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Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic sinonasal disease characterized by heterogeneous inflammation. However, the presence of systemic inflammation heterogeneity in CRSwNP patients remains unknown. This study aims to profile transcriptomic alterations in the blood of CRSwNP patients and characterize the CRSwNP heterogeneity based on blood transcriptomic biomarkers., Methodology: Patients with CRSwNP were prospectively recruited from three hospitals and chronologically divided into exploratory (n=123) and independent validation (n=46) cohorts. Transcriptomic profiles were generated by whole blood mRNA sequencing and subjected to patient clustering, differential expression, and pathway analysis. Differences in immune pattern and clinicopathologic features between clusters were assessed. A transcriptomic signature was defined and applied to an independent cohort to validate the findings., Results: CRSwNP patients showed diverse blood transcriptomic profiles versus healthy controls, or when stratified by tissue and blood eosinophils and asthma comorbidity. Transcriptome-wide correlation analysis revealed a transcriptional signature associated with blood eosinophil levels, consisting of nine T2-related genes (CLC, SIGLEC8, ALOX15, IL5RA, PTGDR2, CCL23, CCR3, EPX and IL1RL1). Three distinct clusters with differing systemic eosinophilic and neutrophilic inflammation patterns and asthma comorbidity were identified based on transcriptomic profiling of T2 and T1/3-related blood biomarkers. A 36-gene signature was developed by machine learning and accurately predicted the three CRSwNP subtypes. Validation on an independent cohort confirmed the prediction robustness., Conclusions: There is heterogeneous systemic inflammation associated with eosinophilic and neutrophilic patterns in patients with CRSwNP. Endotyping based on blood transcriptomic biomarkers might lead to more personalized treatment strategies for CRSwNP in the future.

<b>Introduction:</b> Chronic rhinosinusitis (CRS) is a long-lasting inflammatory condition affecting the sinonasal mucosa, which is likely triggered by a dysfunctional immune response. Vitamin D is recognized as an immunomodulator influencing both innate and adaptive immunity. Recently, this mechanism of action has sparked interest regarding the possible role of vitamin D in CRS pathogenesis and/or course of the disease.<b>Aim:</b> The aim of this study was to investigate the association between preoperative serum vitamin D levels and an early outcome of endoscopic sinus surgery (ESS) as well as its influence on the severity of CRS.<b>Materials and methods:</b> This prospective observational study included 25 patients with CRS with nasal polyps undergoing ESS and 18 healthy controls. The disease was confirmed clinically and radiologically. Demographic and clinical data for each subject were collected. Preoperatively, disease severity was evaluated by the patient using the Visual Analog Scale (VAS) and 22-item Sino-Nasal Outcome Test (SNOT-22), and by a researcher using the Lund-MacKay (LMS) and Lund-Kennedy (LKS) scoring systems. On the day of surgery, serum 25-hydroxyvitamin D was measured with the use of electrochemiluminescence binding assay. Six weeks postoperatively, reassessment was performed, including the VAS, SNOT-22, and LKS.<b>Results:</b> Serum 25-hydroxyvitamin D level was not significantly lower in CRS patients compared to healthy controls. Subjective and objective measures of CRS severity showed no correlation with vitamin D status. However, participants with higher vitamin D levels presented better outcomes 6 weeks postoperatively.<b>Conclusions:</b> Contradicting numerous previous studies, these findings failed to confirm the correlation between the occurrence or severity of CRS and vitamin D status. Nevertheless, vitamin D status seems to affect ESS early outcomes.

Objectives: Some changes in nasal mucus and paranasal sinuses may occur due to zinc deficiency, which can cause chronic rhinosinusitis with nasal polyps (CRSwNP). The current study was designed to compare the serum zinc concentration between patients with chronic rhinosinusitis complicated with eosinophilic or neutrophilic nasal polyps and a control group., Methods: A total of 105 patients participated in the study. Patients in three different groups were evaluated for CRSwNP (35 in the eosinophilia group and 35 in the neutrophil group), and 35 patients underwent surgery for reasons other than polyposis (control group). The serum zinc level was determined., Results: The mean age of the patients was 39.4 ± 12.61 years. Forty-one patients (39%) were female. Based on the enzyme linked immunosorbent assay results, the average serum zinc level in the control group was 137.01 ± 19.42 (μgm/100 mL), and in all patients with CRSwNP, it was 127.27 ± 21.7 (μgm/100 mL). The serum zinc concentration in patients with CRSwNP was significantly lower than that in the control group (p = .027). Among the CRSwNP patients with eosinophilic polyps and neutrophilic polyps, 130.42 ± 21.92 (μgm/100 mL) and 127.27 ± 21.7 (μgm/100 mL), respectively, were detected. Based on the statistical analysis, the neutrophilic and eosinophilic groups were homogenous according to the average serum zinc concentration (p = .631), and the same conditions prevailed for the eosinophilic and control groups (p = .574). There was a noticeable distinction between the neutrophilic group and the control group (p = .034)., Conclusion: Serum zinc concentrations were significantly lower in patients with neutrophilic polyps than in the general population. This difference may be due to the essential role of zinc in the inflammatory process in patients with neutrophilic polyposis., (© 2024 The Author(s). Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

To investigate disparities in sensitisation to Staphylococcus aureus enterotoxin A/B (SEA/SEB) and olfactory function in patients with chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), those with CRS without nasal polyps (CRSsNP), and healthy controls who underwent septoplasty only. We retrospectively reviewed the medical records of 388 subjects aged ≥ 8 years, collected between January 2021 and June 2023. We analysed patient demographics, medical history, serum IgE levels against staphylococcal enterotoxins (SEs), and serum total IgE levels against inhalant allergens. We performed olfactory and taste function tests in the participants to evaluate the relationship between olfactory function and SEs. Of 388 patients enrolled, 145 were healthy controls, 111 had CRSsNP, and 133 had CRSwNP. The prevalence of SEA/SEB positivity was significantly higher among the patients with CRSwNP than among those in the CRSsNP and healthy controls. The olfactory test results showed significant differences among the groups; anosmia was observed in 9.7% of healthy controls, 22.7% of patients with CRSsNP, and 45.1% of patients with CRSwNP. Olfactory threshold deterioration was evident in patients with CRS. Distinction and identification were more impaired in patients with CRSwNP than in those of the other groups. Finally, the olfactory function scores decreased as the serum levels of SEs increased. Sinusitis patients seem to suffer from perceiving odours, and patients with CRSwNP have difficulty distinguishing odours. Olfactory function test scores decreased in patients with a history of asthma, and as serum levels of staphylococcus enterotoxin and blood eosinophil percentage increase. Furthermore, our result suggests a potential role for SE sensitisation and eosinophil percentage in deteriorating olfaction, especially in patients with CRSwNP., (© 2024. The Author(s).)

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

Background: Aspergillus is one of the most common pathogens causing fungal allergy in the respiratory tract. Serum Aspergillus fumigatus- specific immunoglobulin G (Af-sIgG) levels have been used as a biomarker for the diagnosis and treatment response monitoring in airway allergic diseases such as allergic bronchopulmonary aspergillosis and allergic fungal rhinosinusitis. However, its role in common primary chronic rhinosinusitis (CRS) was unclear., Objective: This study aims to evaluate whether serum Af-sIgG level could serve as a biomarker for the disease presentation of primary CRS., Methods: We obtained serum Af-sIgG levels from patients diagnosed as bilateral primary CRS refractory to medical treatment and evaluated the correlations between serum Af-sIgG levels and disease severity in patients with type 2 (T2) and non-T2 CRS., Results: Patients with T2 CRS exhibited significantly higher serum Af-sIgG levels than non-T2 CRS patients. The cut-off value of serum Af-sIgG in T2 CRS was 20.9 mg/L, with an odds ratio of 3.8 (95% CI 1.17-12.20, P  = .026). Furthermore, serum Af-sIgG levels were positively correlated with symptom scores evaluated by the Sino-Nasal Outcome Test-22 (SNOT-22) scores in T2 patients ( P  = .009). While stratified by SNOT-22 total scores, patients with severe disease had higher serum Af-sIgG levels only in T2 CRS ( P  = .034). In individual domains of SNOT-22 analysis, serum Af-sIgG levels showed a significant correlation with "ear/facial" symptom scores in the T2 group ( P  < .001)., Conclusions: Serum Af-sIgG levels may serve as a supplementary objective biomarker that correlates with identification and subjective measurements of T2 CRS, and may be associated with symptoms arising from Eustachian tube dysfunction., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by tissue heterogeneity and high postoperative recurrence risk. This study aims to employ cytokine analyses to identify serum biomarkers associated with postoperative CRSwNP recurrence and elucidate underlying recurrent mechanisms., Methods: A prospective cohort study was conducted on CRSwNP patients undergoing functional endoscopic sinus surgery. Serum and tissue samples were collected and analyzed for multiple cytokines. Participants were followed for 3 years and categorized into recurrent and non-recurrent groups. Cytokine profiles were compared, and potential markers for recurrence were further assessed. Macrophage migration inhibitory factor (MIF) expression in macrophages was modulated, and their polarization and cytokine secretion were assessed., Results: In the discovery cohort (21 recurrent and 40 non-recurrent patients), circulating cytokine profiles differed significantly, with 8 cytokines showing differential expression between the two groups. Among them, serum eotaxin, MIF, RANTES, and TRAIL exhibited promise in predicting recurrence. In the validation cohort (24 recurrent and 44 non-recurrent patients), serum eotaxin, MIF, and TRAIL levels were higher in recurrent cases. Tissue MIF was elevated in recurrent cases and had a strong predictive value for recurrence. Moreover, tissue MIF was co-expressed with CD206 in recurrent cases. Mechanistically, MIF overexpression promoted macrophage M2 polarization and TGF-β, CCL-24, and MIF secretion, and MIF recombinant protein facilitated M2 polarization, and TGF-β1 and CCL-24 production, contributing to CRSwNP recurrence., Conclusions: Serum-specific cytokine signatures were associated with postoperative recurrence risk in CRSwNP. Elevated MIF enhanced macrophage M2 polarization and cytokine secretion, contributing to the recurrent mechanisms of CRSwNP.

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.

The latest European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS2020) defines markers for type2 inflammation in the context of indicating biological therapy in severe uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP) as either a total serum immunoglobulin E (total-IgE) <100 kU/L, a blood eosinophil count (BEC, expressed as -109 cells / L) >=0.25, or a tissue eosinophil count >=10 per high power field (HPF) (1). Recently, an EPOS/EUFOREA expert panel advised to lower the threshold for BEC from >=0.25 (EPOS2020) to >=0.15 (EUFOREA2023) to align with thresholds used for biological indication in asthma patients (2). As far as we know, there is no literature supporting the cut-off value for total-IgE.

Objectives: Predicting the need for surgical treatment among patients with chronic rhinosinusitis (CRS) is challenging. The delta neutrophil index (DNI) has been proposed as a useful laboratory marker of immature granulocytes, which indicates infection or severe inflammation in several diseases. This study evaluated DNI as an early predictor of the need for surgery in patients with CRS., Methods: A total of 117 patients diagnosed with CRS were enrolled in this retrospective and observational study. Medical records, including symptoms data, WBC count, ESR level, LUC count, Lund-Mackay scores, and DNI, were reviewed. The receiver operating characteristic (ROC) curves were analyzed to determine the optimal cut-off values for predicting surgery., Results: Among 117 patients, 49 patients (41.9%) needed surgical intervention. The areas under the WBC, ESR, LUC, and DNI ROC curves were .571, .600, .592, and .782, respectively. The optimal cut-off value of DNI to predict surgery was .9%. The prognostic precision of DNI showed that the sensitivity was 59.2% and the specificity was 98.5%. In the analysis of risk factors, DNI levels were significantly associated with surgical intervention (odds ratio, 2.22; 95% confidence interval, 1.48-3.34; P < .01)., Conclusions: The level of DNI, which reflects the severity of the disease, may be a useful predictor for determining the need for surgical intervention in patients with CRS. This is the first literature to verify the role of DNI in upper airway disease., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Type 1 autoimmune pancreatitis (AIP) is a pancreatic manifestation of IgG4-related disease (IgG4-RD). Although AIP and IgG4-RD are characterized by multiple organ involvement including salivary glands, lung, and kidney, co-occurrence of chronic rhinosinusitis (CRS) and AIP/IgG4-RD has been poorly defined., Objective: We explored molecular mechanism accounting for the co-occurrence of CRS and AIP/IgG4-RD., Methods: Serum concentrations of IFN-α and IL-33 were measured by enzyme-linked immune-sorbent assay., Results: We encountered a patient with concurrent type 1 AIP/IgG4-RD and CRS. Induction of remission by prednisolone (PSL) for type 1 AIP/IgG4-RD led to a marked improvement of CRS. Serum cytokine analysis after PSL treatment revealed a marked reduction in serum concentrations of IFN-α and IL-33, both of which are candidate pathogenic cytokines for AIP/IgG4-RD., Conclusions: Given that IL-33 is shared as one of pathogenic cytokines by type 1 AIP/IgG4-RD and CRS, enhanced IL33 responses may cause concurrent type 1 AIP/IgG4-RD and CRS.

Objective: Our previous study revealed that serum amyloid A (SAA) levels in polyp tissues could serve as a biomarker for the prediction of corticosteroid insensitivity in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). However, their association with disease control status in the patients after endoscopic sinus surgery remains to be assessed., Methods: Polyp tissues and control uncinate process mucosa were collected from 48 patients with CRSwNP and 10 healthy control subjects. SAA expression was examined using immunohistochemistry and enzyme-linked immunosorbent assay. Receiver operating characteristic (ROC) curves were performed to determine the predictive value of SAA in nasal polyps. The clinical characteristics of 2 CRSwNP subtypes (SAA high and SAA low ) were evaluated., Results: The SAA expression levels in polyp tissues were significantly elevated both in non-eosinophilic and eosinophilic CRSwNP as compared to the healthy controls. In patients with CRSwNP, the tissue SAA level was significantly higher in the disease-controlled patients than those of the partly controlled and uncontrolled. ROC curve analysis revealed that a cut-off value of 114.9 ng/mL for the tissue SAA level predicted the patients with disease-controlled status with 93.33% sensitivity and 63.64% specificity (AUC = .8727, P < .001). Furthermore, The SAA high subgroup showed higher tissue eosinophil numbers and percentage of the disease-controlled patients compared to the SAA low subgroup., Conclusions: Our findings suggest that measurements of SAA in polyp tissues may provide useful information for evaluating CRSwNP conditions, especially identifying the CRSwNP patients with disease-controlled status after endoscopic sinus surgery., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Novel biomarkers (BMs) are urgently needed for bronchial asthma (BA) with various phenotypes and endotypes., Objective: We sought to identify novel BMs reflecting tissue pathology from serum extracellular vesicles (EVs)., Methods: We performed data-independent acquisition of serum EVs from 4 healthy controls, 4 noneosinophilic asthma (NEA) patients, and 4 eosinophilic asthma (EA) patients to identify novel BMs for BA. We confirmed EA-specific BMs via data-independent acquisition validation in 61 BA patients and 23 controls. To further validate these findings, we performed data-independent acquisition for 6 patients with chronic rhinosinusitis without nasal polyps and 7 patients with chronic rhinosinusitis with nasal polyps., Results: We identified 3032 proteins, 23 of which exhibited differential expression in EA. Ingenuity pathway analysis revealed that protein signatures from each phenotype reflected disease characteristics. Validation revealed 5 EA-specific BMs, including galectin-10 (Gal10), eosinophil peroxidase, major basic protein, eosinophil-derived neurotoxin, and arachidonate 15-lipoxygenase. The potential of Gal10 in EVs was superior to that of eosinophils in terms of diagnostic capability and detection of airway obstruction. In rhinosinusitis patients, 1752 and 8413 proteins were identified from EVs and tissues, respectively. Among 11 BMs identified in EVs and tissues from patients with chronic rhinosinusitis with nasal polyps, 5 (including Gal10 and eosinophil peroxidase) showed significant correlations between EVs and tissues. Gal10 release from EVs was implicated in eosinophil extracellular trapped cell death in vitro and in vivo., Conclusion: Novel BMs such as Gal10 from serum EVs reflect disease pathophysiology in BA and may represent a new target for liquid biopsy approaches., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Backgroud: Presently, the impact of Chronic rhinosinusitis with nasal polyps (CRSwNP) on asthma onset is unknown., Aims: To evaluate the role of CRSwNP in asthma onset., Materials and Methods: A total of 3107 CRSwNP patients were retrospectively screened from 1 January 2018, to 31 May 2021; 624 patients were enrolled. Clinical data regarding nasal symptoms, Lund-Mackay scores, blood eosinophil percentage, and onset of asthma were analyzed. Patients were divided into different groups according to past history of nasal polyps, Lund-Mackay score, and the extent of blood eosinophilia. Asthma-free rates between these subgroups were analyzed by Kaplan-Meier curves and Cox regression models., Results: The prevalence of asthma was 10.90% in patients with CRSwNP, and new-onset asthma occurred in 3.14% of these patients. Higher Lund-Mackay scores for ethmoid sinus and maxillary sinus (E/M) and blood eosinophil percentages were two independent risk factors for new-onset asthma, with hazard ratios of 1.267 (95%CI, 1.155-1.390) and 1.224 (95%CI, 1.054-1.422), respectively. CRSwNP patients with an E/M ratio > 2.33 or a blood Eos percentage > 5.5% were at risk for asthma onset., Conclusions and Significance: Blood eosinophilia and a higher E/M score ratio were associated with new-onset asthma in patients with CRSwNP.

Background: Chronic rhinosinusitis is known as a common problem with inflammatory and allergic causes. Several factors are associated with developing chronic rhinosinusitis, including immunoglobulin E (IgE) production and vitamin D deficiency., Objective: In this study, we investigated the role of IgE and Vitamin D deficiency and differences between patients with chronic, allergic sinusitis and controls., Methods: A total of 90 subjects were included in 3 groups (n=30) in this cross-sectional, correlational descriptive study. The subjects were divided into three groups, including control (healthy subjects), chronic sinusitis patients, and allergy patients. A checklist was used to collect the necessary data, including age, gender, and body mass index (BMI). To evaluate serum levels of vitamin D3 and IgE, ELISA kits were used., Results: The mean vitamin D was 22 g/ml. Fifty-four participants (60%) out of all included people had insufficient vitamin D, 13% had a deficiency, and the high deficiency and insufficiency were in the group of allergic sinusitis. Our results indicated that gender (female) was significantly associated with vitamin D deficiency (p =0.01). Thirty-nine participants (43.3%) out of all studied subjects had high IgE, and the highest level of abnormality of IgE was in the allergic sinusitis group. Furthermore, it was found that gender and IgE were not significantly related. However, IgE was significantly associated with vitamin D deficiency in the allergic sinusitis group., Conclusion: Our findings highlighted that most of the patients with chronic and allergic sinusitis had insufficient vitamin D. A possible association was also found between low vitamin D and IgE levels and the prevalence of allergic sinusitis. This study showed that patients with allergic sinusitis may be more vulnerable to lower serum levels of vitamin D. Therefore, vitamin D supplementation as an adjunctive therapy may be considered in these patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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: B cell-activating factor (BAFF) is a proinflammatory cytokine involved in inflammatory and allergic diseases, but its role in chronic rhinosinusitis with nasal polyps (CRSwNP) remains unclear. This study aims to explore the predictive value of circulating BAFF in CRSwNP endotypes and postoperative recurrence., Methods: We recruited 120 CRSwNP patients, including 68 non-eosinophilic CRSwNP (neCRSwNP) patients, 52 eosinophilic CRSwNP (CRSwNP) patients, and 60 healthy controls (HCs). Circulating BAFF levels of all participants were measured by enzyme-linked immunosorbent assay (ELISA), and receiver-operating characteristic (ROC) and logistic regression analyses were applied to assess the predictive ability of BAFF levels in distinguishing CRSwNP endotypes. All CRSwNP patients were followed for more than 3 years, and the predictive value of circulating BAFF for postoperative recurrence was evaluated., Results: Serum BAFF levels were elevated in CRSwNP patients compared with the HCs (P < 0.01) and significantly higher in eCRSwNP patients. The increased serum BAFF concentrations positively correlated with blood eosinophil counts and percentages, tissue eosinophil counts, and serum total IgE (P < 0.05). The ROC curve showed that serum BAFF exhibited strong discriminative ability for eCRSwNP. Finally, 99 CRSwNP patients completed the follow-up schedule, 65 patients were classified into non-recurrence group and the other 34 patients were categorized into recurrence group. Serum BAFF levels were significantly higher in recurrence group than non-recurrence group (P < 0.001), and the ROC curve suggested a high predictive value of serum BAFF in predicting postoperative recurrence. Moreover, logistic regression and Kaplan-Meier curves showed that serum BAFF was an independent risk factor for postoperative recurrence (P < 0.05)., Conclusion: Our data suggested that serum BAFF levels were upregulated in CRSwNP patients and correlated with mucosal eosinophil infiltration severity. Serum BAFF seemed to be a novel biomarker for preoperatively distinguishing CRSwNP endotypes and predicting postoperative recurrence., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous disease and can be categorized into eosinophilic CRSwNP (eCRSwNP) and non-eosinophilic CRSwNP (neCRSwNP). Exploring effective biomarkers to distinguish endotypes is important for personalized therapies. The present study aims to evaluate the predictive value of serum MIF in CRSwNP endotypes., Methods: One hundred and twenty CRSwNP patients, including 51 eCRSwNP and 69 neCRSwNP, 40 chronic rhinosinusitis without nasal polyps (CRSsNP) patients and 40 healthy controls (HC) were enrolled. Serum MIF levels were determined by enzyme-linked immunosorbent assay (ELISA). The patients' clinical variables were analyzed for correlations with serum MIF. Receiver operating characteristic (ROC) curve and multivariate analysis were utilized to assess the predictive value of serum MIF in CRSwNP endotypes., Results: The serum MIF levels were significantly higher in CRSwNP group than CRSsNP group and HC group (P < 0.001), and the serum MIF levels were increased in eCRSwNP compared to neCRSwNP group (P = 0.006). Elevated serum MIF levels were significantly correlated with blood eosinophil (B-EOS) count (r = 0.411, P < 0.001), B-EOS percentage (r = 0.377, P < 0.001), visual analog scale score (r = 0.204, P = 0.025), tissue eosinophil (T-EOS) count (r = 0.705, P < 0.001) and T-EOS percentage (r = 0.671, P < 0.001) in CRSwNP patients. ROC curve demonstrated that serum MIF exhibited good preoperative prediction in CRSwNP endotypes (area under the curve = 0.925, P < 0.001). Multivariate regression analysis showed that serum MIF was an independent factor associated with CRSwNP endotypes., Conclusions: This was the first study identifying serum MIF as a possible specific biomarker for preoperatively distinguishing CRSwNP endotypes. Furthermore, the serum MIF levels were found to be closely associated with the degree of mucosal eosinophil infiltration., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The immune pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) remains obscure. Our aim was to compare humoral immunity and white blood cell counts in patients with CRSwNP and controls. A prospective case-control study was carried out in 37 patients with CRSwNP and 34 controls without CRS. Clinical data were gathered through a systematic interview. Computed tomography scan, skin prick test, spirometry, and immunological parameters (leukocyte differential count, immunoglobulin classes, and immunoglobulin [Ig] G subclasses) in serum specimens were obtained. Statistical analysis was performed using SPSS v.23. The prevalence of chronic lower respiratory diseases was greater in the CRSwNP group ( P < .001), but atopic disease had no significant difference. A significantly higher eosinophil ( P < .001) and basophil relative count ( P = .022) and a lower relative neutrophil count ( P = .013) were found among CRSwNP group. Patients with CRSwNP had higher IgG1 ( P = .022), but lower IgG2 ( P = .014) and IgG3 ( P = .018) serum levels compared to controls; IgG4, total IgG, IgA, IgM, and IgE serum levels did not differ between groups, as well as the prevalence of immunoglobulin classes or IgG subclasses deficiency. The variation observed in peripheral relative leukocyte count and the systemic IgG1 subclass shift are similar to what is known to happen in nasal polyp tissue. A unique systemic immune profile seems to be present in patients with CRSwNP.

The mechanisms that lead to disease onset and propagation in patients with chronic rhinosinusitis (CRS) are not fully elucidated. Maresins (MaR) are a family of essential fatty acid-derived lipid mediators that play a central role in the regulation of inflammation with several studies demonstrating that these mediators display protective activities in airway inflammation. Therefore, in the present studies we evaluated whether concentrations of these mediators were altered in both peripheral blood and nasal secretions from CRS patients. Herein, we focused on patients with CRS that also develop nasal polyps (CRSwNP), given that therapeutic options for the treatment of these patients are limited. Thereby, insights into disease mechanisms in these patients may help design more effective treatments. For this purpose, we compared maresin concentrations from CRSwNP patients with those found in healthy volunteers or patients with an upper respiratory tract infection (URTI), as a self-resolving inflammatory condition. Using liquid chromatography tandem mass spectrometry, we found that MaR concentrations were significantly decreased in plasma from patients with CRSwNP when compared to healthy volunteers. MaR concentrations were observed to be significantly upregulated in nasal secretions from patients with CRSwNP when compared with both healthy volunteers and URTI subjects. Concentration of these mediators in both plasma and nasal secretions from CRSwNP patients were positively correlated with quality-of-life scores in these patients. Assessment of the concentrations of other pro-resolving and pro-inflammatory lipid mediators (LM) demonstrated that there was a general shift in LM levels in both plasma and nasal secretions from CRSwNP when compared with healthy volunteers and URTI subjects. Of note, incubation of peripheral blood cells from CRSwNP patients with MaR1 downregulated the expression of activation markers on peripheral blood phagocytes, including CD41 and CD62P, markers of platelet-leukocyte heterotypic aggregates. Together these findings demonstrate that both local and systemic LM concentrations, in particularly those of the MaR family, become altered in patients with CRSwNP. They also suggest that therapeutics designed around MaR1 may be useful in regulating the activation of phagocytes in patients with CRSwNP thereby potentially also limiting the local inflammatory response in these patients., Competing Interests: JD is Scientific founder and director of Resolomics Ltd and Inventor on several patents and patent applications assigned to Brigham and Women’s Hospital (Boston, MA) and Queen Mary University of London (London, UK) for the therapeutic and diagnostic use of specialized pro-resolving mediators. The remaining 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 © 2021 Beegun, Koenis, Alusi and Dalli.)

Objectives/hypothesis: Chronic rhinosinusitis (CRS) is a heterogenic disease with different inflammatory patterns depending on the presence (CRSwNP) or absence (CRSsNP) of polyps and geographical location. A shift toward type 2 endotype has been seen in Asia. We aim to investigate whether there has been type 2 shift in Belgium and to further endotype CRS based on clinical markers., Study Design: Prospective descriptive study., Methods: Four hundred and thirty eight patients with CRS undergoing sinus surgery at Ghent University Hospital between 2007 and 2018 were included and stratified based on phenotype, comorbidities, inflammatory markers in tissue, and two different time points of surgery. Tissue samples from surgery were analyzed for type 2 markers. In a subgroup of CRSwNP blood eosinophils (EBC) was available., Results: There was an increase in type 2 inflammatory markers in the latter group versus the earlier, in non-asthmatic, non-allergic CRS patients regardless of phenotype. The proportion of IL-5+ patients was elevated in the latter group in CRSwNP. Inflammatory markers and comorbidities differ between IL-5+ CRSsNP and CRSwNP subjects, no difference was seen in IL-5- CRS. EBC can together with information on comorbidities help identify type 2 CRSwNP in a clinical setting., Conclusion: There is a shift toward type 2 inflammation within the CRS population over recent 8 years also in Belgium. This shift implies that we expect to see more cases of severe and difficult to treat CRS in the future. Polyp formation is not directly linked to the presence or concentrations of type 2 inflammatory markers. Clinical parameters and EBC > 300 cells/μL can be used to identify type 2 CRSwNP., Level of Evidence: 3. Laryngoscope, 131:E1408-E1414, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

Objectives: Urine leukotriene E4 (uLTE4) is a biomarker of leukotriene synthesis and is elevated in patients with aspirin-exacerbated respiratory disease (AERD). It can also be useful to help delineate aspirin-tolerant chronic rhinosinusitis with nasal polyposis (CRSwNP) patients from AERD patients. The purpose of this study is to determine if uLTE4 biomarker levels are associated with objective and subjective markers of disease severity in patients with CRSwNP., Methods: A retrospective analysis of CRSwNP patients who underwent uLTE4 testing was completed to determine the association of uLTE4 levels to markers of disease severity. uLTE4 levels, as well as presenting subjective (Sinonasal Outcome Test 22 [SNOT22] scores, asthma control test [ACT] scores) and objective data (Lund-Mackay CT score, spirometry and lab values) were collected., Results: Among the 157 CRSwNP patients who met inclusion criteria, uLTE4 levels were associated with history of asthma (P < .001), aspirin sensitivity (P < .001), worse Lund-Mackay CT scores (P = .002) and other objective markers of disease severity including serum IgE (P = .05), presenting blood eosinophil level (P < .001), and the highest recorded eosinophil level (P < .001). In subgroup analysis, associations of uLTE4 to disease markers had stronger correlations in the aspirin sensitive CRSwNP group (R range 0.31-0.52) than the aspirin tolerant CRSwNP group (R range -0.30-0.24). uLTE4 levels were not associated with subjective symptom scores (SNOT22 and ACT scores)., Conclusion: Elevated uLTE4 biomarker levels are associated with worsened objective markers of disease severity in CRSwNP patients but not patient-reported symptom measures., Level of Evidence: 3 Laryngoscope, 131:961-966, 2021., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc. "The Triological Society" and American Laryngological Association (ALA).)

Background: The prevalence of eosinophilic CRSwNP in China has increased significantly over the last 20 years, noninvasive methods that could assist in diagnosis are urgently needed., Aims: The aim of this study is to explore the clinical significance of peripheral blood eosinophil in diagnosing ECRS., Materials and Methods: We conducted a prospective study of 221 patients diagnosed with CRS. Lund-Mackay score, peripheral blood eosinophil absolute count, peripheral blood eosinophil percentage were detection to compare the clinical features with ECRS and non-ECRS. ROC curve was performed to assess the efficiency of clinical index to predict ECRS., Results: The ECRS group of patients had significantly higher scores compared with those of the non-ECRS group. Different extent and severity of mucosal thickening on total Lund-Mackay scores, anterior ethmoidal, posterior ethmoidal and ostiomeatal complex have confirmed different blood eosinophil levels in CRS patients. The combination of peripheral blood eosinophil percentage and posterior ethmoidal score to predict ECRS was 0.807., Conclusions and Significance: The increase in peripheral blood eosinophil percent indicates the deterioration the inflammation of chronic rhinosinusitis and the level of posterior ethmoidal score and peripheral blood eosinophil percentage have a positive predictive value regarding ECRS identification.

Background: The inflammatory mucosa of the sinus cavities is called sinusitis and is divided into various types based on its appearance and sign. Chronic rhinosinusitis is an inflammatory-infectious disease that involves the frontal, sphenoid, ethmoid, and maxillary sinuses. Chronic sinusitis is a multifactorial disease and the range of causes varies from environmental factors to genetic factors. The purpose of this study was to compare blood and tissue eosinophils and serum IgE levels in patients with chronic sinusitis with nasal polyp in Vali-e-Asr hospital in 1397., Methods: In this descriptive-analytical study, the population under study included those with chronic sinusitis referred to Birjand Valiasr Hospital in 1397.3 cc of blood samples were taken 1 day before surgery to evaluate eosinophil counts and serum IgE levels. Also, samples taken from patients during surgery were counted, and then, 100 cells were counted, and eosinophil counts and percentages were calculated. The data were entered into the SPSS software after data collection., Results: This study was performed on 70 patients with chronic rhinosinusitis which included 43 men (61.4%) and 27 women (38.6%) with mean age of 39.11 ± 13 13.72 years. There was no significant difference between sex of patients and mean serum IgE level ( P < 0.05). The mean percentage of eosinophils in blood samples and tissues of patients with chronic sinusitis was significantly increased with the increase in CT scan ( P < 0.05)., Conclusions: Tissue or blood eosinophilia was not observed in patients with chronic rhinosinusitis. Also, the mean eosinophil percentage of blood and tissue increased significantly in patients with increased scanning computed tomography ( P < 0.05)., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Masoud Asghari et al.)

We examined the appearance of serum anti-phage antibodies in 25 patients with chronic sinusitis treated with phage therapy (PT). Approximately 30% of patients with weak antibody responses responded positively to PT, which was similar to the results of treatment achieved in a group of patients with high antibody production. In addition, there was no correlation between antibody level and the outcome of PT. These data, derived from a homogenous group of patients, confirm our earlier findings suggesting that the prognostic significance of serum anti-phage antibodies for the outcome of PT should be determined by relevant clinical trials.

Background: Chronic rhinosinusitis may be associated with nasal polyposis. Recurrence of disease is often observed and may be due to an intolerance of acetylsalicylic acid. Sex hormones are known to modulate allergic reactions and inflammation. Whether they may be involved in the development and progression of nasal polyposis has not been investigated yet., Aim: Examine the relationship between levels of sex hormones and nasal polyposis., Methods: Hormonal levels (estradiol, testosterone and progesterone) in patients with nasal polyposis (n = 26) with or without acetylsalicylic acid-intolerance were determined and compared to hormonal levels in patients with septal deviation (n = 35). Cone-beam computed tomography scans were analysed by using scores as defined by Lund and Mackay and by Kennedy., Results: Our results show a 5 times greater odds (p = 0.01) for developing nasal polyposis in the presence of lowered estradiol plasma levels than in the presence of normal / elevated levels. When analyzing females and males separately, a 6 times greater odds for females to develop nasal polyposis in the presence of lowered estradiol plasma levels was calculated (p = 0.02). Thus, females are more likely to develop nasal polyposis when they have lowered estradiol levels than males. In addition, female patients showed an increased risk for developing ASA intolerance (p = 0.01)., Conclusion: Variation of sex hormones may be involved in nasal polyposis. Further studies including more patients to validate the presented results are required., Significance: Retrospective clinical investigation suggesting a correlation between varying sex hormones and nasal polyposis., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Studies have shown that calprotectin has a strong pro-inflammatory effect. Elevated calprotectin levels in the serum can be used as a strong clinical marker indicating the presence of inflammation., Objective: To investigate serum calprotectin levels in patients with chronic rhinosinusitis (CRS) and to determine the applicability of calprotectin as a potential molecular pro-inflammatory biomarker for CRS., Methods: The study consisted of three groups: chronic rhinosinusitis with polyps (CRSwNP group), chronic rhinosinusitis without polyps (CRSwoNP), and healthy control. CRS patients with polyps were further divided into two groups depending on the presence/absence of Samter's triad. The Nose Obstruction Symptom Evaluation (NOSE) scale score and serum calprotectin value were evaluated in all participants., Results: The mean serum calprotectin value was 79.5±11.8 ng/ml for the CRSwNP group, 71.3±16 ng/ml for the CRSwoNP group, and 61.9±11.6 ng/ml for the control group (p<0.001). The Samter's triad group had a significantly higher calprotectin value than the non-Samter's triad group (p=0.03). There was a significant correlation between the NOSE scores and calprotectin levels (rho=0.734, p<0.001)., Conclusion: Serum calprotectin values were correlated with the severity of symptoms in patients with CRS; thus, it seems to be a valuable pro-inflammatory biomarker for the diagnosis of the disease and determining its severity. Further studies with larger series are needed to evaluate the preoperative and postoperative serum calprotectin values ​​in patients undergoing surgery.

Background: Type 2 chronic rhinosinusitis (CRS), especially eosinophilic CRS (ECRS), is an intractable upper airway inflammatory disease. Establishment of serum biomarkers reflecting the pathophysiology of CRS is desirable in a clinical setting. As IgG4 production is regulated by type 2 cytokines, we sought to determine whether serum IgG4 levels can be used as a biomarker for CRS., Methods: Association between the serum IgG4 levels and clinicopathological factors was analyzed in 336 CRS patients. Receiver operating characteristics (ROC) analysis was performed to determine the cut-off value of serum IgG4 levels that can be used to predict the post-operative recurrence., Results: Serum IgG4 levels were significantly higher in patients with moderate to severe ECRS versus those with non to mild ECRS. The levels were also significantly higher in asthmatic patients and patients exhibiting recurrence after surgery compared to controls. ROC analysis determined that the best cut-off value for the serum IgG4 level to predict the post-operative recurrence was 95 mg/dL. The corresponding sensitivity and specificity were 39.7% and 80.5%, respectively. When we combined the two cut-off values for the serum IgG4 and periostin, patients with high serum levels of either IgG4 or periostin exhibited a high post-operative recurrence (OR: 3.95) as compared to patients having low serum levels of both IgG4 and periostin., Conclusions: The present results demonstrate that the serum IgG4 level is associated with disease severity and post-operative course in CRS. In particular, the combination of serum IgG4 and periostin could be a novel biomarker that predicts post-operative recurrence., (Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Prior studies have demonstrated associations between serum eosinophilia and chronic rhinosinusitis (CRS) pathogenesis. However, the association of serum eosinophilia with histopathology profiling in CRS has not been fully delineated and may help better characterize CRS disease burden prior to surgery., Methods: A structured histopathology report of 13 variables was utilized to analyze sinus tissue removed during functional endoscopic sinus surgery (FESS). Complete blood count (CBC) with differential was drawn within 4 weeks prior to FESS. Serum eosinophilia was defined as >6.0% (>0.60 th/μL). Histopathology variables were compared among patients., Results: A total of 177 CRS patients (37 with serum eosinophilia and 140 with normal serum eosinophilia) were analyzed. Compared to CRS patients with normal serum eosinophil counts, CRS patients with serum eosinophilia demonstrated increased polypoid disease (67.6% vs 35.0%, P  < .001), eosinophil aggregates (45.9% vs 20.7%, P  = .003), and eosinophils per high-power field (>5/HPF) (67.6% vs 40.7%, P  = .003)., Conclusion: CRS patients with serum eosinophilia demonstrated severe disease burden on histopathology with high levels of polypoid disease and tissue eosinophilia. However, a considerable number of patients without serum eosinophilia demonstrated eosinophilic disease on histopathology, indicating that preoperative serum eosinophilia alone could not be reliably used to predict eosinophilic CRS., Level of Evidence: 4.

Background: Recent studies pointed to a crucial role for apolipoproteins in the pathogenesis of inflammatory diseases. However, the role of apolipoprotein-IV (ApoA-IV) in allergic inflammation has not been addressed thoroughly thus far., Objective: Here, we explored the anti-inflammatory effects and underlying signaling pathways of ApoA-IV on eosinophil effector function in vitro and in vivo., Methods: Migratory responsiveness, Ca 2+ -flux and apoptosis of human peripheral blood eosinophils were assessed in vitro. Allergen-driven airway inflammation was assessed in a mouse model of acute house dust mite-induced asthma. ApoA-IV serum levels were determined by ELISA., Results: Recombinant ApoA-IV potently inhibited eosinophil responsiveness in vitro as measured by Ca 2+ -flux, shape change, integrin (CD11b) expression, and chemotaxis. The underlying molecular mechanism involved the activation of Rev-ErbA-α and induced a PI3K/PDK1/PKA-dependent signaling cascade. Systemic application of ApoA-IV prevented airway hyperresponsiveness (AHR) and airway eosinophilia in mice following allergen challenge. ApoA-IV levels were decreased in serum from allergic patients compared to healthy controls., Conclusion: Our data suggest that ApoA-IV is an endogenous anti-inflammatory protein that potently suppresses effector cell functions in eosinophils. Thus, exogenously applied ApoA-IV may represent a novel pharmacological approach for the treatment of allergic inflammation and other eosinophil-driven disorders., (© 2019 The Authors. Allergy published by John Wiley & Sons Ltd.)

Background: In this study we aim to describe presenting characteristics and identify prognostic factors for disease resolution in patients with chronic rhinosinusitis (CRS) in the setting of eosinophilic granulomatosis with polyangiitis (EGPA)., Methods: Patients evaluated at a tertiary care center with diagnoses of EGPA and CRS were identified. Descriptive statistics were obtained. Univariate analysis was used to search for prognostic factors associated with higher Lund-Mackay score at presentation and disease resolution., Results: Forty-four patients were included with a mean age of 52.7 (standard deviation, 14) years. Twenty-one patients (47.7%) were female, all had a diagnosis of asthma, and 36 (83.7%) had eosinophils >10%. Common presenting symptoms for CRS included nasal discharge (87.9%) followed by nasal congestion (83.9%) and facial pain and pressure (83.8%). Medical management of CRS included systemic corticosteroids (93.2%) and systemic antibiotics (75%). Surgical intervention occurred in 29 patients (67%). Nine patients (20.5%) had resolution of sinus symptoms, including 4 with imaging confirmation. Fourteen patients (31.8%) had continued CRS, but with improved symptoms, whereas 9 patients (20.5%) had continued CRS with no improvement in symptoms. Eleven patients (25%) were lost to follow-up and 4 (9.1%) died. Univariate analysis did not show antineutrophil cytoplasmic antibody positivity, presence of peripheral eosinophilia, gender, age, or absence of systemic therapy to be predictive of higher Lund-Mackay score at presentation or predictive of disease resolution., Conclusion: CRS in patients with EGPA is often refractory to medical and surgical management. Treatment of these patients should occur in a multidisciplinary setting., (© 2019 ARS-AAOA, LLC.)

Type 2 inflammation and eosinophilic infiltration are prominent pathologic features of chronic rhinosinusitis with nasal polyps (CRSwNP). The purpose of the present study was to determine the roles of Tregs in controlling type 2 inflammation and inhibiting eosinophilic infiltration in CRSwNP. A total of 134 nasal polyps, 67 ostiomeatal complex from chronic rhinosinusitis (CRS) and 62 normal nasal tissues from controls were collected to study the enumeration and function of Tregs cells and the expressions of cytokine profiles via immunofluorescence staining, flow cytometry, qRT-PCR, ELISA, and/or H&E staining. The effects of Tregs on type2 and type3 inflammations were determined in an eosinophilic chronic sinusitis (ECRS) mice model. It was confirmed that the CRSwNP displayed the features of Th2 and Th17 cells-mediated inflammation, accompanying by an increased level of eosinophilic infiltration and the eosinophil cationic protein (ECP), with a decreased frequency of Treg cells. Furthermore, the percentages of CD4+CD25+CD127lowTreg and CD4+CD25+Foxp3+Treg were only decreased in the polyps of CRSwNP but not in the paired peripheral blood. The CRSwNP possessed the decreased Nrp1+Tregs, Helios+Treg, and low TGF-β and interleukin (IL)-10 expressions in Tregs. The ECRS mice showed similar inflammatory characteristics to CRSwNP patients. The adoptive transfer of CD4+CD25+Foxp3+ Treg cells significantly decreased the inflammatory cytokines, eosinophilic chemotactic factors in the mucosa of the ECRS mice without alteration of the immune balance in the peripheral blood and spleen. In conclusion, CRSwNP showed high type 2 and type3 inflammation and defective Tregs. The induced regulatory T cell (iTreg) may correct the imbalance between immune tolerance and effect via limiting the eosinophil recruitment of mucosa in CRSwNP., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Objective: To investigate the effect of isosorbide mononitrate (ISMN) targeted nanoparticles on inflammatory factors of sinusitis by establishing a rabbit model of rhinosinusitis. Methods: Thirty healthy rabbits, male and female, weighing 2.5-3.5 kg, were randomly divided into 6 groups with 5 rabbits in each group. Group A was the control group. The model of rabbit sinusitis was established in group B to F, and CT was used to confirm the model was successful. After placing tubes into the maxillary sinus in the group C to F, saline, 45 mg/ml ISMN, 45 mg/ml ISMN nanoparticles and 45 mg/ml ISMN targeted nanoparticles were used to wash the maxillary sinus, respectively. Blood samples were collected from the ear vein of rabbits on day 7, 14, 21, 28, 35 and 42 after modeling respectively. Changes in the expression levels of inflammatory factors in rabbits during the modeling process and after drug washing were detected by ELISA. After the drug intervention, the maxillary sinus mucosa was taken for real-time quantitative PCR to detect the changes in the mRNA level of inflammatory factors. SPSS 22.0 software was used to process the data. Results: Rabbit model of sinusitis was successfully established. ELISA showed that after the action of ISMN targeted nanoparticles of 1 week (42th day after modeling), the levels of (interleukin, IL) 4, IL-8, IL-17A and interferon γ (IFN-γ) in the blood were lower compared with that of 35th day after modeling, the difference was statistically significant (5.57±1.20 vs 19.73±0.68, 66.41±11.87 vs 154.68±13.13, 17.96±1.87 vs 28.23±0.80, 53.56±5.66 vs 111.93±7.29, all P< 0.05). Compared with the ISMN nanoparticles and ISMN, the ISMN targeted nanoparticles reduced the levels of IL-4, IL-8, IL-17A and IFN-γ more obviously, the differences were statistically significant (13.26±1.43 vs 8.81±1.33 vs 7.14±2.16, 89.47±17.80 vs 41.07±7.77 vs 15.84±3.72, 10.28±2.07 vs 3.06±1.62 vs 1.82±0.90, 62.16±6.18 vs 35.12±4.62 vs 27.89±10.18, all P< 0.05). Real-Time PCR showed that after the flushing of ISMN targeted nanoparticles, the levels of IL-4, IL-8, IL-17A and IFN-γ mRNA were lowest compared with that of the model group, ISMN nanoparticles and ISMN group. Conclusion: ISMN targeted nanoparticles can reduce the level of inflammatory factors in rabbit sinusitis model.

Objective: The aim of this study was to assess the relationship between serum complement component 3 (C3) levels and disease recurrences in patients with chronic rhinosinusitis with nasal polyps (NPs)., Methods: Ninety-seven patients with NPs and 30 controls were recruited. Clinical features were collected. Serum concentrations of C3 and C4 were measured before and after endoscopic sinus surgery., Results: Compared to the controls, increased C3 levels were found in patients with NPs. Patients with polyp recurrences had higher pre- and postoperative serum C3 levels than patients without polyp recurrences. Serum C3 levels dropped after surgery. After polyp regrowth, the mean C3 level in the recurrent group elevated again to the degree similar to that before surgery. When patients were stratified by tissue eosinophilia, no significant difference was seen in pre-/postoperative, absolute change after surgery, and post-recurrent C3 levels between patients without and with eosinophilic NPs in the group with disease recurrences., Conclusion: Serum C3 may be involved in the pathogenesis of NPs. Higher serum C3 levels may pinpoint patients at high risk of recurrence as an independent factor. Furthermore, the change in C3 levels after surgery may have the potential to serve as a predictor for polyp progression. Adding serum C3 measurement to the routine walk-up in the clinical management of NPs is worth further investigation and may help physicians make a more rational diagnostic and/or therapeutic decision regarding this disease., (© 2020 S. Karger AG, Basel.)

Purpose: Allergic fungal rhinosinusitis (AFRS) forms a subset of chronic rhinosinusitis with nasal polyps (CRSwNP) that is mainly characterized by eosinophilic nasal polyps, allergic mucin detected in the sinuses at surgery, and specific features on computerized tomography. Which biological markers predict disease recurrence in AFRS is still not clear, and the role of blood inflammatory cells in predicting recurrent polyps after surgery has yet to be investigated. The aim of this study was to newly investigate the prognostic role (in terms of recurrence rate) of preoperative blood eosinophil and basophil levels in AFRS., Materials and Methods: A consecutive series of 17 adult patients who underwent endoscopic sinus surgery for AFRS was retrospectively assessed., Results: Sinonasal polyps recurred in 7 of 17 patients. Considering the whole cohort, a significant positive correlation emerged between blood eosinophil and basophil counts, but not between blood and tissue eosinophil counts. Statistical analysis found significantly higher blood eosinophil and basophil levels in AFRS patients who relapsed than in those who did not., Conclusions: Considering the current difficulty of identifying more effective, personalized approaches to postoperative disease management in AFRS, our preliminary data support the impression that blood eosinophil and basophil levels warrant testing in further prospective and larger (preferably multi-institutional) investigations as part of the preoperative work-up for patients with AFRS in order to administer dedicated postoperative medical treatments for patients at higher risk of relapse., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The purpose of this study is to describe both clinical and immunological features in large cohort of adult patients with IgG subclass deficiency, and response to immunoglobulin therapy. This is a retrospective study of data obtained from electronic medical records and paper charts of 78 patients with IgG subclass deficiency seen and followed at our immunology clinics from 2010 to 2016. Both isolated selective IgG subclass deficiency as well as combined (two) subclass deficiencies were observed. IgG3 subclass deficiency, isolated and in combination with other IgG subclass deficiency, is the most frequent of IgG subclass deficiency. A majority of patients presented with upper and lower respiratory tract infections, especially chronic sinusitis. Both allergic and autoimmune manifestations are common; however, there is no subclass preference. The proportions and absolute numbers of CD3 + T cells, CD4 + T and CD8 + T cells, CD19 + B cells, and CD3 - CD16 + CD56 + NK cells were normal in the majority of patients in all IgG subclass deficiencies. Total serum IgG levels did not correlate with IgG subclass levels across all IgG subclass deficiencies. Anti-pneumococcal polysaccharide antibody responses were impaired in 56% of patients. IgG3 subclass deficiency is the most common IgG subclass deficiency, and anti-polysaccharide antibody responses are distributed among IgG subclasses with modest preference in IgG2 subclass. The majority of patients treated with immunoglobulin responded by reduction in frequency of infections and requirement of antibiotics.

Objective: This study aimed to determine the predictors of disease progression after functional endoscopic sinus surgery in patients with chronic rhinosinusitis., Method: A total of 281 adult chronic rhinosinusitis patients who underwent primary bilateral functional endoscopic sinus surgery between 2007 and 2017 and had at least 12 months of follow-up endoscopic evaluation were examined. Patients were divided into eosinophilic (n = 205) and non-eosinophilic chronic rhinosinusitis groups (n = 76). In order to determine adverse factors, post-operative endoscopic appearance scores were analysed in relation to the pre- and intra-operative findings using multiple regression analyses., Results: The post-operative course of eosinophilic cases deteriorated over time, like the early period for non-eosinophilic cases. Frontal sinus polyps recurred early in eosinophilic chronic rhinosinusitis. Multivariate analyses indicated young adulthood, asthma, high computed tomography score and frontal sinus polyps as significant adverse predictors., Conclusion: Early, appropriate estimation of sinonasal conditions appears to be crucial for successful surgical management of chronic rhinosinusitis.

Purpose: To investigate the correlation of tissue eosinophil count and chemosensory functions in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) after endoscopic sinus surgery (ESS)., Methods: This was a cross-sectional study including 40 patients with a history of ESS for CRSwNP recruited consecutively. Visual analog scale score and the Lund-Kennedy endoscopic score were recorded. Biopsies of the ethmoidal sinus mucosal were performed and evaluated. Chemosensory functions were measured by Sniffin' Sticks and chemosensory event-related potentials (CSERP). The associations between chemosensory functions and tissue eosinophil count were analyzed using Spearman correlation and partial correlation after adjusting the confounding factors. Kendall's tau-b correlation was performed between sneezing score and CSERP with ethyl alcohol (EAL) stimulation., Results: Olfactory and trigeminal nerve function was successfully evaluated using CSERP. Postoperative tissue eosinophil count was correlated with threshold (T) score (partial correlation coefficient r = - 0.460, p = 0.012) and CSERP peak latency for olfactory (N1: partial r = 0.471, p = 0.010; P2: partial r = 0.487, p = 0.007) and mixed olfactory-trigeminal (N1: partial r = - 0.516, p = 0.008; P2: partial r = - 0.590, p = 0.002). There were also correlations between T score and N1 latency with phenyl ethyl alcohol (PEA) (partial r = - 0.560, p < 0.001), between sneezing score and N1 latency with EAL (Kendall's tau-b = - 0.40, p = 0.005)., Conclusions: Postoperative tissue eosinophilia is significantly associated with postoperative olfactory disorders as assessed by Sniffin' Sticks and CSERP peak latency. Furthermore, olfaction as measured by T score correlates with olfactory ERP latency in inflammation-associated olfactory dysfunction. Trigeminal sensitivity also appears to relate to tissue eosinophilia, indicating mucosal inflammation can affect both sensory systems in the nose.

Objective: To provide a comprehensive overview of the emerging role of periostin, an extracellular matrix protein, as a key component in the development, diagnosis, and treatment of patients with chronic rhinosinusitis., Data Sources: Medline database., Review Methods: A state of the art review was performed targeting English-language studies investigating the role of periostin in cardiopulmonary, neoplastic, and inflammatory diseases, with emphasis on recent advances in the study of periostin in chronic rhinosinusitis., Conclusions: Periostin has emerged as a novel biomarker and therapeutic target for numerous human pathologies, including cardiac, pulmonary, and neoplastic disease. The upregulation of periostin in chronic rhinosinusitis suggests the potential for similar roles among patients with sinonasal disease., Implications for Practice: Chronic rhinosinusitis is a widespread disease with major clinical and societal impact. A critical limitation in the current treatment of patients with chronic rhinosinusitis is the absence of clinically relevant biomarkers to guide diagnosis and treatment selection. A review of the literature supports a likely role of periostin as a biomarker of chronic rhinosinusitis, as well as a novel therapeutic target in the future treatment of patients with sinonasal disease.

Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory airway disease involving non-eosinophilic and eosinophilic phenotypes, which translate to various endotypes. Activated eosinophils and neutrophils are known to generate extracellular traps consisting of DNA and cytotoxic granule proteins. We sought to investigate the presence of eosinophil and neutrophil extracellular traps (EETs and NETs, respectively) in human CRS tissues and to clarify the associations with their clinical features. Nasal polyp (NP) or ethmoid tissue slides of 43 subjects from endoscopic sinus surgery for CRS were analysed. Quantitative analysis of EETs and NETs was performed by confocal microscopy using immunofluorescent staining. For correlation study, the presence of NPs, number of infiltrating tissue eosinophils, preoperative Lund-Mackay scores, and other comorbidities were analysed. EET formation was observed to varying degrees in all CRS groups and was correlated with the number of tissue eosinophils (r  =  0.83, p  < 0.001) regardless of the presence of NPs. Patients with more EETs demonstrated higher Lund-Mackay scores (r  =  0.51, p  = 0.009), blood eosinophilia (r  =  0.80, p  < 0.001), and decreased olfactory function (r  = -0.65, p  < 0.001). No correlation between the extent of EET formation and the presence of atopy or asthma was apparent. However, none of the CRS groups containing neutrophils formed NETs in this study. Eosinophilic CRS indicates the presence of EETs. Formation of EETs could have a role in clinical decision-making and prediction of treatment outcome of CRS, regardless of NP status.

Background: Chronic rhinosinusitis (CRS), in particular with nasal polyps (CRSwNP), has been linked with skewed T-helper 2 and immunoglobulin E (IgE)-mediated allergic responses. The role of atopy in CRS, however, remains unclear. Correlations between immunological allergic markers and patient-reported outcomes measures (PROMs) were investigated., Methods: A cross-sectional study of adult patients with CRS undergoing endoscopic sinus surgery was conducted. Immunological allergic markers included automated immunoassay testing for serum-specific IgE to common allergens (house dust mite, grass, mold, animal epithelia) and total IgE. PROMs were assessed using the 22-item Sino-Nasal Outcome Test (SNOT-22). Patients were defined as atopic based on either a positive specific IgE or elevated total IgE (>160 kU/L)., Results: A total of 446 patients (45.7% female, age 49.05 ± 14.96 years) were recruited, of which 42.8% had asthma, 51.6% had CRSwNP, and 63.0% had eosinophilic CRS. Positive allergen sensitization was detected in 52.9% patients. Total IgE levels were elevated in 28.0% with mean IgE level of 161 ± 269 kU/L. Atopy was associated with younger age at the time of surgery, CRSwNP, asthma, and eosinophilic CRS (eCRS). Atopy was also associated with increased severity in nasal symptom score (13.1 ± 6.4 vs 11.9 ± 6.0, p = 0.04), as well as worse scores in the loss of smell/taste (χ 2 (1) = 5.97, p = 0.02) and need to blow nose (χ 2 (1) = 4.26, p = 0.04) questions in the CRS population. In the CRSwNP population, there was no significant association between atopy and PROMs., Conclusion: Comorbid atopy in CRS is associated with additional symptom burden, reflected mainly within the nasal symptom quality of life markers. Atopy assessment in CRS is important to ensure appropriate and successful treatment of the disease., (© 2018 ARS-AAOA, LLC.)

Background: IgG4 production is regulated by type 2 (IL-4 and IL-13) and regulatory (IL-10) cytokines involved in the pathophysiology of chronic rhinosinusitis (CRS). We sought to determine the pathophysiological characteristics of IgG4-positive cells in sinonasal tissues in CRS, especially eosinophilic CRS (ECRS)., Methods: IgG4-positive cells in uncinate tissues (UT) and nasal polyps (NP) were examined by immunohistochemistry. Associations between the number of IgG4-positive cells and clinicopathological factors were analyzed. Receiver operating characteristics (ROC) analysis was performed to determine the cut-off value of IgG4-positive cells in tissue that can predict the post-operative course., Results: IgG4 was mainly expressed in infiltrating plasma and plasmacytoid cells, and the number of IgG4-positive cells was significantly higher in NP, especially those from severe ECRS patients, than in UT. In CRS patients, the number of IgG4-positive cells significantly and positively correlated with blood and tissue eosinophilia, radiological severity, and serum level of total IgE. The number of infiltrating IgG4-positive cells was significantly higher in patients with a poor post-operative course (sustained sinus shadow 6 months after surgery) than in those with a good one. The number of IgG4-positive cells in NP could discriminate patients with a good or a poor post-operative course (area under the curve: 0.769). Also, 73.3% sensitivity and 82.5% specificity were achieved when the cut-off value was set at 17 cells/high-power field., Conclusions: Our results suggest that the local expression of IgG4 on cells may be used as a biomarker that reflects the pathophysiology of CRS, including the post-operative course., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Several previous studies have shown that serum 25(OH)D deficiency is associated with increased risk of chronic rhinosinusitis (CRS) in adults and also correlated with disease severity. We aimed to investigate the correlation between serum 25(OH)D level and endoscopy-based CRS in adults using the Korean National Health and Nutrition Examination Survey., Methods: The data were based on the Korean National Health and Nutrition Examination Survey from 2008 to 2011. Diagnosis of endoscopy-based CRS was based on endoscopic findings of mucopurulent rhinorrhea in the middle meatus or nasal polyps, with nasal symptoms satisfying symptom-based CRS based on European Position Paper on Rhinosinusitis and Nasal Polyps 2012 criteria. Nasal symptoms included nasal obstruction, anterior/posterior nasal drip, facial pain, and the loss of smell. Serum 25(OH) D level was defined as deficient (less than 20 ng/mL), insufficient (20â€"29.9 ng/mL), or sufficient (less than or equal to 30 ng/mL)., Results: The serum 25(OH)D level in the CRS group was 19.293 'plus or minus' 7.035 ng/mL, which was higher than that of the control group (18.057 'plus or minus' 6.56 ng/mL, p = 0.0072). Among symptom combinations of endoscopy-based CRS, some combinations with mucopurulent rhinorrhea at the middle meatus were significantly related to normal serum 25(OH)D level., Conclusion: Low serum 25(OH)D level might not be associated with increased prevalence of CRS in Korean adults; rather, patients with CRS showed higher serum 25(OH)D levels than the control group. Thus, these results, contradicting those of previous studies, should be further verified in other countries to investigate the role of the serum 25(OH)D in CRS.

Objectives/hypothesis: Failure after sinus surgery is multifactorial, but often due to recurrence of inflammatory mucosal disease. Postoperative steroid requirements for controlling mucosal inflammation may provide insight into predicting which patients require more aggressive medical therapy to prevent disease relapse., Study Design: Retrospective chart review., Methods: A review was performed of patients who underwent functional endoscopic sinus surgery (FESS) for refractory chronic rhinosinusitis (CRS). Sino-Nasal Outcome Test-22 scores and cumulative prednisone dose (milligrams) requirements at 1, 3, and 6 months postoperatively were reviewed. A structured histopathology report of 11 variables was accessed to correlate histopathology with postoperative steroid requirements., Results: One hundred one patients were reviewed including 42 CRS with nasal polyps and 59 CRS without nasal polyps patients. CRS patients with eosinophilia required greater cumulative steroids to control disease at 1-, 3-, and 6-month postoperative intervals (P < .026, P < .007, P < .013, respectively) compared to patients without eosinophilia. Patients with tissue eosinophil aggregates required the highest cumulative steroids at 1-, 3-, and 6-month postoperative intervals (P < .003, P < .001, P < .001, respectively). When removing patients with eosinophil aggregates from the eosinophilia group, no difference persisted between patients with eosinophilia and those without eosinophilia at all intervals (P = .664, P = .735, P = .800, respectively). No other histopathology variable correlated with postoperative steroid requirement., Conclusions: Tissue eosinophil aggregates appear to be the largest driving factor for increased prednisone requirements after sinus surgery to control mucosal disease than mere presence of eosinophils. This key finding may identify patients at high risk for failure after sinus surgery and guide more proactive postoperative management., Level of Evidence: 4 Laryngoscope, 129:794-799, 2019., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: To discuss the clinical and radiological features of IgG4-related rhinosinusitis. Methods: In this retrospective research, the clinical data of 16 patients diagnosed with IgG4 related rhinosinusitis, who were enrolled in Beijing Tongren Hospital from November 2013 to September 2017, were collected. The clinical features, laboratory findings, radiological findings, histological features, treatment and prognosis were all summarized. Results: There were 12 males and 4 females among 16 patients, and male-to-female ratio was 3︰1. The age was between 30 to 70 years old, with median age of 52 years old. The chief nasal complaints were nasal obstruction and hyposmia, complicated with proptosis and eyelid swelling in 11 patients (11/16). Serum IgG4 levels were elevated in all patients and the value was over 1.44 g/L, and one patient serum IgG4 level was up to 49.70 g/L. Computed tomography (CT) showed the mainly affected sinuses were bilateral ethmoid sinus and olfactory cleft. The classic feature of CT scans was thickening of the involved bilateral ethmoid sinus mucous membrane with ethmoid bone absorption, which was mainly at midline. Histological features were severe inflammation of the mucosal tissue with mass of neutrophils and plasma cell infiltration. All patients were treated by methylprednisolone combined with cyclophosphamide or methotrexate. Remission of symptoms was detected in all patients. Conclusion: The clinical features of IgG4-related rhinosinusitis are often accompanied by orbital tissue involvement, elevated IgG4 serum concentration, associated sinus imaging changes, and sensitive glucocorticoid and immunosuppressive therapy.

Objective: To study the value of olfactory cleft scores through computed tomography (CT) in predicting the oral glucocorticoids (GC) sensitivity in chronic rhinosinusitis with nasal polyps. Methods: Fourty-seven consecutive patients with CRSwNP from the Fifth Affiliated Hospital of Sun Yat-sen University between January and March of 2018 were recruited in this prospective, single-blinded study. There were 28 males and 19 females, with age ranging from 17 to 66 years old. After a course of oral prednisone (30 mg/d for 14 d), these patients were subsequently classified into objectively GC-sensitive and -insensitive subgroup according to the change in nasal polyp size score, or subjectively GC-sensitive and -insensitive subgroup according to the change in total nasal symptom score. The following parameters were compared between GC-sensitive and -insensitve subgroups: Lund-Mackay scores, olfactory cleft scores, and blood eosinophil counts and ratio. T test and χ(2) test were used. Multivariate Logistic regression analysis was used for factor prediction and receiver operating characteristic (ROC) curve was used to analyze the predictive ability of those factors. Results: There were 53.2% (25/47) and 61.7% (29/47) of patients objectively and subjectively sensitive to GC therapy, respectively. All data conformed to normal distribution. The olfactory cleft score and the blood eosinophil counts and ratio in objectively GC-sensitive subgroup were significantly higher than those in objectively GC-insensitive subgroup (3.6±1.0 vs 2.2±1.4, (404.4±200.3)/μl vs (209.5±233.1)/μl, (5.25±2.59)% vs (3.17±3.46)%, t value was 3.98, 3.08, respectively, χ(2)=2.35, all P< 0.05). The cleft score, the blood eosinophil counts and ratio also showed the same trend in subjectively GC-sensitive and -insensitive subgroup (3.6±1.0 vs 1.9±1.3, (401.4±213.6)/μl vs (171.1±200.2)/μl, (5.39±2.76)% vs (2.48±2.99)%, t value was 5.05, 3.68, respectively, χ(2)=3.40, all P< 0.05). Multivariate Logistic regression revealed that olfactory cleft score was an independent risk factor for objective or subjective GC-sensitivity ( OR= 2.882, 95 %CI : 1.301-6.384; OR= 2.508, 95 %CI : 1.248-5.039). The olfactory cleft score exhibited comparable accuracy with the blood eosinophil ratio as predictor of objective and subjective GC-sensitivity (Area under curve of olfactory cleft score was 0.775, 0.829, respectively). An olfactory cleft score of 3.5 could act as a reliable indicator for predicting the clinical response to GC therapy in CRSwNP. Conclusion: Olfactory cleft score through CT scan has the potential value in predicting GC-sensitivity in CRSwNP patients.