Computed tomography findings of paranasal sinuses in patients with eosinophilic granulomatosis with polyangiitis: Comparison with other eosinophilic sinus diseases and clinical relevance of their severity.

BACKGROUND: Although paranasal sinuses are one of the most representative organs affected by eosinophilic granulomatosis with polyangiitis (EGPA), they have not been studied sufficiently. The aim of this study was to compare computed tomography (CT) findings in paranasal sinuses of EGPA with those of other eosinophilic sinus diseases and elucidate the clinical relevance of their severity. METHODS: CT findings of paranasal sinuses in EGPA patients prior to therapeutic intervention (n = 30) were evaluated using the Lund-Mackay staging (LMS) system and compared with those of three control diseases [(NSAID-exacerbated respiratory disease (N-ERD), aspirin-tolerant asthma, and eosinophilic chronic rhinosinusitis without asthma (ECRS)]. We divided EGPA patients into three groups based on their LMS scores and examined their association with disease manifestation. RESULTS: Total scores of the LMS system in EGPA were significantly lower than those of N-ERD and ECRS without asthma. There was a large variation in total LMS scores in EGPA, suggesting considerable heterogeneity of their sinus lesions. Although EGPA with low LMS system scores showed only minor findings in maxillary and anterior ethmoid regions, those with high LMS system scores were characterized by high scores in the ostiomeatal complex. However, the frequencies of patients with a Five-Factor Score ≥2 and with cardiac involvement were significantly higher for EGPA with low LMS system scores. CONCLUSIONS: Although paranasal sinus lesions in EGPA were less severe than those of other eosinophilic sinus diseases, their milder CT findings may be associated with a higher frequency of extra-respiratory organ involvement.

Cysteinyl leukotriene metabolism of human eosinophils in allergic disease.

Eosinophils are multifaceted immune cells with diverse functions that enhance allergic inflammation. Cysteinyl leukotrienes (cys-LTs), mainly synthesized in eosinophils, are a class of inflammatory lipid mediators produced via multiple enzymatic reactions from arachidonic acid. Multiple clinical studies have reported dysregulated fatty acid metabolism in severe asthma and aspirin-exacerbated respiratory diseases. Therefore, understanding the mechanism responsible for this metabolic abnormality has attracted a lot of attention. In eosinophils, various stimuli (including cytokines, chemokines, and pathogen-derived factors) prime and/or induce leukotriene generation and secretion. Cell-cell interactions with component cells (endothelial cells, epithelial cells, fibroblasts) also enhance this machinery to augment allergic responses. Nasal polyp-derived eosinophils from patients with eosinophilic rhinosinusitis present a characteristic fatty acid metabolism with selectively higher production of leukotriene D4. Interestingly, type 2 cytokines and microbiome components might be responsible for this metabolic change with altered enzyme expression. Here, we review the regulation of fatty acid metabolism, especially cys-LT metabolism, in human eosinophils toward allergic inflammatory status.

Effects of Fluticasone Furoate on Clinical and Immunological Outcomes (IL-17) for Patients With Nasal Polyposis Naive to Steroid Treatment.

OBJECTIVES: We investigated the effect of topical steroids on clinical outcomes and related immune response of chronic rhinosinusitis with nasal polyp (CRSwNP) patients and in eradicating some polyps. We want to explore a new potential mechanism linked to Th-17 cells. METHODS: Prospective, double-blind, placebo-controlled studies with 24 allergic and nonallergic patients were randomized to either placebo or fluticasone furoate for 12 weeks. Assessment of clinical response, endoscopic score with biopsies of the inferior turbinate, and polyps before and after treatment were performed. Biopsies were stained for T-cells, eosinophils, neutrophils, and IL-17A/F. RESULTS: Steroid treatment improved the mean symptoms scores from 7.12 to 4.02 (P < .01) and the polyp score from 5.13 to 3.31 (P < .05), but the comparison with placebo was not statistically significant in nonallergics due to insufficient study power. Steroid treatment decreased eosinophil counts on allergics but not neutrophils or T-cells. The IL-17A/F expression was higher in nonallergics with high neutrophil counts and was inclined by steroids. Compared to baselines, IL-17 cells were significantly less in allergic individuals and were not observed in allergics and with high neutrophil counts. CONCLUSION: Topical steroids were more effective on certain nasal polyp phenotypes. Identification of polyp phenotype might be essential to ensure a better therapeutic response to intranasal corticosteroids.

Correlation of Kennedy Osteitis Score with the Tissue and Peripheral Eosinophil Counts in Patients of Eosinophilic Chronic Rhinosinusitis.

Background: The presence of osteoid bone in chronic rhinosinusitis especially the eosinophilic subtype is commonly associated with recalcitrant illness. In practice, the radiological features of osteitis sinus alterations are frequently described, but the clinical and histopathologic implications are not well understood. Objective: This study was done to correlate the radiological and the clinico-histopathological aspects in patients of eosinophilic chronic rhinosinusitis. Methods: A cross-sectional study was done on sixty patients of chronic rhinosinusitis with nasal polyposis (CRSwNP) patients especially the eosinophilic subtype undergoing sinus surgery. Radiologically, osteitis was graded using standards that had already been published in the literature. Analysis was done on the relationships between CT documented osteitis, histopathological, and peripheral eosinophilic counts in patients of eosinophilic chronic rhinosinusitis. Results: The patients with higher tissue eosinophilia and higher peripheral eosinophils had higher osteitis score. Pearson's correlation coefficient between Tissue Eosinophils and KOS was highly significant with p-value <0.001 (0.891). R2 value for KOS versus Tissue Eosinophils was 79.44%,implying that 79.44% variations were explained by Tissue Eosinophils in KOS. And R2 value for KOS versus Peripheral Eosinophils was 74.26%, implying that 74.26% variations were explained by Peripheral Eosinophils in KOS. Thereby, showing a positive relationship between the variables that were studied. Conclusion: Kennedy Osteitis Score, histopathological and peripheral eosinophilia can be used as a marker to predict the disease severity in eosinophilic chronic rhinosinusitis.

Which are the best murine models to study Eosinophilic Chronic Rhinosinusitis? A contemporary review.

OBJECTIVE: Mechanisms that lead to Eosinophilic Chronic Rhinosinusitis (ECRS) are not fully established in the literature. It is desirable to assess ECRS in a model that embraces most of the related events. This article reviewed the murine models for ECRS and compared them regarding eosinophilic polypoid formation. METHODS: The authors reviewed the articles that included the terms "chronic rhinosinusitis" OR "chronic sinusitis" AND "animal model". We analyzed articles in English that evaluated both the number of polyps and the number of eosinophils in the sinus mucosa of mouse models. RESULTS: We identified a total of 15 articles describing different models of ECRS that used BALB/c or C57BL/6 mice, and different triggers/stimulants such as Staphylococcus aureus Enterotoxin B (SEB) + Ovalbumin (OVA); House Dust Mite (HDM) ±â€¯Ovalbumin (OVA); and Aspergillus oryzae Protease (AP) + Ovalbumin (OVA). OVA associated with SEB was the commonest protocol to induce ECRS in both BALB/c and C57BL/6 mice, and it produced a robust response of eosinophilic nasal polyps in both. AP + OVA protocol also led to a good ECRS response. The other models were not considered adequate to produce eosinophilic polyps in mice. CONCLUSION: In conclusion, OVA associated with SEB seems to produce the most robust eosinophilic sinonasal inflammation.

Eosinophilic otitis media; state-of-the-art diagnosis and treatment.

Eosinophilic otitis media (EOM) is an intractable otitis media with highly viscous middle ear effusion and is usually associated with bronchial asthma. Since the diagnostic criteria of EOM were established in 2011, the concept of EOM has been known worldwide. EOM is caused by Type 2 inflammation in the respiratory tract, similar to bronchial asthma and eosinophilic rhinosinusitis. With the appreciation of Type 2 inflammatory diseases, EOM is no longer considered to be a rare disease and should be specifically treated to improve quality of life. The diagnosis of EOM needs to be reconsidered because many reports have described varying pathogenesis and mechanisms of rare middle ear conditions. Systemic and topical administration of corticosteroids is presently the most effective treatment to control EOM. However, EOM treatments are developing because various biologics have been used to treat patients with bronchial asthma with and without eosinophilic rhinosinusitis and EOM. Surgical intervention is also no longer contraindicated with the use of biologics. These advances represent the beginning of a new stage of basic and clinical research for EOM. This review focuses on the diagnosis and treatment of EOM based on the most recent advances regarding EOM.

Rapid and remarkable effectiveness of benralizumab for treating severe bronchial asthma with intractable eosinophilic rhinosinusitis and eosinophilic otitis media: A case report.

Severe bronchial asthma is a challenging disorder to treat and can impair quality of life (QOL) under conventional therapeutic modalities. We report the case of a 52-year-old woman with severe asthma associated with eosinophilic chronic rhinosinusitis (ECRS) and eosinophilic otitis media (EOM). Although the patient was treated with a full dose of inhaled corticosteroid, leukotriene receptor antagonist (LTRA), theophylline, burst use of oral corticosteroids (OCS), her asthmatic condition aggravated, disrupting her daily life. ECRS and EOM symptoms were also getting worse despite treatment with topical application of corticosteroids to the nose and ears, LTRA, and occasional use of OCS. In addition to asthmatic symptom, the patient always suffered from intractable nasal obstruction and hearing disturbance, which contributed to the heavily impaired QOL. However, the administration of benralizumab showed rapid and remarkable improvement not only in her asthmatic conditions but also in the symptoms of ECRS and EOM within a month. These results suggest that the use of benralizumab for the treatment of severe asthma with intractable ECRS and EOM should be considered when the patient's QOL is severely deteriorated.

Topography of polyp recurrence in eosinophilic chronic rhinosinusitis.

BACKGROUND: Eosinophilic chronic rhinosinusitis (eCRS) is an inflammatory endotype of CRS. Contemporary treatment includes creation of a "neo-sinus" cavity and postoperative corticosteroid irrigations. Not all patients gain control with local therapy. This study aims to determine, in patients with polyp recurrence, the most common sinuses involved. METHODS: A prospective case-series was conducted on consecutive adult (≥18 years) post-FESS eCRS patients followed for a minimum of 12 months. All patients had a neo-sinus cavity created surgically and used corticosteroid irrigations daily for 3-6 months, then tapered to disease control. Sinus cavities were assessed by endoscopy on last follow-up. Polyp recurrence was defined as a score of 5 or 6 in the MLMES in ≥3 sinus cavities. Patient-reported outcomes based on SNOT22 and NSS, frequency of corticosteroid irrigations, and courses of systemic antibiotics and corticosteroid were collected. The pattern of sinus involvement was analyzed. RESULT: A total of 342 sinus cavities were assessed (mean ± standard deviation, 54.9 ± 13.4 years, 43.2% female). Polyp recurrence occurred in 4.3% (6.4% of patients, n = 7 unilateral) of sinus cavities. Frontal and ethmoid sinus cavities were most affected in those with polyp recurrence, compared to the maxilla and sphenoid (100% vs 100% vs 53% vs 53%, p < 0.01). Although those patients with polyp recurrence utilized more systemic corticosteroids courses per year (0.4 ± 0.4 vs 0.1 ± 0.3, p < 0.01), the use of corticosteroid irrigations was similar (% >4/week; 66.7% vs 48.9%, p = 0.13). Prior surgery was more common in patients with polyp recurrence (86.7% vs 53.5%, p = 0.01). CONCLUSION: The frontal and ethmoid sinuses were most affected in those patients with polyp recurrence. Whether the disease is more active in this location or topical therapy has limited access requires further evaluation.

Which are the best murine models to study Eosinophilic Chronic Rhinosinusitis? A contemporary review

Abstract Objective: Mechanisms that lead to Eosinophilic Chronic Rhinosinusitis (ECRS) are not fully established in the literature. It is desirable to assess ECRS in a model that embraces most of the related events. This article reviewed the murine models for ECRS and compared them regarding eosinophilic polypoid formation. Methods: The authors reviewed the articles that included the terms "chronic rhinosinusitis" OR "chronic sinusitis" AND "animal model". We analyzed articles in English that evaluated both the number of polyps and the number of eosinophils in the sinus mucosa of mouse models. Results: We identified a total of 15 articles describing different models of ECRS that used BALB/c or C57BL/6 mice, and different triggers/stimulants such as Staphylococcus aureus Enterotoxin B (SEB) + Ovalbumin (OVA); House Dust Mite (HDM) ± Ovalbumin (OVA); and Aspergillus oryzae Protease (AP) + Ovalbumin (OVA). OVA associated with SEB was the commonest protocol to induce ECRS in both BALB/c and C57BL/6 mice, and it produced a robust response of eosinophilic nasal polyps in both. AP + OVA protocol also led to a good ECRS response. The other models were not considered adequate to produce eosinophilic polyps in mice. Conclusion: In conclusion, OVA associated with SEB seems to produce the most robust eosinophilic sinonasal inflammation.

Vitamin D pathway regulatory genes encoding 1α-hydroxylase and 24-hydroxylase are dysregulated in sinonasal tissue during chronic rhinosinusitis.

BACKGROUND: Vitamin D deficiency is associated with many inflammatory respiratory disease states. However, serum vitamin D concentrations may not reflect tissue-specific availability. In this study we sought to assess the local expression of genes essential in vitamin D regulation in chronic rhinosinusitis (CRS). METHODS: A cross-sectional study of adult patients undergoing endoscopic sinus surgery was performed. Patients were defined as having CRS with polyps (CRSwNP) or without polyps (CRSsNP), or normal sinus mucosa. Sinus mucosal biopsies were assessed using quantitative polymerase chain reaction to determine expression of genes encoding the vitamin D receptor (VDR), 25-hydroxylase (CYP2R1), 1α-hydroxylase (CYP27B1), and 24-hydroxylase (CYP24A1). Expression levels correlated with serum 25(OH)D [sum 25(OH)D2  and 25(OH)D3 ], the 22-item Sinonasal Outcome Test (SNOT-22), and Nasal Symptom Score (NSS). Separate analyses were performed for patients grouped by tissue eosinophilia. RESULTS: Thirty-one patients were assessed (age 49.47 ± 18.14 years, 48.4% female), including 8 CRSsNP, 10 CRSwNP, and 13 controls. CRSsNP and CRSwNP mucosa exhibited decreased CYP27B1 compared with controls (0.0437 [Interquartile range (IQR) 0.0999] vs 0.3260 [IQR 2.9384] vs 0.6557 [IQR 1.1005], p = 0.039), whereas CYP24A1 was upregulated (0.8522 [IQR 1.3170] vs 1.2239 [IQR 4.4197] vs 0.1076 [IQR 0.1791], p = 0.025). CYP24A1 was upregulated in both non-eosinophilic CRS and eosinophilic CRS (1.1337 [IQR 2.3790] vs 0.9555 [IQR 3.2811] vs 0.1076 [IQR 0.1791], p = 0.033). Significant correlations were observed between NSS and CYP2R1 (r = -0.432, p = 0.022), CYP24A1 (r = 0.420, P = 0.026), and VDR (r = 0.425, p = 0.024), although no correlations with serum 25(OH)D were observed. CONCLUSIONS: The local regulation of vitamin D in sinonasal tissue during CRS may be independent of serum 25(OH)D levels. Vitamin D may be dysregulated at multiple levels, with decreased transcription of the metabolic gene CYP27B1 and increased transcription of the catabolic gene CYP24A1 observed.

Correlation between olfactory acuity and sinonasal radiological findings in adult patients with chronic rhinosinusitis.

OBJECTIVE: This study aimed to clarify the correlation between olfactory disorder severity and radiological findings in patients with chronic rhinosinusitis (CRS) in the preoperative stage. METHODS: From 2007 to 2014, 272 adult patients (163 men, 109 women; age range 22-80 years) with olfactory disorder due to bilateral CRS who were scheduled to undergo primary endoscopic sinus surgery (ESS) were enrolled. Two groups were studied: eosinophilic CRS (ECRS, n=193); and non-ECRS (n=79). T&T olfactometer recognition and intravenous olfaction tests were used. Computed tomography (CT) scores for sinuses and olfactory clefts (OC) were applied. Correlations between olfactory acuity and CT score were statistically analysed. RESULTS: In both groups, recognition threshold correlated significantly with CT score. Recognition threshold and CT score were significantly more severe in ECRS than in non-ECRS. CT score at OC showed the strongest correlation with recognition threshold. CT scores for total sinuses and OC in patients showing a positive response to the intravenous olfaction test (239 patients) were significantly milder than those in the negative group (29 patients), but ethmoid CT score was not. CONCLUSION: Olfactory disorder severity correlated significantly with CT opacification. Olfactory disorder and CT findings were more severe in patients with ECRS than in those with non-ECRS.

Differences in urinary leukotriene E4 levels and distribution of eosinophils between chronic rhinosinusitis patients with aspirin-intolerant and -tolerant asthma.

OBJECTIVE: Urinary leukotriene E4 (U-LTE4) concentrations are significantly elevated in patients with aspirin-intolerant asthma (AIA). However, the relationship between the clinicopathogenetic features of eosinophilic rhinosinusitis and U-LTE4 concentration remains unknown. Here we examined the relationship between U-LTE4 level and eosinophil in chronic rhinosinusitis. METHODS: We measured the U-LTE4 concentrations and eosinophil counts in ethmoidal and maxillary sinuses and peripheral blood in 30 asthmatic patients (including 15 AIA patients). RESULTS: Eosinophil counts in ethmoidal sinuses and peripheral blood were markedly higher in asthmatic patients than in controls. Although there were no significant differences between eosinophil counts in maxillary and ethmoidal sinuses for ATA group, eosinophil counts were higher in ethmoidal sinus compared to that in maxillary sinus in the AIA group (P<.05). Eosinophil counts were higher in the maxillary than in ethmoidal sinuses for control patients (P<.05). Despite low correlation between eosinophil counts in peripheral blood and eosinophil counts in maxillary sinus (rs=0.4323, P<.001), moderate correlation was observed between eosinophil counts in peripheral blood and eosinophil counts in ethmoidal sinus (rs=0.5249, P<.0001). Basal U-LTE4 concentrations were higher in AIA patients than in those with aspirin-tolerant asthma. Despite low correlation between eosinophil counts and U-LTE4 concentration in maxillary sinus (rs=0.3849, P<.01), moderate correlation was observed between eosinophil counts and U-LTE4 concentrations in ethmoidal sinus (rs=0.4736, P<.001). CONCLUSION: We describe the differences in U-LTE4 and other parameters in AIA compared to ATA, and correlation among parameters. We demonstrate that eosinophil-dominant inflammation starts in ethmoidal sinus clinicopathogenetically in CRS with asthma. U-LTE4 concentration was not exclusively associated with eosinophil counts in ethmoidal sinus. Eosinophils in ethmoidal sinus may be a major production site for CysLTs, particularly in AIA. CRS with AIA is assumed to be characterized by leukotriene-eosinophil cross-interaction in ethmoidal sinus.