Interleukin-25 and interleukin-33 as mediators of eosinophilic inflammation in chronic rhinosinusitis.

BACKGROUND: The initiating mediators of T-helper 2 inflammation, often seen in eosinophillic chronic rhinosinusitis (CRS), remains poorly understood. Interleukin (IL) 25, IL-33, and thymic stromal lymphopoietin (TSLP) are epithelial-derived cytokines implicated in the initiation of T-helper 2 inflammation and eosinophilia in other diseases. The expression of these cytokines was compared with phenotypic and histopathologic markers to investigate the factors that may drive eosinophilic inflammation in CRS. METHOD: Sinus mucosal samples from patients with CRS who were undergoing sinus surgery as part of their management were analyzed for IL-25, IL-33, and TSLP messenger RNA (mRNA) expression by quantitative polymerase chain reaction. Patients with tumor and who were undergoing surgery via an endonasal approach with normal sinus mucosa were controls. The mRNA expression was compared with CRS phenotype and histopathologic measures of eosinophilic inflammation. Immunohistochemical staining was used to confirm mRNA expression. RESULTS: Thirty-nine patients (mean ± standard deviation age; 48.2 ± 15.0 years, 38% women), 12 patients with CRS with nasal polyps, 20 patients with CRS without nasal polyps, and 7 controls were recruited. Higher IL-25 (p = 0.005) and IL-33 (p = 0.003) mRNA and protein expression was observed in patients with >10 eosinophil/hpf. TSLP showed no significant associations (p = 0.39). Similar overexpression was seen in eosinophilic dominated inflammation (IL-25, p = 0.01; IL-33, p = 0.02) and patients with greater inflammatory severity. CONCLUSION: IL-25 and IL-33 overexpression was observed in eosinophilic CRS, The release of these cytokines by dysfunctional endothelium may perpetuate the eosinophillic inflammation in CRS.

The fate of chronic rhinosinusitis sufferers after maximal medical therapy.

BACKGROUND: Many chronic rhinosinusitis (CRS) treatment regimes revolve around "one-off" maximal medical therapy (MMT) protocols, and although many patients initially respond, long-term control is unpredictable. The value of imaging, endoscopy, and patient progress after MMT for CRS is assessed. METHODS: Symptomatic CRS patients with computed tomography (CT)-confirmed disease were recruited at a tertiary rhinology clinic. All patients received at least a 3-week oral prednisone course as part of their MMT. Pretreatment and posttreatment nasal symptoms scores (NSS), quality of life (22-item SinoNasal Outcomes Test [SNOT-22]), and CT (Lund-Mackay [LM]) scores were recorded along with post-MMT endoscopy status. RESULTS: A total of 86 patients (38% female, age 46 ± 13 years) met inclusion criteria. Pre-MMT and post-MMT LM scores were 10.9 ± 5.3 and 8.3 ± 5.5 (change 2.6 ± 3.8, p < 0.001). Median follow-up after their initial post-MMT assessment was 6.3 (interquartile range [IQR] 17) months. At initial post-MMT review, 43 (50%) were symptomatic with persistent radiologic disease ("symptomatic CRS"), 12 (14%) were asymptomatic with no radiologic disease ("resolved CRS"), 21 (24%) were asymptomatic with persistent radiologic disease ("asymptomatic CRS"), and 10 (12%) were symptomatic with no radiologic disease ("alternate diagnosis"). Pre-MMT NSS and SNOT-22 were similar among groups. The "asymptomatic CRS" group had the highest age (52 ± 11 years, p = 0.07). The "alternate diagnosis" group had the lowest initial LM scores (5.2 ± 2.9, p = 0.001). Of the "asymptomatic CRS" patients, 43% relapsed between 3 and 23 months (median 6; IQR 4.4 months) post-MMT and 29% eventually underwent surgery. CONCLUSION: Although MMT for CRS achieved symptomatic relief in 38% patients, objective evidence of disease was associated with clinical relapse. The concepts of "response" to medical therapy and the need to "control" long-term inflammatory burden need to be balanced.

Clinical severity and epithelial endotypes in chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous disease defined by epithelial inflammation. The link between measures of traditional disease severity and markers of epithelial inflammation is poorly understood as prior research has focused on presence of polyps or degree of eosinophilia. The expression of 3 epithelial derived cytokines implicated in initiation of T-helper 2 (Th2) inflammation and an eosinophil chemoattractant were compared with clinical measures used in CRS. METHODS: Sinus mucosal samples from CRS patients undergoing sinus surgery were analyzed for interleukin-25 (IL-25), IL-33, thymic stromal lymphopoietin (TSLP), and eotaxin-3 messenger RNA (mRNA) expression by quantitative polymerase chain reaction (PCR). Tumor patients undergoing surgery transnasally with normal sinus mucosa were controls. Gene expression was compared with symptom, radiology, and endoscopy scores, serological markers, presence of reactive airways disease (RAD), and atopy. RESULTS: Thirty-seven patients (38% female, mean age 48 ± 15 years), 12 CRS with nasal polyps (CRSwNP), 18 CRS without nasal polyps (CRSsNP), and 7 controls were recruited. CRSwNP phenotype predicted elevated IL-25, IL-33, and eotaxin-3 levels. Increased eotaxin-3 correlated with poorer computed tomography (CT) (p = 0.004) and endoscopic scores (p = 0.049). Increased IL-25 correlated with poorer CT scores (p = 0.012) and raised serum eosinophils (p = 0.006). No associations with RAD, atopy, and symptom measures were found. No associations for IL-33 and TSLP were found. CONCLUSION: Inflammatory mediators of the epithelium in CRS has some correlation with traditional measures of disease burden. Certain epithelial profiles may predict highly dysfunctional epithelial barriers and prospective evaluation of the clinical outcomes from interventions is required. Future endotyping of the epithelium in CRS may be able to provide prognostic information.