BACKGROUND:Chronic rhinosinusitis with nasal polyps involves mixed type 2-type 3 inflammation, associated with disease severity and treatment resistance, yet mechanisms remain unclear. OBJECTIVE:We sought to investigate the role of IL-2 and its interaction with type 3 inducers (TNF-α, IL-1β, and IL-23) in driving mixed type 2-type 3 inflammation. METHODS:IL-2 and receptor expression in nasal polyps was analyzed using tissue homogenates and public RNA-sequencing data. Dispersed nasal polyp cells were treated with IL-2/type 3 inducers, with cytokine production, proliferation, and gene expression analyzed via immunoassays, flow cytometry, and RNA sequencing. IL-2 receptor/Janus kinase (JAK) blockade studies were conducted. Furthermore, CD4+ and CD8+ T cells were magnetically isolated from nasal polyps to evaluate their response to cytokine stimulation. RESULTS:IL-2 levels were increased in chronic rhinosinusitis with nasal polyps, particularly in type 3-dominant and mixed type 2-type 3 subgroups, and correlated with type 3 cytokines. RNA sequencing supported upregulated IL-2 receptors and their coexpression with type 3 genes. IL-2 synergized with type 3 inducers to enhance both type 2 and type 3 cytokine production in dispersed nasal polyp cells. Direct functional evidence from isolated CD4+ and CD8+ T cells confirmed this synergy, with CD8+ T cells emerging as a novel source of IL-13. Flow cytometry further supported these findings, showing synergistic cytokine production across diverse cell populations, including T-cell subsets and natural killer cells. Memory T cells mediated T-cell receptor-independent cytokine production. Transcriptomic analysis identified activated type 3, type 2, and JAK-signal transducer and activator of transcription signaling pathways. IL-2 receptor blockade, particularly JAK inhibition, attenuated IL-2/type 3 inducer-mediated synergistic inflammation. CONCLUSIONS:A novel mechanism was identified whereby IL-2 synergizes with proinflammatory type 3 inducers to amplify mixed type 2-type 3 inflammation via innate-like T-cell activation, and targeted JAK inhibition was validated as a potential therapy.

BACKGROUND:Chronic rhinosinusitis with nasal polyps (CRSwNP) can be classified into Eosinophilic CRSwNP (ECRSwNP) and non-Eosinophilic CRSwNP (nECRSwNP) based on eosinophilic infiltration in nasal polyps. However, no consensus criteria exist for eosinophilic infiltration in nasal polyps, including different cutoffs for eosinophil (EOS) counts or different EOS proportions among inflammatory cells. METHODS:Inferior turbinate (IT) tissues from controls (n = 27) and nasal polyp (NP) tissues from ECRSwNPs (n = 50) were collected. ECRSwNPs (n = 38) underwent 2-year post-FESS follow-up. Clinical assessments (SNOT-22, Lund-Mackay, Lund-Kennedy scores), eosinophil indicators (polyp/blood EOS counts, EETs area), and Th2 cytokines pre/post-FESS were recorded for correlation analysis and prognostic model building. Subsequently, functional nanosheets TLPGA targeting EETs were synthesized and tested for EETs clearance in human EOS, epithelial cell models, and NP models. RESULTS:Our findings demonstrated positive correlations between EETs area and ECRSwNP severity, including Lund-Mackay CT scores (r = 0.72, p < 0.001), Lund-Kennedy Endoscopic score (r = 0.57, p < 0.001), IL-4 (r = 0.50, p < 0.001), IL-5 (r = 0.50, p < 0.001), IL-13 (r = 0.39, p < 0.01), and Periostin (r = 0.34, p < 0.05). And we first demonstrated that increased preoperative EETs area predicts both impaired mucosal recovery and elevated nasal polyp uncontrolled risk within 2 years post-FESS. Furthermore, we developed novel nanosheets TLPGA and demonstrated that TLPGA effectively scavenges EETs and alleviates the type 2 inflammatory cascade in human nasal polyp tissues and epithelial cell model. CONCLUSION:These findings highlight the potential of EETs and EOS morphology in assessing preoperative ECRSwNP severity and predicting postoperative prognosis. Moreover, this also supports TLPGA as a promising therapeutic approach for managing ECRSwNP with high EETs levels.

BACKGROUND:Staphylococcal superantigen-specific IgE (SAg-IgE) correlates with disease severity in patients with type 2 (T2) chronic rhinosinusitis with nasal polyps (CRSwNP). Although Staphylococcus aureus is recognized as a primary source of SAgs, SAg-IgE is detected even in patients with culture-negative S aureus. OBJECTIVE:We sought to identify the source of SAgs in SAg-IgE-positive patients with T2 CRSwNP with culture-negative S aureus. METHODS:Metagenomic sequencing was conducted in patients with T2 CRSwNP with repeatedly negative S aureus cultures, stratified by SAg-IgE status. We screened clinical isolates for SAg genes and evaluated SAg functionality by measuring SAg-specific T-cell receptor repertoire expansion and T2 inflammatory responses in an ex vivo infection model. RESULTS:The SAg-IgE-positive group showed significantly higher abundances of S epidermidis, S aureus, Lysinibacillus xylanilyticus, and S capitis compared with the SAg-IgE-negative group. Interestingly, in all participants in whom S aureus was detected, S capitis was also present, albeit at low abundance. Redundancy analysis demonstrated clustering of the Staphylococcus genus, SAg-IgE, and IL-5, supporting a potential link between the Staphylococcus genus and SAg-driven immune responses. Notably, a clinical S capitis isolate carried SEA (staphylococcal enterotoxin A) and SEC genes and secreted functional SAgs, which triggered the clonal expansion of SEA/SEC-specific T-cell receptors and exacerbated the T2 inflammatory response via IL-33 induction. CONCLUSIONS:Metagenomic sequencing reveals that S capitis, beyond S aureus, produces functional SAg to drive T2 response in SAg-IgE-positive patients with CRSwNP when conventional cultures fail to detect S aureus. Independent of culturable bacterial load, tissue SAg-IgE positivity reliably indicates bacterial colonization and SAg exposure in CRSwNP.

Group 2 innate lymphoid cells (ILC2s) directly contribute to local inflammation in type 2 inflammatory airway diseases. Here, we identify ILC2 subsets by single cell RNA sequencing in chronic rhinosinusitis with nasal polyps (CRSwNP) and in a memory inflammatory mouse model. We find that toll-like receptor 4 (TLR4)+ILC2s, with similar markers to their human counterparts, expresse memory cell markers, persist over time, and respond more vigorously to a secondary unrelated antigen challenge in the mouse model. Genetic ablation of TLR4 or blockade by anti-TLR4 antibodies leads to the reduction of IL-13 expression from ILC2s and mucus production in mice. The assay for transposase-accessible chromatin sequencing further confirms the importance of accessible TLR4 gene loci and its down-stream signaling pathway in maintaining trained immunity of TLR4+ILC2s after repeated stimulation by HDM. Taken together, TLR4 has a function in trained immunity maintenance within ILC2s, which may contribute to disease chronicity through a non-specific immunological memory.

BACKGROUND:Immunoglobulin overproduction was observed in type 2 chronic rhinosinusitis with nasal polyps (CRSwNP). Endoplasmic reticulum (ER) stress is linked to aggregation in various inflammatory diseases, yet its presence and extent in nasal polyps remain to be elucidated. OBJECTIVE:To assess the impact of B-cell ER stress on local immunoglobulin production in CRSwNP and investigate its correlation with disease severity. METHODS:Single-cell mapped transcriptional profiles at cellular resolution. Electron microscopy revealed ultrastructural features, complemented by immunohistochemistry/immunofluorescence mapping marker localisation. Western blotting quantified protein expression, with QuantiGene Plex and Luminex enabling multiplex cytokine analysis. Bulk RNA sequencing and targeted protein expression validation in ex vivo experiments confirmed critical findings. RESULTS:HSPA5 and HSP90B1 were found to be two major elevated ER stress markers in type 2 CRSwNP, compared to the control nasal tissue, and their expression correlated with the expression of IGHE and type 2 inflammatory markers. In CRSwNP, the ER stress signature score and increased marker expression predominantly originated from B and plasma cells. Electron microscopy revealed dilated ER and enlarged lumen in sorted B cells from nasal polyps. MZB1 exhibited co-localisation with plasma cells and mature B cells. Immunofluorescence staining demonstrated that MZB1 co-localised with HSPA5 and HSP90B1. In vitro, stimulation with MZB1 upregulated mRNA expression of ER stress markers and IgE. Increased IGHE expression was detected in response to ER stress induced in vitro. Finally, anti-IgE treatment inhibited the expression of ER stress-related genes. CONCLUSION:ER stress markers were significantly upregulated in CRSwNP. Specifically, ER stress levels were significantly elevated in B cells of CRSwNP compared to controls. In type 2 CRSwNP, B-cell ER stress may play a role in promoting local IgE production.

Exposure to occupational noise has emerged as a major health issue worldwide. To better evaluate changes in the health impacts of occupational noise exposure from 1990 to 2021, this study conducted stratified analyses of spatiotemporal variations across regions, genders, age, and sociodemographic index (SDI) levels. Results indicate that low-income and rapidly industrializing countries bear higher burdens of occupational noise-related diseases. Males and middle-aged to elderly populations are the primary high-risk groups for occupational noise exposure, with a particularly notable increase in the burden among those aged 45-74. Disability-adjusted life years (DALYs) significantly decreased with increasing SDI, while estimated annual percentage change (EAPC) showed significant positive correlations with both DALYs (R = 0.3) and SDI (R = 0.4). Regions with an SDI of 0.4-0.6 experienced the most pronounced EAPC growth. By 2035, DALYs rates are projected to decrease to 125.0 ± 1.9 per 100,000, although the burden for individuals aged 65 and above is expected to increase significantly. Population growth and aging were identified as key drivers of DALYs increases, contributing 68.2% and 20.9%, respectively. From 1990 to 2021, the slope inequality index changed from - 9.6 to 2.5, and the concentration index curve became smoother. Although health inequality has improved, the disease burden in low-SDI countries remains significantly higher than theoretical minimum levels. This study provides robust support for reducing global occupational noise exposure and its associated health inequalities.

BACKGROUND:Mast cells (MCs) are involved in type 2 inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP), which depends on interleukin (IL)-33 stimulation. MiR-221 is reported to be an important regulator of MCs, and miR-221-3p can be expressed in CRSwNP. However, the role of miR-221-3p in CRSwNP is unclear. METHODS:Ethmoid tissues from control subjects (n = 12) and polyps from patients with CRSwNP (n = 40) were collected. The expression of miR-221-3p and cytokines was detected by real-time quantitative polymerase chain reaction (qPCR). The activation of P65 and ERK was determined by western blotting. The localization of miR-221-3p was detected via in situ hybridization combined with immunofluorescence (IF), and its target was identified via a luciferase reporter system. Human MCs were incubated with IL-33 or stem cell factor. MicroRNA mimics/inhibitor and lentiviral plasmids were used to determine the role of miR-221-3p in MCs. RESULTS:We observed increased expression of miR-221-3p in CRSwNP, and localized its expression in MCs. The expression of miR-221-3p was negatively correlated with that of IL-4, IL-5, and IL-13 in CRSwNP. MiR-221-3p can be induced by IL-33 in MCs and plays a negative regulatory role in cytokine expression and signaling pathways in IL-33-induced MC activation. As the direct target of miR-221-3p, the receptor KIT was negatively correlated with miR-221-3p and decreased in CRSwNP. In MCs, KIT is essential for an effective response to IL-33 stimulation. We here demonstrated that miR-221-3p regulates cytokine expression by targeting KIT in IL-33-activated MCs. CONCLUSIONS:MiR-221-3p inhibits MC-dependent type 2 inflammatory conditions, rendering it a negative regulator of CRSwNP.

BACKGROUND:Chronic rhinosinusitis with nasal polyps (CRSwNP) is generally characterized by tissue-infiltrating eosinophils. Various biologic treatments, targeting the inflammation, have demonstrated efficacy in reducing nasal polyp size and symptoms. However, their specific impact on granulocyte populations within polyps remains largely unclear. This study explores how different biological treatments modulate local nasal polyp inflammation by assessing changes in granulocyte presence and recruitment before and after treatment. METHODS:Type 2-high CRSwNP patients received treatment with mepolizumab, benralizumab, omalizumab, or dupilumab. Immunohistochemistry and protein measurements were performed on their nasal polyp tissue. Bulk RNA-sequencing was conducted on pre- and post-treatment nasal samples, identifying differentially expressed genes. These results were integrated with single-cell data from CRSwNP patients. RESULTS:Nasal polyp tissue from type 2-high patients exhibited substantial eosinophil infiltration and limited neutrophils present. All tested biologics reduced eosinophil-related proteins and genes in nasal tissue. However, our data suggest that benralizumab, mepolizumab and omalizumab could induce a concurrent upregulation of neutrophilic markers. In these patients, chemoattractant genes for neutrophils primarily originated from the epithelial cell cluster, whereas receptors for these biologics were expressed by plasma cells, dendritic cells, and mast cells. CONCLUSION:Biological treatments effectively reduced eosinophilic inflammation in nasal polyps. However, most biologics could induce an eosinophil-to-neutrophil shift, indicating that solely targeting eosinophils may be insufficient as a treatment approach. Understanding these secondary effects on local immune pathways is critical for optimizing CRSwNP treatment strategies.

BACKGROUND:Eosinophils easily accumulate in the intra-epithelial layer and subepithelial regions in eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP). While several factors influence the migration of eosinophils from peripheral blood to extravascular tissues, the triggers and role of eosinophils near the epithelial layer in CRSwNP remain unclear. METHODS:We examined interactions between eosinophils and epithelial cells using co-culture systems. We assessed the expression of amphiregulin (AREG) in CRSwNP epithelial cells and investigated its impact on epithelial barrier function, eosinophil activation, and migration. These effects were further validated in a CRSwNP mouse model treated with an AREG-blocking antibody. RESULTS:Co-culturing blood eosinophils and primary epithelial cells from CRSwNP patients decreased tight junction expression and increased eosinophil activation. Epithelial cells from ECRSwNP patients expressed higher levels of AREG than those from non-eosinophilic CRSwNP (non-ECRSwNP) patients, particularly in basal cells. As measured in the culture medium by ELISA, both blood eosinophils and primary epithelial cells automatically secreted AREG. Our in vitro experiments demonstrated that AREG impaired epithelial barrier function and facilitated eosinophil migration and activation. Confirmatory studies in a CRSwNP mouse model indicated that blocking AREG reduced the number of nasal polyp-like lesions, mucosal thickness, and eosinophil infiltration, while restoring the expression of tight junction proteins. CONCLUSION:The upregulation of AREG triggers eosinophil migration and mediates the interaction between epithelial cells and eosinophils, thereby enhancing chronic inflammation in CRSwNP. Our study highlights the therapeutic potential of anti-AREG antibodies in CRSwNP, offering a promising strategy for treating human eosinophilic sinus diseases.

BACKGROUND:Chronic rhinosinusitis with nasal polyp (CRSwNP) is classified into type 2 and non-type 2 inflammation based on mucosal cytokine level. For 20 years, the type 2/non-type 2 ratio has increased, potentially influenced by air pollution and aeroallergens. OBJECTIVE:To investigate the association between long-term exposure to air pollutants and aeroallergens and the endotype shift in CRSwNP. METHODS:We enrolled 2358 patients with CRSwNP from Guangzhou and 416 from Ghent. Endotypes were defined using a diagnostic model or interleukin 5 levels in nasal polyps. Pollutant exposure was estimated based on residential ZIP code. Generalized additive models with restricted cubic splines and generalized linear mixed models were used to assess the effects of particulate matters (PMs) less than or equal to 2.5 µm, PM less than or equal to 10 µm, nitrogen dioxide, sulfur dioxide, ozone, and aeroallergen exposure on type 2 CRSwNP risk compared with non-type 2. RESULTS:Higher air pollutant exposure was linked to a lower type 2/non-type 2 ratio. In Guangzhou, every 1 μg/m3 increase in 3-year cumulative PMs less than or equal to 2.5 µm exposure was associated with an odds ratio of 0.97 (95% CI: 0.96-0.98, P < .001) for type 2 CRSwNP. In Ghent, the relative risk was 0.78 (95% CI: 0.65-0.94, P = .009) for the same exposure increase. Elevated total IgE and Dermatophagoides pteronyssinus sensitization increase type 2 risk than non-type 2 CRSwNP in Guangzhou, whereas allergic rhinitis, elevated total IgE, pollen sensitization, and multi-allergen sensitization increased type 2 CRSwNP risk in Ghent. CONCLUSION:Decreasing long-term air pollution exposure and increasing allergen sensitization are associated with higher type 2/non-type 2 CRSwNP ratio, highlighting the role of environmental factors in endotype shifting. TRIAL REGISTRATION:Chinese Clinical Trial Registry Identifier: ChiCTR2400082123.

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Background: The expression of MZB1 genes is significantly elevated in patients who have chronic rhinosinusitis with nasal polyp (CRSwNP) disease compared with healthy controls. Objective: To characterize MZB1-positive B cells in CRSwNP and to estimate the contribution of distinct subsets of B cells to the local overproduction of immunoglobulins. Methods: Single-cell RNA-sequencing with Cellular Indexing of Transcriptomes and Epitopes by Sequencing technology, Switching Mechanism At the 50 end of RNA Template sequencing, flow cytometry, immunohistochemistry and immunofluorescence staining, Western blot, QuantiGene Plex assay, B-cell ImmunoSpot assay, Luminex assay, and enzyme-linked immunosorbent assay were performed. Results: Significantly higher mRNA expression of MZB1 and HSP90B1 was found in type 2 CRSwNP compared with controls. In CRSwNP, MZB1 expression correlated with the local production of IgE. MZB1 could be colocalized with plasma and mature B cells, especially marginal zone (MZ) B cells. Single-cell transcriptome and epitope studies revealed prominent populations of B cells in type 2 CRSwNP with unexpectedly high MZB1 gene expression. The MZ B-cell population was significantly increased in CRSwNP compared with healthy controls in both peripheral blood mononuclear cells and nasal tissue single-cell suspensions. When those single cells were cultured overnight, the MZ B-cell numbers were positively correlated with local IgE production but negatively correlated with local IgM production. In vitro, MZB1 stimulation up-regulated the mRNA expression of IgE. Conclusion: MZB1 was primarily expressed by plasma and mature B cells in nasal mucosa. MZB1 expression level was increased in CRSwNP compared with controls. MZB1 contributed to the local IgE production in type 2 CRSwNP. (c) 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Background: The Spike protein mutation severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to decreased protective effect of various vaccines and mAbs, suggesting that blocking SARS-CoV-2 infection by targeting host factors would make the therapy more resilient against virus mutations. Angiotensin-converting enzyme 2 (ACE2) is the host receptor of SARS-CoV-2 and its variants, as well as many other coronaviruses. Downregulation of ACE2 expression in the respiratory tract may prevent viral infection. Antisense oligonucleotides (ASOs) can be rationally designed on the basis of sequence data, require no delivery system, and can be administered locally. Objective: We sought to design ASOs that can block SARSCoV-2 by downregulating ACE2 in human airway. Methods: ACE2-targeting ASOs were designed using a bioinformatic method and screened in cell lines. Human primary nasal epithelial cells cultured at the air-liquid interface and humanized ACE2 mice were used to detect the ACE2 reduction levels and the safety of ASOs. ASO-pretreated nasal epithelial cells and mice were infected and then used to detect the viral infection levels. Results: ASOs reduced ACE2 expression on mRNA and protein level in cell lines and in human nasal epithelial cells. Furthermore, they efficiently suppressed virus replication of 3 different SARS-CoV-2 variants in human nasal epithelial cells. In vivo, , ASOs also downregulated human ACE2 in humanized ACE2 mice and thereby reduced viral load, histopathologic changes in lungs, and increased survival of mice. Conclusions: ACE2-targeting ASOs can effectively block SARSCoV-2 infection. Our study provides a new approach for blocking SARS-CoV-2 and other ACE2-targeting virus in high- risk populations. (J Allergy Clin Immunol 2024;154:1044-59.)

Alphaherpesviruses, including herpes simplex virus type 1 (HSV-1), pseudorabies virus (PRV), and bovine herpesvirus type 1 (BoHV-1), are significant pathogens affecting humans and animals. These viruses penetrate the upper respiratory tract mucosa, yet the mechanisms facilitating this invasion are not fully understood. This study investigates the role of the gE/gI glycoprotein complex and proteases in mucosal invasion by these viruses. Using species-specific respiratory mucosal explants, we observed that the removal of extracellular calcium disrupts epithelial junction integrity, enhancing viral infection across all viruses and suggesting a common mechanism of targeting a basolaterally located receptor. PRV exhibited significantly faster replication and deeper invasion compared to HSV-1 and BoHV-1. The gE glycoprotein was consistently polarized at the basement membrane across all viruses, indicating a critical role in the process of viral entry and subsequent spread through the epithelium. In this context, "infection" refers to the virus's attachment to its cell-surface receptor, entry into the cell, and completion of the viral life cycle, culminating in the production of progeny virions. Notably, in gE/gI null mutants of PRV and HSV-1, while the infection was not abortive and the viral life cycle was completed, the infection was delayed, and the invasion into the deeper layers of the epithelium and underlying mucosa was significantly reduced. In BoHV-1 mutants, this effect was even more pronounced, with infection restricted to the apical cells, failing to progress to the basal cells. In addition, PRV and HSV-1 invasion involved serine protease activity, unlike BoHV-1, which correlates with its slower invasion pace. Notably, the protease facilitating PRV invasion was identified as a urokinase plasminogen activator (uPA), while the specific protease for HSV-1 remains unidentified. These findings highlight the critical roles of the gE/gI complex and proteases in alphaherpesvirus pathogenesis, offering potential targets for therapeutic intervention. IMPORTANCE:Herpes simplex virus type 1 (HSV-1) infections are a worldwide issue. More than three billion people are infected with HSV-1 globally. Although most infections with HSV-1 occur subclinically, severe symptoms and complications are numerous and can be life-threatening. Complications include encephalitis and blindness. Recently, HSV-1 infections have been associated with the development of Alzheimer's Disease. To date, no effective vaccines against HSV-1 are on the market. Pseudorabies virus (PRV) and bovine herpesvirus type 1 (BoHV-1) are two alphaherpesviruses of major veterinary importance. Although efforts have been made to eradicate these viruses from livestock animals, clinical problems still occur, resulting in great economic losses for farmers. It is evident that new insights into the pathogenesis of alphaherpesviruses are needed, to develop effective treatments and novel preventive therapies.

INTRODUCTION:In recent years, endotypes of chronic rhinosinusitis (CRS) based on the underlying immune mechanisms provided a better understanding of this heterogeneous disease and are frequently applied in diagnosis and treatment.AREAS COVERED:In this manuscript, we aim to review novel treatment approaches for this often uncontrolled disease and highlight endotype-driven medical algorithms that could be beneficial in daily clinical practice.EXPERT OPINION:With the development of endotyping and the mucosal inflammatory concept, several type 2-targeted biologics and surgical options are nowadays available for treating CRS. However, a better understanding based on clinical trials and real-life experience in daily practice is needed to optimize patient selection, biological drug selection, treatment duration, prediction, and long-term follow-up strategies. Indirect comparison analysis suggested that dupilumab might be the most effective biologic for treating CRS with nasal polyps, but the role and timing of surgery remain unclear. More real-life studies and comparative trials are needed for the optimal integration of biologics into clinical pathways in combination with established treatment approaches such as nasal and oral glucocorticosteroids and adequate surgery to provide long-term perspectives.

Background:Type 2 CRSwNP is characterized by severe symptoms, multiple comorbidities, longer recovery course and high recurrence rate. A simple and cost-effective diagnostic model for CRSwNP endotype integrating clinical characteristics and histopathological features is urgently needed. Objective:To establish a clinical diagnostic model of inflammatory endotype in CRSwNP based on the clinical characteristics, pathological characteristics, and cytokines profile in the polyp tissue of patients. Methods:A total of 244 participants with CRSwNP were enrolled at 2 different centers in China and Belgium from 2018 to 2020. IL-5 level of nasal polyp tissue was used as gold standard. Clinical characteristics were used to establish diagnostic models. The area under the receiver operating curve (AUC) was used to evaluate the diagnostic performance. The study was approved by the ethics board of the First Affiliated Hospital of Sun Yat-sen University ([2020] 302), and written informed consent was obtained from all subjects before inclusion. Results:In total, 134 patients from China (training set) and 110 patients from Belgium (validation set) were included. The logistic regression (LR) model in predicting inflammatory endotype of CRSwNP showed the AUC of 83%, which was better than the diagnostic performance of machine learning models (AUC of 61.14%-82.42%), and single clinical variables. We developed a simplified scoring system based on LR model which shows similar diagnostic performance to the LR model Conclusion:The LR model in this diagnostic study provided greater accuracy in prediction of inflammatory endotype of CRSwNP than those obtained from the machine learning model and single clinical variable. This indicates great potential for the use of diagnostic model to facilitate inflammatory endotype evaluation when tissue cytokines are unable to be measured.

IntroductionStaphylococcus aureus (S. aureus) is a common pathogen that frequently colonizes the sinonasal cavity. Recent studies demonstrated the essential role of Staphylococcus aureus in the pathophysiology of uncontrolled severe chronic rhinosinusitis with nasal polyps (NP) by initiating an immune response to the germ and its products, resulting in type 2 inflammation.Areas coveredThis review aims to summarize the evidence for the role of S. aureus in the development of NP disease including S. aureus-related virulence factors, the pathophysiologic mechanisms used by S. aureus, and the synergistic effects of S. aureus and other pathogens. It also describes the current management of S. aureus associated with NPs as well as potential therapeutic strategies that are used in clinical practice.Expert opinionS. aureus is able to damage the nasal mucosal epithelial barrier, impair the clearance of the host immune system, and trigger adaptive and innate immune reactions which lead to the formation of inflammation and nasal polyp growth. Further studies should focus on the development of novel therapeutic strategies, such as biologics, bacteriophages, probiotics, and nanomedicine, which could be used to treat S. aureus and its immunological consequences in the future.

Background: Previous studies on the endotyping of chronic rhinosinusitis (CRS) that were based on inflammatory factors have broadened our understanding of the disease. However, the endotype of CRS combined with inflammatory and remodeling features has not yet been clearly elucidated. Objective: We sought to identify the endotypes of patients with CRS according to inflammatory and remodeling factors. Methods: Forty-eight inflammatory and remodeling factors in the nasal mucosal tissues of 128 CRS patients and 24 control subjects from northern China were analyzed by Luminex, ELISA, and ImmunoCAP. Sixteen factors were used to perform the cluster analysis. The characteristics of each cluster were analyzed using correlation analysis and validated by immunofluorescence staining. Results: Patients were classified into 5 clusters. Clusters 1 and 2 showed non-type 2 signatures with low biomarker concentrations, except for IL-19 and IL-27. Cluster 3 involved a low type 2 endotype with the highest expression of neutrophil factors, such as granulocyte colony-stimulating factor, IL-8, and myeloperoxidase, and remodeling factors, such as matrix metalloproteinases and fibronectin. Cluster 4 exhibited moderate type 2 inflammation. Cluster 5 exhibited high type 2 inflammation, which was associated with relatively higher levels of neutrophil and remodeling factors. The proportion of CRS with nasal polyps, asthma, allergies, anosmia, aspirin sensitivity, and the recurrence of CRS increased from clusters 1 to 5. Conclusion: Diverse inflammatory mechanisms result in distinct CRS endotypes and remodeling profiles. The explicit differentiation and accurate description of these endotypes will guide targeted treatment decisions. (J Allergy Clin Immunol 2023;151:458-68.)

BackgroundLittle evidence exists regarding an integrated multidimensional evaluation methodology to analyze the within-patient effects of medical treatment for chronic rhinosinusitis with nasal polyps (CRSwNP). We aimed to use an integrated evaluation model to analyze the effects of short-course oral corticosteroid (OCS) followed by intranasal corticosteroid spray (INCS) therapy in patients with severe CRSwNP.MethodsIn all, 32 patients with severe CRSwNP received oral methylprednisolone for three weeks followed by intranasal budesonide spray for nine weeks in this prospective single-arm study. An evaluation model integrating the concepts of the core outcome set (COS), clinical control and minimum clinically important difference (MCID) was longitudinally evaluated.ResultsAll uncontrolled patients at baseline showed similar progressive improvements from baseline and more than 1 MCID response across core outcomes during the OCS period, with severe CRSwNP being partly controlled in 31 (96.9%) patients and uncontrolled in 1 (3.1%) patient at 3 weeks. During the subsequent INCS period, 14 (43.8%) patients gradually deteriorated to an uncontrolled status at 12 weeks, whereas 18 (56.2%) exhibited partly controlled CRSwNP until 12 weeks.ConclusionsIn more than half of the patients, severe CRSwNP was partly controlled with the initial OCS followed by INCS therapy. An integrated evaluation model was used to facilitate the comprehensive evaluation of within-patient response, especially in patients with different responses to the same treatment.