Search

Key Points: Asian-American (AA) patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have comparable rates of tissue eosinophilia compared to Caucasians when defined as >10 eosinophils/high-powered field (HPF). AA patients with CRSwNP have significantly higher incidence of mixed inflammation defined as >10 eosinophils/HPF and >10 neutrophils/HPF., (© 2024 ARS‐AAOA, LLC.)

Background: Altered biosynthesis of eicosanoids is linked to type 2 inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP), but their role in recalcitrant NPs is unclear., Objectives: We sought to identify endotypes that are linked to recalcitrant CRSwNP, based on eicosanoids, their biosynthetic enzymes, and receptors as well as cytokines and the presence of eosinophils and mast cells in recurrent NPs., Methods: Mucosal tissue collected at the time of sinus surgery from 54 patients with CRSwNP and 12 non-CRS controls were analysed for leukotriene (LT) E4, prostaglandin (PG) D2, 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) and 17 cytokines with ELISAs and Bio-Plex immunoassays. Patient subgroups were identified by cluster analysis and the probability of NP recurrence were tested with logistic regression analyses. Gene expressions were analysed with qPCR. Tryptase and eosinophil-derived neurotoxin (EDN) were measured with ELISAs as indications of the presence of mast cells and eosinophils, respectively., Results: Clustering of patients showed that an inflammatory signature characterised by elevated LTE 4 , PGD 2 , 15(S)-HETE and IL-13 was associated with NP recurrence. Previous NP surgery as well as aspirin-exacerbated respiratory disease were significantly more common among these patients. Expression of cyclooxygenase 1 was the only gene associated with NP recurrence. Levels of EDN, but not tryptase, were significantly higher in patients with recurrent NPs., Conclusion: Distinguishing endotypes that include LTE 4 , PGD 2 , 15HETE and conventional biomarkers of type 2 inflammation could help predict recurrent nasal polyposis and thus identify cases of recalcitrant CRSwNP., Competing Interests: Declaration of Competing Interest None of the authors have any conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: We aimed to review the latest evidence regarding the value of tissue histopathological analysis in chronic rhinosinusitis with nasal polyps (CRSwNP) and to facilitate tissue analysis by proposing a pragmatic checklist for clinical settings., Recent Findings: CRSwNP is a chronic inflammatory disease that severely impairs the patient's quality of life. The severity of the disease can be correlated with nasal polyps enriched in eosinophils/IL-5 and, although ≥ 10 eosinophils per high power field are considered enough to determine an eosinophilic CRS, this cut-off value, the biopsy method, and the sampling location are still a matter of debate. Besides, tissue eosinophil values might also have some added value when combined with other cellular counts (e.g., eosinophil-to-lymphocyte ratio, Charcot-Leyden crystals). Structured histopathology analysis of sinonasal tissue-including, for instance, tissue remodelling biomarkers, fibrosis, and eosinophilic aggregates-has proven to be a valuable tool for healthcare professionals to identify different pheno-endotypes of CRSwNP and to improve the prioritisation of candidates to targeted therapies. Patients with CRSwNP are treated according to their severity with corticosteroids (intranasal and systemic), endoscopic sinus surgery, and/or biological therapy. A panel of expert ear, nose, and throat specialists and pathologists proposed a pragmatic checklist to improve the clinical practice around tissue analysis in CRSwNP, to facilitate communication between hospital-based healthcare professionals, and to standardize the evaluation of inflammatory biomarkers., (© 2024. The Author(s).)

Background: Chronic rhinosinusitis (CRS) is a common inflammatory condition affecting the nasal and paranasal sinus mucosa, often accompanied by olfactory dysfunction. Eosinophilic CRS with nasal polyps (ECRSwNP) is a subtype of CRS characterized by eosinophilic infiltration. Animal models for ECRSwNP with olfactory dysfunction are necessary for exploring potential therapeutic strategies., Objective: The aim of this study was to establish a mouse model of ECRSwNP combined with olfactory dysfunction in a shorter time frame using intranasal ovalbumin and Aspergillus protease (AP) administration. The efficacy of the model was validated by evaluating sinonasal inflammation, cytokine levels, olfactory function, and neuroinflammation in the olfactory bulb., Methods: Male BALB/c mice were intranasally administered ovalbumin and AP for 6 and 12 weeks to induce ECRSwNP. The resultant ECRSwNP mouse model underwent histologic assessment, cytokine analysis of nasal lavage fluid, olfactory behavioral tests, and gene expression profiling to identify neuroinflammatory markers within the olfactory bulb., Results: The developed mouse model exhibited substantial eosinophil infiltration, increased levels of inflammatory cytokines in nasal lavage fluid, and confirmed olfactory dysfunction through behavioral assays. Furthermore, olfactory bulb inflammation and reduced mature olfactory sensory neurons were observed in the model., Conclusion: This study successfully established a validated mouse model of ECRSwNP with olfactory dysfunction within a remarkably short span of 6 weeks, providing a valuable tool for investigating the pathogenesis and potential therapies for this condition. The model offers an efficient approach for future research in CRS with nasal polyps and olfactory dysfunction., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Chronic sinusitis with nasal polyps (CRSwNP) is a complex inflammatory condition characterized by recurring nasal polyps, often necessitating repeated interventions. Blood eosinophilia has emerged as a potential biomarker for predicting disease recurrence. The present study aims to assess the predictive significance of blood eosinophilia for the recurrence of nasal polyps. To accomplish this objective, we employed the appropriate search keywords to explore international databases such as Web of Science, PubMed, Embase, and Scopus. Through this process, we extracted scholarly articles that assessed the prognostic value of blood eosinophilia in the recurrence of nasal polyps. The statistical software STATA (version 15) was employed, along with random and fixed-effects models, to appraise the compiled data. Nine articles met inclusion criteria, with a total sample size of 1279 individuals (569 recurrent polyp individuals and 710 non-recurrent polyp individuals). Cumulative Odds ratio analysis revealed that CRSwNP is associated with high blood eosinophile percentage compared to the non-CRSwNP group (p=0.01, OR=1.26, 95%Cl (1.15,1.36). The cut-off value of blood eosinophil percentage (>0.78) had relatively good, and statistically significant predictive potential. No significant publication bias was observed for the included studies. Our findings indicate that the utilization of blood eosinophils holds significant predictive value and can serve as a valuable tool for detecting recurrence in patients with CRSwNP. Based on the outcomes of our comprehensive analysis, we propose a threshold of >0.78 as a reliable indicator for assessing the probability of recurrence in CRSwNP patients.

Objective: Structured histopathology (SHP) is a method of analyzing sinonasal tissue to characterize endotypes of chronic rhinosinusitis with nasal polyps (CRSwNP). Allergic fungal rhinosinusitis (AFRS) shares several features with certain endotypes of CRSwNP. Our objective was to compare the histopathology of AFRS and eosinophilic CRSwNP to further understand whether they are separate endotypes or disease entities altogether., Methods: A retrospective review of AFRS and CRSwNP patients undergoing endoscopic sinus surgery was performed. Data were collected on demographics, comorbidities, subjective and objective severity scores, and 13-variable SHP reports. CRSwNP patients with >10 eosinophils per high-power field (eCRSwNP) were included. Chi-squared and t-tests were used for statistical analysis., Results: A total of 29 AFRS and 108 eCRSwNP patients were identified. AFRS patients were younger and more often Black. Symptom severity scores (SNOT-22, Lund-MacKay, and Lund-Kennedy) were uniform between groups. AFRS patients had a higher rate of Charcot-Leyden crystals (41.4% vs. 10.2%; p < 0.001). Severe degree of inflammation, eosinophilic inflammatory predominance, eosinophil aggregates, subepithelial edema, and basement membrane thickening were common in both groups, and their rates were not statistically significantly different between groups. Metaplasia, ulceration, fibrosis, and hyperplastic/papillary change rates were low (<30%) and similar between groups., Conclusion: The SHP of eCRSwNP and AFRS are highly consistent, which suggests AFRS is a severe subtype of CRSwNP overall rather than a separate disease entity. This also lends credence to AFRS belonging on the endotypic spectrum of CRSwNP., Level of Evidence: 3 Laryngoscope, 134:2617-2621, 2024., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: The PI3K/Akt/mTOR pathway and autophagy are important physiological processes. But their roles in eCRSwNP remains controversial., Methods: In this study, we used the eCRSwNP mouse model, PI3K/Akt/mTOR pathway inhibitors, and autophagy inhibitors and activators to investigate the regulatory effects of the PI3K/Akt/mTOR pathway on autophagy, and their effects on eosinophilic inflammation, and tissue remodeling. The role of ILC2s in eCRSwNP was also studied, and the relationship between ILC2s and autophagy was preliminarily determined., Results: Our results show that eosinophilic inflammation in eCRSwNP mice could be inhibited by promoting the autophagy; otherwise, eosinophilic inflammation could be promoted. Meanwhile, inhibition of the PI3K/Akt/mTOR pathway can further promote autophagy and inhibit eosinophilic inflammation. Meanwhile, inhibiting the PI3K/Akt/mTOR pathway and promoting autophagy can reduce the number of ILC2s and the severity of tissue remodeling in the nasal polyps of eCRSwNP mice., Conclusions: We conclude that the PI3K/Akt/mTOR pathway plays roles in eosinophilic inflammation and tissue remodeling of eCRSwNP, in part by regulating the level of autophagy. The downregulation of autophagy is a pathogenesis of eCRSwNP; therefore, the recovery of normal autophagy levels might be a new target for eCRSwNP therapy. Furthermore, autophagy might inhibit eosinophilic inflammation and tissue remodeling, in part by reducing the number of ILC2s., (© 2024 The Author(s). Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

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.)

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: There is a large diversity of mucosal immunologic chronic rhinosinusitis with nasal polyps (CRSwNP) endotypes across Western and Asian patient populations., Objectives: The objective of the study was whether the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) 2020 criteria for type 2 inflammation are appropriate for biological use in CRSwNP patients., Methods: A total of 207 participants are enrolled for the study. Retrospective evaluations of the tissues taken during surgery and the patients' clinical features were performed. We investigated whether the criteria described in the EPOS2020 guideline were appropriate based on the criteria for type 2 inflammation identified based on prior studies using receiver-operating characteristic (ROC) analyses., Results: The EPOS 2020 criteria are also shown to be an insufficient evaluation approach with low specificity (area under curve [AUC] = 0.645, specificity 8.4%). The authors created a novel scoring method using the total serum IgE level, blood eosinophil percentage, and tissue eosinophil percentage. This novel scoring system (AUC = 0.862, p  < .001) fared better in ROC analyses than the EPOS 2020 criteria (AUC = 0.645) and Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis scoring system (AUC = 0.647)., Conclusions and Significance: A novel standard for type 2 inflammation in Asian CRSwNP patients must be established, as the EPOS 2020 criteria do not appear to be sufficient.

Background: Regulatory T (Treg) cells, which prevent inflammation-induced eosinophil infiltration, are deficient in nasal polyps (NPs) in patients with eosinophilic chronic rhinosinusitis (ECRS). It is concomitant with loss of Foxp3 after certain inflammatory stimuli., Objective: We sought to determine the inflammatory cytokines involved in inducing the loss of Treg cells in NPs., Methods: The abundance of cytokines in ECRS patients or mice were tested using ELISA, immunochemistry, immunofluorescence, quantitative reverse transcription PCR (qPCR), and/or flow cytometry. Expression of eosinophil cationic protein (ECP), CD4 + T cells, IL-4, and IL-17A and eosinophils in nasal mucosa of mouse model was investigated by immunochemistry, immunofluorescence, and hematoxylin and eosin staining. The percentage and death of induced Treg (iTreg) cells, source of IL-21 in NPs from ECRS and non-ECRS patients, and abundance of different systemic phenotypes of CD4 + T cells in a mouse model were studied by flow cytometry. Western blot analysis, scanning, and transmission electronic microscopy were used to detect pyroptosis of iTreg cells., Results: IL-21 was highly expressed in nasal mucosa of ECRS patients and mice, causing pyroptosis and preventing development of iTreg cells in vitro. The elevated IL-21 in NPs from ECRS patients was mainly produced by CD3 + T cells, including T follicular helper, T peripheral helper, T H 2, and T H 17 cells and CD3 + CD4 - T cells. T peripheral helper cells and CD3 + CD4 - T cells were the predominant source of IL-21 in NPs from non-ECRS patients. Blocking IL-21/IL-21R signaling significantly reduced the number of eosinophils and CD4 + T cells along with ECP, IL-4, and IL-17A expression in the nasal mucosa of ECRS mice. It also increased Treg cell percentage and systemically decreased T H 2 and T H 17 ratios. Akt-mTOR inhibition prevented IL-21-induced pyroptosis in human and mouse iTreg cells., Conclusion: Elevated IL-21 drives pyroptosis and prevents Treg cell development in ECRS patients. IL-21 induced pyroptosis via activating Akt-mTOR-NLRP3-caspase 1 signaling., (Copyright © 2023. Published by Elsevier Inc.)

Background: A definitive diagnosis of eosinophilic chronic rhinosinusitis (eCRS) requires invasive surgical tissue sampling and histologic enumeration of intact eosinophils. Eosinophil peroxidase (EPX) is an accurate biomarker of sinonasal tissue eosinophilia in CRS regardless of polyp status. A less invasive and rapid method that accurately identifies tissue eosinophilia would be of great benefit to patients., Objective: We sought to evaluate a new clinical tool that uses a nasal swab and colorimetric EPX activity assay to predict a diagnosis of eCRS., Methods: A prospective, observational cohort study was conducted using nasal swabs and sinonasal tissue biopsies obtained from patients with CRS electing endoscopic sinus surgery. Patients were classified as non-eCRS (n = 19) and eCRS (n = 35) on the basis of pathologically determined eosinophil counts of less than 10 or greater than or equal to 10 eosinophils/HPF, respectively. Swab-deposited EPX activity was measured and compared with tissue eosinophil counts, EPX levels, and CRS-specific disease metrics., Results: EPX activity was significantly increased in patients with eCRS than in patients without eCRS (P < .0001). With a relative absorbance unit cutoff value of greater than or equal to 0.80, the assay demonstrated high sensitivity (85.7%) and moderate specificity (79.0%) for confirming eCRS. Spearman correlations between EPX activity and tissue eosinophil counts (r s  = 0.424), EPX levels (r s  = 0.503), and Lund-Kennedy endoscopy scores (r s  = 0.440) in eCRS were significant (P < .05)., Conclusions: This investigation evaluates a nasal swab sampling method and EPX activity assay that accurately confirms eCRS. This method could potentially address the unmet need to identify sinonasal tissue eosinophilia at the point-of-care, as well as to longitudinally monitor eosinophil activity and treatment response., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

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.)

Background: Histopathology of nasal polyps contains rich prognostic information, which is difficult to extract objectively. In the present study, we aimed to develop a prognostic indicator of patient outcomes by analyzing scanned conventional hematoxylin and eosin (H&E)-stained slides alone using deep learning., Methods: An interpretable supervised deep learning model was developed using 185 H&E-stained whole-slide images (WSIs) of nasal polyps, each from a patient randomly selected from the pool of 232 patients who underwent endoscopic sinus surgery at the First Affiliated Hospital of Sun Yat-Sen University (internal cohort). We internally validated the model on a holdout dataset from the internal cohort (47 H&E-stained WSIs) and externally validated the model on 122 H&E-stained WSIs from the Seventh Affiliated Hospital of Sun Yat-Sen University and the University of Hong Kong-Shenzhen Hospital (external cohort). A poor prognosis score (PPS) was established to evaluate patient outcomes, and then risk activation mapping was applied to visualize the histopathological features underlying PPS., Results: The model yielded a patient-level sensitivity of 79.5%, and specificity of 92.3%, with areas under the receiver operating characteristic curve of 0.943, on the multicenter external cohort. The predictive ability of PPS was superior to that of conventional tissue eosinophil number. Notably, eosinophil infiltration, goblet cell hyperplasia, glandular hyperplasia, squamous metaplasia, and fibrin deposition were identified as the main underlying features of PPS., Conclusions: Our deep learning model is an effective method for decoding pathological images of nasal polyps, providing a valuable solution for disease prognosis prediction and precise patient treatment., (© 2022 ARS-AAOA, LLC.)

Objectives: Patients with eosinophilic chronic rhinosinusitis with nasal polyps (eosCRSwNP) usually have more extensive sinus disease, severe symptoms, and poorer disease control compared with patients with non-eosCRSwNP. Separating these entities will be crucial for patient management. The purpose of this study is to investigate T 1, T 2 , and apparent diffusion coefficient (ADC) values of the nasal polyps in patients with CRSwNP and evaluate the usefulness of these parameters for differentiating these diseases., Methods: Sinonasal magnetic resonance imaging was performed in 36 patients with eosCRSwNP and 20 patients with non-eosCRSwNP (including T 1 mapping, T 2 mapping, and diffusion-weighted imaging) before surgery. The T 1 , T 2 , and ADC values were calculated and correlated with pathologically assessed inflammatory cells of nasal polyps., Results: Significant higher T 2 value, higher eosinophil count, and lower lymphocyte count of the nasal polyps were observed in eosCRSwNP than those in non-eosCRSwNP. There was no significant difference in T 1 or ADC values between the 2 groups. T 2 value was correlated with eosinophil count and lymphocyte count in CRSwNP. The area under the curve of T 2 value for predicting eosCRSwNP was 0.78 with 89.9% sensitivity and 60.0% specificity., Conclusion: T 2 value is a promising imaging biomarker for predicting eosCRSwNP. It can help to distinguish eosCRSwNP from non-eosCRSwNP., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: This study aimed to identify the histopathologic characteristics associated with difficult-to-treat chronic rhinosinusitis with nasal polyps (CRSwNPs), enabling physicians to predict the risk of poor outcome after endoscopic sinus surgery (ESS)., Methods: A prospective cohort study performed at the First Affiliated Hospital of Sun Yat-sen University between January 2015 and December 2018 with CRSwNP patients who underwent ESS. Polyp specimens were collected during surgery and were subjected to structured histopathological evaluation. Difficult-to-treat CRSwNPs were determined at 12-15 months post-operation according to the European Position Paper. Multiple logistic regression model was used to assess the association between histopathological parameters and the difficult-to-treat CRSwNP., Results: Among 174 subjects included in the analysis, 49 (28.2%) were classified with difficult-to-treat CRSwNP, which had higher numbers of total inflammatory cells, tissue eosinophils, and percentages of eosinophil aggregates and Charcot-Leyden crystals (CLC) formation but a lower number of interstitial glands than the nondifficult-to-treat CRSwNP. Inflammatory cell infiltration (adjusted OR: 1.017), tissue eosinophilia (adjusted OR: 1.005), eosinophil aggregation (adjusted OR: 3.536), and CLC formation (adjusted OR: 6.972) were independently associated with the difficult-to-treat outcome. Furthermore, patients with tissue eosinophil aggregation and CLC formation had an increasingly higher likelihood of uncontrolled disease versus those with tissue eosinophilia., Conclusion: The difficult-to-treat CRSwNP appears to be characterized by increased total inflammatory infiltrates, tissue eosinophilia, eosinophil aggregation, and CLC formation in structured histopathology., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Patients with eosinophilic chronic rhinosinusitis (ECRS) respond poorly to many treatment modalities. Overproduction of periostin in the nasal mucosa is reported to contribute to polyp formation. This study examined periostin levels in patients with ECRS in comparison with levels in patients with non-ECRS., Methods: Fifty-nine patients with chronic rhinosinusitis were grouped into those with ECRS and those with non-ECRS. We compared the relationships between peripheral blood eosinophil level, serum periostin level, histopathological findings, clinical and laboratory findings, nose findings, diagnostic score of the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis Study, and postoperative recurrence of nasal polyps in each group., Results: In the ECRS group, a positive correlation was found between peripheral blood eosinophil level and serum periostin level (r s  = 0.49, P < 0.01: Spearman's rank correlation coefficient). ROC curve analysis was used to evaluate the serum periostin level that could predict postoperative recurrence of nasal polyps in the ECRS group: the area under the curve (AUC) was 0.95, sensitivity was 92%, and specificity was 100%; the serum periostin cutoff value for postoperative recurrence of nasal polyps was 130 ng/ml. In ROC curve analysis to evaluate peripheral blood eosinophil level, the AUC was 0.73, sensitivity was 69.2%, and specificity was 85.0%; the cutoff value was 8.8%., Conclusions: periostin was implicated in the pathophysiology of ECRS. Periostin shown to be a more useful biomarker than eosinophils in ECRS. Periostin was shown to likely be an important biomarker for pathological severity of ECRS and postoperative recurrence of nasal polyps., (Copyright © 2022 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Introduction: Chronic rhinosinusitis with nasal polyps (CRSwNPs) in China is characterized by a mixed eosinophilic-neutrophilic inflammation, linking to a more heterogeneous clinical phenotype. However, the relationship between eosinophilic and neutrophilic inflammation in Chinese patients with CRSwNP remains largely unknown. We aimed to further characterize the correlation between neutrophils with eosinophils in relation to clinical characters and disease control status after endoscopic sinus surgery (ESS)., Methods: A total of 242 patients were recruited and stratified based on tissue (≥10%) eosinophilia and (≥20/per high-power field) neutrophilia. Clinical characteristics and disease control status were compared between subgroups. Associations between tissue eosinophils and neutrophils were analyzed., Results: The uncontrolled patients accounted for 41.3%, 41.3%, 17.1%, and 22.2% in subjects with concomitant tissue eosinophilia and neutrophilia (EN-high), isolated eosinophilia (E-high), isolated neutrophilia (N-high), and no eosinophilia and neutrophilia (EN-low), respectively. Positive correlations between tissue eosinophils and neutrophils were observed in patients with CRSwNP as well as in EN-high and N-high subgroups but not in E-high and EN-low subgroups. The EN-high subgroup had higher tissue eosinophil numbers than the other three subgroups. Both EN-high and E-high subgroups had higher rates of uncontrolled subjects than the N-high and EN-low subgroups; however, there was no difference in the rate of uncontrolled subjects between EN-high and E-high subgroups and between N-high and EN-low subgroups., Conclusion: Tissue neutrophils might have a potential interaction and mutual promotion effect with eosinophils in CRSwNP. However, tissue neutrophilia would not pose significant risk for poor disease control after ESS. Further larger, prospective studies are needed to confirm our findings., (© 2023 S. Karger AG, Basel.)

Background: Adult and pediatric patients with chronic rhinosinusitis (CRS) may have differing philosophies in therapeutic management. Few studies have examined sinonasal tissue-level comparisons of these groups. This study examines histopathologic differences between children and adults with CRS, with the goal of understanding disease pathogenesis and optimizing medical management for both populations., Methods: In a retrospective cohort of CRS patients who underwent functional endoscopic sinus surgery (FESS), demographic factors, pertinent comorbidities, and a structured histopathologic report of 13 variables were compared across pediatric and adult CRS patients with and without nasal polyps (pCRSwNP, pCRSsNP, aCRSwNP, aCRSsNP, respectively)., Results: A total of 378 adult (181 aCRSsNP, 197 aCRSwNP) and 50 pediatric (28 pCRSsNP, 22 pCRSwNP) patients were analyzed. Significantly more children compared with adults had a comorbid asthma diagnosis (64.5% vs. 37.2%, p = 0.003). Adults with CRS exhibited significantly more tissue neutrophilia (28.9% vs. 12.0%, p = 0.006), basement membrane thickening (70.3% vs. 44.0%, p < 0.001), subepithelial edema (61% vs. 30.0%, p < 0.001), squamous metaplasia (22.0% vs. 4.0%, p < 0.001), and eosinophil aggregates (22.8% vs. 4.0%, p < 0.001) than children with CRS. The majority (66.5%) of adult CRS patients exhibited a lymphoplasmacytic-predominant inflammatory background, whereas the majority (57.8%) of children with CRS exhibited a lymphocyte-predominant inflammatory background., Conclusions: Sinonasal tissue of adult and pediatric CRS patients demonstrates clear histopathologic differences. Our findings provide insight into differing pathophysiology, which may enable optimization of targeted therapies for patients in each of these unique clinical groups., (© 2022 ARS-AAOA, LLC.)

Background: The pathologic features and potential predictive biomarkers for recurrence of antrochoanal polyps (ACPs) in children are not fully understood., Objectives: To identify the pathologic differences between recurrent and nonrecurrent group and to explore potential clinical markers which predict recurrence of ACPs in children., Material and Methods: A total of 11 recurrent and 21 nonrecurrent ACPs children were enrolled into this retrospect study. Clinical basic information was collected before the first surgery. The counts of vessels were evaluated by hematoxylin-eosin (HE) staining, and CD34 was detected by immunohistochemistry. Meanwhile, the percentage of each tissue inflammatory cells (eosinophils, neutrophils, lymphocytes, and plasma cells) was assessed by HE staining., Results: No statistical significance was observed between the 2 groups in the basic clinical features. Moreover, both the counts of blood vessels and the tissue neutrophils percentage were enhanced significantly in group with ACPs recurrence ( P < .05). According to the receiver operating characteristic curves, the area under the curve for the counts of blood vessels and tissue neutrophils percentage in the prediction of ACPs' recurrence was 0.779 ( P = .0105) and 0.989 ( P < .0001) respectively., Conclusions and Significance: It was concluded that the counts of blood vessels and the percentage of tissue neutrophils appeared to be potential excellent predictors of ACPs recurrence in children.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common inflammatory disease with high heterogeneity and postoperative recidivation. The IL-33/ST2 axis is known to be involved in Th2 immune responses. This study is aimed at exploring levels of serum IL-33 and soluble ST2 (sST2) in CRSwNP patients and their potential for predicting CRSwNP endotypes and postoperative recurrence., Methods: The present study recruited 149 CRSwNP patients, 80 of whom were noneosinophilic (neCRSwNP) and 69 eosinophilic (eCRSwNP), as well as 60 healthy controls (HCs). Serum samples were collected from all participants, and sST2 and IL-33 concentrations were measured using ELISA. Multivariate analysis, receiver operating characteristic (ROC) curves, and Kaplan-Meier curves were used to evaluate the value of serum sST2 and IL-33 levels in distinguishing CRSwNP endotypes and predicting postoperative recurrence., Results: The levels of serum sST2 and IL-33 in CRSwNP patients were significantly higher than those in HCs, especially in the eCRSwNP group. Increased sST2 and IL-33 levels were associated with eosinophil counts and percentages in both tissue and blood. Multivariate regression and ROC curve analysis showed that serum sST2 and IL-33 exhibited potential for distinguishing CRSwNP endotypes, and the combination of serum IL-33 and sST2 showed even more predictive power. Finally, 124 CRSwNP patients completed the entire 3-year follow-up. Multivariate analysis and Kaplan-Meier curves showed that serum sST2 and IL-33 levels were associated with recurrence; serum sST2 and IL-33 each exhibited potential for predicting postoperative recurrence, and combining serum sST2 and IL-33 exhibited better accuracy and practicability., Conclusion: Our results suggested that serum sST2 and IL-33 levels were upregulated in CRSwNP patients and related to the degree of mucosal eosinophil infiltration and postoperative recurrence. Serum sST2 and IL-33 might serve as objective biomarkers for distinguishing phenotypes and predicting recurrence in CRSwNP, and their combined use outperformed either marker alone., 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 © 2022 Yanni Zhang et al.)

Background: Asthma is significantly related to chronic rhinosinusitis (CRS) both in prevalence and severity. However, the clinical patterns of uncontrolled asthma with and without comorbid CRS are still unclear. This study aimed to explore the clinical characteristics and cytokine patterns of patients with uncontrolled asthma, with and without comorbid CRS., Methods: 22 parameters associated with demographic characteristics, CRS comorbidity, severity of airflow obstruction and airway inflammation, and inflammation type of asthma were collected and assessed in 143 patients with uncontrolled asthma. Different clusters were explored using two-step cluster analysis. Sputum samples were collected for assessment of Th1/Th2/Th17 and epithelium-derived cytokines., Results: Comorbid CRS was identified as the most important variable for prediction of different clusters, followed by pulmonary function parameters and blood eosinophil level. Three clusters of patients were determined: Cluster 1 (n = 46) characterized by non-atopic patients with non-eosinophilic asthma without CRS, demonstrating moderate airflow limitation; Cluster 2 (n = 54) characterized by asthma patients with mild airflow limitation and CRS, demonstrating higher levels of blood eosinophils and immunoglobulin E (IgE) than cluster 1; Cluster 3 (n = 43) characterized by eosinophilic asthma patients with severe airflow limitation and CRS (46.5% with nasal polyps), demonstrating worst lung function, lowest partial pressure of oxygen (PaO 2 ), and highest levels of eosinophils, fraction of exhaled nitric oxide (FeNO) and IgE. Sputum samples from Cluster 3 showed significantly higher levels of Interleukin (IL)-5, IL-13, IL-33, and tumor necrosis factor (TNF)-α than the other two clusters; and remarkably elevated IL-4, IL-17 and interferon (IFN)-γ compared with cluster 2. The levels of IL-10 and IL-25 were not significantly different among the three clusters., Conclusions: Uncontrolled asthma may be endotyped into three clusters characterized by CRS comorbidity and inflammatory cytokine patterns. Furthermore, a united-airways approach may be especially necessary for management of asthma patients with Type 2 features., (© 2022. The Author(s).)

Purpose of Review: Non-allergic rhinitis (NAR) includes different subtypes, among which NAR with eosinophilia syndrome (NARES) is the most important because of severity of symptoms and the high risk of comorbidities. Its pathophysiology is still object of debate, but a crucial role of chronic eosinophilic inflammation has been recognized. The aim of this review is to critically analyze the current evidence regarding the hypothesis that NARES may be considered a type 2 inflammatory disorder., Recent Findings: The definition and diagnostic criteria for NARES are not universally shared and adopted, thus generating difficulties in reproducing the results. At present, there is extreme heterogeneity in sampling methods and disagreement in the cut-off of local eosinophilic count to determine a diagnosis of NARES. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standard was applied to identify English-language experimental and clinical articles regarding NARES. The search was performed in April 2021. Twenty-six articles were included. Our data suggest a particular heterogeneity regarding sampling and specific cut-offs adopted for diagnosis of NARES and consensus should be reached. We suggest that eosinophil count should be reported as an absolute value for at least 10 observed rich fields in order to increase the level of standardization. Consensus among authors on this topic should be reached with particular attention to the cut-off for diagnosis. In the future, this limitation may be overcome by the identification of repeatable biomarkers to refine diagnosis and prognosis of NARES. Furthermore, our data strongly suggest that NARES have numerous similarities with clinical features of the most common type 2 diseases such as eosinophilic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP): late onset, association with type 2 comorbidities, selective eosinophilic tissue infiltration, remarkable response to oral and intranasal corticosteroids, and progression in a type 2 CRSwNP., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The objective of this study was to analyze the histopathologic changes in recurrent nasal polyps (NPs) in terms of tissue inflammatory cells infiltration and mucosal remodeling., Methods: Thirty-five patients with primary NPs requiring a revision surgery during follow-up and a matched control group of 35 primary NP patients without recurrence were retrospectively enrolled. Histopathologic examination was performed of tissue inflammatory cells, subepithelial edema, epithelial cell hyperplasia, basement membrane thickness, and fibrosis., Results: The mean eosinophil and neutrophil counts, proportions of eosinophil and neutrophil, as well as total inflammatory cell count were significantly higher in the recurrent group than those in the controls. Higher subepithelial edema was seen in the recurrent group. Within the recurrent group, the mean tissue eosinophil count and relative eosinophilia reduced from the first operation to revision surgery, whereas neutrophil count and proportion, and total inflammatory cell counts remained unchanged. Subepithelial edema and epithelial cell hyperplasia were significantly reduced after the first surgical procedure., Conclusion: NP recurrence is associated with higher inflammatory grade (especially in eosinophilia and neutrophilia). Surgical and corticoid treatments may have an impact on mucosal histopathologic changes but need further certification., (© 2021 S. Karger AG, Basel.)

Introduction: Eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) exhibits a poorer prognosis than noneCRSwNP. The aim of this study was to analyze the potential of total immunoglobulin E (tIgE) and specific IgE (sIgE) levels in tissues for distinguishing and assessing eCRSwNP., Methods: We enrolled 10 control and 88 CRSwNP patients. The clinical data of patients were collected before surgery. Nasal mucosa tissues were taken during surgery for measurements of tIgE, sIgE (weed pollen, epidermal and animal protein, mold, house dust, tree pollen), and subepithelial eosinophil (EOS) counts. The predictive significance of the potential predictors for eCRSwNP was assessed with receiver operating characteristic (ROC) curves., Results: Nasal polyps tIgE and mold-sIgE were positively correlated with blood and tissue EOSs, comorbid allergic rhinitis and asthma, ethmoid score/total maxillary score ratio, visual analog scale, and CT score. The ROC curve analysis showed that tissue tIgE (p = 0.0004), mold-sIgE (p = 0.0030), blood EOS percentage (p = 0.0003), and absolute blood EOS count (p = 0.0010) acted as predictive factors for eCRSwNP. According to the cutoff value of tissue tIgE of 34.55 ku/L, patients with a high level were more likely to suffer from asthma (p = 0.016) and showed a significantly higher EOS count (p = 0.022), EOS percentage (p = 0.029), and tIgE (p = 0.002) in blood., Conclusion: Tissue tIgE and mold-sIgE had a significant relationship with the clinical and pathological characteristics of CRSwNP patients and might be reliable for distinguishing and assessing eCRSwNP., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: The precise mechanisms underlying pathogenesis of different subtypes of chronic rhinosinusitis with nasal polyps (CRSwNP) are still unclear. Emerging evidence indicates that microRNAs may play a role in the pathogenesis of CRSwNP. This study aimed to identify the dysregulated microRNA-messenger RNA (miRNA-mRNA) regulatory networks in eosinophilic (E) and non-eosinophilic (non-E) CRSwNP., Methods: Whole-transcriptome sequencing was performed on nasal tissues of patients with ECRSwNP and non-ECRSwNP, and control subjects. An integrated analysis of miRNA and mRNA expression was conducted to identify key mRNAs and miRNAs involved in the pathogenesis of ECRSwNP and non-ECRSwNP. The miRNAs of interest and their target genes were validated using quantitative real-time polymerase chain reaction (PCR)., Results: A group of differentially expressed mRNAs (DE-mRNAs) and miRNAs (DE-miRs) were identified in ECRSwNP patients vs control subjects, non-ECRSwNP patients vs control subjects, and non-ECRSwNP vs ECRSwNP patients, respectively. Pathway enrichment analysis showed distinct immune and inflammatory functions associated with DE-mRNAs and target genes of DE-miRs in ECRSwNP vs control and non-ECRSwNP vs control groups. The miRNA-mRNA regulatory networks constructed with Cytoscape highlighted the roles of miR-154, miR-221, and miR-223 family miRNAs relating to both ECRSwNP and non-ECRSwNP, and the roles of the let-7 and miR-34/449 families in the development of non-ECRSwNP. Assessment using real-time PCR for the expression of miRNAs and target genes demonstrated highly consistent data with the RNA sequencing data., Conclusion: ECRSwNP and non-ECRSwNP patients express distinct miRNA-mRNA regulatory networks compared with control subjects, thus providing potential targets for future development of novel therapeutic approaches for the management of CRSwNP., (© 2021 ARS-AAOA, LLC.)

Background: Chronic Rhinosinusitis is currently classified into eosinophilic and non-eosinophilic, according to the histologic quantification of the number of eosinophils in nasal mucosa biopsy. There is a lack of unanimous histopathologic criteria and methodology for this classification and no consensus regarding a cut-off point for Eosinophils per High power field., Methodology: A systematic electronic search was performed on BVS, PUBMED, PUBMED PMC, SCOPUS, WEB OF SCIENCE, EMBASE, COCHRANE and PROQUEST databases looking for studies that reported a cut point for classification of Eosinophilic Chronic Rhinosinusitis (eCRS), and data concerning methodology of classification was extracted., Results: We identified 142 studies that reported 29 different cut-off values for classification of eCRS, and different methods of histologic analysis. Out of these studies 13 reported their own methodology to establish the cut-off point, and used different reference standards as polyp recurrence, asthma and allergy, immunocytochemistry, quality of life index, standard deviation of the control population and cluster analysis., Conclusions: Further studies are needed to determine a precise cut-off point, especially international multicentered cluster analysis. Moreover, methodologic standardization of biopsy and analysis is needed to certify comparable results. Multiple biopsy sites, densest cellular infiltration area examination and oral steroids restriction at least four weeks before sampling are advisable.

Background: Eosinophilic asthma and nasal polyposis are hallmarks of aspirin-exacerbated respiratory disease (AERD), and IL-5 inhibition has been shown to provide therapeutic benefit. However, IL-5Rα is expressed on many cells in addition to eosinophils, and the mechanisms by which IL-5 inhibition leads to clinical benefit in eosinophilic asthma and nasal polyposis are unlikely to be due exclusively to antieosinophil effects., Objective: We sought to identify the mechanisms by which anti-IL-5 treatment with mepolizumab improves respiratory inflammation in AERD., Methods: The clinical characteristics, circulating granulocytes, nasal scraping transcripts, eosinophilic cationic protein, tryptase, and antibody levels, and urinary and nasal eicosanoid levels were measured for 18 subjects with AERD who were taking mepolizumab and compared with those of 18 matched subjects with AERD who were not taking mepolizumab., Results: Subjects taking mepolizumab had significantly fewer peripheral blood eosinophils and basophils, and those cells that remained had higher surface CRTH2 expression than did the cells from subjects not taking mepolizumab. Nasal prostaglandin F 2α , prostaglandin D 2 metabolites, leukotriene B 4 , and thromboxane levels were lower in subjects taking mepolizumab, as were urinary levels of tetranor-prostaglandin D 2 and leukotriene E 4 . The nasal epithelial cell transcripts that were overexpressed among subjects with AERD who were taking mepolizumab were enriched for genes involved in tight junction formation and cilium organization. Nasal and urinary prostaglandin E 2 , tryptase, and antibody levels were not different between the 2 groups., Conclusion: IL-5 inhibition in AERD decreases production of inflammatory eicosanoids and upregulates tight junction-associated nasal epithelial cell transcripts, likely due to decreased IL-5 signaling on tissue mast cells, eosinophils, and epithelial cells. These direct effects on multiple relevant immune cells contribute to the mechanism of benefit afforded by mepolizumab., (Copyright © 2021. Published by Elsevier Inc.)

Introduction/objectives: The histopathological study of inflammatory cells and their tendency to form aggregates in chronic rhinosinusitis with nasal polyps (CRSwNP) has shown promising results in determining the pathogenesis and predicting clinical outcome. Bilateral nasal polyps also occur in over 70% of patients with eosinophilic granulomatosis with polyangiitis (EGPA). The study aim was to investigate neutrophil infiltrates and eosinophil aggregates in CRSwNP and EGPA tissues of Caucasian patients., Method: A histopathological study was performed on surgical specimens of nasal polyps from 144 adults (15 with allergic fungal rhinosinusitis; 19 with nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease (NERD); 16 with intrinsic asthma; 21 with extrinsic asthma; 21 with allergy; 22 with eosinophil CRSwNP (ECRSwNP); 17 with non-ECRSwNP; 13 with EGPA)., Results: Focusing on the presence of tissue eosinophil aggregates, NERD and ECRSwNP were the sub-cohorts with the highest rate. Neutrophil infiltrate rate was significantly higher in EGPA sub-cohort than in all CRSwNP sub-cohorts apart from non-ECRSwNP., Conclusions: Structured histopathology is increasingly identifying the different histotypes of CRSwNP. This analysis can be used to better understand CRSwNP endotypes and develop targeted therapies. The response to therapy and therefore control of CRSwNP relapses definitely depends on our ability to act on the underlying inflammatory pattern. Key points • Systematic analysis of how neutrophil infiltrates and eosinophilic aggregates are distributed in the different phenotypes of CRSwNP and EGPA. • Neutrophil infiltrates and eosinophil aggregates are strong risk factors for nasal polyps' refractoriness. • NERD and ECRSwNP are the sub-cohorts of CRSwNP with the highest rate of tissue eosinophil aggregates. • Neutrophil infiltrates are significantly higher in EGPA.

Background: Eosinophilic chronic rhinosinusitis (ECRS) is a chronic inflammatory disease, characterized by eosinophilic infiltration, T-helper type 2 (Th2-type) response, and olfactory dysfunction. A master regulator of Th2-type inflammation, thymic stromal lymphopoietin (TSLP), is important for basophil activation. TSLP-elicited basophils are a key factor in the pathogenesis of ECRS., Methods: In order to elucidate the mechanisms of ECRS in humans, we aimed to establish a murine model of ECRS based on TSLP production in response to the topical application of MC903 (a vitamin D3 analog) and the subsequent TSLP-induced basophil activation. Histological analyses were performed to assess immune cell infiltration into the nasal mucosa and to explore the impact of eosinophilic inflammation on the olfactory epithelium. The status of Th2-type inflammation was evaluated by quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA)., Results: Eosinophils, basophils, and M2 macrophages increased significantly in the nasal mucosa of the mice treated with MC903 and ovalbumin (OVA), compared to those treated with OVA alone or the controls. Quantitative real-time PCR and ELISA revealed elevated expression of interleukin (IL)-4, IL-5, IL-13, TSLP, the chemokine CCL11, and CCL24 in the nasal mucosa of the ECRS mice. In parallel, thinned olfactory epithelium and decreased mature olfactory sensory neurons were observed in the ECRS mice., Conclusions: Our model of ECRS displayed Th2-type inflammation in the sinonasal region, including both eosinophil infiltration and basophil infiltration. Additionally, olfactory epithelium turned out to be affected by eosinophilic inflammation. These features are consistent with the characteristics of the human ECRS., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Very few studies have compared blood eosinophil and basophil levels before and after surgery in patients with eosinophilic CRSwNP (eCRSwNP). No investigations seem to have repeatedly measured them pre- and postoperatively in eCRSwNP patients with recurring versus non-recurring disease to examine how their levels evolved., Objective: Hence this study to analyze blood eosinophil and basophil levels in patients with eCRSwNP immediately before surgery and afterwards, at 4 months, 1 year, and then yearly up to 5 years., Methods: Fifty-one eCRSwNP patients were enrolled, who all had preoperative laboratory data and the results of at least 4 of the 6 scheduled postoperative follow-up tests., Results: Seventeen patients had recurrent disease. Blood eosinophil counts (p = 0.005) and percentages (p = 0.002) were both higher in these patients than in those whose eCRSwNPs did not recur after surgery. Blood basophil counts (p = 0.04) and percentages (p < 0.05) were also significantly higher in patients whose eCRSwNPs relapsed. The time by relapse interaction was not significant for either counts or percentages, though an effect of time was detected for basophil counts (p = 0.01)., Conclusions: In eCRSwNP, the statistical analysis of repeated quantitative laboratory data can shed light on the evolution of a patient's systemic inflammatory picture in response to previous treatments, and above all to long-term therapies. Long-term monitoring of blood eosinophil and basophil levels could be of significant value when monoclonal antibodies that inhibit IL signaling will widely enter in clinical practice for eCRSwNP treatment to follow the effectiveness of therapy over time.

Background: Patients with eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) have poorer outcomes after endoscopic sinus surgery and a higher recurrence rate. Objective: This study aimed to investigate the profile of clinical symptoms of eCRSwNP and the related risk factors. Methods: We prospectively enrolled 298 inpatients with CRSwNP from February 2019 to December 2019. The patients were divided into eCRSwNP and non-eCRSwNP groups based on the percentage of blood eosinophils; the cutoff value was set at 3.05%. Clinical data on questionnaires, visual analog scale (VAS) scores, and laboratory tests were collected. The differences in clinical symptoms, including nasal congestion, rhinorrhea, olfactory disorders, and head and/or facial pain, between the two groups were analyzed to identify the influential factors. Logistic analysis and receiver operating characteristic curves were used to determine the diagnostic benefit for the specific symptom in the patients in the eCRSwNP group. Results: Nasal congestion and olfactory disorders were significantly different between the eCRSwNP and non-eCRSwNP groups. The patients in the eCRSwNP group more frequently had concerns about olfactory disorders (p = 0.002), whereas patients in the non-eCRSwNP group mostly had nasal congestion (p = 0.001). The logistic analysis showed that the primary risk factors for olfactory disorders of eCRSwNP were disease duration (p = 0.014) and alcohol intake (p = 0.012). Olfactory disorders were not associated with the disease course of the eCRSwNP group but were correlated with the disease duration of non-eCRSwNP (p = 0.008). A VAS score for the olfactory disorders of >5.75 could be used to predict the diagnosis of eCRSwNP (area under the curve, 0.674 [95% confidence intervals, 0.559-0.689]; P < 0.001). Conclusion: Olfactory disorder might be the major nasal symptom that could be used to distinguish a peripheral eosinophilia-based definition of eCRSwNP and non-eCRSwNP. The disease duration was a limiting factor for using olfactory to distinguish two subgroups of nasal polyp. The investigation with regard to the accurate time boundary should be further addressed.

To understand the inflammatory microenvironment and microbiome factors for prognosis of chronic rhinosinusitis with polyps (CRSwNP), we explored the difference in characteristics of the microbiome of the nasal sinuses and inflammatory cytokines between recurrent and non-recurrent groups. We collected nasal secretions and polyp tissue from 77 CRSwNP patients. Then, we extracted microbial DNA from cotton swabs, performed high-throughput sequencing based on 16S rRNA to detect bacterial community composition, and analyzed cytokines such as IL-5, IL-8, IL-17a, IL-17e, IL-18, IL-27 and INF-gamma from polyp tissue using Luminex. The eosinophil and neutrophil cells in the peripheral blood and polyp tissue were counted. Postoperative follow-up of patients with CRSwNP for 1 year was conducted to record the recurrence of nasal polyps and analyze the correlation between the recurrence of nasal polyps and the characteristics of inflammatory cytokines, inflammatory cell count and nasal microbial diversity. After 1 year of follow-up, there were 12 recurrent patients, including 5 males and 7 females. Postoperative recurrence of nasal polyps was not significantly correlated with age, sex, asthma, allergic rhinitis or other allergic diseases in CRSwNP patients. In terms of the total nasal symptom score, the recurrent group was significantly higher than the non-recurrent group. In nasal polyp tissues, eosinophils (40.83/HP) and neutrophils (30.83/HP) in patients with CRSwNP in the recurrent group were significantly higher than those in the non-recurrent group (13.72/HP), and neutrophils (18.5/HP) were also significantly higher in the recurrent group than the non-recurrent group. The expression levels of IFN-, IL-17A, IL-17E and IL-18 were significantly higher in the recurrent group than in the non-recurrent group, and the positive rates were not different. In Southwest China, Enterobacteria and anaerobic bacteria may be correlated with the inflammatory pattern expression of nasal polyps. The neutrophil-mediated inflammatory response plays an important role in patients with CRSwNP in Southwest China and is correlated with nasal polyp recurrence. Recurrence of nasal polyps after endoscopic sinus surgery may be potentially associated with a reduced abundance of protective microorganisms and an increased number of pathogenic microorganisms.

Objective: To investigate the roles of nasal nitric oxide（nNO） in diagnosis and endotypes of CRSwNP. Methods: Eighty-two CRSwNP patients and thirty healthy volunteers were recruited for this study. The patients were classified into eosinophilic CRSwNP （Eos CRSwNP） and non-eosinophilic CRSwNP （non-Eos CRSwNP） endotypes by tissue eosinophil percentage. nNO levels were measured with an electrochemical sensor-based device. nNO levels and clinical factors were compared among the groups. Receiver-operating characteristic （ROC） curve and logistic regression analyses were performed to evaluate the predictive ability of the nNO for diagnosis and endotypes of CRSwNP. Results: Eos CRSwNP patients（143.9±106.2） ×10-9 had lower nNO levels than non-Eos CRSwNP[（228.3±109.2） ×10-9, P =0.000 9） and healthy subjects（366.5±88.0） ×10-9, P <0.000 1）. Patients with atopy exhibited significantly higher levers of nNO compared with patients without atopy（ P <0.05）. For Eos CRSwNP diagnosis, nNO had the highest predictive value（AUC: 0.939; sensitivity: 76.74%; specificity: 96.67%; cut-off value: 231×10-9, P <0.001）. Furthermore, nNO levels were associated with CRSwNP endotypes（odds ratio: 1.010; 95% confidence interval: 1.003%, 1.016%; P =0.002）. When the nNO concentration was 158 ×10-9, we could discriminate Eos CRSwNP from non-Eos CRSwNP（AUC=0.710, sensitivity: 76.92%; specificity, 60.47%, P =0.001）. After it was combinated by nNO, periphera blood eosinophil count（PEAC） and VAS score, the AUC was increased to 0.894（95% CI =0.807 to 0.951, P <0.000 1, sensitivity: 76.74%, specificity: 89.74%）. Conclusion: nNO may has potential for non-invasive diagnosis and endotype of CRSwNP. nNO combined with PEAC and VAS score may be an ideal diagnostic tool for endotyps of Eos CRSwNP. However, the atopic status of the patients influenced the levels of nNO., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Introduction: Recent studies have shown that inflammatory patterns of nasal polyps from patients with chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) in East Asia have changed over time. However, to date there is a marked lack of similar data for CRSwNP in Northern China. This study thus aimed to assess the changes in the clinical and histological characteristics of CRSwNP patients from Northern China over the past 2-3 decades., Methods: This was a retrospective study, which examined data from 2 groups of 150 CRSwNP patients each, who had undergone endoscopic sinus surgery in Beijing Tongren Hospital from 1993 to 1995 (group A) and from 2015 to 2019 (group B). All relevant data for demographic, clinical, and histological parameters were collected for each patient from the 2 groups and compared for overall changes between the 2 groups., Results: The comorbidity of CRSwNP and asthma increased over time and the cellular phenotype of CRSwNPchanged significantly; in particular, the proportion of eosinophil-dominant CRSwNP increased, lymphocyte-dominant and plasma-dominant CRSwNP decreased significantly, and the proportions of neutrophil-dominant and mixed CRSwNP were not altered. The rate of polyp recurrence increased in CRSwNP but did not in eosinophilic CRSwNP. Smoking and age did not significantly impact the inflammatory patterns of CRSwNP., Conclusions: The inflammatory patterns of CRSwNP patients have changed and comorbidity of asthma significantly increased in CRSwNP patients in Northern China over the past 2-3 decades., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Purpose: Chronic rhinosinusitis with nasal polyps can be classified as eosinophilic or neutrophilic based on the major inflammatory cell type in the tissue. There is a need for predictive parameters to enable rhinologists to identify the type of nasal polyp in a patient without surgery. The aim of the present study was to test the predictive value of the markers of inflammation to estimate eosinophilic nasal polyps., Methods: The study analyzed 299 patients who underwent sinus surgery for nasal polyps from 2012 to 2019. Patients were divided into two groups according to pathology results (eosinophilic polyps = group 1, neutrophilic polyps = group 2). The values of preoperative complete blood count, systemic immune inflammation index, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio were compared., Results: In our series, results of ROC analyses for both mean eosinophil count and systemic immune inflammation index were statistically significant. For the eosinophil count (AUC = 0.681, p < 0.001) and systemic immune inflammation index (AUC = 0.621, p = 0.001). Patients with an eosinophil cut-off value of 0.25 cells × 10 9 /L had ORs of 49.27 (95% CI 11.68-207.81) and sensitivity: 0.69, specificity: 0.64. Patients with a systemic immune inflammation index cut-off value of 332.39 had ORs of 1.003 (95% CI 1.002-1.004) and sensitivity: 0.84, specificity: 0.39., Conclusion: The systemic immune inflammation index and absolute blood eosinophil count could be used to predict nasal polyp subtypes before surgery. We believe that systemic immune inflammation index should also be studied to estimate postoperative recurrence.

Inflammation plays an important role in the pathogenesis of nasal polyps. Understanding the biomolecular action mechanisms of inflammatory elements can contribute to improving the prognosis of these lesions. The study analyzed the distribution and immunohistochemically quantified eosinophils [eosinophil major basic protein (BMK-13)], lymphocytes [cluster of differentiation (CD) 4, CD8, CD20] and plasmocytes (CD138) in both the epithelial and stromal compartment in relation to composite scores, which included specific histopathological parameters for 50 sinonasal polyps. Inflammatory elements predominated at stromal level, the high histological composite scores being frequently associated with increased expression of inflammatory elements. Also, the numerical distribution of inflammatory elements indicated positive linear relations within the groups BMK-13∕CD8 and CD4∕CD20∕CD138, and a negative linear relation between the two groups. This aspect can support the existence of alternative or sequential pathogenic mechanisms involved in the pathogenesis of sinonasal polyps, and the results obtained can be used for a better stratification of patients in order to optimize the therapy.

Chronic rhinosinusitis (CRS) is one of the most common chronic diseases worldwide. It is a heterogeneous disease, and geographical or ethnic differences in inflammatory pattern in nasal mucosa are major issues. Tissue eosinophilia in CRS is highly associated with extensive sinus disease, recalcitrance, and a higher nasal polyp (NP) recurrence rate after surgery. The prevalence of eosinophilic CRS (ECRS) is increasing in Asian countries within the last 2 decades, and this trend appears to be occurring across the world. International consensus criteria for ECRS are required for the accurate understanding of disease pathology and precision medicine. In a multicenter large-scale epidemiological survey, the "Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis study," ECRS was definitively defined when the eosinophil count in nasal mucosa is greater than or equal to 70 eosinophils/hpf (magnification, ×400), and this study proposed an algorithm that classifies CRS into 4 groups according to disease severity. The main therapeutic goal with ECRS is to eliminate or diminish the bulk of NP tissue. NPs are unique abnormal lesions that grow from the lining of the nasal and paranasal sinuses, and type 2 inflammation plays a critical role in NP development in patients with ECRS. An imbalance between protease and endogenous protease inhibitors might play a pivotal role in the initiation and exacerbation of type 2 inflammation in ECRS. Intraepithelial mast cells in NPs, showing a tryptase+, chymase- phenotype, may also enhance type 2 inflammation. Intense edema and reduced fibrosis are important histological features of eosinophilic NPs. Mucosal edema mainly consists of exuded plasma protein, and excessive fibrin deposition would be expected to contribute to the retention of proteins from capillaries and thereby perpetuate mucosal edema that may play an etiological role in NPs. Upregulation of the coagulation cascade and downregulation of fibrinolysis strongly induce abnormal fibrin deposition in nasal mucosa, and type 2 inflammation plays a central role in the imbalance of coagulation and fibrinolysis., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Chronic rhinosinusitis with nasal polyposis (CRSwNP) represents a heterogeneous disorder that can be classified into either eosinophilic or noneosinophilic endotypes. However, the immunological mechanisms of each remain unclear. The purpose of the present study was to compare and analyze inflammatory signatures of eosinophilic CRSwNP (ECRSwNP) and noneosinophilic CRSwNP (NECRSwNP). Cytokine antibody array was used to identify inflammatory mediators that were differentially expressed among ECRSwNP, NECRSwNP, and control groups. Then, bioinformatics approaches were conducted to explore biological functions and signaling pathways. In addition, pairwise correlation analyses were performed among differential levels of inflammatory mediators and tissue eosinophil infiltration. The results showed that nine mediators were significantly up-regulated in ECRSwNP, including eotaxin-2, eotaxin-3, CCL18, IL-4, IL-5, IL-10, IL-12p70, IL-13, and IL-15. Bioinformatics analysis indicated that these mediators were mainly enriched in leukocyte chemotaxis and proliferation, JAK-STAT cascade, asthma, and Th1 and Th2 cell differentiation. Furthermore, seven mediators were identified to be significantly up-regulated in NECRSwNP, including CCL20, resistin, transforming growth factor (TGF)-β2, triggering receptor expressed on myeloid cells 1 (TREM-1), CD14, glucocorticoid-induced tumor necrosis factor receptor related protein (GITR), and lipocalin-2. These mediators were closely associated with LPS responses, neutrophil chemotaxis and migration, and IL-17 signaling pathway. In addition, pairwise correlation analyses indicated that differential levels of inflammatory mediators in ECRSwNP and NECRSwNP were broadly correlated with each other and with tissue eosinophil infiltration. In conclusion, we found that ECRSwNP and NECRSwNP exhibited different patterns of inflammatory signatures. These findings may provide further insights into heterogeneity of CRSwNP., (© 2020 The Author(s).)

Purpose of Review: The current understanding of eosinophilic chronic rhinosinusitis (CRS) has developed rapidly over the past decades. Classification of CRS based on the inflammatory endotype more accurately reflects the underlying pathophysiology and better directs treatment. Corticosteroids and more recently biologic agents, target the eosinophil inflammatory that drives this subtype of CRS. Tissue sampling is not always accessible or available and surrogate markers are sought to define this endotype of CRS. The purpose of this review is to assess current systemic predictors of eosinophilic CRS (eCRS) diagnosis., Recent Findings: Blood eosinophils are a moderate surrogate predictor of eCRS. A blood eosinophil count of more than 0.24 × 10/l predicts eCRS with tissue eosinophilia of more than 10 eosinophils per high-power field. It has been further shown that a blood eosinophil count more than 0.45 × 10/l is associated with need for long-term systemic therapy following endoscopic sinus surgery. Other biomarkers reviewed include IgE, eosinophilic cationic protein, eosinophil-derived neurotoxin, eosinophil peroxidase, IL-5, periostin, eotaxin-3 and IL-16., Summary: There remains limited data surrounding the prognostic use of biomarkers in eCRS. However, peripheral eosinophilia best predicts the eosinophilic density that best predicts the eCRS phenotype. In addition, it is also prognostic of need for more intensive therapy. Simple haematoxylin and eosin stained sinus mucosa still remains the most reliable tissue for assessment and is more accessible than bronchial biopsies.

Aims: In chronic rhinosinusitis with nasal polyps (CRSwNP), tools based on objective evidence, such as histopathology, are needed to assist clinical decision-making. The main aim of this exploratory investigation was to determine whether structured histopathology could be used to classify CRSwNP in homogeneous histological clusters., Methods and Results: A cohort of 135 CRSwNP patients was assessed, on the basis of clinicopathological features: allergic fungal rhinosinusitis (17 patients); non-steroidal anti-inflammatory drug-exacerbated respiratory disease (19 patients); intrinsic asthma (18 patients); extrinsic asthma (21 patients); allergy (21 patients); histologically eosinophilic (22 patients); and histologically non-eosinophilic (17 patients). For structured histopathology, we considered: the degree of inflammation; eosinophil count; eosinophil aggregates; neutrophil infiltration; goblet cell hyperplasia; basement membrane thickening; fibrosis; hyperplastic/papillary changes; squamous metaplasia; mucosal ulceration; and subepithelial oedema. Cluster analysis identified four distinct sets of cases. On discriminant analysis, the global error rate was 1.48%, and the stratified error rates were 4.34%, 0%, 0%, and 0% for clusters 1, 2, 3 and 4, respectively. Cluster 1 was characterised by infrequent fibrosis (<4.5% of cases). Cluster 2 mainly featured neutrophil infiltration in 100% of cases, hyperplastic/papillary changes in 70% of cases, and fibrosis in 65% of cases. Cluster 3 showed fibrosis in 100% of cases. Cluster 4 showed hyperplastic/papillary changes in 100% of cases, and fibrosis in 92% of cases., Conclusions: This study shows that cluster analysis can identify different histotypes among CRSwNP patients. The next step will be to investigate, in a larger series, the clinical (e.g. prognostic) implications of identifying such homogeneous clusters of patients with CRSwNP on the basis of their structured histopathology., (© 2019 John Wiley & Sons Ltd.)

Background and Objective: Omalizumab is a human anti-IgE antibody approved for the treatment of severe allergic asthma (SAA). However, its effectiveness in SAA associated with chronic rhinosinusitis with nasal polyposis (CRSNP+) is less well documented. Objective: The aim of this study was to evaluate the real-life effectiveness of omalizumab in patients with SAA and CRSNP+ who tolerated and did not tolerate aspirin., Methods: We performed a retrospective, observational, multicenter, real-life study of patients with SAA and CRSNP+ treated with omalizumab for 6 months. Asthma outcome parameters (symptoms, number of salbutamol rescues/wk, number of moderate/severe exacerbations, Asthma Control Test score, and lung function), sinonasal outcome parameters (symptoms, number of episodes of acute rhinosinusitis, sinus computed tomography images, nasal polyps endoscopy score), and serum eosinophil levels were analyzed 6 months before and after treatment with omalizumab., Results: Twenty-four adult patients were included (9 with documented aspirin intolerance). All respiratory parameters were significantly improved by the treatment. In parallel, a significant improvement was observed in sinonasal clinical outcomes and sinus computed tomography images, with no major effect on the nasal polyps endoscopy score. The serum eosinophil count decreased significantly after 6 months of treatment with omalizumab., Conclusion: Treatment of SAA with omalizumab improves the outcome of associated CRSNP+, thus supporting the concept of a "one airway disease".

Background: A hallmark of eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) is mucosal eosinophil-predominant inflammation. Nasal nitric oxide (nNO) is a known biomarker of eosinophilic inflammation in the upper airway. However, the utility of nNO measurement in the upper airway remains controversial. The present study aimed to compare the use of other clinical parameters with nNO to prediagnose patients with eCRSwNP from Central China., Methods: From June 2019 to December 2019, 70 patients with CRSwNP undergoing endoscopic sinus surgery and 30 healthy subjects were enrolled. nNO measurements were performed in all of these subjects. Computed tomography scans, full blood count with differential analysis, and determination of total immunoglobulin E (total IgE) and plasma cytokines were performed before surgery. Receiver operating characteristic curves and logistic regression analysis were used to assess the predictive potential of the clinical parameters., Results: We recruited 24 patients with eCRSwNP and 46 with noneosinophilic CRSwNP (non-eCRSwNP). In patients with eCRSwNP, nNO levels were significantly higher than those in patients with non-eCRSwNP (p < 0.0001). Blood eosinophil percentages and counts, total IgE, and CT-derived ethmoid sinus and maxillary sinus ratio (E/M ratio) were all significantly higher compared with those in patients with non-eCRSwNP (p < 0.05). To diagnose eCRSwNP, the highest area under the curve (0.803) was determined for nNO. At a cutoff of >329 parts per billion (ppb), the sensitivity was 83.30% and the specificity was 71.70%. However, the levels of plasma cytokines Th1/Th2 were not significantly different between the histological types of CRSwNP (p > 0.05)., Conclusion: Measurement of nNO is useful for the early diagnosis of eCRSwNP., (© 2020 S. Karger AG, Basel.)

Background: Eosinophilic nasal polyps (NPs) are associated with the presence of asthma in chronic rhinosinusitis (CRS) patients. Serum periostin has been considered a relevant biomarker for unified airway diseases., Objective: To determine the utility of biomarkers including serum periostin that reflects reduction of exacerbations of comorbid asthma in CRS patients., Methods: We prospectively recruited 56 CRS patients who were subjected to undergo endoscopic sinus surgery (ESS) (20 with asthma) between October 2015 and December 2017 and followed them for 1 year after ESS. Blood eosinophil count, serum periostin, and fractional nitric oxide (FeNO) were measured at enrollment. How these type 2-driven biomarkers reflect comorbid asthma was determined using receiver operating characteristic (ROC) analysis. The frequency of asthma exacerbations during 1 year was counted both before and after ESS. Associations between preoperative biomarkers including eosinophils in NPs and asthma exacerbations were evaluated., Results: Blood eosinophil count, FeNO, and serum periostin levels were significantly higher in CRS patients with asthma than in those without (p < 0.01 for all) and discriminated comorbid asthma among CRS patients (p < 0.05; AUC > 0.80 for all). The increased preoperative serum periostin correlated with lower absolute number of postoperative exacerbations (ρ = -0.49, p = 0.03) and its relative reduction after ESS (ρ = 0.53, p = 0.03) in asthmatic patients. Increased eosinophils in NPs were also associated with reduced asthma exacerbations., Conclusion: Preoperative increased serum periostin and eosinophils in NPs are associated with the preventive effect of ESS for asthma exacerbations in CRS patients comorbid with asthma., (© 2020 S. Karger AG, Basel.)

Background: The interaction between epithelial cells and immune cells plays an important role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP); however, the mechanism or mechanisms underlying T H -biased inflammation in this process are largely unknown. Profiling protein expression in patients with CRSwNP by using shotgun proteomics suggested that cystatin SN (CST1), a type 2 cysteine protease inhibitor, might play a role because this was expressed with the greatest difference in patients with eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) and those with noneosinophilic chronic rhinosinusitis with nasal polyps (nonECRSwNP)., Objectives: We sought to investigate the expression and role of CST1 in modulating eosinophilic inflammation in patients with CRSwNP., Methods: Sinonasal tissues were collected from 192 patients with ECRSwNP, 52 patients with nonECRSwNP, and 40 control subjects. CST1 mRNA expression, localization, and concentration in the tissues were measured by using real-time PCR, in situ hybridization, immunohistochemistry, and an ELISA. Recombinant CST1 was used to further explore the function of the molecule in dispersed nasal polyp cells and eosinophils extracted from polyp tissues and peripheral blood., Results: CST1 was mainly expressed by epithelial cells and significantly increased in patients with ECRSwNP but decreased in patients with nonECRSwNP compared with that in control subjects. CST1 expression was further increased in patients with ECRSwNP and comorbid asthma and correlated with eosinophil percentages in tissue samples. CST1 was induced by IL-4 and IL-13 in tissue from both patients with ECRSwNP and those with nonECRSwNP and repressed by IL-17A in patients with nonECRSwNP in the presence of neutrophils. CST1 enhanced eosinophil activation and recruitment through induction of IL-5., Conclusion: Epithelium-derived CST1 modulates eosinophil activation and recruitment, expression of which could be regulated by T H 2 and T H 17 cytokines., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)