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Objectives: The purpose of this study is to investigate the lung function in Chronic Rhinosinusitis (CRS) patients with Chronic Cough (CC)., Methods: A total of 1413 CC patients were retrospectively screened and 109 CRS patients with CC were enrolled. Lung function, Lund-Mackay Computed Tomography (CT) score, smoking status, peripheral blood eosinophil count, and immunoglobulin E concentration in serum samples, and Sino-Nasal Outcome Test were examined. Normal control subjects are also recruited., Results: The Forced Expiratory Volume in 1 second (FEV 1.0 ), Percent Predicted FEV 1.0 , and FEV 1.0 /Forced Vital Capacity (FVC) ratio in the patients were significantly low as compared with the control subjects. The FEV 1.0 /FVC ratio was negatively correlated with the Lund-Mackay CT scores of the patients with a high CT score., Conclusions: The CRS patients with CC should be investigated with lung function. In addition, the multidisciplinary evaluation including a pulmonologist is needed to manage the CRS patients with CC., Level of Evidence: Level 4., (Copyright © 2024 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier España S.L.U. All rights reserved.)

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

Objective: To ensure that the best possible information is available for selecting treatment options in patients who have chronic rhinosinusitis with nasal polyps (CRSwNP), it is necessary to assess experiences with surgical procedures in real-world clinical practice., Methods: We used an internet questionnaire to survey 300 patients who had a history of CRSwNP surgery or had been recommended for such surgery., Results: The patients who underwent surgery showed high satisfaction with the effectiveness of the surgery. However between 20% and 30% were notably dissatisfied with the safety of the procedure, its effects on quality of life (QOL), its economic impact, and its influence on societal activities, such as attendance at work or school. This dissatisfaction tended to be particularly pronounced among older patients and those who had multiple surgeries. The primary reasons given for avoiding surgery were "afraid of surgery," "no time for hospitalization and treatment," and "surgery is too expensive.", Conclusion: Our research indicates that, although recipient patients are highly satisfied with the effectiveness of surgery for CRSwNP, a number of patients hesitate because of concerns about safety, cost, and societal activities such as work and school attendance. These findings suggest that treatment in a clinical setting should consider not only therapeutic effects but also the patient's attitude and situation.

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.)

Cross-linking of antigen-specific IgE bound to the high-affinity IgE receptor (FcεRI) on the surface of mast cells with multivalent antigens results in the release of mediators and development of type 2 inflammation. FcεRI expression and IgE synthesis are, therefore, critical for type 2 inflammatory disease development. In an attempt to clarify the relationship between eosinophilic chronic rhinosinusitis (ECRS) and mast cell infiltration, we analyzed mast cell infiltration at lesion sites and determined its clinical significance. Mast cells are positive for c-kit, and IgE in uncinated tissues (UT) and nasal polyps (NP) were examined by immunohistochemistry. The number of positive cells and clinicopathological factors were analyzed. Patients with ECRS exhibited high levels of total IgE serum levels and elevated peripheral blood eosinophil ratios. As a result, the number of mast cells with membranes positive for c-kit and IgE increased significantly in lesions forming NP. Therefore, we classified IgE-positive mast cells into two groups: membrane IgE-positive cells and cytoplasmic IgE-positive cells. The amount of membrane IgE-positive mast cells was significantly increased in moderate ECRS. A positive correlation was found between the membrane IgE-positive cells and the radiological severity score, the ratio of eosinophils, and the total serum IgE level. The number of cytoplasmic IgE-positive mast cells was significantly increased in moderate and severe ECRS. A positive correlation was observed between the cytoplasmic IgE-positive cells and the radiological severity score, the ratio of eosinophils in the blood, and the total IgE level. These results suggest that the process of mast cell internalization of antigens via the IgE receptor is involved in ECRS pathogenesis.

The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.

Purpose: Chronic cough is a common complaint. Because the pathophysiology of chronic cough is complicated, the management of chronic cough is challenging. To the best of our knowledge, no previous study has examined the effect of macrolide antibiotics in chronic cough patients with chronic rhinosinusitis. The purpose of this study is to determine the changes in lung function for chronic cough patients with chronic rhinosinusitis who are treated by clarithromycin and carbocisteine., Materials and Methods: Thirty-two chronic cough patients with chronic rhinosinusitis were recruited. Patients using inhaled corticosteroids and/or a bronchodilator, asthmatic patients, and patients with abnormal findings on auscultation and/or chest X-ray examination were excluded from this study. The patients received low-dose clarithromycin treatment for 3 months. Both before and after the treatment, a computed tomography (CT) scan of the paranasal sinuses, lung function test, peripheral blood test, and sino-nasal outcome test (SNOT-20) were applied., Results: Both the lung function and Lund-MacKay CT scores were improved by the long-duration therapy with macrolide antibiotics. The change in obstructive pulmonary function and the improvement of the CT score in each subject were significantly correlated. SNOT scores also improved after the treatment., Conclusions: The macrolide antibiotics treatment has beneficial effects on lung function in non-asthmatic chronic cough patients with normal chest X-ray findings. The improvement of chronic rhinosinusitis may have some role in the lung condition. Upper respiratory tract examination and treatment may be useful for the management of chronic cough., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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: Baker's rhinitis is a kind of occupational allergic rhinitis mainly caused by intranasal exposure to wheat and/or rye flour in bakery workers. Continuous exposure to flour may induce the onset of asthma in these patients., Method: We experienced a case of 34-year-old male with baker's rhinitis without asthma, and investigated responses of IgE and peripheral blood mononuclear cells (PBMCs) to flour extracts used in the bakery in practice., Result: In the immunoblotting, the patient's IgE reacted with 18 and 30kDa molecules in the extracts of 6 flours used in the bakery. The patient's PBMC produced a substantial amount of IL-5 and IL-13 in response to these flour extracts., Conclusion: It is suggested that water/salt soluble components of wheat flour selectively induce type 2 cytokines production in baker's rhinitis.

We previously reported that chronic rhinosinusitis with nasal polyps (CRSwNP) was subdivided into four chronic rhinosinusitis (CRS) subtypes using the JESREC scoring system. We sought to identify the gene expression profile and biomarkers related with CRSwNP by RNA-sequence. RNA-sequencing was performed to identify differentially expressed genes between nasal polyps (NPs) and inferior turbinate mucosa from 6 patients with CRSwNP, and subsequently, quantitative real-time PCR was performed to verify the results. ELISA was performed to identify possible biomarkers for postoperative recurrence. In the RNA-sequencing results, periostin (POSTN) expression was the highest in NP. We focused on POSTN and investigated the protein level of POSTN by immunohistochemistry and ELISA. POSTN was diffusely expressed in moderate and severe eosinophilic CRS using immunohistochemistry, and its staining pattern was associated with the severity of the phenotype of the CRSwNP (P < 0.05). There was a significant difference between the POSTN high/low groups for postoperative recurrence when the cutoff point was set at 115.5 ng/ml (P = 0.0072). Our data suggests that the protein expression level of POSTN was associated with the severity of CRSwNP, and serum POSTN can be a novel biomarker for postoperative recurrence of CRSwNP.

Background: IL-10 is a major anti-inflammatory cytokine that prevents inflammation-mediated tissue damage. We characterized the production of IL-10 by sinonasal tissue cells following exposure to Staphylococcus aureus enterotoxin B (SEB), which elicits cellular responses and is associated with the pathogenesis of eosinophilic chronic rhinosinusitis (ECRS)., Methods: Dispersed nasal polyp (NP) cells and uncinate tissue (UT) cells were prepared from patients with CRS with and without NP, respectively. Cells were incubated with SEB, and then the levels of IL-10 in the cell supernatants were determined. The effect of neutralizing IL-10 on SEB-induced IL-5, IL-13, IFN-γ, and IL-17A production was examined. Expression of IL-10 in NPs was also determined., Results: IL-10 was expressed in infiltrating inflammatory cells in NPs. NP cells, especially non-adherent NP cells, produced substantial amounts of IL-10 in response to SEB. Although baseline production of IL-10 was significantly higher in NP cells than UT cells, the degree of IL-10 response to SEB was not significantly different between the cell types. The degree of IL-10 production was negatively correlated with the degree of eosinophilia both in tissues and peripheral blood whereas positively correlated with the 1-s forced expiratory volume/forced vital capacity ratio. Patients with severe ECRS displayed a significant decrease in IL-10 production compared with those with non-ECRS. IL-10 neutralization significantly augmented SEB-induced IL-13 and IFN-γ production by NP cells., Conclusions: Impaired IL-10 production in response to SEB in NP may exacerbate the pathophysiology of ECRS including eosinophilia and lower airway obstruction., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Objective: There is a close relationship between upper and lower respiratory tract diseases. Chronic rhinosinusitis patients frequently have lung diseases including asthma and chronic obstructive pulmonary disease. Eosinophilic chronic rhinosinusitis is considered a refractory and intractable subtype of chronic rhinosinusitis. However, there has been no report on pulmonary function in patients with eosinophilic chronic rhinosinusitis. The purpose of this study is to examine the pulmonary function in eosinophilic chronic rhinosinusitis patients and non-eosinophilic chronic rhinosinusitis patients, and evaluate clinical factors associated with the pulmonary function of these patients., Methods: Pulmonary function was measured in 53 patients with eosinophilic chronic rhinosinusitis with asthma, 58 patients with eosinophilic chronic rhinosinusitis without asthma, and 30 patients with non-eosinophilic chronic rhinosinusitis. The diagnosis of chronic rhinosinusitis was based on the definition in the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) 2012. Eosinophilic chronic rhinosinusitis was diagnosed based on the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) scoring system. The relationship between pulmonary function and clinical parameters was assessed. These parameters included radiographic severity of chronic rhinosinusitis, peripheral blood eosinophil percentage, serum total immunoglobulin E level, and eosinophilic infiltration in nasal polyps., Results: The pulmonary function of the patients with eosinophilic chronic rhinosinusitis was significantly affected. The eosinophilic chronic rhinosinusitis patients had more peripheral airway obstruction as compared to the patients with non-eosinophilic chronic rhinosinusitis., Conclusion: Our findings indicated latent obstructive lung function changes in the eosinophilic chronic rhinosinusitis patients. The patients with eosinophilic chronic rhinosinusitis should be carefully monitored in order to detect lung diseases., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Conclusions: Chronic rhinosinusitis diagnosed according to the European Position Paper on Rhinosinusitis and Nasal Polyps 2012, not by computed tomography alone, is one of the prognostic factors affecting long-term survival in patients with lung transplantation. Endoscopic sinus surgery might play a beneficial role in the management of lung transplantation recipients with chronic rhinosinusitis., Objective: To show the effect of paranasal sinus infection on post-lung transplantation survival., Method: Lung transplantation recipients were included in this study. Computed tomography was performed before and after lung transplantation. The severity of chronic rhinosinusitis was evaluated by Lund-Mackay scoring system. The survival rate was calculated by the Kaplan-Meier method., Results: One hundred and forty-eight patients received lung transplantation for various indications. Chronic rhinosinusitis was found in 18.9% (28/148) of the lung transplantation recipients. Of 28 patients with chronic rhinosinusitis, seven patients underwent endoscopic sinus surgery due to persistent post-nasal drip. The recipients with chronic rhinosinusitis who did not receive endoscopic sinus surgery (n = 21) showed a significantly lower survival rate as compared to the patients without chronic rhinosinusitis. There was no statistically significant difference in the survival rate between the recipients with (n = 50) and without (n = 98) paranasal sinus abnormality on computed tomography.

Background: IL-22 is an IL-10-family cytokine that regulates chronic inflammation. We investigated the role of IL-22 and its receptor, IL-22R1, in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP)., Methods: IL-22 and IL-22R1 protein and mRNA expression in NP and in uncinate tissues (UT) from CRS and non-CRS patients was examined using immunohistochemistry and real-time PCR, respectively. Dispersed NP and UT cells were cultured with the Staphylococcus aureus exotoxins, staphylococcal enterotoxin B and alpha-toxin, following which exotoxin-induced IL-22 levels and their association with clinicopathological factors were analyzed. Effects of IL-22 on MUC1 expression and cytokine release in NP cells were also determined., Results: IL-22 and IL-22R1 in NP were mainly expressed in infiltrating inflammatory cells and in epithelial cells, respectively. IL-22 mRNA levels in NP were significantly higher than those in UTs from non-CRS patients whereas IL-22R1 levels were conversely lower in NPs. NP cells produced substantial amounts of IL-22 in response to exotoxins. Exotoxin-induced IL-22 production by NP cells significantly and negatively correlated with the degree of local eosinophilia and postoperative computed tomography (CT) score, whereas conversely it positively correlated with the forced expiratory volume in 1s (FEV 1 )/forced vital capacity (FVC) ratio. IL-22 significantly enhanced MUC1 mRNA expression in NP cells. IL-22-induced MUC1 mRNA levels were significantly and positively correlated with IL-22R1 mRNA levels in NPs., Conclusions: These data suggest that imbalance of IL-22/IL-22R1 signaling regulates the pathogenesis of CRSwNP, including local eosinophilia, via alteration of MUC1 expression., (Copyright © 2016 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Toll-like receptor 3 (TLR3) is expressed in upper airways, however, little is known regarding whether Toll-like receptor 3 (TLR3) signals exert a regulatory effect on the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP), especially on eosinophilic inflammation. We sought to investigate the effect of Poly(IC), the ligand for TLR3, on cytokine production by dispersed nasal polyp cells (DNPCs)., Methods: DNPCs were pretreated with or without Poly(IC), and were then cultured in the presence or absence of staphylococcal enterotoxin B (SEB), following which the levels of IL-5, IL-10, IL-13, IL-17A and interferon (IFN)-γ in the supernatant were measured. To determine the involvement of IL-10 and cyclooxygenase in Poly(IC)-mediated signaling, DNPCs were treated with anti-IL-10 monoclonal antibody and diclofenac, the cyclooxygenase inhibitor, respectively. Poly(IC)-induced prostaglandin E2 (PGE2) production was also determined., Results: Exposure to Poly(IC) induced a significant production of IL-10, but not of IL-5, IL-13, IL-17A or IFN-γ by DNPCs. Pretreatment with Poly(IC) dose-dependently inhibited SEB-induced IL-5, IL-13 and IL-17A, but not IFN-γ production. Neutralization of IL-10 significantly abrogated the inhibitory effect of Poly(IC). Treatment with diclofenac also abrogated the inhibitory effect of Poly(IC) on SEB-induced IL-5 and IL-13 production. However, unlike exposure of diclofenac-treated DNPCs to lipopolysaccharide, the ligand for TLR4, exposure of these cells to Poly(IC) did not enhance IL-5 or IL-13 production. Poly(IC) did not significantly increase PGE2 production by DNPCs., Conclusions: These results suggest that TLR3 signaling regulates eosinophilia-associated cytokine production in CRSwNP, at least in part, via IL-10 production., (Copyright © 2015 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: A close relationship between upper and lower respiratory tract diseases has been reported. The purpose of this study was to evaluate lung function in patients with chronic rhinosinusitis (CRS) who have never smoked., Methods: A total of 208 patients with CRS were enrolled in this study. Of these subjects, 96 patients were ever smokers and 112 patients were never smokers. CRS patients with lower pulmonary diseases including chronic obstructive pulmonary disease (COPD) and asthma were excluded from this study. Age-matched normal control subjects (n = 55) who were never smokers were also recruited. Pulmonary function testing was performed using spirometry. Lund-Mackay computed tomography (CT) score, peripheral blood eosinophil count, and immunoglobulin E (IgE) level in serum samples were examined. Nasal obstruction was evaluated by active anterior rhinomanometry., Results: CRS patients who were ever smokers have decreased lung function. Never-smoking patients with CRS also showed significant obstructive lung function changes as compared with normal controls. No significant correlation was detected between the clinical parameters (CT score, eosinophil count, IgE level, and nasal resistance) and lung function., Conclusion: Asymptomatic obstructive lung function changes were observed in never-smoking patients with CRS. Our findings suggest that patients with CRS should be followed carefully in order to detect lung diseases., (© 2015 ARS-AAOA, LLC.)

Background: Chronic rhinosinusitis (CRS) can be classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). CRSwNP displays more intense eosinophilic infiltration and the presence of Th2 cytokines. Mucosal eosinophilia is associated with more severe symptoms and often requires multiple surgeries because of recurrence; however, even in eosinophilic CRS (ECRS), clinical course is variable. In this study, we wanted to set objective clinical criteria for the diagnosis of refractory CRS., Methods: This was a retrospective study conducted by 15 institutions participating in the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC). We evaluated patients with CRS treated with endoscopic sinus surgery (ESS), and risk of recurrence was estimated using Cox proportional hazard models. Multiple logistic regression models and receiver operating characteristics curves were constructed to create the diagnostic criterion for ECRS., Results: We analyzed 1716 patients treated with ESS. To diagnose ECRS, the JESREC scoring system assessed unilateral or bilateral disease, the presence of nasal polyps, blood eosinophilia, and dominant shadow of ethmoid sinuses in computed tomography (CT) scans. The cutoff value of the score was 11 points (sensitivity: 83%, specificity: 66%). Blood eosinophilia (>5%), ethmoid sinus disease detected by CT scan, bronchial asthma, aspirin, and nonsteroidal anti-inflammatory drugs intolerance were associated significantly with recurrence., Conclusion: We subdivided CRSwNP in non-ECRS, mild, moderate, and severe ECRS according to our algorithm. This classification was significantly correlated with prognosis. It is notable that this algorithm may give useful information to clinicians in the refractoriness of CRS before ESS or biopsy., (© 2015 The Authors. Allergy Published by John Wiley & Sons Ltd.)

Background: Recent studies have revealed that Staphylococcus aureus and its components participate in the pathogenesis of eosinophilic airway diseases, such as chronic rhinosinusitis with nasal polyps., Objective: We sought to determine whether staphylococcal protein A (SpA) from S aureus regulated cellular responses in nasal polyps, especially when coupled to immunoglobulins in immune complexes (ICs)., Methods: Dispersed nasal polyp cells (DNPCs) or peripheral blood monocytes were cultured in vitro with SpA in the presence or absence of IgG, and IL-5, IL-13, IFN-γ, IL-17A, and IL-10 levels were measured in the supernatants. The effect of SpA exposure on staphylococcal enterotoxin B-induced cytokine production by DNPCs in the presence and absence of IgG, IgA, and autologous serum was also examined., Results: Exposure to SpA induced DNPCs to produce significantly higher IL-10, IL-13, and IL-17A levels than DNPCs without SpA, although the magnitude of the IL-17A increase was less than that of IL-10 and IL-13. SpA induced IL-10 production mainly from adherent DNPCs, and this was significantly enhanced in the presence of IgG; similar results were observed in peripheral blood monocytes. IC formation between SpA and IgG (SpA-IgG ICs) was confirmed by using native polyacrylamide gel electrophoresis. SpA-IgG ICs, but not SpA alone, almost completely suppressed staphylococcal enterotoxin B-induced IL-5, IL-13, IFN-γ, and IL-17A production by DNPCs; similar inhibition was observed in DNPCs treated with SpA in the presence of either IgA or autologous serum., Conclusions: Our results suggest that SpA can regulate the pathogenesis of enterotoxin-induced inflammation in patients with chronic rhinosinusitis with nasal polyps through coupling to immunoglobulins., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: In contrast to Staphylococcus aureus-derived superantigenic exotoxins, the role of non-superantigenic exotoxins in the pathogenesis of eosinophilic airway diseases remains obscure. We sought to characterize S. aureus alpha-toxin-induced cellular responses in chronic rhinosinusitis with nasal polyps (CRSwNP)., Methods: Dispersed nasal polyp cells and uncinate tissue cells were prepared from patients with CRS with and without nasal polyps, respectively. Cells were incubated with various concentrations of alpha-toxin or staphylococcal enterotoxin B and then the levels of IL-5, IL-13, IFN-γ, IL-17A, and IL-10 in the cell supernatants were determined. The pathophysiological significance of alpha-toxin-induced cytokine production was also determined including radiological severity of rhinosinusitis, tissue and blood eosinophilia, serum total IgE level, and 1-s forced expiratory volume/forced vital capacity ratio (FEV1/FVC)., Results: Nasal polyp cells produced substantial amounts of IL-5, IL-13, IFN-γ, IL-17A, and IL-10 in response to alpha-toxin. Cytokine production was higher in nasal polyp cells than in uncinate tissue cells. The potency of alpha-toxin in stimulating IL-5, IL-13, and IL-10 production was comparable to that of enterotoxin. Alpha-toxin-induced IFN-γ, IL-17A, and IL-10 production significantly and negatively correlated with the degree of eosinophil infiltration into nasal polyps. Conversely, alpha-toxin-induced IFN-γ and IL-10 production significantly and positively correlated with FEV1/FVC. IL-10 production was significantly lower in asthmatic patients compared to non-asthmatics, Conclusions: S. aureus-derived alpha-toxin can provoke cellular responses in nasal polyps. These responses, especially failure to synthesize IL-10, may play a role in the pathophysiology of CRSwNP.

Background: The relationship between upper and lower airway diseases has been reported. However, the pulmonary function of patients with chronic rhinosinusitis (CRS) has not been fully examined., Methods: Pulmonary function was measured in 273 patients with CRS and 100 age-matched normal control subjects. No patients with chronic obstructive pulmonary disease (COPD) were included in this study. The patients with CRS were divided into 8 subgroups based on the presence of asthma, sensitization to common inhaled antigens, and nasal polyposis. The relationships between pulmonary function and clinical parameters, including radiographic severity of CRS according to the Lund-Mackay computed tomography (CT) staging system, eosinophil count in the peripheral blood, and serum total immunoglobulin E (IgE) levels, were assessed., Results: In pulmonary function testing, the CRS patients had affected pulmonary function. The CRS patients without asthma showed latent obstructive pulmonary function changes when compared to normal controls. No significant correlations were observed between pulmonary function and any clinical parameters (Lund-Mackay CT staging score, eosinophil count in the peripheral blood, and serum total IgE levels)., Conclusion: CRS patients had significant obstructive lung function changes regardless of the presence of asthma. The patients with CRS who had not been clinically diagnosed as having lower respiratory tract diseases might have had subclinical lower airway diseases. Therefore, clinicians should be aware of pulmonary function and lower lung diseases in patients with CRS., (© 2014 ARS-AAOA, LLC.)

Background: A close relationship between upper and lower respiratory tract diseases has been reported. However, little is known about pulmonary function in patients with upper respiratory tract diseases., Methods: Pulmonary function was measured in: 68 patients with chronic rhinosinusitis without nasal polyps, 135 patients with chronic rhinosinusitis with nasal polyps, 89 patients with allergic rhinitis and 100 normal control subjects. The relationships between pulmonary function and clinical parameters were assessed. These parameters included radiographic severity of chronic rhinosinusitis, serum total immunoglobulin E levels, concentrations of cytokines in nasal secretions and exhaled nitric oxide levels., Results: The pulmonary function of patients with chronic rhinosinusitis was significantly affected. The level of interleukin-5 in nasal secretions was significantly correlated with pulmonary function in patients with chronic rhinosinusitis., Conclusion: The findings indicated latent obstructive lung function changes in chronic rhinosinusitis patients. The cytokines in nasal secretions might be related to obstructive lung function changes in chronic rhinosinusitis.

Background: Interleukin-18 (IL-18) is a member of the IL-1 cytokine family that affects chronic inflammation. We sought to characterize IL-18 expression and investigate its release during chronic rhinosinusitis (CRS)., Methods: The expression of IL-18 in nasal polyps (NPs) and uncinate tissues (UTs) from both CRS and non-CRS patients was examined via immunohistochemistry. After culturing dispersed NP cells (DNPCs) with or without various stimulations, IL-18 levels were measured in the culture supernatants. Furthermore, the effect of IL-18 neutralization on staphylococcus enterotoxin B (SEB)-induced cytokine production was also examined., Results: Similar expression of IL-18 in the epithelial layers was observed between the NPs and UTs. However, there was a significantly higher number of IL-18(+) cells in the lamina propria from NPs compared to UTs without CRS. This increased number was significantly correlated with the radiological severity of sinusitis and local eosinophilia. After the dispersion, IL-18 was spontaneously released by NP cells in a phase-dependent manner. While SEB, fungal antigens, and TLR agonists did not enhance the release, exposure to protease or one cycle of a freeze-and-thaw treatment did induce release of IL-18 from rested DNPCs. In addition, neutralization of IL-18 significantly suppressed SEB-induced IL-5, IL-13, and IFN-γ, but not IL-17A production., Conclusions: These results suggest that the pro-inflammatory effect of IL-18 released by danger signals may be involved in the pathogenesis of CRS, which includes eosinophilic inflammation and NP formation, via the augmentation of both Th2- and Th1-associated cytokine production., (Copyright © 2012 S. Karger AG, Basel.)

Background: Silencing of genes using small interfering RNA (siRNA) is a recently developed strategy to regulate the synthesis of target molecules. Signal transducer and activator of transcription 6 (STAT6) is a nuclear transcription factor that mediates Th2-type immunity., Methods: To elucidate the therapeutic potential of using siRNA to inhibit STAT6 in allergic reactions, we determined the nucleotide sequences of siRNA specific for STAT6., Results: The selected sequences of STAT6 siRNA specifically inhibited the generation of STAT6 synthesis in dermal fibroblasts and eotaxin (CCL11) production in response to IL-4/TNF-α in vitro. Local administration of STAT6 siRNA in vivo alleviated contact hypersensitivity responses to chemical haptens. This was accompanied by reduced local production of IL-4, IL-13, eotaxin (CCL11), TARC (CCL17) and MDC (CCL22). Similarly, consecutive intranasal instillation of STAT6 siRNA markedly inhibited inflammatory cellular infiltration of mucosal tissues in allergic rhinitis responses in association with reduced IL-4 and IL-5 production from regional lymph node cells. Immediate responses, such as sneezing and nasal rubbing behaviors, were also improved by STAT6 siRNA., Conclusions: Local administration of STAT6 siRNA is thus a promising therapeutic strategy for both Th2-mediated cutaneous diseases and allergic rhinitis., (© 2010 John Wiley & Sons A/S.)

Background: Prostaglandin (PG)D(2) and E(2), two major cyclooxygenase (COX) products, are generated by PGD(2) synthase (PGDS) and PGE(2) synthase (PGES), respectively, and appear to mediate airway inflammation., Objective: We sought to determine the role of PGDS and PGES in the pathophysiology of chronic rhinosinusitis (CRS)., Methods: The study examined the expression of PGDS and PGES in nasal polyps of 22 CRS patients. As controls, uncinate process mucosae were obtained from 12 CRS patients not having nasal polyps and five subjects without sinusitis. Immunohistochemistry and quantitative real-time PCR were used to evaluate the expression., Results: Both PGDS and PGES were detected in nasal polyps by immunohistochemistry. Significantly greater levels of PGDS mRNA and lesser levels of PGES mRNA were observed in the nasal polyps as compared with uncinate process mucosae, and an inverse correlation between PGDS and PGES expression was observed. Levels of PGDS mRNA in nasal polyps were positively correlated with degree of infiltration by EG2+ eosinophils, whereas the levels of PGES were inversely correlated. Significantly increased levels of PGDS and conversely decreased levels of PGES were observed in asthmatics as compared with non-asthmatics. In addition, PGDS and PGES levels were positively and inversely correlated with the radiological severity of sinusitis, respectively., Conclusions: These results suggest that PGDS and PGES display an opposite and important role in the pathophysiology of CRS such as polyp formation, and more specifically, a biased expression of these synthases might contribute to the development of CRS by affecting eosinophilic inflammation.

Allergic rhinitis is a common airway disease characterized by hypersensitivity, exudation, hypersecretion, inflammatory cell infiltration and remodelling. Intranasal glucocorticosteroids are the most effective drugs for controlling the inflammation caused by allergic rhinitis. Glucocorticosteroids exert anti-inflammatory effects through at least two pathways: the transactivation pathway and the transrepression pathway. Glucocorticosteroids also exert regulatory functions by inducing regulatory cytokines and forkhead box P3 (FoxP3+) regulatory T cells. Evidence suggests that intranasal glucocorticosteroids control not only nasal symptoms but also ocular symptoms. In contrast to sedating H1 receptor antagonists, intranasal glucocorticosteroids can improve impaired performance symptoms, such as daytime sleepiness, associated with allergic rhinitis. Recent studies suggest that intranasal glucocorticosteroids might also be useful for the prophylactic treatment of pollinosis; this possibility is supported by the molecular mechanism of the anti-inflammatory action of glucocorticosteroids. These findings suggest that intranasal glucocorticosteroids might be positioned as first-line drugs for the treatment of both perennial and seasonal allergic rhinitis. [ABSTRACT FROM AUTHOR]

Glucocorticosteroids are the most effective drugs for controlling inflammation of allergic rhinitis (AR). Because of their strong pharmacological action, which can be a so-called ‘double-edged sword’, glucocorticosteroids are usually taken intranasally so as to reduce their potential for eliciting adverse effects. Accumulating evidence suggests that intranasal glucocorticosteroids control not only nasal symptoms but also ocular symptoms. In contrast to sedating H1-receptor antagonists, intranasal glucocorticosteroids can improve impaired performance such as daytime sleepiness associated with AR. In Japanese cedar pollinosis, treatment begun immediately after initiation of pollen release or onset of initial symptoms, known as prophylactic (initial) treatment, is recommended. The current version of the practical guideline for management of allergic rhinitis in Japan recommends the use of chemical mediator release inhibitors, second-generation H1-receptor antagonists, or leukotriene receptor antagonists for prophylactic treatment. However, recent evidence suggests that intranasal glucocorticosteroids might also be useful as first-line drugs for prophylactic treatment. The molecular mechanism of anti-inflammatory action of glucocorticosteroids supports this contention. Moreover, a meta-analysis of studies of intranasal glucocorticosteroids given as monotherapy has revealed that these agents are superior to oral H1-receptor antagonists and leukotriene antagonists for controlling major symptoms of AR. These findings suggest that glucocorticosteroids, especially intranasal glucocorticosteroids, might be positioned as first-line drugs for the treatment of both perennial and seasonal AR. [ABSTRACT FROM AUTHOR]

Staphylococcal enterotoxins (SEs) appear to play a role in the pathogenesis of allergic disease. However, little is known whether the nasal exposure to SE affects the development of allergic rhinitis (AR).We sought to determine thein vivoeffect of nasal exposure to SE on the development of AR using mouse model.BALB/c mice were intranasally sensitized withSchistosoma mansoniegg antigen (SmEA) in the presence or absence of staphylococcal enterotoxin B (SEB). Control mice were intranasally sensitized with either SEB or SmEA alone. The production of antigen-specific antibodies including IgE, nasal eosinoplilia and cytokines by nasal mononuclear cells was compared among mice that had or had not received SEB treatment.Nasal exposure to SEB enhanced the development of AR in SmEA-sensitized mice, as manifested by SmEA-specific IgE production, nasal eosinophilia, and IL-4 and IL-5 production by nasal mononuclear cells after Ag challenge. This treatment also elicited IFN-γ production by SmEA-primed cells. In addition, these mice produced SEB-specific IgE whereas mice treated with SEB without SmEA sensitization did not produce SEB-specific IgE or demonstrate nasal eosinophilia.These results suggest that the nasal exposure to SEB enhances susceptibility to AR although the exposure to SE solely does not induce AR. [ABSTRACT FROM AUTHOR]

Dendritic cells are one of the most potent antigen-presenting cells and when pulsed with allergen can modulate allergen-specific T-cell responses. We sought to establish a single-step method by which to generate allergen-specific monocyte-derived dendritic cells (MoDCs).Dermatophagoides farinae(Df)-prepulsed MoDCs were generated from monocytes by culturing with Df in the presence interleukin (IL)-4, granulocyte-macrophage colony-stimulating factor (GM-CSF)and tumour necrosis factor (TNF)-α simultaneously. Df-prepulsed MoDC were incubated with autologous naïve and memory T cells in the absence of recall antigen, then proliferation and cytokine production by T cells was determined.Generation of allergen-prepulsed MoDCs was confirmed by examining expression of surface molecules. Df-prepulsed MoDC selectively induced proliferation of Df-specific T cells in the absence of recall antigen. Under these conditions, Df-prepulsed MoDCs augmented but did not alter the cytokine production profile. In addition, Df-prepulsed MoDCs activated naïve T cells leading to proliferation and selective production of IFN-γ in allergic patients but not in healthy subjects.These results suggest that Df-prepulsed MoDC generated from monocytes by a simple single-step manipulation can induce Df-specific cellular responses from both naïve and memory T cells in the absence of recall antigen, and these cells potentially can be utilized as immune adjuvants in allergen-specific immunotherapy. [ABSTRACT FROM AUTHOR]