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Item Cumulative Comorbidity Burden Does Not Worsen Outcomes in Management of Chronic Rhinosinusitis(Wiley, 2022) Gill, Amarbir S.; Mace, Jess C.; Rimmer, Ryan; Ramakrishnan, Vijay R.; Beswick, Daniel M.; Soler, Zachary M.; Manor, James; Orlandi, Richard R.; Smith, Timothy L.; Alt, Jeremiah A.; Otolaryngology -- Head and Neck Surgery, School of MedicineBackground: The impact of multiple coexisting medical comorbidities on treatment outcomes in chronic rhinosinusitis (CRS) is unknown. In this study we sought to evaluate the effect of comorbidities on sinonasal quality of life (QOL) and general health utility values by utilizing the Functional Comorbidity Index (FCI) in CRS patients. Methods: Patients with CRS were prospectively enrolled in a cross-sectional study of medical and surgical therapies. The 22-item Sino-Nasal Outcome Test (SNOT-22) and Medical Outcomes Study Short-Form 6D (SF-6D) scores were recorded at enrollment and 6-month follow-up; Lund-Kennedy endoscopy and Lund-Mackay computed tomography scores were recorded at enrollment. The FCI was calculated using the electronic medical record. The impact of cumulative comorbidity burden on baseline and posttreatment outcomes was assessed using univariate and bivariate correlations. Results: A total of 428 participants with CRS were included. The average (mean standard ± deviation) FCI score was 3.03 ± 2.28 (range, 0-12). Significant linear correlations were identified between increasing FCI score and baseline SNOT-22 and SF-6D scores (R = 0.166, p = 0.001 and R = -0.245, p < 0.001, respectively). There was no correlation between FCI and change in SNOT-22 or SF-6D scores after CRS treatment (R = 0.066, p = 0.17 and R = -0.087, p = 0.074, respectively). Achievement of a minimally clinically important difference was also independent of FCI. Conclusion: Although cumulative comorbidity burden, as measured by FCI, is associated with worse baseline SNOT-22 and SF-6D scores, it does not appear to limit posttreatment improvement in either outcome measure. On average, patients with high comorbidity burden report substantial improvement in both QOL and health utility after CRS treatment, similar to those with fewer comorbidities.Item Disease control after surgery for chronic rhinosinusitis: Prospective, multi-institutional validation of the Sinus Control Test (SCT)(Wiley, 2021) Little, Ryan E.; Schlosser, Rodney J.; Smith, Timothy L.; Storck, Kristina A.; Alt, Jeremiah A.; Beswick, Daniel M.; Mace, Jess C.; Mattos, Jose L.; Ramakrishnan, Vijay R.; Soler, Zachary M.; Otolaryngology -- Head and Neck Surgery, School of MedicineBackground: The Sinus Control Test (SCT) is a 4-question, patient-reported questionnaire that assesses disease control in chronic rhinosinusitis (CRS). This prospective, multicenter study examines SCT outcomes following endoscopic sinus surgery (ESS), further validating its use as a control instrument for CRS. Methods: Adults with CRS undergoing ESS were prospectively enrolled from 5 centers across North America. The SCT was administered at baseline and once 6 months after surgery. Quality of life and disease burden were evaluated using the 22-item Sino-Nasal Outcome Test (SNOT-22) and Lund-Kennedy endoscopy scores. Linear regression was used to determine whether specific demographic, comorbidity, or disease severity measures were independently associated with changes in SCT scores postoperatively. Results: A total of 218 patients, 111 females (50.9%) and 107 males (49.1%), were enrolled, with mean ± standard deviation age of 50.1 ± 15.6 years. Mean SCT score improved from 8.9 ± 3.5 to 4.3 ± 3.7 postoperatively (p < 0.001). Preoperatively, 21.6% were uncontrolled, 71.5% partially controlled, and 6.9% controlled. Postoperatively, 6.0% were uncontrolled, 42.6% partially controlled, and 51.4% controlled (p < 0.001). Change in SCT score correlated independently with change in SNOT-22 (r = 0.500, p < 0.001) and endoscopy scores (r = 0.310, p < 0.001). Endoscopy scores did not correlate with control status among patients with CRS without nasal polyposis (CRSsNP) nor between uncontrolled and partially controlled patients. Demographics and comorbidities were not associated with changes in SCT. Conclusion: Improvement in disease control following ESS as measured by the SCT correlated with improvements in SNOT-22 and endoscopy scores. The SCT is an easily administered instrument that provides information complementary to existing patient-reported and objective measures of disease severity.Item Ethmoid-to-Maxillary Opacification Ratio: A Predictor of Postoperative Olfaction and Outcomes in Nasal Polyposis?(Wiley, 2021) Beswick, Daniel M.; Smith, Timothy L.; Mace, Jess C.; Alt, Jeremiah A.; Farrell, Nyssa F.; Ramakrishnan, Vijay R.; Schlosser, Rodney J.; Soler, Zachary; Otolaryngology -- Head and Neck Surgery, School of MedicineBackground: Inflammatory profiles for patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) vary between North American and Asian populations. An elevated ethmoid-to-maxillary (E/M) opacification ratio on preoperative imaging is associated with certain postoperative outcomes in Asian populations and populations that are non-type 2 dominant. In this study we explore this factor in North American/type 2-based populations. Methods: Adult patients (n = 165) from a North American population with CRSwNP who underwent endoscopic sinus surgery (ESS) were prospectively enrolled into an observational, multi-institutional study. The 22-item Sino-Nasal Outcome Test (SNOT-22), Brief Smell Identification Test (BSIT), and Lund-Kennedy (LK) endoscopic scores were obtained pre- and postoperatively. Patients were stratified according to increasing E/M ratios based on Lund-Mackay (LM) scores. Results: On average, significant within-subject postoperative improvement was found in all patients for SNOT-22 total and domain scores, and also BSIT results (p ≤ 0.019). Preoperatively, elevated E/M ratio correlated with worse BSIT scores (r = -0.343, p < 0.001). Postoperatively, elevated E/M ratio correlated with BSIT improvement (r = 0.284, p = 0.002), but did not correlate with SNOT-22 improvement or polyp recurrence. An elevated E/M ratio was associated with greater likelihood of reporting a minimal clinically important difference in BSIT scores (χ2 = 9.96, p = 0.041). Conclusion: Elevated E/M ratios were found to associated with worse baseline olfaction and an increased likelihood of achieving a clinically meaningful postoperative improvement in olfaction in this North American population with CRSwNP. Elevated E/M ratios did not predict postoperative changes in SNOT-22 measures or polyp recurrence. This suggests that prognostic factors may vary according to geography and generalized inflammatory profiles (type 2 vs non-type 2) in patients with CRS.Item Evaluating Distance Bias in Chronic Rhinosinusitis Outcomes(American Medical Association, 2022) Gill, Amarbir S.; Beswick, Daniel M.; Mace, Jess C.; Menjivar, Dennis; Ashby, Shaelene; Rimmer, Ryan A.; Ramakrishnan, Vijay R.; Soler, Zachary M.; Alt, Jeremiah A.; Otolaryngology -- Head and Neck Surgery, School of MedicineImportance: The distance traveled by patients for medical care is associated with patient outcomes (ie, distance bias) and is a limitation in outcomes research. However, to date, distance bias has not been examined in rhinologic studies. Objective: To evaluate the association of distance traveled by a cohort of patients with chronic rhinosinusitis with baseline disease severity and treatment outcomes. Design, setting, and participants: A total of 505 patients with chronic rhinosinusitis were prospectively enrolled in a multi-institutional, cross-sectional study in academic tertiary care centers between April 2011 and January 2020. Participants self-selected continued appropriate medical therapy or endoscopic sinus surgery. The 22-item Sinonasal Outcome Test (SNOT-22) and Medical Outcomes Study Short Form 6-D (SF-6D) health utility value scores were recorded at enrollment and follow-up. Data on the distances traveled by patients to the medical centers, based on residence zip codes, and medical comorbid conditions were collected. Exposures: Distance traveled by patient to obtain rhinologic care. Main outcomes and measures: SNOT-22 and SF-6D scores. Scores for SNOT-22 range from 0 to 110; and for SF-6D, from 0.0 to 1.0. Higher SNOT-22 total scores indicate worse overall symptom severity. Higher SF-6D scores indicate better overall health utility; 1.0 represents perfect health and 0.0 represents death. Results: The median age for the 505 participants was 56.0 years (IQR, 41.0-64.0 years), 261 were men (51.7%), 457 were White (90.5%), and 13 were Hispanic or Latino (2.6%). These categories were collected according to criteria described and required by the National Institutes of Health and therefore do not equal the entire cohort. Patients traveled a median distance of 31.6 miles (50.6 km) (IQR, 12.2-114.5 miles [19.5-183.2 km]). Baseline (r = 0.00; 95% CI, 0.00-0.18) and posttreatment (r = 0.01; 95% CI, -0.07 to 0.10) SNOT-22 scores, as well as baseline (r = -0.12; 95% CI, -0.21 to -0.04) and posttreatment (r = 0.07; 95% CI, -0.02 to 0.16) SF-6D scores, were not associated with distance. There was no clinically meaningful correlation between distance traveled and mean comorbidity burden. Nevertheless, patients with a history of endoscopic sinus surgery were more likely to travel longer distances to obtain care (Cliff delta = 0.28; 95% CI, 0.19-0.38). Conclusions and relevance: Although this cross-sectional study found that some patients appear more willing to travel longer distances for chronic rhinosinusitis care, results suggest that distance traveled to academic tertiary care centers was not associated with disease severity, outcomes, or comorbidity burden. These findings argue for greater generalizability of study results across various cohorts independent of distance traveled to obtain rhinologic care.Item Objective and patient‐based measures of chronic rhinosinusitis in people with cystic fibrosis treated with highly effective modulator therapy(Wiley, 2022) Beswick, Daniel M.; Humphries, Stephen M.; Miller, Jessa E.; Balkissoon, Connor D.; Khatiwada, Aastha; Vladar, Eszter K.; Ramakrishnan, Vijay R.; Lynch, David A.; Taylor-Cousar, Jennifer L.; Otolaryngology -- Head and Neck Surgery, School of MedicineItem Olfactory cleft mucus inflammatory proteins in CRS: A case control study(Wiley, 2021) Smith, Timothy L.; Schlosser, Rodney J.; Soler, Zachary M.; Mace, Jess C.; Mattos, Jose L.; Ramakrishnan, Vijay R.; Beswick, Daniel M.; Alt, Jeremiah A.; Mulligan, Jennifer K.; Otolaryngology -- Head and Neck Surgery, School of MedicineBackground: Multiple hypotheses are evolving that suggest several, potentially overlapping etiologies for olfactory dysfunction (OD) in chronic rhinosinusitis (CRS). Understanding inflammatory cytokine profiles of the olfactory cleft (OC) and their association with olfactory function is foundational for future clinical care and research. Methods: This cross-sectional, case-control study evaluates associations among OC mucus inflammatory proteins, psychophysical olfactory testing, and computed tomography (CT) analysis of the OC and sinuses. Normative reference intervals were determined for each protein and odds ratios (ORs) were used to compare proportions of altered expression between CRS without nasal polyposis (CRSsNP) and CRS without nasal polyposis (CRSwNP). Results: Case subjects with CRS (n = 151) and controls (n = 74) were evaluated. A majority of OC proteins tested were found within detectable ranges for cases and controls. The CRS cohort had significantly higher concentrations for 23 of 26 proteins. CRS cases with abnormal levels of C-C motif chemokine ligand 2 (CCL2), CCL3, interleukin 5 (IL5), IL10, and IL13 associated with greater olfactory deficits. The prevalence of elevated IL5 and IL13 in anosmic patients was 64.6% and 62.5%, respectively (p < 0.004). CRS cases with the highest odds of elevated expression in CRSwNP were IL5 (OR = 10.83) and IL13 (OR = 8.36). However, both IL5 and IL13 were still elevated in approximately 14% of CRSsNP patients. The highest magnitude of correlation between the total percent of OC opacification was found to be with IL5 (r = 0.543; p < 0.001), whereas other moderate correlations were noted with immunoglobulin E (IgE), IL10, and IL13. Conclusion: This study confirmed that OC inflammatory proteins vary both by disease phenotype and in their association with OD. Type 2 inflammatory mediators are increased in CRS, especially within the CRSwNP group. However, a substantial proportion of CRSsNP also express type 2 inflammatory mediators. Further research is necessary to understand the complex roles OC mucous inflammatory proteins might play in defining endotype and in impacting CRS-related OD.Item Olfactory dysfunction in cystic fibrosis: Impact of CFTR modulator therapy(Elsevier, 2022) Beswick, Daniel M.; Humphries, Stephen M.; Balkissoon, Connor D.; Strand, Matthew; Vladar, Eszter K.; Ramakrishnan, Vijay R.; Taylor-Cousar, Jennifer L.; Otolaryngology -- Head and Neck Surgery, School of MedicineBackground: Elexacaftor-tezacaftor-ivacaftor (ETI) improves pulmonary health and chronic rhinosinusitis (CRS) for people with cystic fibrosis (PwCF), however its impact on olfaction has not been investigated. Olfactory dysfunction impairs quality-of-life (QOL). This study evaluated the impact of ETI on multiple olfactory metrics. Methods: Adult PwCF/CRS with CF transmembrane conductance regulator genotype F508del/F508del or F508del/minimal function who clinically initiated ETI participated in a prospective, observational study. Endpoints included changes after 6 months of ETI in quantitative olfactory function (Smell Identification Test, SIT), olfactory QOL (Questionnaire of Olfactory Disorders, QOD) and percent olfactory cleft opacification (%OCO), representing superior nasal cavity inflammation where afferent olfactory neurons are concentrated. Results: 30 PwCF/CRS met inclusion criteria; 25 completed the study. Mean ETI adherence was 93%. At baseline, participants were hyposmic (mean SIT 31.3), had significant %OCO (mean 65.6%), yet reported non-impaired olfactory QOL (mean QOD 6.1). At follow-up, mean SIT worsened mildly (p=0.009), mean %OCO remained stable (p=0.46), and mean QOD improved modestly (p=0.008). No outcomes were impacted by prior modulator use, genotype, nasal polyps, or CF-related diabetes. Prior sinus surgery was associated with QOD improvement (p=0.04). Increased (worse) baseline QOD scores and %OCO were associated with greater improvements (p<0.003), but not SIT (p=0.44). Conclusions: ETI was not associated with improvement in quantitative olfaction or olfactory cleft opacification after 6 months. PwCF/CRS have hyposmia but do not report impairment in olfactory QOL. Further study to investigate mechanisms explaining olfactory dysfunction and whether olfaction improves with greater duration of ETI or in younger age groups is warranted.Item Olfactory Function After Surgical Treatment of CRS: A Comparison of CRS Patients to Healthy Controls(Sage, 2021) Mattos, Jose L.; Soler, Zachary M.; Schlosser, Rodney J.; Mace, Jess C.; Alt, Jeremiah A.; Ramakrishnan, Vijay R.; Payne, Spencer C.; Smith, Timothy L.; Beswick, Daniel M.; Otolaryngology -- Head and Neck Surgery, School of MedicineBackground: Many patients with chronic rhinosinusitis (CRS) have persistent olfactory dysfunction (OD) following endoscopic sinus surgery (ESS). Few studies compare outcomes to control subjects so it is unknown if residual OD is due to persistent CRS. Objective: Compare postoperative measures of OD in case patients with CRS to healthy controls without sinonasal disease. Methods: Prospective, observational, multicenter cohort study between October, 2016 and May, 2019. Case participants were selected from referred adult patients diagnosed with CRS, with or without nasal polyposis (NP), electing ESS as subsequent treatment modality. Controls voluntarily enrolled from a community-based sample without a history of CRS. Primary outcomes included measures of preoperative and postoperative OD using "Sniffin' Stick" pens which summarize odorant threshold (T), discrimination (D), and identification (I) scores. Secondary outcomes included the Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS) survey and olfactory cleft endoscopy scores (OCES). Results: Outcomes were compared between 113 cases and 164 controls of similar average age and gender. Cases reported significantly worse baseline Sniffin' Sticks TDI total scores (-6.8[SE ± 1.0]; 95% CI: -4.9 to -8.7), QOD-NS (8.9[SE ± 1.1]; 95% CI: 6.8-10.9), and OCES (3.5[SE ± 0.4]; 95% CI: 2.9-4.2) on average. Cases reported significant postoperative improvement in TDI total score (3.7[SD ± 8.2]; 95% CI: 2.2-5.2), QOD-NS (-5.9[SD ± 8.7]; 95% CI: -7.6 to -4.3), and OCES (-1.7[SD ± 3.8]; 95% CI: -2.7 to -0.8) on average, while 63% of anosmics reported improved postoperative olfaction. Multivariate regression identified that NP (OR = 0.4; 95% CI: 0.2-1.0) and previous ESS (OR = 0.3; 95% CI: 0.1-0.8) decreased the odds of postoperative improvement equal to mean TDI scores of controls, while septoplasty increased those odds (OR = 4.5; 95% CI: 1.5-13.7). Conclusion: ESS improved olfactory metrics and restored olfactory function in approximately 50% of patients with CRS to that of healthy controls. Concurrent septoplasty increased the likelihood of achieving normal olfaction, while NP and previous ESS decreased those odds.Item Psychometric Properties of the Brief Version of the Questionnaire of Olfactory Disorders in Patients with Chronic Rhinosinusitis(Wiley, 2021) Mattos, Jose L.; Bodner, Todd E.; Mace, Jess C.; Schlosser, Rodney J.; Beswick, Daniel M.; Ramakrishnan, Vijay; Alt, Jeremiah; Payne, Spencer C.; Smith, Timothy L.; Soler, Zachary; Otolaryngology -- Head and Neck Surgery, School of MedicineBackground: The Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS) is a 17-item instrument measuring olfactory-specific quality of life (QOL). However, in clinical research patients can be overwhelmed with multiple questionnaires. We recently developed the 7-item brief QOD-NS (B-QOD). Our objective was to evaluate the psychometric properties of the B-QOD in both the development (D) sample, and in a separate replication (R) sample. Methods: Testing on D (n = 203) and R (n = 281) samples included initial exploratory factor analysis (EFA), followed by internal reliability, information loss, and confirmatory factor analysis (CFA). Finally, incremental predictive utility analysis (IPUA) was performed by correlating the B-QOD with the 22-item Sino-Nasal Outcome Test (SNOT-22) survey. Results: EFAs of both D and R demonstrated an underlying single-factor structure (eigenvalue = 4.17 and 3.57, respectively) with comparable loading factors (R > 0.30 for both). B-QOD also had good internal reliability in both D and R (Cronbach's alpha = 0.88 and 0.83, respectively). Also, there is minimal information loss with B-QOD compared to QOD-NS in both D and R (R = 0.98 and 0.96, respectively). CFA indicates that the B-QOD single-factor model has good overall fit as measured by the Comparative Fit Index (CFI) and the Standardized Root Mean Squared Residuals (SRMSR) in the D and R samples (CFI = 0.99 and 0.97; SRMSR = 0.035 and 0.053). IPUA shows that the QOD-NS offers no additional predictive benefit of SNOT-22 scores when compared with B-QOD. Conclusion: The 7-item B-QOD captures a structurally coherent and reliable single dimension, with minimal information loss and excellent external predictive utility when compared to the QOD-NS.