Utilization of RNA sequencing to investigate olfactory dysfunction in chronic rhinosinusitis without nasal polyps: A pilot study.

Objectives: Prior research on olfactory dysfunction in chronic rhinosinusitis (CRS) has focused on patients with polyps and suggests that direct inflammation of the olfactory cleft mucosa plays a contributory role. The purpose of this study was to evaluate gene expression in superior turbinate mucosal specimens, comparing normosmic and dysosmic CRS patients without polyps (CRSsNP). Methods: Tissue samples were obtained from the superior turbinates of patients with CRSsNP at the time of endoscopic sinus surgery. Samples subsequently underwent RNA sequencing and functional analysis to investigate biological pathways associated with differentially expressed genes between dysosmic (n = 7) and normosmic (n = 4) patients. Results: Differential gene expression analysis comparing dysosmic and normosmic CRSsNP patients showed upregulation of 563 genes and downregulation of 327 genes. Using stringent criteria for multiple comparisons, one upregulated gene (Immediate Early Response 3 [IER3]) had an false discovery rate (FDR) correction adjusted P value considered statistically significant (P < 0.001, fold change 2.69). Reactome functional analysis revealed eight biological pathways significantly different between dysosmic and normosmic patients (P < 0.05, FDR correction) including IL-4 and IL-13 signaling, IL-10 signaling, and rhodopsin-like receptors. Conclusions: RNA sequencing of the superior turbinates in patients with CRSsNP can provide valuable information regarding biological pathways and genes involved in olfactory dysfunction. This study supports literature suggesting that Type 2 inflammation may play a role in olfactory dysfunction in at least some patients with CRSsNP. This study also prompts questions regarding the role of IL-10, rhodopsin-like receptors, and IER3 in the pathogenesis of olfactory dysfunction.

Comparison of trigeminal lateralization with differing stimulants.

Trigeminal-specific stimulants have been shown to activate different receptors preferentially and this likely accounts for variation in sensory perception. It is unclear whether trigeminal sensitivity is similar across different transient receptor potential (TRP) receptors or if dysfunction of different receptors results in differing patient symptoms. Therefore, a prospective cohort study was conducted, consisting of trigeminal lateralization testing with three different stimulants (eucalyptol, isothiocyanate, acetic acid), olfaction testing with Sniffin' Sticks, and measurement of various patient-reported outcome measures (PROMs). A total of 50 participants were enrolled across the olfactory spectrum. Mean TDI score was 27.1 ± 8.3 (range 7.0-39.5) with 38% normosmic and 62% dysosmic. Mean trigeminal lateralization scores out of 20 in the overall cohort were 16.18 (2.78) for eucalyptol, 14.94 (3.49) for mustard oil, and 15.28 (3.68) for vinegar. Eucalyptol showed a significant correlation with threshold scores of Sniffin' Sticks. A significant correlation was found between acetic acid and various PROMs. None of the lateralization scores of the trigeminal stimulants correlated to each other significantly and there was no correlation to age. The lack of correlation suggests that the measured sensitivity of one type of TRP receptor may not translate to similar sensitivity of the other receptors. Additional investigations with TRPV1 and TRPA1 agonists are needed to corroborate our findings.

Allergy and Asthma Prevalence and Management Across Nasal Polyp Subtypes.

Allergy and asthma prevalence vary across different subsets of chronic rhinosinusitis with nasal polyposis. In this article, the authors investigate the management of allergy and asthma within populations of patients with aspirin-exacerbated respiratory disease, allergic fungal rhinosinusitis, and central compartment atopic disease. Topical steroids, nasal rinses, and endoscopic sinus surgery are frequently employed in the management of nasal polyposis. Further, other causes of upper and lower airway inflammation like allergy and asthma should be considered in the overall treatment plan in order to optimize outcomes.

Impact of Nasal Cavity CT Opacification Upon Sinonasal Quality of Life.

BACKGROUND: Current methods of quantifying inflammation in chronic rhinosinusitis (CRS) on computed tomography (CT) imaging focus on opacification of the paranasal sinuses and show limited correlation with patient-reported outcome measures. OBJECTIVE: This study aimed to determine if quantifying CT opacification of the nasal cavity correlated with Sino-Nasal Outcomes Test scores (SNOT-22). METHODS: Thirty patients with CRS were enrolled. Lund-Mackay and SNOT-22 scores were measured. Nasal cavity regions of interest (ROIs) were measured by 2 independent raters using ImageJ at 3 points on coronal CT scans: anteriorly at the lacrimal duct, at the approximate midpoint demarcated by the posterior aspect of the globe, and posteriorly at the transition from the hard to soft palate. Superior and inferior regions were defined based upon the root of the inferior turbinate. Percent opacification was calculated for each ROI. Analyses were conducted bilaterally and for the side with greater opacification (worse side). RESULTS: Interrater reliability was strong for all ROIs. Lund-Mackay scores correlated with nasal blockage only (r = .495, P = .01) and did not correlate with nasal cavity ROI opacification. Inferior nasal cavity opacification for worse-sided anterior ROI and middle ROI correlated with SNOT-22 scores for nasal blockage (anterior r = .41, P = .03) (middle r = .42, P = .023) and runny nose (anterior r = .44, P = .02) (middle r = .38, P = .04). Posterior ROIs did not correlate with SNOT-22. CONCLUSIONS: Traditional CT scoring of sinus opacification does not correlate well with nasal cavity opacification or SNOT-22. Inferior nasal cavity inflammation provides unique correlations with SNOT-22 nasal questions and may guide targeted interventions in these regions.

Association of computed tomography scores to psychophysical measures of olfaction: A systematic review and meta-analysis.

BACKGROUND: While various sinus computed tomography (CT) scoring systems have been proposed and used in the literature, no single system has been identified as superior. The strength of associations between CT scoring systems and measures of olfaction also remains unclear. METHODS: A systematic review of PubMed, CINAHL, Scopus, and the Cochrane Library was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies that reported both CT scores and measures of olfaction in a cross-sectional manner were included. RESULTS: A total of 37 studies were eligible for meta-analysis. Of 8035 patients with chronic rhinosinusitis, 55.6% were male patients and 53.2% had chronic rhinosinusitis with nasal polyps. Analysis by meta-regression was performed of Lund-Mackay (LM) versus Smell Identification Test-40 (SIT-40; 12 studies), Brief Smell Identification Test (BSIT; 10 studies), Sniffin' Sticks (SS; 10 studies), and Toyota & Takagi (T&T) olfactometry (four studies). A significant moderate association was found between LM and SIT-40 (R2  = 0.612, p < 0.001) and LM and SS (R2  = 0.612, p < 0.001). An association between LM and BSIT approached significance (R2  = 0.461, p = 0.054). No significant associations were noted between LM and T&T olfactometry and between LM and SS when stratified by nasal polyp status. CONCLUSION: There is a significant moderate association of current CT scoring systems to SIT-40 and SS. Further research should focus on associations of objective measures of olfaction to CT scores of the nasal cavity, sinuses, and olfactory cleft, as well as other disease markers.

Association of Sinonasal Computed Tomography Scores to Patient-Reported Outcome Measures: A Systematic Review and Meta-analysis.

OBJECTIVE: To perform a systematic review of proposed sinus computed tomography (CT) scoring systems and determine their association with patient-reported outcome measures (PROMs). DATA SOURCES: PubMed, CINAHL, Scopus, and Cochrane Library. REVIEW METHODS: A systematic search was conducted following the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-analyses) for studies describing CT scores and PROMs in patients with chronic rhinosinusitis. RESULTS: A total of 144 studies were included. Out of 20,741 patients, 53.6% were male and 55.5% had nasal polyposis. A meta-analysis of correlations revealed a moderate correlation between Lund-McKay (LM) and the 22-item Sinonasal Outcome Test (SNOT-22; r = 0.434, P < .001) and a weaker correlation between LM and the 20-item Sinonasal Outcome Test (SNOT-20; r = 0.257, P = .039). Meta-regression also revealed a weak association between LM and SNOT-20 (n = 25 studies) but no significant associations between Zinreich score and SNOT-22 or LM scores and PROMs, including SNOT-22 (n = 94 studies), Rhinosinusitis Disability Index (n = 25), nasal obstruction visual analog scale (n = 15), Chronic Sinusitis Survey (n = 12), Total Nasal Symptom Score (n = 4), Total Symptom Score (n = 3), and 12-Item Short Form Health Survey (n = 3). CONCLUSION: There is essentially little association between radiologic grade and PROMs. CT grading systems with improved clinical utility are needed.

Profiles of Odorant Specific Performance in Olfactory Testing.

BACKGROUND: Olfactory dysfunction (OD) can occur from a variety of etiologies. However, there are few reports examining whether varying etiologies have unique profiles of psychophysical testing that may provide insight into the pathophysiology of OD. METHODS: Adults with chronic rhinosinusitis with and without nasal polyps (CRSwNP/CRSsNP) and healthy control adults with no sinus complaints underwent olfactory assessment with Sniffin' Sticks. Profiles of identification and discrimination were compared between CRS and non-CRS subjects across the spectrum of OD. RESULTS: Normosmics with or without CRS identified apple, pineapple, and turpentine less frequently than expected (range 52%-68% correct). Hyposmics with CRS correctly identified orange more frequently than control hyposmics (83%-93% vs 68% for controls) with similar findings for rose. Hyposmics of all cohorts were unable to identify apple (26%). Discrimination profiles were similar across the spectrum of OD and between diagnostic groups. CONCLUSIONS: Identification and discrimination rates of specific odorants may provide unique information regarding the etiology of OD, however psychophysical testing is a complex interplay of olfactory and trigeminal function, the strength of target odorant, distractor choices, and familiarity with odorants.

Prevalence of Rhinorrhea in Parkinson Disease: A Systematic Review and Meta-analysis.

Purpose of Review: To perform a systematic review and determine the prevalence of rhinorrhea in Parkinson disease (PD). Recent Findings: Of 451 patients with PD and 233 controls, the pooled prevalence of rhinorrhea in patients with PD was 45.0% (95% confidence interval 33.94-56.40), which was significantly greater than that in controls (p < 0.001). The prevalence of self-reported olfactory dysfunction was greater in patients with PD; however, a pooled analysis of studies using objective scores showed no difference. The mean age of patients with PD was greater than that of controls (p = 0.002). The mean age of patients with PD with rhinorrhea was also greater than that of patients with PD without rhinorrhea (p < 0.001), but disease characteristics did not differ. Summary: There is a high prevalence of rhinorrhea in patients with PD; therefore, providers should query for rhinorrhea during visits and understand the treatment options available. Future studies should explore the pathophysiology of rhinorrhea in PD and the relationship between rhinorrhea and disease severity and duration, as well as determine whether treatment-specific outcomes differ in patients with PD.

A Prospective Analysis of Systemic and Local Aeroallergen Sensitivity in Central Compartment Atopic Disease.

OBJECTIVE: To compare systemic allergen sensitivity and local allergen sensitivity in the sinonasal tissue of patients with a recently identified subtype of chronic rhinosinusitis strongly associated with allergy: central compartment atopic disease (CCAD). STUDY DESIGN: Prospective cohort study. SETTING: Academic tertiary care rhinology clinic. METHODS: Fifteen participants with endoscopic and radiographic evidence of CCAD underwent systemic allergy testing with skin testing and measurement of serum specific immunoglobulin E (sIgE) to 15 regionally common aeroallergens. Local allergen sensitivity was determined by measuring sIgE to these same 15 allergens in their sinonasal tissue. sIgE testing was performed by ImmunoCAP assay. RESULTS: Of the 15 participants, 14 were sensitive to at least 1 allergen locally in the central compartment and systemically on skin or serum testing. Among all participants, 4 were sensitive to allergens on central compartment sIgE testing that they were not sensitive to on skin and serum sIgE testing (range, 1-8 discordant allergens). Comparisons between local and systemic aeroallergen sensitivity results showed statistically significant correlations (P < .05) ranging from weak to strong. CONCLUSION: Systemic allergy testing is recommended in the initial workup for CCAD. Local allergen sensitivities may be present in a subset of patients with CCAD. Further study of the clinical significance of these sensitivities should be undertaken in CCAD, with evaluation of the role of medical therapies and allergen immunotherapy in the treatment of CCAD.

Eustachian tube dysfunction (ETD) in chronic rhinosinusitis with comparison to primary ETD: A systematic review and meta-analysis.

BACKGROUND: Otologic symptoms consistent with Eustachian tube dysfunction (ETD) are common in patients with chronic rhinosinusitis (CRS), but can also occur independently of CRS as primary ETD. It is unclear if CRS+ETD is similar to primary ETD or how treatment outcomes compare. METHODS: A systematic search of PubMed, CINAHL, Scopus, and Cochrane Library was conducted following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Any study describing ETD in CRS was included. Primary ETD studies were limited to those with preoperative and postoperative Eustachian Tube Dysfunction Questionnaire (ETDQ-7) scores in ETD treated only with Eustachian tube balloon dilation (ETBD). RESULTS: Sixteen studies were included: nine studies with 1336 consecutive patients with CRS and seven studies with 161 patients with primary ETD. In studies with specific data, 225 (47.2%) patients with CRS had a score >14.5, consistent with ETD. In CRS+ETD, baseline mean ± standard deviation (SD) ETDQ-7 score was 20.7 ± 8.4 and did not differ by polyp status. In primary ETD, mean ETDQ-7 score was significantly higher than CRS+ETD (29.5 ± 8.1, p < 0.0001). Regarding treatment outcomes, CRS+ETD treated with endoscopic sinus surgery (ESS) alone resulted in mean ETDQ-7 in the normal range (13.2 ± 5.3), with a mean change of -7.4 (95% confidence interval [CI], -10.82 to -3.99) (p < 0.00001). Patients with primary ETD treated with ETBD had postoperative ETDQ7 scores of 14.9 ± 7.5 with mean change of -13.9 (95% CI, -18.01 to -9.88), p < 0.00001. CONCLUSION: ETD is noted in approximately half of patients with CRS. Outcomes of CRS+ETD treated with ESS alone are similar to those of patients with primary ETD treated with ETBD.

Intermediate Invasive Fungal Sinusitis, a Distinct Entity From Acute Fulminant and Chronic Invasive Fungal Sinusitis.

BACKGROUND: The current classification system of invasive fungal sinusitis (IFS) includes acute (aIFS) and chronic (cIFS) phenotypes. Both phenotypes display histopathologic evidence of tissue necrosis, but differ by presence of angioinvasion, extent of necrosis, and disease progression. aIFS is defined by a rapid onset of symptoms, while cIFS slowly progresses over ≥12 weeks. However, a subset of IFS patients do not fit into the clinical presentation and histopathologic characteristics of either aIFS or cIFS. OBJECTIVES: To investigate the demographic, clinical, and histopathologic characteristics of a distinct subset of IFS. METHODS: Retrospective review of patients with IFS from a single tertiary-care institution (2010-2020). Patients with symptoms for ≤4 weeks were classified as aIFS if they displayed endoscopic evidence of mucosal necrosis or fungal angioinvasion on pathology. Patients with slowly progressive IFS for ≥12 weeks were classified as cIFS. Patients with symptom duration between 4 and 12 weeks with evidence of invasive fungal disease were classified as a new entity and were further investigated. RESULTS: Of the 8 patients identified, 50% were immunosuppressed at presentation. The mean symptom duration prior to presentation was 50.5 days (SD 16.8), and common symptoms included facial pain (100%), vision change (87.5%), and blindness (37.5%). Two patients (25%) died of their disease. Sites of fungal involvement confirmed by histopathology included sphenoid (62.5%) and ethmoid sinuses (12.5%), orbital apex (25%), optic nerve (12.5%), pterygopalatine fossa (12.5%), and clivus (12.5%). Fungal elements but without obvious angioinvasion, were identified in all specimens, and fungus balls (50%), granulomas (37.5%), and giant cells (25%) were also observed on histopathology. CT and MRI radiographic imaging showed findings consistent with orbital, intracranial, or skull base involvement in all patients. CONCLUSION: We propose intermediate IFS as a new subgroup of patients with IFS who do not fit into the standard classification of aIFS or cIFS.

Inhalation and deposition of spherical and pollen particles after middle turbinate resection in a human nasal cavity.

Middle turbinate resection significantly alters the anatomy and redistributes the inhaled air. The superior half of the main nasal cavity is opened up, increasing accessibility to the region. This is expected to increase inhalation dosimetry to the region during exposure to airborne particles. This study investigated the influence of middle turbinate resection on the deposition of inhaled pollutants that cover spherical and non-spherical particles (e.g. pollen). A computational model of the nasal cavity from CT scans, and its corresponding post-operative model with virtual surgery performed was created. Two constant flow rates of 5 L/min, and 15 L/min were simulated under a laminar flow field. Inhaled particles including pollen (non-spherical), and a spherical particle with reference density of 1000 kg/m3 were introduced in the surrounding atmosphere. The effect of surgery was most prominent in the less patent cavity side, since the change in anatomy was proportionally greater relative to the original airway space. The left cavity produced an increase in particle deposition at a flow rate of 15 L/min. The main particle deposition mechanisms were inertial impaction, and to a lesser degree gravitational sedimentation. The results are expected to provide insight into inhalation efficiency of different aerosol types, and the likelihood of deposition in different nasal cavity surfaces.

A Comparison of the Bacterial Nasal Microbiome in Allergic Rhinitis Patients Before and After Immunotherapy.

OBJECTIVES/HYPOTHESIS: Recent research has examined the nasal microbiome in rhinosinusitis and nondiseased states. Given immunologic alterations in allergic rhinitis (AR) and after allergen immunotherapy (IT), we evaluated the nasal microbiome in these conditions. STUDY DESIGN: Cross-sectional comparison. METHODS: In this cross-sectional study, nasal swabs for microbiome analysis were collected from three patient groups: IT-naïve AR patients, AR patients undergoing IT for greater than 12 months, and a control group without sinonasal inflammatory disease. RESULTS: Nasal swabs were successfully collected for 14 IT-naïve AR patients, 20 post-IT patients, and 17 controls. The α diversity showed a statistical difference in evenness but not in richness amongst samples, whereas the ß-diversity was significantly different between groups. Corynebacterium and Staphylococcus were the most prevalent bacteria across all groups. CONCLUSIONS: ß-diversity was found to be significantly different across the three groups, but the AR groups were found to be more similar to each other than to the controls. Although there is symptomatic improvement in the AR group undergoing IT, the microbiome does not appear to transition to a healthy microbiome composition. LEVEL OF EVIDENCE: 4 Laryngoscope, 2020.

Clinical Applications of Sublingual Immunotherapy.

Sublingual immunotherapy (SLIT) is effective for the treatment of allergic rhinitis and allergic asthma in adults and children. In a limited number of studies, SLIT efficacy has been demonstrated for the treatment of food allergy. SLIT has a higher safety profile versus subcutaneous immunotherapy, although some systemic reactions have been reported. Appropriate patient selection, meticulous patient education, and routine follow-up are key for the safe and effective administration of SLIT. With organization and attention to detail, adding SLIT to one's practice can provide a highly valued patient service.