Background Chronic rhinosinusitis (CRS) is strongly associated with comorbid asthma. This study compares early-onset and late-onset asthma in a CRS population using patient-reported and clinical characteristics. Methods At enrollment into a clinical registry, CRS patients completed the 22-item Sino-Nasal Outcome Test (SNOT-22), Asthma Control Test (ACT), mini-Asthma Quality of Life Questionnaire (miniAQLQ), the 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29), and medication use questionnaires. Patients also reported comorbid asthma and age at first asthma diagnosis. Early-onset (<18 years) and late-onset (>18 years) asthma groups were defined. Analysis of variance (ANOVA), chi-square, and Kruskal-Wallis tests were used to compare patient responses. Results A total of 199 non-asthmatic (56.1%), 71 early-onset asthmatic (20.0%), and 85 late-onset asthmatic (23.9%) CRS patients completed the survey. Body mass index (BMI) was significantly higher in late-onset asthmatic (p = 0.046) while age, gender, race, and smoking history did not differ with time of asthma onset. SNOT-22, ACT, and miniAQLQ were not different between asthma groups, but late-onset asthmatics had significantly lower physical function than non-asthmatics (p = 0.008). Compared to non-asthmatics, late-onset asthmatics showed increased rates of nasal polyps (p < 0.001), higher Lund-Mackay scores (p = 0.005), and had received more oral steroid courses (p < 0.001) and endoscopic surgeries (p = 0.008) for CRS management. Late-onset asthmatics compared to early-onset asthmatics showed increased nasal polyposis (p =0.011) and oral steroid courses for CRS (p = 0.003). Conclusion While CRS-specific and asthma-specific patient-reported outcome measures (PROMs) were not significantly different among groups, CRS patients with late-onset asthma had poorer physical function, more frequent nasal polyposis, and required increased treatment for CRS. Late-onset asthma may predict more severe disease in CRS.

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Background Immunoglobulin D (IgD) is an enigmatic antibody isotype best known when co-expressed with IgM on naïve B cells. However, elevated soluble IgD (sIgD) and increased IgD+IgM− B cell populations have been described in the human upper respiratory mucosa. Objective We assessed whether levels of sIgD and IgD+ B cells are altered in nasal tissue from patients with chronic rhinosinusitis (CRS). We further characterized IgD+ B cell populations and explored clinical and local inflammatory factors associated with tissue sIgD levels. Methods sIgD levels were measured by ELISA in nasal tissues, nasal lavages, serum, and supernatants of dissociated nasal tissues. IgD+ cells were identified by immunofluorescence and flow cytometry. Inflammatory mediator levels in tissues were assessed by real-time PCR and multiplex immunoassay. Bacterial cultures from the middle meatus were performed. Underlying medical history and medicine use were obtained from medical records. Results sIgD levels and the number of IgD+ cells were significantly increased in uncinate tissue (UT) of CRS without nasal polyps (CRSsNP) compared to control (4-fold, P<.05). IgD+ cells were densely scattered in the periglandular regions of CRSsNP UT. We also found that IgD+CD19+CD38bright plasmablasts were significantly elevated in CRSsNP tissues compared to control (P<.05). Among numerous factors tested, IL-2 levels were increased in CRSsNP UT and were positively correlated with tissue IgD levels. Additionally, the supernatants of IL-2-stimulated dissociated CRSsNP tissue had significantly increased sIgD levels compared to IL-2-stimulated dissociated control tissue ex vivo (P<.05). Tissue from CRS patients with preoperative antibiotic use or those with pathogenic bacteria presence showed higher IgD levels compared to tissue from patients absent these variables (P<.05). Conclusion sIgD levels and IgD+CD19+CD38bright plasmablasts were increased in nasal tissue of CRSsNP. IgD levels were associated with increased IL-2 and the presence of pathogenic bacteria. These findings suggest that IgD might contribute to enhance mucosal immunity, inflammation, or respond to bacterial infections in CRS, especially CRSsNP.

Background: Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease subdivided based on the presence or absence of nasal polyps (NPs). Histologic features of chronic rhinosinusitis with nasal polyps (CRSwNP) include inflammatory cell infiltration and excessive fibrin deposition in NPs. Thrombin-activatable fibrinolysis inhibitor (TAFI) is an enzyme that plays an antifibrinolytic role in the body. The significance of TAFI has been documented in patients with chronic inflammatory diseases, including chronic lung disease; however, it has not been evaluated in the pathogenesis of NPs. Objective: The objective of this study was to evaluate the potential role of TAFI in the pathogenesis of NPs. Methods: Nasal lavage fluid was collected from control subjects and patients with CRS. We measured levels of thrombin/antithrombin complex (TATc) and TAFI protein using an ELISA. Results: TATc levels in nasal lavage fluid were significantly increased in patients with CRSwNP and patients with chronic rhinosinusitis without nasal polyps (CRSsNP) compared with control subjects, and TAFI levels in nasal lavage fluid were also significantly increased in patients with CRSwNP compared with those in control subjects and patients with CRSsNP. There was a significant correlation between TATc and TAFI levels in nasal lavage fluid. Interestingly, patients with CRS and asthma showed increased TATc and TAFI levels in nasal lavage fluid compared with those in patients with CRS without asthma, especially patients with CRSwNP. Conclusions: Increased TATc and TAFI levels in nasal passages of patients with CRSwNP might participate in fibrin deposition in NPs and might play a role in the pathogenesis of CRSwNP and asthma.

Summary Background Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is excessive fibrin deposition, which is associated with down-regulation of tissue plasminogen activator (t-PA) in NPs. As t-PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t-PA would be a potential new strategy for the treatment of NPs. Objective The objective of this study was to determine whether short-chain fatty acids (SCFAs) can induce t-PA in airway epithelial cells via their known receptors GPR41 and GPR43. Methods We performed immunohistochemistry (IHC) to determine whether receptors for SCFAs, known as G protein-coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2, are expressed in nasal tissue. Primary normal human bronchial epithelial (NHBE) cells were stimulated with different concentrations of SCFAs to test induction of t-PA, which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA. Results Immunohistochemistry study revealed that airway epithelial cells expressed GPR41 and GPR43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t-PA expression from two- to tenfolds. The strongest inducer of t-PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t-PA into the supernatant in its active form. Gene silencing of GPR41 and GPR43 revealed that induction of t-PA by SCFAs was dependent upon both GPR41 and GPR43. Conclusions and Clinical Relevance Short-chain fatty acids were shown to induce airway epithelial cell expression of t-PA via GPR41 and GPR43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) has a high propensity for recurrence. Studies suggest that eosinophilia influences disease severity and surgical outcomes, but the selection of sinonasal site for measuring eosinophilia has not been examined. The aim of this study was to investigate how region-specific tissue eosinophilia affects radiographic severity, comorbidity prevalence, and polyp recurrence risk following sinus surgery. Methods Eosinophil cationic protein (ECP) levels in uncinate tissue (UT) and nasal polyp (NP) homogenates from 116 CRSwNP patients were measured using enzyme-linked immunosorbent assay (ELISA). Clinical history, radiographic severity, and time to polyp recurrence were obtained from electronic health records. The correlations between baseline Lund-Mackay scores and comorbidities were compared between UT and NP ECP levels. Cox regression and Kaplan-Meier analysis were then performed to assess whether UT or NP ECP better predicted recurrence. Censoring occurred at 4 years or at last follow-up if there was no endoscopic diagnosis of recurrent polyps. Results Lund-Mackay scores were significantly correlated with UT and NP ECP (r = 0.46 and 0.26 respectively, p < 0.05). UT but not NP ECP was significantly higher in patients with asthma (p < 0.01) and aspirin-exacerbated respiratory disease (AERD) (p < 0.05). Polyp recurrence risk was only significantly higher for patients with eosinophilic UT tissue (hazard ratio [HR] = 2.84, p = 0.025). When measured in NP, eosinophilia did not predict recurrence. Conclusion Although ECP in NP was higher than in UT tissue, eosinophilia in UT tissue was a more clinically coherent biomarker of baseline radiographic severity, comorbid asthma and AERD, and prospective polyp recurrence risk than NP eosinophilia.

PCR-based sequencing allowed for the rapid and sensitive diagnosis of HRV, and the discovery of a novel HRV-C species in 2006. 2 Researchers using advanced molecular diagnostic techniques have determined that HRV infections, in particular HRV-A and HRV-C species, are the major viral trigger for childhood and adult exacerbations of asthma and chronic obstructive pulmonary disease. 3 However, the role of HRV infections in chronic rhinosinusitis (CRS) is not well understood. 4 Given that different HRV species have been shown to exhibit varying degrees of disease severity in chronic airway disorders,

RATIONALE: Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on presence or absence of nasal polyps (NPs). Excessive fibrin deposition is one of the features of NPs. Tissue plasminogen activator is expressed in epithelial cells and initiates fibrin degradation, however, t-PA expression is reduced in NPs. Identifying compounds that can induce expression of t-PA would be a potential new strategy for the treatment of NPs. We hypothesized that short chain fatty acids (SCFAs) can induce t-PA in airway epithelial cells via their receptors, G protein coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2. METHODS: We performed immunohistochemistry (IHC) to reveal whether GPR41 and GPR43 are present in nasal tissue. To test induction of t-PA, primary normal human bronchial epithelial (NHBE) cells were stimulated with SCFAs. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA. RESULTS: IHC study revealed that airway epithelial cells expressed both GPR41 and GPR43 in vitro and in vivo. Propionic acid, butyric acid, and valeric acid strongly induced expression of t-PA mRNA and protein (range X fold to Y fold, p<.05) in NHBE cells. T-PA released into the supernatant was shown to be in the active form. The induction of t-PA by SCFAs was dependent upon both GPR41 and GPR43. CONCLUSIONS: SCFAs were shown to induce airway epithelial cell expression of t-PA via GPR41 and GPR43. Potent compounds that activate these receptors in vivo may have value by reducing fibrin deposition and shrinking nasal polyps. Abstracts AB91 SATURDAY