in CRSwNP. Furthermore, our results suggest that deregulated inflammatory signaling in tissue-resident fibroblasts could support a Type-2 inflammatory response. Further investigations will be necessary to demonstrate the functionality of these novel results.

Backgroud: Biofilm formation has been recently recognised as one of the most important etiopathological mechanisms underlying chronic rhinosinusitis (CRS) and its recalcitrance. In this context, nasal cytology (NC) has become an integral part of diagnostic work up of patients suffering from sino-nasal diseases, since it is an easy-to-apply, reproducible and non-invasive diagnostic tool that allows to assess both the nasal inflammatory infiltrate and the presence of biofilms on nasal mucosal surface, further orienting the therapeutic choices in case of infectious diseases for eradicating infections and biofilms. Nevertheless, biofilms are typically resistant to common antibiotic treatments and may trigger or maintain chronic inflammation. Hence, the importance of correctly detecting the presence of biofilm and identifying new effective treatments., Purpose: The aim of this brief review is to better clarify the role of biofilm in the pathogenesis and recurrence of sino-nasal disorders and to highlight the role of nasal cytology (NC) in the rhino-allergologic diagnostic path and in the evaluation of the effectiveness of new treatments., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)