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BACKGROUND - It is hypothesized that uncontrolled inflammation is responsible for many of the manifestations and symptoms of chronic rhinosinusitis (CRS). Although earlier work has demonstrated an association between olfactory loss and mucus cytokines, the impact on other symptoms is unknown. In this study we investigated the relationship between cytokines, inflammatory cell counts, and patient-reported outcomes measures to better understand how the inflammatory microenvironment correlates with CRS symptomatology.
METHODS - The 22-item Sino-Nasal Outcome Test (SNOT-22) and 8-item Short Form Health Survey (SF-8) were administered to 76 patients undergoing endoscopic sinus surgery for CRS. Mucus was collected intraoperatively from the middle meatus and tested for 17 cytokines using a multiplex flow cytometric bead assay. Eosinophil/neutrophil counts were obtained from histopathologic slide review. Spearman correlations between cytokines, cell counts, and quality-of-life subdomain scores were assessed without multiple comparisons correction due to the small sample size.
RESULTS - Interleukin-4 (IL-4) correlated significantly with the Rhinologic domain (R = 0.25, p = 0.03), whereas eosinophil and neutrophil counts were inversely correlated with the Extranasal Rhinologic domain (R = -0.32, p = 0.01; and R = -0.27, p = 0.03). Subgroup analysis for nasal polyposis (CRSwNP) showed significant correlations between IL-6 and Total SF-8 (R = 0.35, p = 0.02), General Health (R = 0.34, p = 0.03), and Emotional (R = 0.47, p = 0.002) scores. In patients without polyps (CRSsNP), IL-21 correlated positively with Extranasal Rhinologic Symptoms domain (R = 0.41, p = 0.01).
CONCLUSION - This pilot study identifies possible pairwise correlations between mucus cytokine levels and baseline quality-of-life measures that need confirmation in larger, targeted studies. Due to the exploratory methodology, positive results may be spurious and should only be used as a starting point for future confirmatory work.
© 2019 ARS-AAOA, LLC.
BACKGROUND - Olfactory dysfunction is a common symptom of chronic rhinosinusitis (CRS). We previously identified several cytokines potentially linked to smell loss, potentially supporting an inflammatory etiology for CRS-associated olfactory dysfunction. In the current study we sought to validate patterns of olfactory dysfunction in CRS using hierarchical cluster analysis, machine learning algorithms, and multivariate regression.
METHODS - CRS patients undergoing functional endoscopic sinus surgery were administered the Smell Identification Test (SIT) preoperatively. Mucus was collected from the middle meatus using an absorbent polyurethane sponge and 17 inflammatory mediators were assessed using a multiplexed flow-cytometric bead assay. Hierarchical cluster analysis was performed to characterize inflammatory patterns and their association with SIT scores. The random forest approach was used to identify cytokines predictive of olfactory function.
RESULTS - One hundred ten patients were enrolled in the study. Hierarchical cluster analysis identified 5 distinct CRS clusters with statistically significant differences in SIT scores observed between individual clusters (p < 0.001). A majority of anosmic patients were found in a single cluster, which was additionally characterized by nasal polyposis (100%) and a high incidence of allergic fungal rhinosinusitis (50%) and aspirin-exacerbated respiratory disease (AERD) (33%). A random forest approach identified a strong association between olfaction and the cytokines interleukin (IL)-5 and IL-13. Multivariate modeling identified AERD, computed tomography (CT) score, and IL-2 as the variables most predictive of olfactory function.
CONCLUSION - Olfactory dysfunction is associated with specific CRS endotypes characterized by severe nasal polyposis, tissue eosinophilia, and AERD. Mucus IL-2 levels, CT score, and AERD were independently associated with smell loss.
© 2018 ARS-AAOA, LLC.
BACKGROUND - Potential effects of aging on chronic rhinosinusitis (CRS) pathophysiology have not been well defined but might have important ramifications given a rapidly aging US and world population.
OBJECTIVE - The goal of the current study was to determine whether advanced age is associated with specific inflammatory CRS endotypes or immune signatures.
METHODS - Levels of 17 mucus cytokines and inflammatory mediators were measured in 147 patients with CRS. Hierarchical cluster analysis was used to identify and characterize inflammatory CRS endotypes, as well as to determine whether age was associated with specific immune signatures.
RESULTS - A CRS endotype with a proinflammatory neutrophilic immune signature was enriched in older patients. In the overall cohort patients 60 years and older had increased mucus levels of IL-1β, IL-6, IL-8, and TNF-α when compared with their younger counterparts. Increases in levels of proinflammatory cytokines were associated with both tissue neutrophilia and symptomatic bacterial infection/colonization in aged patients.
CONCLUSIONS - Aged patients with CRS have a unique inflammatory signature that corresponds to a neutrophilic proinflammatory response. Neutrophil-driven inflammation in aged patients with CRS might be less likely to respond to corticosteroids and might be closely linked to chronic microbial infection or colonization.
Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Chronic rhinosinusitis (CRS) is a diverse clinical syndrome with a heterogeneous pathophysiology. Early attempts to identify CRS endotypes and biomarkers have largely relied on analysis of surgically obtained tissue, thus limiting their practical utility. This study examined the ability of mucus T helper 2 (Th2) biomarkers to predict CRS disease severity and clinical characteristics.
METHODS - CRS (n = 90) and healthy control subjects (n = 17) were prospectively enrolled prior to surgical intervention and mucus levels of interleukin (IL)-4, IL-5, and IL-13 were determined using a multiplex cytometric bead assay. Data for relevant cytokines was then scaled, normalized, and later combined to develop standardized metrics indicative of Th2-associated inflammation. Th2-high and Th2-low subgroups were consequently identified and validated against factors associated with disease severity and clinical outcomes.
RESULTS - Mucus levels of IL-5 and IL-13 were elevated in CRS subjects compared to controls, while no significant difference was noted for IL-4. IL-5 and IL-13 high CRS were associated with worse objective measures of disease severity and greater rates of revision surgery. Similar relationships were noted for both cytokines when CRS with nasal polyps (CRSwNP) patients were analyzed separately. Th2-high CRS and Th2-low CRS were then categorized using a scaled IL-5/IL-13 metric. Th2-high CRS was characterized by an increased number of subjects with nasal polyps and comorbid asthma, and worse symptom and computed tomography (CT) scores.
CONCLUSION - The Th2-associated cytokines, IL-5 and IL-13, are detectable in sinonasal mucus and their levels can be used to define Th2-high and Th2-low CRS. Identification of Th2-high and Th2-low endotypes using mucus-based biomarkers could facilitate stratification of CRS subgroups and guide personalized therapies.
© 2018 ARS-AAOA, LLC.
BACKGROUND - Olfactory dysfunction is 1 of the hallmark symptoms of chronic rhinosinusitis (CRS). Eosinophilic inflammation has been implicated as a potential causative factor. However, prior studies have been limited by retrospective study designs, concomitant use of systemic corticosteroids, and other confounding factors.
METHODS - CRS and healthy non-CRS control subjects undergoing endoscopic sinus or skull-base surgery were prospectively enrolled and completed olfactory testing utilizing the 40-item Smell Identification Test (SIT) immediately prior to surgery. Histopathological evaluation of tissue excised from the ethmoid bulla was performed by a pathologist in a blinded fashion. Disease severity and patient-reported outcomes were measured via the Lund-Mackay computed tomography (CT) grading system and 22-item Sino-Nasal Outcome Test (SNOT-22), respectively. The associations between olfactory function, tissue eosinophilia, and disease severity were analyzed using Spearman rank order correlation and multiple linear regression.
RESULTS - Twenty-seven (27) subjects with CRS without nasal polyps (CRSsNP), 32 subjects with CRS with nasal polyps (CRSwNP), and 10 healthy non-CRS controls were enrolled. CRSwNP was associated with higher mean tissue eosinophil counts (71.6 vs 28.1 eosinophils/high-power field [HPF], p < 0.05) and lower age/sex-adjusted SIT scores (-17.4 vs -6.2, p < 0.001) when compared to CRSsNP. SIT scores were strongly negatively correlated with tissue eosinophil counts in CRSwNP (r = -0.60, p = 0.0003), but not CRSsNP (r = 0.16, p = 0.42). The correlation between olfactory function and tissue eosinophilia in CRSwNP persisted after adjusting for disease severity.
CONCLUSION - Tissue eosinophilia is associated with olfactory loss in CRSwNP, independent of disease severity. These results suggest a possible role for eosinophils or eosinophil-associated cytokines in CRS-associated olfactory loss.
© 2017 ARS-AAOA, LLC.
BACKGROUND - Trefoil factor family (TFF) peptides are mucin-associated secretory products that are produced in the airways and gastrointestinal tract. These peptides appear to play an important role in mucosal healing and epithelial protection and are overexpressed in chronically inflamed gastrointestinal tissues. We hypothesize that TFF peptides may also be differentially expressed in the sinonasal tissue of patients with and without chronic rhinosinusitis (CRS).
METHODS - Ethmoid sinus tissue was obtained from patients with CRS without nasal polyps (CRSsNP) (n = 12), CRS with nasal polyps (CRSwNP) (n = 12), and nondiseased controls (n = 7). Messenger RNA (mRNA) and protein were extracted from samples and expression of TFF1, TFF2, and TFF3 were assessed using quantitative real-time polymerase chain reaction qRT-PCR and Western blots, respectively. Tissue localization of TFF expression was confirmed using immunohistochemistry.
RESULTS - TFF1 and TFF3 were both highly expressed in sinonasal tissue, while TFF2 was expressed at near-undetectable levels. CRSsNP tissue had a statistically significant increase in the expression of both TFF1 and TFF3. No difference in TFF expression was found between control and CRSwNP patients.
CONCLUSION - TFF1 and TFF3 are overexpressed in CRSsNP. The role of TFF peptides in mucosal protection and repair suggests a possible important physiologic role in maintaining the sinonasal epithelial barrier and modulating innate immunity in the sinonasal tract.
© 2014 ARS-AAOA, LLC.
Cysteinyl leukotriene (cysLT) overproduction is a hallmark of aspirin-exacerbated respiratory disease (AERD), but its mechanism is poorly understood. Because adherent platelets can convert the leukocyte-derived precursor leukotriene (LT)A(4) to LTC(4), the parent cysLT, through the terminal enzyme LTC(4) synthase, we investigated the contribution of platelet-dependent transcellular cysLT production in AERD. Nasal polyps from subjects with AERD contained many extravascular platelets that colocalized with leukocytes, and the percentages of circulating neutrophils, eosinophils, and monocytes with adherent platelets were markedly higher in the blood of subjects with AERD than in aspirin-tolerant controls. Platelet-adherent subsets of leukocytes had higher expression of several adhesion markers than did platelet nonadherent subsets. Adherent platelets contributed more than half of the total LTC(4) synthase activity of peripheral blood granulocytes, and they accounted for the higher level of LTC(4) generation by activated granulocytes from subjects with AERD compared with aspirin-tolerant controls. Urinary LTE(4) levels, a measure of systemic cysLT production, correlated strongly with percentages of circulating platelet-adherent granulocytes. Because platelet adherence to leukocytes allows for both firm adhesion to endothelial cells and augmented transcellular conversion of leukotrienes, a disturbance in platelet-leukocyte interactions may be partly responsible for the respiratory tissue inflammation and the overproduction of cysLTs that characterize AERD.