Inflammatory characteristics of central compartment atopic disease.

BACKGROUND: Central compartment atopic disease (CCAD) is an emerging phenotype of chronic rhinosinusitis with nasal polyposis (CRSwNP) characterized by prominent central nasal inflammatory changes. This study compares the inflammatory characteristics of CCAD relative to other phenotypes of CRSwNP. METHODS: A cross-sectional analysis of data from a prospective clinical study was performed on patients with CRSwNP who were undergoing endoscopic sinus surgery (ESS). Patients with CCAD, aspirin-exacerbated respiratory disease (AERD), allergic fungal rhinosinusitis (AFRS), and non-typed CRSwNP (CRSwNP NOS) were included and mucus cytokine levels and demographic data were analyzed for each group. Chi-squared/Mann-Whitney U tests and partial least squares discriminant analysis (PLS-DA) were performed for comparison and classification. RESULTS: A total of 253 patients were analyzed (CRSwNP, n = 137; AFRS, n = 50; AERD, n = 42; CCAD, n = 24). Patients with CCAD were the least likely to have comorbid asthma (p = 0.0004). The incidence of allergic rhinitis in CCAD patients did not vary significantly compared to patients with AFRS and AERD, but was higher compared to patients with CRSwNP NOS (p = 0.04). On univariate analysis, CCAD was characterized by less inflammatory burden, with reduced levels of interleukin 6 (IL-6), IL-8, interferon gamma (IFN-γ), and eotaxin relative to other groups and significantly lower type 2 cytokines (IL-5, IL-13) relative to both AERD and AFRS. These findings were supported by multivariate PLS-DA, which clustered CCAD patients into a relatively homogenous low-inflammatory cytokine profile. CONCLUSIONS: CCAD has unique endotypic features compared to other patients with CRSwNP. The lower inflammatory burden may be reflective of a less severe variant of CRSwNP.

Association of cytokine profile with prior treatment failure and revision surgery in chronic rhinosinusitis.

BACKGROUND: Inflammatory patterns in chronic rhinosinusitis (CRS) may predict disease severity, need for multiple sinus surgeries, and treatment response. This study analyzes nasal mucus inflammatory cytokine patterns in patients with (CRSwNP) and without (CRSsNP) nasal polyposis and their association with revision sinus surgery. METHODS: A total of 319 CRS patients who underwent sinus surgery were included. Cytokines were quantified in intraoperative mucus specimens using a multiplex flow cytometric bead assay. Cytokine expression patterns in patients with 0, 1, and ≥2 previous surgeries were analyzed using Kruskal-Wallis and principal component (PC) regression analyses. RESULTS: There were 122 (38%) patients with CRSsNP and 197 (62%) with CRSwNP. On univariate analysis, interleukin (IL)-1ß, IL-6, IL-8, and IL-21 were associated with increasing number of sinus surgeries in CRSsNP, as were IL-2, IL-4, IL-5, IL-6, IL-9, IL-17A, and tumor necrosis factor (TNF)-α in CRSwNP. PC analysis with continuous Poisson regression in CRSwNP demonstrated that high IL-5 and IL-13 and low IL-1ß, IL-12, and IL-21 were associated with more prior surgeries. In CRSsNP low IL-13 and high IL-5 and regulated-on-activation, normal T-cell-expressed and secreted (RANTES) were associated with more prior surgeries. Age remained a significant covariate in the full regression model for CRSsNP, but was nonsignificant in CRSwNP. CONCLUSION: In CRSwNP, elevated IL-5 and IL-13 levels were higher at time of surgery in patients with more prior surgeries. Type 2 cytokines in CRSsNP demonstrated mixed associations with revision surgery. For both phenotypes, IL-10, IL-12, and IL-21 were consistently lower as number of prior surgeries increased, suggesting that treatment-resistant disease may be modulated by impairment in these signaling pathways.

Current insight into treatment of chronic rhinosinusitis: Phenotypes, endotypes, and implications for targeted therapeutics.

Chronic rhinosinusitis is characterized by persistent locoregional mucosal inflammation of the paranasal sinuses and upper airway that has substantial associated health care costs. Personalized approaches to care that incorporate use of molecular biomarkers, phenotypes, and inflammatory endotypes is a major focus of research at this time, and the concurrent rise of targeted therapeutics and biologic therapies has the potential to rapidly advance care and improve outcomes. Recent findings suggest that improved understanding of chronic rhinosinusitis phenotypic and endotypic heterogeneity, and incorporation of these characteristics into clinical care pathways, may facilitate more effective selection of surgical and/or therapeutic interventions. Ultimately, these personalized approaches have the potential to target specific inflammatory pathways, increase efficacy, reduce costs, and limit side effects. This review summarizes recent advances in the identification and characterization of chronic rhinosinusitis phenotypes, endotypes, and biomarkers and reviews potential implications for targeted therapeutics.

Anti-phospholipid antibodies are elevated and functionally active in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Polyps from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) contain increased levels of autoreactive antibodies, B cells and fibrin deposition. Anti-phospholipid antibodies (APA) are autoantibodies known to cause thrombosis but have not been implicated in chronic rhinosinusitis (CRS). OBJECTIVE: To compare APA levels (anti-cardiolipin, anti-phosphatidylethanolamine (anti-PE), and anti-ß2 -glycoprotein (anti-B2GP)) in nasal polyp (NP) tissue with tissue from control and CRS without nasal polyp (CRSsNP) patients, we tested whether NP antibodies affect coagulation, and correlate APAs with anti-dsDNA IgG and markers of coagulation. METHODS: Patient specimens were assayed for APA IgG, anti-dsDNA IgG and thrombin-anti-thrombin (TaT) complex by ELISA. Antibodies from a subset of specimens were tested for modified activated partial thromboplastin time (aPTT) measured on an optical-mechanical coagulometer. RESULTS: Anti-cardiolipin IgG in NP was 5-fold higher than control tissue (p < .0001). NP antibodies prolonged aPTT compared to control tissue antibodies at 400 µg/mL (36.7 s vs. 33.8 s, p = .024) and 600 µg/mL (40.9 s vs. 34.7 s, p = .0037). Anti-PE IgG antibodies were increased in NP (p = .027), but anti-B2GP IgG was not significantly higher (p = .084). All APAs correlated with anti-dsDNA IgG levels, which were also elevated (R = .77, .71 and .54, respectively, for anti-cardiolipin, anti-PE, and anti-B2GP; all p < .001), but only anti-cardiolipin (R = .50, p = .0185) and anti-PE (R = 0.45, p = .037) correlated with TaT complex levels. CONCLUSIONS: APA IgG antibodies are increased in NP and correlate with autoreactive tissue antibodies. NP antibodies have in vitro anti-coagulant activity similar to those observed in anti-phospholipid syndrome, suggesting that they may have pro-coagulant effects in polyp tissue.

Organ-Preserving Treatment Strategy for Extra-Axial Chordoma Metastatic to the Larynx Causing Airway Compromise.

Chordomas are rare, malignant bone tumors that arise from embryological remnants of the notochord, typically affecting the skull base, mobile spine, and sacrum with uncommon metastasis to the larynx. Patients with metastasis to the larynx may present with slowly progressive dysphonia and dyspnea. Here, we report an organ-preservation treatment strategy for a patient with widely metastatic extra-axial chordoma presenting with airway compromise who was found to have a new metastasis to the cricoid cartilage.

Preoperative quality-of-life measures predict acute postoperative pain in endoscopic sinus surgery.

OBJECTIVES: Recent increases in opioid-related mortality have prompted a critical evaluation of postoperative pain management across all specialties. However, successfully limiting narcotic overprescription requires perioperative identification of patients who are at risk for high postoperative pain. Unfortunately, quality data to guide practice patterns are lacking. We therefore prospectively investigated several possible predictive factors of postoperative pain after endoscopic sinus surgery (ESS). METHODS: Sixty-four consecutive patients undergoing ESS were enrolled. Baseline 22-item SinoNasal Outcomes Test (SNOT-22) and Short-Form 8 (SF-8) scores were obtained. Pain scores were collected postoperatively using a numeric rating scale. Spearman correlations and univariate linear regression models were used to investigate relationships between postoperative pain, patient factors, and SNOT-22/SF-8 domain scores. Multivariate linear regression was then performed to control for potential confounding variables. RESULTS: Day-of-surgery pain scores were significantly correlated with the SF-8 role-physical domain (Rs = 0.32, P = 0.04). Whereas SF-8 pain scores were initially nonsignificant, at postoperative day 3 (POD3) the preoperative SF-8 pain score became correlated with self-reported pain (Rs = 0.39, P = 0.02). SNOT-22 total and subdomain scores were not associated with pain scores at any time point. Multivariate linear regression modelling identified baseline SF-8 role-physical and pain scores, smoking status, and undergoing a modified Lothrop procedure as significant independent predictors of POD3 pain (adjusted R2 = 0.359, P < 0.0001). CONCLUSION: Baseline patient-reported global quality-of-life measures are associated with postoperative pain after ESS. Large multicenter studies are necessary to validate these findings and investigate additional factors associated with postoperative pain following ESS. LEVEL OF EVIDENCE: 2c Laryngoscope, 129:1274-1279, 2019.

Randomized controlled trial comparing the supraglottic airway to use of an endotracheal tube in sinonasal surgery.

BACKGROUND: The supraglottic airway (SGA) represents an alternative to endotracheal intubation (endotracheal tube [ETT]) in many types of ambulatory surgery. Adoption of the SGA has progressed slowly in sinonasal surgery due to concerns about airway protection. The purpose of this study was to compare quality of life measures and indices of airway protection between patients undergoing sinonasal surgery who were ventilated via an SGA or ETT. METHODS: Patients undergoing outpatient sinonasal surgery were enrolled into a randomized, single-blind study in which patients would be ventilated with either an SGA or ETT. At the first postoperative visit, a symptom severity and quality of life questionnaire was completed. Additional objective metrics were extracted from the anesthesia record. RESULTS: A total of 102 patients were enrolled; 49 assigned to the SGA group and 53 assigned to the ETT group. No significant differences in swallowing function or cough were identified. SGA patients reported more difficulty returning to a normal diet (p = 0.03) with a trend toward reduced throat pain (p = 0.07) and improved phonation (p = 0.06). No significant difference in perioperative oxygen desaturations, emesis, recovery time, or airway blood penetration were identified. CONCLUSION: While the use of the SGA results in patient diet modification postoperatively, it may also be associated with a reduction in throat pain and dysphonia. SGA use had no appreciable effect on postanesthesia recovery times, oxygen desaturations, or emesis. Use of the SGA in sinonasal surgery appears to be a safe and reliable option for airway management in selected adult patients undergoing routine ambulatory sinonasal surgery.

Olfactory and middle meatal cytokine levels correlate with olfactory function in chronic rhinosinusitis.

OBJECTIVES/HYPOTHESIS: The etiology of chronic rhinosinusitis (CRS)-associated olfactory loss is unclear, but may result from inflammatory changes in the olfactory epithelium that result in signaling dysfunction or loss of olfactory neurons. Several proinflammatory cytokines have been associated with CRS, but their expression within the olfactory cleft microenvironment and association with olfactory function is unknown. STUDY DESIGN: Prospective case-control study. METHODS: Mucus was collected from the olfactory cleft and middle meatus of 31 CRS without nasal polyps subjects, 36 CRS with nasal polyps (CRSwNP) subjects, and 12 healthy controls. Olfactory function was assessed using the validated Smell Identification Test (SIT). Site-specific levels of 14 cytokines/chemokines (interleukin [IL]-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17A, tumor necrosis factor-α, Eotaxin, RANTES [regulated on activation, normal T cell expressed and secreted]) were assessed using a multiplex flow cytometric bead assay and correlated with SIT scores. RESULTS: Mucus cytokine levels in the olfactory cleft were strongly or moderately correlated with levels in the middle meatus for all but one measured inflammatory mediators. SIT scores were inversely correlated with levels of IL-2 (P = .006), IL-5 (P < .0001), IL-6 (P = .0009), IL-10 (P < .0001), and IL-13 (P < .0001), with significance largely driven by CRSwNP patients. CONCLUSIONS: The inflammatory microenvironment within the olfactory cleft mirrors that within the middle meatus. Elevated levels of IL-2, IL-5, IL-6, IL-10, and IL-13 in olfactory cleft mucus are associated with reduced olfactory identification scores in CRS patients. Altered levels of select olfactory mucus cytokines could potentially have deleterious effects on olfactory neuron function and turnover. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E304-E310, 2018.

Evaluating the sinus and Nasal Quality of Life Survey in the pediatric cystic fibrosis patient population.

INTRODUCTION: The Sinus and Nasal Quality of Life Survey (SN-5) is a validated quality of life (QOL) questionnaire for chronic rhinosinusitis in patients age 2-12. Its utility in the cystic fibrosis (CF) has been studied, but not yet validated. The purpose of this study is to determine the effectiveness of the SN-5 for evaluation of sinonasal symptoms in the pediatric CF population. METHODS: This retrospective study analyzed SN-5 surveys completed between 2012 and 2015 by pediatric CF patients and caregivers. Baseline and follow-up overall QOL scores and specific symptom scores were obtained from surveys completed in the three-year span. Non-parametric statistics were conducted to identify differences in survey data. RESULTS: A total of 165 patients completed baseline and follow-up surveys. The overall QOL of the patient cohort did not change over the duration of the study (p = 0.660). Thirty-seven patients indicated higher overall QOL, with all five symptom scores showing significant improvement. Analysis by age group showed that QOL was significantly correlated with all five symptoms for children ages 0-4. In patients 5-12 years, overall QOL was only correlated with sinus infection (r = -0.3090, p = 0.01). QOL was significantly correlated with sinus infection (r = -0.2903, p = 0.04) and allergy symptoms (r = -0.5644, p < 0.01) in patients >12 years of age. CONCLUSION: There remains a need for a validated CRS QOL tool for children with CF. Though the SN-5 has previously been described as a potential instrument, our data suggest that it may be more valuable in children ages 0-4.

Classical complement pathway activation in the nasal tissue of patients with chronic rhinosinusitis.

BACKGROUND: Complement plays a major role in inflammatory diseases, but its involvement and mechanisms of activation in patients with chronic rhinosinusitis (CRS) are not known. OBJECTIVES: After earlier studies discovering autoantibodies in patients with CRS, we sought to investigate the nature, extent, and location of complement activation in nasal tissue of patients with CRS. Specifically, we were interested in whether antibody-mediated activation through the classical pathway was a major mechanism for complement activation in patients with CRS. METHODS: Nasal tissue was obtained from patients with CRS and control subjects. Tissue homogenates were analyzed for complement activation products (ELISA-C5b-9, C4d, activated C1, and C5a) and major complement-fixing antibodies (Luminex). Tissue sections were stained for C5b-9, C4d, and laminin. Antibodies were purified with protein A/G columns from nasal polyps (NP), matching patient serum, and control serum and assayed for basement membrane binding by means of ELISA. RESULTS: C5b-9 levels were significantly increased in NP tissue compared with uncinate tissue (UT) of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and those with chronic rhinosinusitis without nasal polyps (CRSsNP; P < .01). Similarly, C4d levels were increased in NPs compared with UT of patients with CRSwNP, patients with CRSsNP, and control subjects (P < .05). Activated C1 levels were also increased in NP tissue compared with UT of patients with CRSsNP and control subjects (P < .05) and correlated with levels of C5a (P < .01), local immunoglobulins (especially IgM, P < .0001), and anti-double-stranded DNA IgG (P < .05). Immunofluorescence showed that C5b-9 and C4d deposition occurred linearly along the epithelial basement membrane. NP tissue extracts had significantly more anti-basement membrane antibodies than sera from patients with CRSwNP and control subjects (P < .0001). CONCLUSION: Levels of C5b-9, C4d, and activated C1 were significantly increased locally in NP tissue. C5b-9 and C4d were almost universally deposited linearly along the basement membrane of NP tissue. Furthermore, activated C1 levels were best correlated with local immunoglobulin and C5a levels. Together, these data suggest that the classical pathway plays a major role in complement activation in patients with CRS.