Chemokine CCL19 and Its Receptors CCR7 and CCRL1 in Chronic Rhinosinusitis.

Background: CCL19 has been shown to predict disease severity in COVID-19 and treatment response in rheumatoid arthritis. CCL19 can exert both pro- and anti-inflammatory effects and is elevated in chronic rhinosinusitis (CRS). However, its role in CRS remains unknown. This study sought to determine the transcriptional changes in CCL19, its receptors, and associated cytokines and their association with disease severity in CRS. Methods: A clinical database of control subjects and patients with CRS was examined. Lund-Kennedy, Lund-Mackay, Sinonasal Outcomes Test 22 (SNOT-22), and rhinosinusitis disability index (RSDI) scores were collected at enrollment. mRNA was extracted from sinonasal tissues and subjected to multiplex gene expression analysis. Gene transcript differences between patients with CRS and controls were compared and correlated with disease severity metrics. Immunohistochemical analyses of CCL19, CCR7, and CCRL1 were conducted to compare differences in protein expression between cohorts. A subgroup analysis was performed to compare transcriptional and protein expression difference between patients with (CRSwNP) and without (CRSsNP) nasal polyps and controls. Results: Thirty-eight subjects (control group, n=7; CRS group, n=31) were included in this study. CCRL1 (p=0.0093) and CCR7 (p=0.017) levels were significantly elevated in CRS compared to those in controls. CCL19 (p=0.038) and CCR7 (p=0.0097) levels were elevated in CRSwNP and CCRL1 was elevated in CRSsNP (p=0.0004). CCR7 expression was significantly elevated in sinonasal epithelial cells in CRSwNP (p=0.04). CCL19 expression was positively correlated with TNFA expression (p<0.0002). CCL19 and CCR7 expression was positively correlated with SNOT-22 and RSDI scores (p<0.05). Conclusion: CCL19 and CCR7 may modulate TNF-α-driven pro-inflammatory signaling and contribute to increased disease severity in CRS. Mechanistic studies are required to further elucidate the role of CCRL1 in CRS.

An eosinophil peroxidase activity assay predicts acute exacerbations in post-operative chronic rhinosinusitis.

KEY POINTS: EPX activity has been correlated with eCRS diagnosis and baseline disease severity. Herein, EPX activity is shown to correlate with post-operative antibiotic and steroid use in CRS. EPX activity has potential to act as a prognostic biomarker of CRS disease severity and control.

An eosinophil peroxidase activity assay accurately predicts eosinophilic chronic rhinosinusitis.

BACKGROUND: A definitive diagnosis of eosinophilic chronic rhinosinusitis (eCRS) requires invasive surgical tissue sampling and histologic enumeration of intact eosinophils. Eosinophil peroxidase (EPX) is an accurate biomarker of sinonasal tissue eosinophilia in CRS regardless of polyp status. A less invasive and rapid method that accurately identifies tissue eosinophilia would be of great benefit to patients. OBJECTIVE: We sought to evaluate a new clinical tool that uses a nasal swab and colorimetric EPX activity assay to predict a diagnosis of eCRS. METHODS: A prospective, observational cohort study was conducted using nasal swabs and sinonasal tissue biopsies obtained from patients with CRS electing endoscopic sinus surgery. Patients were classified as non-eCRS (n = 19) and eCRS (n = 35) on the basis of pathologically determined eosinophil counts of less than 10 or greater than or equal to 10 eosinophils/HPF, respectively. Swab-deposited EPX activity was measured and compared with tissue eosinophil counts, EPX levels, and CRS-specific disease metrics. RESULTS: EPX activity was significantly increased in patients with eCRS than in patients without eCRS (P < .0001). With a relative absorbance unit cutoff value of greater than or equal to 0.80, the assay demonstrated high sensitivity (85.7%) and moderate specificity (79.0%) for confirming eCRS. Spearman correlations between EPX activity and tissue eosinophil counts (rs = 0.424), EPX levels (rs = 0.503), and Lund-Kennedy endoscopy scores (rs = 0.440) in eCRS were significant (P < .05). CONCLUSIONS: This investigation evaluates a nasal swab sampling method and EPX activity assay that accurately confirms eCRS. This method could potentially address the unmet need to identify sinonasal tissue eosinophilia at the point-of-care, as well as to longitudinally monitor eosinophil activity and treatment response.

Comorbidities Known to Affect Physical Function Negatively Impact Baseline Health-Related Quality-of-Life in Patients With Chronic Rhinosinusitis.

BACKGROUND: Medical comorbidities are commonly encountered in chronic rhinosinusitis (CRS) and may impact both physical function and patient reported health-related quality-of-life (HRQOL). The functional comorbidity index (FCI) is designed to elucidate the role of comorbidities on functional prognosis. The objective of this study was to understand the impact of comorbidities known to impact physical function on baseline HRQOL using the FCI.Methodology: Patients meeting diagnostic criteria for CRS were prospectively enrolled in a cross-sectional study. Responses from the Sinonasal Outcomes Test-22 (SNOT-22), a measure of patient HRQOL, as well as the Lund-Kennedy and Lund-Mackay scores were recorded at enrollment. FCI was calculated retrospectively using the electronic medical record. Information was collected and compared for patients without (CRSsNP) and with nasal polyps (CRSwNP) using chi-square and t-tests. Spearman's correlations, followed by multivariate regression analysis, were used to assess the association between FCI and SNOT-22 scores. RESULTS: One hundred and three patients met inclusion criteria for analysis. There were no significant differences in age, gender, and SNOT-22 scores between patients with CRSsNP and those with CRSwNP. FCI was significantly and independently associated with worse SNOT-22 scores (P = .012). FCI did not correlate with endoscopy and computed tomography scores. The mean FCI for patients with CRSsNP and CRSwNP was 2.02 and 2.24, respectively, and did not differ significantly between the two cohorts (P = .565). CONCLUSIONS: Major medical comorbidities known to affect physical function are associated with worse SNOT-22 scores in patients with CRS as measured by the FCI.

Cystic Fibrosis Increases Long-Term Revision Rates of Endoscopic Sinus Surgery in Patients With Comorbid Chronic Rhinosinusitis.

Background: Comorbid chronic rhinosinusitis (CRS) of adulthood is increasing among patients with cystic fibrosis (CF) due to improved median survival. However, little is known about the natural history of endoscopic sinus surgery (ESS) in this cohort. The objective of this study was to evaluate the revision rate of ESS and associated risk factors among adults with CRS and CF (CRSwCF). Methods: The Utah Population Database was queried for patients age >18 with CRS who underwent at least one ESS between 1996 and 2018. Demographic information and ESS history were collected and compared for CRSwCF versus CRS without CF (CRSsCF) using chi-square and t-tests. Risk factors for revision were analyzed using Cox proportional hazard models and logistic regression analysis. Results: A total of 34 050 patients (33 639 CRSsCF and 411 CRSwCF) were included in the final analysis. The mean duration of follow-up was 9.3 and 9.3 years, respectively (P = .98). Adult patients with CF were significantly more likely to undergo revision ESS (18.7%) than those without CF (13.4%; P < .01). Logistic regression analysis indicated that a diagnosis of CF independently elevated the risk for revision ESS in the absence of nasal polyps (odds ratio [OR] 2.18, confidence interval [CI] 1.34-3.54), asthma (OR 1.36, CI 0.94-1.98), and allergies (OR 1.29, CI 0.90-1.73). Conclusion: In the era before highly effective modulator therapies, the mean revision rate of ESS among adults with CRSwCF was 18.7%, significantly greater than that of adults with CRSsCF. CF was an independent risk factor for revision ESS in the absence of nasal polyps, asthma, and allergies.

Cell Adhesion Molecules are Upregulated and May Drive Inflammation in Chronic Rhinosinusitis with Nasal Polyposis.

PURPOSE: Chronic rhinosinusitis with nasal polyps (CRSwNP) is predominantly characterized by eosinophil- and T helper 2 cell (Th2)-biased inflammation. Integrins and intercellular adhesion molecules (ICAMs) are superfamilies of cell adhesion molecules (CAMs) that facilitate the recruitment and trafficking of immune cells and have been implicated in coordinating eosinophil and Th2 cell adhesion and signaling in asthma. The roles of CAMs in CRSwNP, however, remain poorly understood. The purpose of this study was to characterize the systemic and local expression of CAMs and identify which CAMs are potentially involved in CRSwNP pathology. MATERIALS AND METHODS: A prospective observational study was conducted using peripheral blood and anterior ethmoid tissues of patients with CRSwNP (n=32) and controls (n=15). Multiplex gene analysis and Pearson correlations were performed to identify associations between systemically and locally expressed CAMs. Based on the gene expression results, immunohistochemical evaluation and quantification of cells expressing integrins ITGAM, ITGAX, and ITGB2, as well as ICAM-3 in sinonasal tissues were conducted to compare local protein expression patterns. RESULTS: Integrin and ICAM genes were significantly elevated in the blood (p<0.001 to p<0.05) and sinuses (p<0.0003 to p<0.05) of patients with CRSwNP compared to controls. Strong positive correlations of genes expressed in the blood (p<0.01 to p<0.05) and sinuses (p<0.01) were observed between ITGAM, ITGAX, ITGB2, and ICAM3. ITGAM-, ITGB2-, ICAM-3-, and ICAM-3/ITGB2-positive cell counts were significantly increased in CRSwNP compared to controls (p<0.0001 to p<0.04), and a positive correlation between ICAM-3/ITGB2- and ITGAM-positive cell counts was observed (p<0.02). CONCLUSION: The systemic and local expression of ITGAM, ITGB2, and ICAM-3 is significantly upregulated in CRSwNP, suggesting that integrin complex ITGAM/ITGB2 and ICAM-3 serve a potential role in inflammation-mediated signaling in CRSwNP.

Transcriptional Changes in Chronic Rhinosinusitis with Asthma Favor a Type 2 Molecular Endotype Independent of Polyp Status.

BACKGROUND: Data regarding the inflammatory profile of patients with asthma and chronic rhinosinusitis (CRS-A) with (CRSwNP-A) and without (CRSsNP-A) nasal polyposis remain limited. OBJECTIVE: Define and compare systemic transcriptional changes in patients with CRS-A to those with non-asthma-related CRS with (CRSwNP) and without nasal polyposis (CRSsNP). METHODS: Thirty-four patients with CRS-A (n=19) and CRS (n=15) were prospectively enrolled into an observational study. Demographic information and subjective and objective disease severity measures were recorded. Multiplex gene expression analysis of mRNA extracted from peripheral blood was performed. A total of 594 genes associated with innate/adaptive immunity were analyzed using NanoString technology. Gene expression ratios were reported for genes that were differentially expressed among these cohorts. Linear regression analysis was used to compare the mRNA transcript copy numbers for each gene with disease severity. RESULTS: There was no significant difference in age, gender, nasal polyposis, or health-related quality of life measures between the two groups (p>0.05). HLA class II histocompatibility antigen, DRB3-1 beta chain (HLA-DRB3) was significantly upregulated in the peripheral blood of patients with CRSsNP-A compared to CRSsNP, whereas chemokine (C-C motif) ligands 4 (CCL4) and zinc finger protein helios (IKZF2) were significantly upregulated in CRSwNP-A compared to CRSwNP (p<0.05). CONCLUSION: Patients with CRSsNP-A demonstrate a molecular endotype associated with a Th2-dominant inflammatory profile compared to CRSsNP. Patients with CRSwNP-A similarly demonstrate an overrepresentation of genes associated with Th2-driven inflammation compared to patients with CRSwNP.

Sleep Dysfunction is an Independent Predictor of Productivity Losses in Patients with Chronic Rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is known to have a significant impact on economic productivity. Sleep dysfunction is associated with staggering productivity losses and is highly prevalent in patients with CRS. The effect of sleep dysfunction on productivity in CRS has not been elucidated. The objective of this study was to determine the relationship between sleep dysfunction and lost productivity in patients with CRS. METHODS: Eighty-two adult patients with CRS were prospectively enrolled into a cross-sectional cohort study. Patients with obstructive sleep apnea were excluded. Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI). Presenteeism (reduced work efficiency), absenteeism (missed work days), and lost work, household, and overall productivity were analyzed. The primary aim was assessing the correlation between PSQI and productivity. Regression analyses were performed to account for disease severity, pain, and depression. RESULTS: Sleep dysfunction is significantly correlated with overall lost productivity (R2 = 0.397, P < .05). Presenteeism is the most strongly affected by sleep dysfunction (R2 = -0.441, P < .001). Higher PSQI scores were significantly associated with productivity losses, whereas lower scores were not. Sleep remained an independent predictor of productivity when regression analysis accounted for disease severity, depression, and pain. CONCLUSION: Sleep dysfunction has a significant association with lost productivity in patients with CRS, particularly with worsening PSQI scores. More clearly defining those components of CRS that most impact a patient's daily function will allow clinicians to more optimally manage and counsel patients with CRS.

The Sinonasal Outcome Test (SNOT-22) Is a Poor Diagnostic Tool for Chronic Rhinosinusitis.

BACKGROUND: The SNOT-22 is a validated and widely used outcomes tool in chronic rhinosinusitis (CRS). We hypothesized that SNOT-22 scores and response patterns could be used as a diagnostic tool to differentiate between patients with CRS and those who present with CRS-like symptoms but prove not to have CRS. METHODOLOGY/PRINCIPAL: SNOT-22 measurements were collected from 311 patients who presented with a chief complaint of sinusitis to a tertiary rhinology practice. Following a full diagnostic evaluation, patients were diagnosed with CRS or determined to have non-CRS diagnoses. A response pattern "heatmap" of the SNOT-22 scores for each group was compared. An optimal cutoff point for total SNOT-22 score in predicting CRS was sought using a receiver operating characteristic (ROC) curve. RESULTS: A total of 109 patients were diagnosed with CRS and 202 patients were assigned to non-CRS. The non-CRS SNOT-22 total score histogram had lower overall scores compared to the CRS group, although there was substantial overlap. The CRS SNOT-22 heatmaps had a distinctive pattern compared to the non-CRS group. As individual measures, 3 of the 4 cardinal symptoms of CRS (nasal congestion, loss of smell, and rhinorrhea) were found to be significantly different between the 2 groups (P < .002). However, the ROC analysis showed the total SNOT-22 score to be a poor instrument to differentiate CRS from non-CRS patients. CONCLUSIONS: Our results cause us to reject our hypothesis and conclude that, while an effective outcomes tool, the SNOT-22 (using total score and response pattern) is a poor differentiator between CRS and non-CRS patients.

Asthma increases long-term revision rates of endoscopic sinus surgery in chronic rhinosinusitis with and without nasal polyposis.

BACKGROUND: Chronic rhinosinusitis with asthma (CRS-A) has a significant impact on patient morbidity and quality of life. Nevertheless, little is known about the natural history of endoscopic sinus surgery (ESS) in this cohort. The objective of this study was to evaluate revision rates of ESS in CRS-A and identify risk factors associated with increased likelihood for revision surgery compared to those with CRS without asthma (CRS-alone). METHODS: The Utah Population Database was queried for patients age >18 years with CRS who underwent at least 1 ESS between 1996 and 2018. Demographic information and history of ESS were collected and compared between CRS-A and CRS-alone using chi-square tests for categorical variables and t tests for continuous variables. Risk factors for revision surgery were analyzed using Cox proportional hazard models. RESULTS: A total of 33,090 patients (7693 CRS-A and 25,397 CRS-alone) were included in the final analysis. Mean follow up was 9.8 years in CRS-A and 9.1 years in CRS-alone (p < 0.001). The revision rate among patients with CRS-A (21.5%) was twice that of CRS-alone (10.8%) (p < 0.001). Among patients with CRS, a history of allergy (p < 0.001), asthma (p < 0.001), and nasal polyposis (p < 0.001) was independently associated with increased risk of revision ESS. Patients with CRS-A and nasal polyposis were 6 times more likely to require revision surgery than those with CRS-alone (p < 0.010). CONCLUSION: The rate of revision ESS in CRS-A was twice that of CRS-alone; patients with CRS-A and nasal polyposis were 6 times more likely to require revision than those with CRS-alone. ©2021 ARSAAOA, LLC.

The Role of Macrolides and Doxycycline in Chronic Rhinosinusitis.

Antibiotic therapy has become an important adjunct in the management of recalcitrant chronic rhinosinusitis (CRS) because of some antibiotics' immunomodulatory properties even at subtherapeutic antimicrobial levels. Macrolide antibiotics, such as clarithromycin and azithromycin, decrease production of proinflammatory cytokines, impair neutrophil recruitment, inhibit bacterial biofilm formation, and improve mucus quality. Doxycycline, a tetracycline antibiotic, inhibits the activity of matrix metalloproteinases in CRS with nasal polyposis. This article reviews the clinical applications for macrolide and doxycycline use in CRS, considerations for dosing and duration of treatment, and important side effects and drug interactions associated with these medications.

Application of hybrid cranioendoscopic approaches in anterior skull base surgery.

Anterior skull base approaches have included endoscopic or open microsurgical approaches for intracranial pathologies. However, discussion of a combined hybrid, cranioendoscopic approach, leveraging the benefits of both techniques, has been limited. Here we describe a case of a combined endoscopic, endonasal, and open microsurgical frontotemporal approach for resection of a complex anterior skull base lesion. A 62-year-old man with a large meningioma extending intradurally through the cribiform plate and sphenoethmoidal sinuses underwent a cranioendoscopic resection. Surgical techniques, including repair of the anterior skull base defect as well as complication avoidance and the coordination of multiple surgeons, are discussed. The video can be found here: https://youtu.be/Ti9tUUdWgJc.

Factors Associated With Patient Nonattendance in Rhinology Clinics.

BACKGROUND: Nonattendance to clinical appointments is a global problem appreciated by clinicians with an ambulatory presence. There are few reports of nonattendance in otolaryngology clinics, and no reports on nonattendance for a single otolaryngology subspecialty. OBJECTIVE: To describe the no-show population in rhinology clinics. METHODS: A retrospective chart review was performed involving rhinology clinics from 2 academic medical centers in the United States. All patients who either attended their clinic appointment(s) or did not attend without previously cancelling from June 2016 to May 2017 were included. Data collected included patient demographics, appointment status, season and time of visit, insurance status, type of visit (new vs established), and provider seen. RESULTS: There were 2791 clinical appointments evaluated over a 12-month period at 2 rhinology clinics involving 4 fellowship-trained rhinologists. Ninety-two percent of patients kept their appointments, while 8% did not. Sex, season of visit, time of visit (am vs pm), type of visit, provider sex, provider location, or provider's experience (<10 years vs ≥10 years) were not associated with patient's attendance status. Univariate analysis showed that patient's age ≤50 ( P = .001) and primary insurance type ( P < .001) were associated with nonattendance. Medicaid as the primary insurance type was associated with clinic nonattendance. Multivariable analysis showed that age ≤ 50 years, odds ratio (OR) 1.62 (95% confidence interval [CI] 1.14-2.30), P = .007, and primary insurance type (Medicaid: OR 3.75 [95% CI 2.58-5.45], P < .001) remained significant predictors of nonattendance. CONCLUSION: Patients younger than 50 years and patients with Medicaid as the primary insurance types are associated with risk of missing rhinology clinic appointments. As a subspecialty, delivery of timely care and clinical efficiency could be improved by interventions directed toward improving attendance among this population.

Nocardial clival osteomyelitis secondary to sphenoid sinusitis: an atypical skull base infection.

Clival osteomyelitis is a life-threatening complication of untreated malignant otitis externa or paranasal sinus infection. Although various pathogens have been implicated, to our knowledge, primary nocardial clival osteomyelitis has never been reported. We describe a 74-year-old woman who presented with headaches, abducens and hypoglossal nerve palsies, facial numbness, photophobia, and neck stiffness. Imaging revealed a heterogeneous mass within the sphenoid sinus with clival extension. The lesion was extirpated via a binostril endoscopic endonasal transsphenoidal approach. Histopathological and microbiological examination revealed a nocardial source. Clival osteomyelitis associated with sphenoid sinusitis should be included in the differential diagnosis of progressive skull base lesions in the setting of an underlying infection. Early recognition and intervention with antibiotics and surgical debridement is essential in the management of this rare entity.

An analysis of RUC methodology for determining the RVU valuation of sinus surgery.

BACKGROUND: The Relative Value Scale Update Committee, commonly known as the RUC, is responsible for defining the value of Current Procedural Terminology (CPT) codes. The RUC process uses survey responses reporting operative times to determine procedure reimbursement, but it is limited by low response rates, small sample sizes, and unclear generalizability of the results. By comparing actual reported intraoperative times to the times determined by the RUC process, in this study we sought to assess the performance of RUC methodology in endoscopic sinus surgery (ESS). METHODS: The ESS CPT codes that were reassessed in 2016 using the RUC method were examined in this study. Intraoperative time data for these codes were retrospectively collected from 14 medical facilities, using time stamps in the electronic health record. These actual intraoperative times were compared with the 2016 RUC survey results. RESULTS: There were 143 RUC physician survey responses and 446 actual procedure times included in the final analysis. There was significant variability within the RUC survey responses (ie, unilateral anterior ethmoidectomy times varied from 5 to 90 minutes). There was also a significant difference between the RUC survey results and actual intraoperative times (p < 0.001). For example, frontal sinus surgeries showed a particularly poor correlation between actual and RUC times. CONCLUSION: The RUC process may not accurately estimate or value actual intraoperative times. Real-world intraoperative times are readily accessible and may be an alternative to survey-based methodology in the future.

Long-term revision rates for endoscopic sinus surgery.

BACKGROUND: Reported revision rates for endoscopic sinus surgery (ESS) for chronic rhinosinusitis (CRS) vary significantly. Several investigations examining revision rates for ESS have been limited by duration of follow-up, academic centers, or small surgeon cohorts. The objective of this study was to define the long-term revision rates for ESS and to determine those unique patient factors that increase the risk of revision ESS. METHODS: The Utah Population Database was queried for Current Procedural Terminology codes for ESS from 1996 to 2016. Patient demographics and comorbid diagnoses were collected. Revision rates and risk factors for surgery were determined by Cox proportional hazard modeling. RESULTS: A total of 29,934 patients were identified, with a mean length of follow-up of 9.7 years. The long-term revision rate was found to be 15.9%. The mean time between surgeries decreased with higher number of revision surgeries. The time between the first and second surgery was 4.39 years and the time between the fourth and fifth surgery decreased to 2.18 years. Female gender, older age at first surgery, nasal polyps, comorbid asthma, allergy, and a family history of CRS all increased the risk of requiring revision surgery (p < 0.001). CONCLUSION: The long-term revision rate for ESS exceeds 15% and the time between revision surgeries decreased with each additional surgery being performed. Unique patient factors increased the risk of requiring revision ESS. Understanding patients' risk for revision surgery may help physicians select and counsel patients with CRS undergoing ESS.

Total intravenous anesthesia improves intraoperative visualization during surgery for high-grade chronic rhinosinusitis: a double-blind randomized controlled trial.

BACKGROUND: Total intravenous anesthesia (TIVA) has been proposed as a method to reduce blood loss during endoscopic sinus surgery (ESS). Impaired sinonasal visualization due to mucosal bleeding may be burdensome in cases of chronic rhinosinusitis (CRS) with high-grade inflammatory disease, suggesting a role for TIVA in that disease subgroup. METHODS: A double-blind, randomized controlled trial was conducted of adults undergoing ESS at a tertiary medical center. Patients considered for inclusion had high-grade CRS defined as either sinonasal polyposis or a preoperative Lund-Mackay score of ≥12. Subjects were randomized to receive either TIVA or inhaled anesthesia (IA) during ESS. The primary outcome measure was intraoperative visibility as rated by 3 blinded reviewers utilizing the 10-point Wormald Surgical Field Grading Scale. Secondary outcomes included operative blood loss, complications, and change in quality of life evaluated by the 22-item Sino-Nasal Outcome Test (SNOT-22). RESULTS: A total of 72 patients were randomized into TIVA (n = 37) and IA (n = 35) study arms. Aggregate median (interquartile range) Wormald scores across all reviewers demonstrated a more favorable visual field with TIVA compared to IA (3.5 [2.4-3.9] vs IA 4.1[3.0-5.8], p = 0.0089). There was significantly less blood loss in the TIVA group compared to the IA group (200 mL [100-450] vs 300 mL [200-500], p = 0.046). Baseline patient characteristics were comparable between cohorts with no significant postoperative complications. No significant changes were detected between postoperative SNOT-22 scores at 3 months (p = 0.278) and at 6 months (p = 0.396) following ESS. CONCLUSION: TIVA contributes to improved intraoperative visualization and decreased blood loss in patients undergoing ESS for high-grade inflammatory sinus disease.