Eosinophilic Chronic Rhinosinusitis Group Research Articles

Clinical feature-based diagnosis criteria of eosinophil and non-eosinophil chronic rhinosinusitis in Taiwan.

The prevalence of eosinophilic chronic rhinosinusitis (ECRS) has increased in Taiwan with a higher recurrence rate of nasal polyps after surgery. Therefore, we aimed to formulate the pre-operative diagnostic criteria for patients with ECRS in Taiwan. This case-control study included patients diagnosed with CRS with nasal polyps (CRSwNP) who underwent functional endoscopic sinus surgery (FESS) at a tertiary hospital in Taiwan. The patients were classified into ECRS and non-eosinophilic CRS (NECRS) groups based on their histopathology. Demographic data, symptom severity scores, and computed tomography findings of the two groups were analyzed. We utilized receiver operating characteristic curve (ROC) analysis to evaluate parameters that could predict the diagnosis of ECRS. Total 408 CRSwNP patients were enrolled (ECRS group: 163; NECRS group: 245). ECRS group was strongly associated with asthma (6.1% vs. 2.0%, p = .03), higher blood eosinophil counts (4.3% vs. 2.7%, p < .01), higher serum IgE (285.3 vs. 50.2 IU/mL, p = .02), and higher 22-item Sino-Nasal Outcome Test (SNOT-22) score (40.5 vs. 36.7, p = .03). The ECRS criteria based on ROC curve included the SNOT-22 (>45, 2 points), serum eosinophil count percentage (>4%, 4 points), asthma (4 points), total serum IgE (>140 IU/mL, 4 points), Lund-Mackay score (>9.5, 4 points), and ethmoid-to-maxillary opacification ratio on CT (>1.5, 5 points). The cutoff score was 14 points (sensitivity, 70.2%; specificity, 93.3%). Clinical-feature-based criteria may predict the diagnosis of ECRS before FESS in Taiwan. Level 3.

IL-17A facilitates type 2 inflammation in a modified eosinophilic chronic rhinosinusitis mouse model.

Eosinophilic chronic rhinosinusitis (ECRS) is predominantly characterized by nasal type 2 inflammation. The pathogenesis of this condition is complex. High levels of IL-17A are associated with eosinophil infiltration in some inflammatory diseases and contribute to the severity and insensitivity of corticosteroid therapy for chronic rhinosinusitis. In the first experiment, we constructed a modified ECRS mouse model using four groups of mice: phosphate-buffered saline (PBS)-sensitized and nasal instillation (control); PBS-sensitized and Staphylococcus aureus enterotoxin B (SEB) nasal instillation after nasal tamponade (SEB group); ovalbumin (OVA)-sensitized and nasal instillation (OVA group); and OVA-sensitized combined with OVA and SEB nasal instillation after nasal tamponade (OVA+SEB group). In the second experiment, we examined the role of IL-17A by dividing the mice into four groups: control group; ECRS group; ECRS+anti-IL-17A group; and ECRS + IL-17A group. The latter two groups received intraperitoneal injections of anti-IL-17A antibody or IL-17A, respectively. We constructed a modified ECRS mouse model (OVA+SEB group), where the IL-17A levels were upregulated in the nasal sinus of ECRS mice and the IL-17A levels were significantly correlated with eosinophil infiltration. We further demonstrated that IL-17A induced type 2 inflammation and eosinophil infiltration in the ECRS group of mice. In contrast, IL-17A neutralization attenuated type 2 inflammatory cytokine secretion and eosinophil infiltration. OVA sensitization and unilateral nasal tamponade, combined with SEB and OVA alternate nasal instillation (OVA+SEB group), could be used to construct a more typical ECRS mouse model in which IL-17A enhanced the expression of type 2 cytokines and eosinophil infiltration.

Periostin is an aggravating factor and predictive biomarker of eosinophilic chronic rhinosinusitis

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

Effects of Endoscopic Sinus Surgery for Eosinophilic Chronic Rhinosinusitis on Respiratory Functions and FeNO Production in the Lower Respiratory Tract.

To confirm the relevance of upper and lower airway inflammation in eosinophilic chronic rhinosinusitis (ECRS), the effects of endoscopic sinus surgery (ESS) on lower airway functions and inflammation need to be examined in ECRS patients. Chronic rhinosinusitis patients with nasal polyps (25 non-ECRS, 28 ECRS) were enrolled. The 12 patients in the ECRS group had comorbid asthma, in contrast to none in the non-ECRS group. We divided ECRS patients into 2 groups of ECRS with and without asthma. Clinical markers, including fraction of exhaled nitric oxide (FeNO), respiratory functions, and the Asthma Control Test (ACT) questionnaire, were investigated before and after ESS. The FeNO levels in the ECRS with asthma group decreased after ESS. The mean FeNO levels in this group were 56.3 ppb before ESS and 24.9, 25.1, 25.0, and 15.5 ppb 1, 2, 3, and 4 months, respectively, after ESS. The mean forced expiratory rates in 1 second before and after ESS were 67.6% and 73.0%, respectively. The mean maximal expiratory flow rates at 50% of the vital capacity before and after ESS were 45.8% and 58.0%, respectively. Significant differences were observed in respiratory functions before and after ESS. The mean ACT scores in the ECRS with asthma group before and after ESS were 17.5 and 23.5, respectively. The ACT scores were significantly higher after than before ESS. The present results indicate that ECRS and bronchial asthma are common eosinophilic airway inflammatory diseases, and ESS for eosinophilic sinusitis may improve lower airway function.

High chemokine ligand 11 levels in nasal lavage fluid: A potential predictor of and therapeutic target for murine eosinophilic chronic rhinosinusitis

AimWe aimed to discover whether group 2 innate lymphoid cells (ILC2s) and cytokines in nasal lavage fluid could be used to predict eosinophilic infiltration in mice with eosinophilic chronic rhinosinusitis (ECRS). MethodsTen mice were divided into two groups. The ECRS group received an intranasal challenge of Aspergillus oryzae protease (AP) and ovalbumin (OVA) to establish disease. A control group received intranasal phosphate-buffered saline. Histopathology of nasal cavities and paranasal sinuses, and cytokine and ILC2s levels in nasal lavage fluid were analyzed and compared between the ECRS and control mouse groups. Key findingsILC2s numbers were not significantly higher in the nasal lavage fluid of the ECRS group mice compared with those of the control group. Eotaxin/chemokine (CC motif) ligand 11 (CCL11) levels were significantly higher in the nasal lavage fluid of mice in the ECRS group compared with those in the control group. However, no statistical differences were seen in the classic proinflammatory cytokines, IL-33, IL-25, and thymic stromal thymopoietin (TSLP), or the classic type 2 cytokines, IL-4, IL-5, and IL-13 between groups. SignificanceEotaxin/CCL11 levels in nasal lavage fluid rather than that of ILC2s and classic proinflammatory and type 2 cytokines were significantly higher in ECRS mice compared with control ones. Eotaxin/CCL11 showed diagnostic and therapeutic value; however, more studies are needed to test and verify its value.

Evaluation of olfactory dysfunction to estimate the presence of eosinophilic chronic rhinosinusitis in patients with asthma.

Eosinophilic chronic rhinosinusitis (ECRS) is often complicated by asthma and can be difficult to diagnose. This study aimed to clarify the usefulness of the self-administered odor questionnaire (SAOQ) and visual analog scale (VAS) to identify olfactory disorders in patients with asthma. This retrospective study was conducted on patients with asthma who were referred to the Otolaryngology clinic between May and September 2018. The treatment step of asthma, asthma control test (ACT), pulmonary function test, peripheral blood eosinophils, and fractional exhaled nitric oxide (FeNO) were analyzed. ECRS was diagnosed based on the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis Study score. Olfactory dysfunction was evaluated using the SAOQ and VAS for olfactory disorders. The study included 56 patients (18 males and 38 females), who were divided into two groups; those with ECRS (n=18) and those without ECRS (n=38). Age, sex, treatment step, ACT score, and pulmonary function were not significantly different between the groups. The ECRS group had a significantly higher FeNO value (89.1ppb vs. 39.1ppb) and a significantly lower SAOQ score (40.1% vs. 96.1%). The area under the receiver operating characteristic curve for the efficacy of ECRS diagnosis was 0.88, 0.889, 0.799, and 0.757 for SAOQ, VAS, blood eosinophil count, and FeNO, respectively. The SAOQ and VAS scores were useful tools that presented similar results to the blood eosinophil count and FeNO, and may help to improve the diagnosis of ECRS in patients with asthma.

Comparison of olfactory and taste functions between eosinophilic and non-eosinophilic chronic rhinosinusitis

ObjectiveMost patients with chronic rhinosinusitis (CRS) complain of olfactory and/or taste dysfunctions. However, olfactory and taste dysfunctions depending on the subtype of CRS, classified as eosinophilic CRS (ECRS) and non-eosinophilic CRS (NCRS), have not been clearly reported. Therefore, the purpose of this study was to investigate the clinical features in olfactory and taste functions according to the subtype classified as ECRS and NCRS. MethodsWe retrospectively analyzed the electronic medical records of patients who underwent endoscopic sinus surgery and were diagnosed with CRS. The patients were divided into ECRS and NCRS groups, according to their Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) scores. We analyzed demographic characteristics, Sino-Nasal Outcome Test findings, Lund-Mackay score, and the results of previously-validated tests, including the Korean Version of Sniffin' Stick test and chemical gustatory function test. ResultsPatients with ECRS and NCRS had decreased olfactory and taste functions compared to the control group. In particular, the olfactory score of ECRS patients was lower than that of NCRS patients (18.1 ± 9.5 vs 23.7 ± 8.5, respectively, p <0.001). On the other hand, taste scores of ECRS patients were not statistically different compared to NCRS patients (19.1 ± 4.7 vs. 18.3 ± 4.7, respectively, p = 0.166). Olfactory score decreased with increase in JESREC score (r=-0.203, p = 0.002), but it had no correlation with taste score (r = 0.072, p = 0.276). ConclusionWe found a difference in olfactory function but no difference in taste function between patients in ECRS and NCRS groups. These results may provide valuable clinical features in terms of olfactory and taste functions according to the subtypes of CRS.

Postoperative evaluation of olfactory dysfunction in eosinophilic chronic rhinosinusitis – comparison of histopathological and clinical findings

Background: Olfactory dysfunction in eosinophilic chronic rhinosinusitis (ECRS) is poorly understood.Objective: To compare olfactory mucosal injury due to eosinophil infiltration in ECRS with postoperative olfactory function.Methods: Seventeen ECRS patients (ECRS group) and 18 bilateral rhinosinusitis (non-ECRS group) patients were compared. At 3 and 12 months post-endoscopic sinus surgery (ESS), all patients were evaluated for subjective symptoms (nasal obstruction, nasal discharge and olfactory dysfunction), endoscopic nasal findings, CT score and T&T olfactometer recognition threshold test. The eosinophil count, OMP-positive cells and epithelial erosion in olfactory mucosa collected during ESS were compared with the postoperative olfactory function.Results: The non-ECRS group showed significant improvement in all clinical findings at 3 and 12 months, but the ECRS group showed worsening of the olfactory dysfunction symptoms and T&T olfactometer recognition threshold at 12 months because of recurrence of sinusitis. The groups differed significantly in the ΔT&T value (i.e. pre-ESS T&T recognition threshold – post-ESS T&T recognition threshold) at both 3 and 12 months, and the degree of olfactory improvement differed. Histologically, the ECRS group showed significantly more eosinophils, fewer OMP-positive cells and greater epithelial erosion than the non-ECRS group.Conclusions: Eosinophilic inflammation was thought to cause olfactory mucosal injury/dysfunction.

Multiple airborne allergen-induced eosinophilic chronic rhinosinusitis murine model.

Several murine models have been established to mimic human eosinophilic chronic rhinosinusitis (ECRS). However, in most of these models, ECRS was induced using ovalbumin, which does not cause sinusitis in humans. Thus, we aimed to develop a more clinically relevant murine model of ECRS using multiple airborne allergens. We also investigated the effects of exposure duration of the allergens on ECRS development. C57BL/6 mice were intranasally administered multiple airborne allergens (house dust mite, Aspergillus fumigatus, Alternaria alternata, and protease from Staphylococcus aureus) three times weekly for 4, 8, 12, and 16 consecutive weeks. Histopathological changes, the levels of cytokines and chemokines in the nasal lavage fluid, and immune cells of the blood and spleen were analyzed. The mice administered multiple allergens showed significantly increased eosinophil infiltration, epithelial thickening and disruption, and subepithelial collagen deposition from 8weeks compared to the control group. Goblet cell hyperplasia, polyp-like lesions, and blood eosinophils, as well as the levels of interleukin-5 and eotaxin in the nasal lavage fluid were considerably increased in the ECRS group from 12weeks compared to those of controls. Instillation of allergens for 16weeks exacerbated the eosinophil infiltration and eotaxin increase in the nasal lavage fluid. We successfully established a new murine model of ECRS using more clinically relevant multiple airborne allergens. Prolonged exposure to airborne allergens for 12weeks or more, corresponding to the definition of human ECRS, strongly induced eosinophil infiltration as well as epithelial remodeling.

Reduced nasal nitric oxide levels in patients with eosinophilic chronic rhinosinusitis

BackgroundIn Eosinophilic chronic rhinosinusitis (ECRS), it is difficult to estimate the refractoriness and recurrence risk for each patient. Fraction of exhaled nitric oxide (FeNO) is known as a biomarker of eosinophilic inflammation in lower airway. It has been reported that nasal NO has some crucial functions in the upper and lower airways. However, in upper airway, paranasal sinuses, the usefulness of NO measurement remains controversial. The purpose of this study is to identify the usefulness of nasal NO measurement in ECRS and the involvement of nasal NO in the pathogenesis of ECRS. MethodsWe compared the nasal NO levels of ECRS, non-ECRS, and normal control groups. Correlation between nasal NO levels and clinical findings were observed. Then, we compared nasal NO levels before and after endoscopic sinus surgery (ESS). We also examine whether nasal NO levels might discriminate ECRS by the receiver operating characteristic (ROC) curve analysis. ResultsNasal NO levels were significantly decreased in ECRS compared to the other two groups. Moreover, nasal NO levels in ECRS significantly and negatively correlated with eosinophil levels and CT score. However, they did not correlate with the nasal polyp score. Nasal NO levels were not upregulated soon after opening the sinus ostium by ESS. The ROC curves for nasal NO levels were used to discriminate all CRS patients and ECRS patients from normal controls. ConclusionsNasal NO may be useful as a marker of ECRS severity and low nasal NO levels in ECRS may contribute to its pathogenesis.

Usefulness of our proposed olfactory scoring system during endoscopic sinus surgery in patients with chronic rhinosinusitis.

The primary aim of the current study was to examine the usefulness of our proposed olfactory scoring system in chronic rhinosinusitis (CRS) patients with olfactory disorders (n = 213) receiving endoscopic sinus surgery (ESS). Analyzed patients were divided into two groups: an eosinophilic CRS (ECRS) group (n = 153); and a non-ECRS group (n = 60). The T&T recognition threshold test was used to evaluate olfaction at baseline and at 3 and 12 months after ESS. Patients with mean recognition threshold < 2.0at 3 or 12months or with a decrease of ≥ 1.0 as compared with baseline were defined as showing clinical improvement. We scored mucosal conditions as normal (0 points), edema (1 point), and polyp (2 points) at the canopy of olfactory cleft (OC), middle and superior turbinates, superior nasal meatus, and sphenoethmoidal recess during ESS. The total score of OCs (SOCs) was calculated (range 0-20 points). We compared SOCs between ECRS and non-ECRS groups. Factors related to olfactory improvement were also investigated using uni- and multivariate analyses. SOCs in the ECRS and non-ECRS groups showed significant correlations with mean recognition thresholds at baseline and at 3 and 12months. In the multivariate analysis for predicting improvement of mean recognition threshold, lower SOCs were significantly associated with olfactory improvement factors at 3 and 12months postoperatively in the ECRS group. SOCs appears promising for estimating olfactory prognosis after ESS in CRS patients.

IL-5 and IL-6 are increased in the frontal recess of eosinophilic chronic rhinosinusitis patients

BackgroundEosinophilic chronic frontal sinusitis is difficult to treat compared with non-eosinophilic sinusitis because of recurring inflammation and polyp formation in the frontal recess after the post-operative follow-up period. Studying inflammatory mediators in the frontal recess of eosinophilic chronic rhinosinusitis (ECRS) patients and non-eosinophilic chronic rhinosinusitis (non-ECRS) patients may lead to a better understanding of the pathogenesis of chronic frontal sinusitis.MethodsHomogenates of sinonasal mucosa from 20 non-ECRS patients and 36 ECRS patients were measured for levels of transforming growth factor (TGF)-β, interleukin (IL)-5, IL-6, and inducible nitric oxide synthase (iNOS) using real-time RT-PCR and TaqMan gene expression assays. Sinonasal mucosal specimens were obtained from the frontal recess, ethmoid sinus, and nasal polyp separately.ResultsThe expression of IL-5 was significantly elevated in all sinonasal regions tested in the ECRS group, but absent in non-ECRS patients. Furthermore, the ECRS patients showed significantly increased levels of IL-5 in the frontal recess mucosa compared with ethmoid sinus mucosa. IL-6 was also significantly increased in the frontal recess mucosa compared with ethmoid sinus mucosa and nasal polyps in these patients. There were no significant differences in the levels of TGF-β or iNOS between the ECRS and non-ECRS groups in any sinonasal region tested.ConclusionsThis study is the first to characterize the cytokine milieu in the frontal recess of ECRS patients. We should keep these cytokine profiles in mind when we treat ECRS patients with frontal sinusitis.

Expression of IL‐33 and its receptor ST2 in chronic rhinosinusitis with nasal polyps

Interleukin (IL)-33 is a novel member of the IL-1 cytokine family and a ligand for the orphan IL-1 family receptor ST2. IL-33 induces T helper 2-type inflammatory responses and is considered to play a crucial role in allergic inflammatory reactions such as asthma and atopic dermatitis. However, the role of IL-33 and its receptor ST2 in chronic rhinosinusitis remains unclear. In vitro study. The expression patterns of IL-33 and ST2 at both mRNA and protein levels in nasal polyps from eosinophilic chronic rhinosinusitis (ECRS) patients (n = 10) and non-ECRS patients (n = 13), as well as in seemingly normal mucosa of the uncinate processes in patients without sinusitis (control; n = 5), were compared using immunohistochemical staining, enzyme-linked immunosorbent assay, and real-time polymerase chain reactions. ST2-positive cells in the inflammatory cells in the subepithelial layer were significantly higher in the ECRS group than other groups. The expression of ST2 mRNA in polyps of the ECRS group was significantly increased compared with controls. Many ST2-positive eosinophils were observed in the mucosa of ECRS but not in the mucosa of non-ECRS patients. The expression level of IL-33 mRNA was not significantly different among the three groups. The current study suggests that IL-33 and its receptor ST2 may play important roles in the pathogenesis of chronic rhinosinusitis, especially in ECRS, through the increased expression of ST2 in eosinophils. N/A.

Pro-inflammatory effects of ochratoxin A on nasal epithelial cells

Eosinophilic chronic rhinosinusitis (ECRS) largely consists of allergic fungal sinusitis, non-allergic fungal rhinosinusitis, aspirin-exacerbated ECRS, and superantigen-induced ECRS. The pathophysiology of ECRS is not completely understood, in particular, the role of mycotoxins remains unknown. The aim of this study was to evaluate the effects of one of the most widespread mycotoxin, ochratoxin A (OTA), on the release of pro-inflammatory cytokines such as interleukin-(IL)-6 and the CXC-chemokine IL-8 from nasal epithelial cell cultures (NEC) of subjects with and without ECRS. NEC (ECRS group: n = 16; controls: n = 7) were stimulated with OTA for 24 h. Protein concentrations of IL-6 and IL-8 levels were measured in NEC supernatants by ELISA prior and 24 h after addition of OTA. Baseline levels in the supernatants of NEC were 183.3 pg/ml for IL-6 and 384.6 pg/ml for IL-8. Stimulation with OTA induced a significant increase of IL-6 (p < 0.001) and IL-8 (p < 0.001) in both NEC of controls and ECRS, respectively. There were no significant differences between controls and ECRS. This is the first study evaluating the effects of a mycotoxin on epithelial airway cells. Our data show that the ubiquitous mycotoxin OTA has a strong pro-inflammatory effect on NEC resulting in the release of IL-6 and IL-8. Mycotoxins may promote inflammation in nasal mucosa.

Expression and distribution of glucocorticoid receptor isoforms in eosinophilic chronic rhinosinusitis

Objective Patients with eosinophilic chronic rhinosinusitis (ECRS) show a high percentage of eosinophilic infiltration in the paranasal sinus mucosa. It is well documented that topical steroids have a beneficial effect in ECRS with nasal polyposis. We investigated mucosal distribution and cellular localization of glucocorticoid receptor (GR) isoform expression in human paranasal sinuses in relation to the clinical characteristics of eosinophilic chronic rhinosinusitis (ECRS) patients. Methods Mucosal specimens were obtained from 20 sinusitis patients by endoscopic sinus surgery (ESS). Quantitative fluorescence immunohistochemical analysis was employed to examine the degree of glucocorticoid receptor (GR) isoform expression in sinus mucosa specimens. An RT-PCR procedure was performed to determine the relative quantities of mRNA for the human GRα and GRβ genes. Results Patients in the ECRS group showed significant increases in peripheral blood eosinophils as compared to the non-ECRS group (16.98% vs. 2.31%). Positive immunoreactivity of GRβ expression was predominantly found to be positive in inflammatory cells. The absolute number of GRβ-positive cells in the ECRS group was increased in comparison with that in the non-ECRS group. The difference was statistically significant both in the maxillary (179.7 cells/mm 2 vs. 82.5 cells/mm 2) and ethmoid sinus (302.0 cells/mm 2 vs. 61.5 cells/mm 2) mucosa. The GRβ/GRα cell ratio in the ECRS group was elevated when compared with that in the non-ECRS group both in the maxillary and the ethmoid sinus mucosa, with the latter difference being significant. Conclusions The presence of high peripheral eosinophilia indicates a high likelihood of ECRS disease. Our results support the association of GRβ expression with ECRS. The expression of GRβ immunoreactivity, an endogenous inhibitor of steroid action previously associated with steroid insensitivity, may be one of major contributing factors in ECRS.