Abstract
Introduction:
Chronic rhinosinusitis (CRS) is one of the most common causes of olfactory loss but the pathophysiology underlying olfactory dysfunction in CRS has not been fully elucidated. Prior studies have found correlations between olfactory cleft (OC) inflammatory cytokines/chemokines and olfaction in CRS. The purpose of this study was to evaluate the relationship between OC mucus inflammatory proteins and olfaction in a multi-institutional cohort.
Methods:
Adults with CRS were prospectively recruited. Demographics, comorbidities, olfactory assessment (Sniffin’ Sticks), computed tomography (CT), and OC mucus for protein analysis were collected. Statistical analysis was performed to determine associations between olfactory function, OC mucus protein concentrations and CT opacification.
Results:
Sixty-two patients were enrolled in the study, with average age of 48.2 years (SD=16.2) 56.5% female, and 59.7% classified as CRS with nasal polyps (CRSwNP). Ten of 26 OC mucus proteins were significantly correlated with TDI scores and OC opacification. Subgroup analysis by polyp status revealed that within the CRSwNP group, CCL2, IL5, IL6, IL13, IL10, IL9, TNF-α, CCL5, and CCL11 were significantly correlated with olfaction. For CRS without polyps (CRSsNP), only CXCL5 correlated. In CRSwNP, IL6, IL10, VEGF-A, and IgE correlated with OC opacification, while in CRSsNP, only CXCL5 correlated. OC mucus proteins and Lund-Mackay score correlated only in the CRSsNP group (CXCL5, IL5, IL13, IgE).
Conclusions:
Several OC mucus proteins have been found to correlate with olfactory function and OC opacification. The profile of OC mucus proteins differs between CRSsNP and CRSwNP subgroups, suggesting different mechanisms between groups but further study is required.
Introduction
Chronic rhinosinusitis (CRS) is one of the most common causes of olfactory dysfunction in the general population, impacting 5–15% of adults worldwide.1,2 Impaired olfaction is one of the cardinal symptoms of CRS and can be found in 30–78.2% of patients, varying somewhat by age, gender, and presence of polyps.3 Medications, primarily in the form of oral or topical corticosteroids, have been shown to provide demonstrable improvement in olfaction.4–6 Similarly, numerous studies have confirmed significant improvement in olfactory function following sinus surgery.7 However, improvements after treatment tend to be inconsistent and most patients with baseline olfactory dysfunction fail to return to normal levels despite surgery and ongoing medical management.
The pathophysiology underlying olfactory dysfunction in CRS has not been fully elucidated. One common hypothesis is that mucosal inflammation in the form of edema or polyps blocks nasal airflow, restricting odorant delivery to the olfactory cleft (OC).8,9 This could explain why patients with CRS with nasal polyps (CRSwNP) tend to have more olfactory loss compared to those with CRS without polyps (CRSsNP). Another hypothesis is that mucosal inflammation can occur directly in the OC, interfering with olfaction via mechanisms independent of nasal airflow.9–11 Kern published one of the first studies supporting this concept, wherein biopsies of the OC mucosa done at the time of surgery demonstrated inflammatory infiltrate may be linked to olfactory dysfunction.12 Although the inflammation seen in OC histopathology usually mirrored that seen in the sinus mucosa proper, OC inflammation was not seen in all patients with CRS. Additional studies have demonstrated similar histopathologic changes in the OC of patients with CRS, with several recent studies highlighting the potential impact of local eosinophilia.10,13
Biopsies of OC mucosa have advantages, but there are distinct drawbacks which limit their clinical usefulness. The most important limitation is the difficulty performing an olfactory biopsy. A number of studies describe techniques to harvest OC mucosa, some in the clinic setting, but none have found widespread adoption.10,13–15 Furthermore, these biopsies by necessity sample a focal region of the OC cleft on a single side. Given the oftentimes patchy geographic distribution of OC mucosa and potential asymmetry of CRS involvement, a focused biopsy might not be representative.14 In order to overcome these issues, we developed a technique to directly place absorbent material into the OC in the clinical setting in order to collect olfactory cleft mucus. The idea was to sample mucus in closest proximity to the underlying olfactory mucosa. This technique would collect mucus from the OC, although it does not allow one to determine whether it was produced by olfactory mucosa or respiratory mucosa. In a small single institution pilot study, we were able to detect inflammatory proteins in mucus collected from the olfactory cleft and show that some correlate with objective olfactory function.16 The goal of the current study was to confirm and expand on these findings, utilizing a cohort recruited from several centers across North America. The main aim of the study was to determine whether inflammatory proteins present in mucus sampled from the OC correlate with objective olfaction in patients with CRS. Secondary aims were to compare OC proteins between CRSwNP and CRSsNP subgroups and to determine whether correlations between proteins and olfaction persist within subgroups. Findings from this study may offer additional insights into the pathophysiology of olfactory dysfunction in CRS.
Methods
Study overview and patient population
Adults ≥18 years meeting diagnostic criteria for CRS established by the Clinical Practice Guideline of the American Academy of Otolaryngology-Head and Neck Surgery17 were recruited from rhinology clinics at Medical University of South Carolina (Charleston, SC), Oregon Health and Sciences University (Portland, OR), University of Utah (Salt Lake City, UT), University of Virginia (Charlottesville, VA), and University of Colorado (Aurora, CO) as part of a prospective, olfactory outcomes study (Clinical Trial # NCT02720653; National Institutes of Health, Federal grant identifier: R01 DC005805). Exclusion criteria included endoscopic sinus surgery in the previous 6 months, immunomodulatory medications within the last 30 days, history of immunodeficiency, systemic inflammatory condition (ie sarcoidosis or granulomatosis with polyangiitis), prior head trauma, dementia, Alzheimer’s disease, or Parkinson’s disease. The study was approved by the institutional review board at each site and all subjects were provided with written, informed consent.
Demographic information and history of comorbidities, such as asthma and aspirin exacerbated respiratory disease (AERD), were collected using standardized questionnaires for all participants, based on patient report of a prior physician’s diagnosis. Allergic rhinitis was established for those who carried a physician’s diagnosis and had confirmation with previous positive objective testing. Patients were categorized as CRSwNP and CRSsNP based upon the presence of visible, bilateral nasal polyps on nasal endoscopy as determined by the enrolling physician.
Olfactory assessment
Objective olfaction was quantified using the Sniffin’ sticks (Burgardt, Wedel, Germany). The test is comprised of odor threshold, odor discrimination and odor identification. Odor threshold for n-butanol was assessed using a single-staircase procedure with three alternative choices. Only one of the three pens contained an odor, and subjects had to correctly detect the odor-containing pen. The odor discrimination test involved triplets of pens, two with the same scent and one with a different scent. Subjects were required to identify which pen contained the “different” scent. Odor identification consisted of 16 common odors that were presented individually with multiple choice options. The three component scores have a maximum of 16 and are summed to give a composite TDI score of 1–48 with higher scores representing superior olfaction.
Radiologic evaluation
All subjects had non-contrast computed tomography (CT) scans performed as part standard clinical care if indicated. A subset of patients did not undergo CT scan as a part of their clinical care. Cross-sectional analysis of CT scans was performed using OsiriX MD imaging software (Pixmeo, Bernex, Switzerland) as previously reported.18 This analysis required specific formatting with thin (0.6 mm) cuts axial, coronal and sagittal planes for consistency, thus some CT scans were excluded. Anterior, middle and posterior 2D cross sectional areas were demarcated in the coronal plane using the axial and sagittal planes for reference of anatomic landmarks. In short, the region of the OC was demarcated on each section and all pixels in Hounsfield unit range of bone were excluded. Pixels representing soft tissue were then divided by all remaining pixels (soft tissue + air) to determine the percentage opacification for each section. The average opacification of the OC was then determined by averaging across the three sections and this was reported as a percentage (%) opacification. Additionally, each CT scan was graded using the standard Lund-Mackay scoring method, with reviewers blinded to all data regarding olfaction. No alterations to the Lund-Mackay scoring system was used in scoring patients with previous sinus surgery. Total Lund-Mackay scores were calculated (0–24), with higher scores representing greater opacification.
Olfactory cleft mucus collection and analysis
Nasal endoscopy was performed on each study subject using rigid 3mm, 0 degree endoscopes (Karl Storz, Tuttlingen, Germany) after application of topical lidocaine and phenylephrine to the nasal cavity via atomizer. Under direct visualization, a 1 cm by 2 cm Leukosorb filter paper (Pall Scientific, Port Washington, NY) strip was placed directly into the OC of each side, and allowed to dwell for three minutes, as described in a previously published study.16 The Leukosorb paper was then removed and placed into cuvettes that were immediately centrifuged at 4°C for 30 minutes. The mucus was then combined from each side, transferred by pipette to a cryotube, and stored at −80°C until performance of assays. An array of growth factors, cytokines and chemokines was chosen for analysis based on previous evidence suggesting a role in CRS, olfactory dysfunction, or inflammation/remodeling. All proteins, except those noted below, were quantified by LegendPlex Mix & Match Cytometric Bead Array (BioLegend, San Diego, CA) following the manufacturer’s recommended protocol and read on a Guava easy Cyte 8HT flow cytometer (EMD Millipore, Burlington, MA). Data analysis was performed with LegendPlex software provided by the manufacture. Total IgE was quantified via ELISA following the kit instructions (GenWay Biotech. Inc, San Diego, CA). All samples were analyzed at the Medical University of South Carolina (MUSC). Mucus samples from other sites were collected via the Leukosorb paper as described, and prepped via centrifuge and frozen at the originating site. Samples were then shipped in expedited fashion, packed with dry ice. Upon arrival at MUSC, the samples were then stored in −80° C until performance of assays. Assays were performed on all samples with adequate volume of mucus collected. A small subset of samples (n = 8) had inadequate volume for all analyses and sample size for each variable is indicated in the result tables.
Statistical Analysis
Descriptive statistics were performed for all study subjects, including demographics and comorbidities. For each OC mucus protein analyzed, the descriptive statistics including mean, median, standard deviation (SD), maximum and minimum were generated. The frequency with which each OC mucus protein was found to be within detectable limits of the assay was recorded. For the purposes of analysis, samples with protein concentrations outside of the detectable limits, either too high or too low, were assigned the maximum and minimum values of detection set by the assay manufacturer, respectively. Association between the TDI score and concentration of OC proteins was determined using Spearman rank-order correlations. Significance was set at p < 0.05. Statistical analysis was performed using SPSS v25.0 (IBM Corporation, Armonk, NY).
Results
A total of 62 patients were enrolled and had OC mucus available for analysis. Just over half of the study cohort was female (56.5%) and the group had an average age of 48.2 years (SD=16.2). A full description of demographics and comorbidities is presented in Table 1. With regard to comorbidities, asthma was seen in 40.3% and atopy in 53.2%. Over half of the cohort was classified as CRSwNP (n=37; 59.7%), but no differences were seen between CRSsNP and CRSwNP groups with regard to factors known to impact olfaction including age, gender, asthma, allergic rhinitis, diabetes mellitus, depression, and smoking status.
Table 1.
Demographics and comorbidities of sample (n=62) and by NP status
| All Participants n=62 Mean (SD) Count (%) |
CRSsNP n=25 Mean (SD) Count (%) |
CRSwNP N=37 Mean (SD) Count (%) |
P-Value (sNP vs. wNP) |
||
|---|---|---|---|---|---|
| AGE | 48.2 (16.2) | 51.0 (15.7) | 46.2 (16.4) | .252 | |
| GENDER | Female | 35 (56.5%) | 14 (56.0%) | 21 (56.8%) | .953 |
| Male | 27 (43.5%) | 11 (44.0%) | 16 (43.2%) | ||
| ETHNICITY | Hispanic / Latino | 1 (1.6%) | 0 (0.0%) | 1 (2.7%) | 1.000 |
| Non-Hispanic / Latino | 61 (98.4%) | 25 (100.0%) | 36 (97.3%) | ||
| RACE | African American / Black | 16 (25.8%) | 3 (12.0%) | 13 (35.1%) | .041 |
| White / Caucasian | 46 (74.2%) | 22 (88.0%) | 24 (64.9%) | ||
| NASAL POLYPOSIS | 37 (59.7%) | - | - | - | |
| ALLERGIC FUNGAL RHINOSINUSITIS | 8 (12.9%) | 0 (0.0%) | 8 (21.6%) | .017 | |
| ASTHMA | 25 (40.3%) | 10 (40.0%) | 15 (40.5%) | .966 | |
| AERD | 6 (9.7%) | 0 (0.0%) | 6 (16.2%) | .073 | |
| ALLERGIC RHINITIS | 37 (59.7%) | 13 (52.0%) | 24 (64.9%) | .311 | |
| GERD | 15 (24.2%) | 9 (36.0%) | 6 (16.2%) | .074 | |
| FIBROMYALGIA | 1 (1.6%) | 1 (4.0%) | 0 (0.0%) | .403 | |
| DIABETES | Yes (Insulin + Non-Insulin) | 5 (8.0%) | 2 (8.0%) | 3 (8.1%) | 1.000 |
| No | 57 (91.9%) | 23 (92.0%) | 34 (91.9%) | ||
| DEPRESSION | 18 (29.0%) | 7 (28.0%) | 11 (29.7%) | .883 | |
| ANXIETY | 14 (22.6%) | 7 (28.0%) | 7 (18.9%) | .402 | |
| OSA | Yes | 5 (8.1%) | 5 (20.0%) | 0 (0.0%) | .008 |
| No | 57 (91.9%) | 20 (80.0%) | 37 (100.0%) | ||
| SMOKING HISTORY | Current smoker | 3 (4.8%) | 2 (8.0%) | 1 (2.7%) | .683 |
| Former smoker | 9 (14.5%) | 4 (16.0%) | 5 (13.5%) | ||
| None | 50 (80.6%) | 19 (76.0%) | 31 (83.8%) | ||
| ALCOHOL HISTORY | Current drinker | 31 (50.0%) | 15 (60.0%) | 16 (43.2%) | .465 |
| Former drinker | 7 (11.3%) | 2 (8.0%) | 5 (13.5%) | ||
| None | 24 (38.7%) | 8 (32.0%) | 16 (43.2%) | ||
Descriptive statistics for each OC mucus chemokine, cytokine, immunoglobulin, or growth factor are provided in Table 2. The vast majority of proteins were found within the detectable range for each assay, with 16 out of 26 detectable in >90% of samples. Notable dispersion was seen across samples as evident by relatively wide ranges and high standard deviations, highlighting the variability across patients. The notable exceptions were interleukin 17A (IL17A) (29.6%), IL4 (37.0%), and (IL2) (48.1%) which were below the detectable limits in more than half of patients.
Table 2.
Cytokine descriptive statistics and percent within detectable limit
| n | Minimum | Maximum | Mean | Std. Deviation | n(%) Detectable | n(%) above detectable range | n(%) below detectable range | |
|---|---|---|---|---|---|---|---|---|
| CCL11 | 62 | 24.1 | 3010.8 | 533.5 | 545.1 | 62 (100%) | - | - |
| CCL2 | 62 | 392.4 | 21950.6 | 3149.1 | 3962.0 | 62 (100%) | - | - |
| CCL20 | 62 | 33.1 | 29066.1 | 4803.9 | 8367.9 | 47 (75.8%) | 4 (6.5%) | 11 (17.7%) |
| CCL3 | 62 | 3.4 | 7313.7 | 401.7 | 1266.8 | 58 (93.5%) | - | 4 (6.5%) |
| CCL5 | 62 | 8.1 | 7778.4 | 349.1 | 1188.2 | 45 (72.6%) | - | 17 (27.4%) |
| CXCL1 | 62 | 2165.8 | 22069.1 | 9865.6 | 5731.3 | 56 (90.3%) | 6 (9.7%) | - |
| CXCL11 | 62 | 11.8 | 30507.5 | 713.9 | 3866.1 | 56 (90.3%) | 1 (1.6%) | 5 (8.1%) |
| CXCL5 | 62 | 109.5 | 11224.5 | 4774.9 | 3913.8 | 53 (85.5%) | 9 (14.5%) | - |
| CXCL9 | 62 | 84.5 | 16371.7 | 4386 | 4094.5 | 62 (100%) | - | - |
| EGF | 62 | 93.3 | 9349.5 | 962.6 | 1348.0 | 62 (100%) | - | - |
| bFGF | 62 | 55.8 | 18027.1 | 2415.8 | 3790.8 | 62 (100%) | - | - |
| IgE | 57 | 0.0 | 10023.4 | 976.2 | 2063.6 | 57(100%) | - | - |
| IL2 | 54 | 4.0 | 104.5 | 20.6 | 21.3 | 26 (48.1%) | - | 28 (51.9%) |
| IL4 | 54 | 3.4 | 102.4 | 11.9 | 17.5 | 20 (37.0%) | - | 34 (63.0%) |
| IL5 | 54 | 2.8 | 22197.8 | 1376.1 | 3519.6 | 47 (87.0%) | - | 7 (13.0%) |
| IL6 | 54 | 10.6 | 15311.2 | 903 | 2236.4 | 54 (100%) | - | - |
| IL8 | 54 | 2600.6 | 18414.1 | 11067.7 | 3470.1 | 54 (100%) | - | - |
| IL9 | 54 | 2.6 | 764.7 | 41.3 | 112.8 | 34 (63.0%) | - | 20 (37.0%) |
| IL10 | 54 | 1.5 | 2059.4 | 47.8 | 279.1 | 52 (96.3%) | - | 2 (3.7%) |
| IL13 | 54 | 6.4 | 2814 | 258.7 | 477 | 41 (75.9%) | - | 13 (24.1%) |
| IL17A | 54 | 7.8 | 128.5 | 19.0 | 21.5 | 16 (29.6%) | - | 38 (70.4%) |
| IL17F | 54 | 4.1 | 139.6 | 16.0 | 29.4 | 27 (50.0%) | - | 27 (50.0%) |
| IL23 | 54 | 5.3 | 280.8 | 25.6 | 46.5 | 47 (87.0%) | - | 7 (13.0%) |
| IL33 | 54 | 29.2 | 140501.1 | 8934.8 | 25669.7 | 53 (98.1%) | 1 (1.9%) | - |
| TNFα | 54 | 2.5 | 3703.5 | 114.9 | 509.3 | 49 (90.7%) | - | 5 (9.3%) |
| VEGF-A | 62 | 1591 | 10730.2 | 4611.3 | 1863.6 | 62 (100%) | - | - |
Descriptive statistics for radiographic and olfactory metrics are noted in Table 3. Lund-Mackay scores were significantly greater on average in the CRSwNP group (17.5 ± 4.7) compared to the CRSsNP (9.0 ± 5.7) (p = 0.001). Percent opacification of the olfactory cleft was also significantly higher in the CRSwNP (75.4 ± 24.4) group compared to the CRSsNP group (39.2 ± 17.5) (p < 0.001). In terms of olfaction, the CRSwNP group (18.2 ± 9.7) had significantly worse olfactory function compared to the CRSsNP group (27.2 ± 7.8) (p = 0.009). With regard to age and its effect on olfaction, Pearson correlation was performed between age and today TDI revealing no significant correlation (Pearson ρ = −0.174, p = 0.175).
Table 3.
Descriptive statistics for Lund-Mackay, Olfactory Cleft Opacification and TDI scores by polyp status.
| CRSsNP | CRSwNP | P Value | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mean | Standard Deviation | Median | Min | Max | n | Mean | Standard Deviation | Median | Min | Max | n | ||
| Radiographic Metrics | |||||||||||||
| Lund McKay | 9.0 | 5.7 | 9.0 | .0 | 18.0 | 23 | 17.5 | 4.7 | 18.0 | 8.0 | 24.0 | 30 | 0.001 |
| Anterior Opacification | 32.7 | 19.9 | 29.0 | 7.0 | 100.0 | 16 | 70.6 | 27.7 | 75.0 | 25.0 | 100.0 | 27 | <0.001 |
| Mid Opacification | 38.5 | 19.5 | 37.0 | 18.0 | 100.0 | 16 | 75.4 | 26.1 | 90.0 | 24.0 | 100.0 | 27 | <0.001 |
| Post Opacification | 46.4 | 22.9 | 38.5 | 16.0 | 100.0 | 16 | 80.4 | 25.3 | 95.0 | 24.0 | 100.0 | 27 | 0.004 |
| Total Opacification | 39.2 | 17.5 | 35.8 | 26.0 | 100.0 | 16 | 75.4 | 24.4 | 80.7 | 27.0 | 100.0 | 27 | <0.001 |
| Olfactory Metrics | |||||||||||||
| Threshold | 5.0 | 3.0 | 4.8 | 1.0 | 11.8 | 25 | 3.1 | 2.9 | 1.0 | 1.0 | 9.3 | 37 | 0.009 |
| Discrimination | 11.2 | 2.9 | 12.0 | 5.0 | 16.0 | 25 | 7.8 | 2.9 | 7.0 | 4.0 | 13.0 | 37 | 0.002 |
| Identification | 11.2 | 3.8 | 12.0 | 4.0 | 16.0 | 25 | 7.3 | 4.6 | 5.0 | 1.0 | 15.0 | 37 | 0.019 |
| Total TDI | 27.2 | 7.8 | 27.5 | 11.0 | 39.5 | 25 | 18.2 | 9.7 | 14.0 | 8.0 | 35.8 | 37 | 0.009 |
The correlation between individual OC mucus proteins and olfaction as measured by TDI is described in Table 4, ranked by the strength of statistical association. In total, 10 of 26 OC mucus proteins were significantly correlated with objective olfaction, including chemokines (CCL2, CCL3), cytokines (IL5, IL6, IL13, IL10, IL9, IL23), IgE, and a growth factor (VEGF-A). The majority of OC proteins had in inverse relationship with olfaction, such that the higher the specific protein level the worse the olfactory function. The one notable exception was VEGF-A, for which higher levels was associated with better olfactory performance. For the most part, the correlations between individual OC mucus proteins and olfaction were similar across threshold, discrimination, and identification testing (Table 5).
Table 4.
Correlation between TDI and olfactory cleft mucus protein concentration, overall cohort and by polyp status
| All | CRSsNP | CRSwNP | |||||||
|---|---|---|---|---|---|---|---|---|---|
| r | p | n | r | p | n | r | p | n | |
| CCL2 | −.509 | <.001 | 62 | −.137 | .514 | 25 | −.501 | .002 | 37 |
| CCL3 | −.460 | <.001 | 62 | −.147 | .482 | 25 | −.316 | .057 | 37 |
| IL5 | −.427 | .001 | 54 | −.016 | .948 | 20 | −.341 | .048 | 34 |
| IL6 | −.443 | .001 | 54 | −.027 | .910 | 20 | −.477 | .004 | 34 |
| IL13 | −.408 | .002 | 54 | −.004 | .988 | 20 | −.374 | .029 | 34 |
| IL10 | −.419 | .002 | 54 | .059 | .805 | 20 | −.442 | .009 | 34 |
| IL9 | −.367 | .006 | 54 | −.135 | .570 | 20 | −.338 | .050 | 34 |
| IgE | −.313 | .018 | 57 | −.009 | .965 | 24 | −.319 | .070 | 33 |
| IL23 | −.310 | .023 | 54 | −.035 | .882 | 20 | −.289 | .097 | 34 |
| VEGF-A | .258 | .043 | 62 | −.106 | .615 | 25 | .309 | .063 | 37 |
| TNFα | −.249 | .070 | 54 | .208 | .379 | 20 | −.342 | .047 | 34 |
| CXCL5 | .207 | .106 | 62 | .465 | .019 | 25 | .300 | .072 | 37 |
| IL17A | −.184 | .184 | 54 | .361 | .118 | 20 | −.192 | .278 | 34 |
| IL17F | −.179 | .195 | 54 | −.005 | .984 | 20 | −.277 | .113 | 34 |
| CXCL11 | .156 | .225 | 62 | .077 | .714 | 25 | .068 | .691 | 37 |
| CCL20 | −.153 | .234 | 62 | −.083 | .694 | 25 | −.198 | .241 | 37 |
| CCL5 | −.151 | .243 | 62 | .114 | .586 | 25 | −.342 | .038 | 37 |
| IL8 | −.106 | .447 | 54 | −.208 | .378 | 20 | −.079 | .657 | 34 |
| CXCL9 | .098 | .450 | 62 | .058 | .784 | 25 | .076 | .656 | 37 |
| CCL11 | −.097 | .452 | 62 | .076 | .717 | 25 | −.345 | .037 | 37 |
| IL2 | −.104 | .455 | 54 | .138 | .562 | 20 | −.077 | .663 | 34 |
| IL33 | .082 | .554 | 54 | .155 | .514 | 20 | −.048 | .790 | 34 |
| IL4 | −.077 | .579 | 54 | −.062 | .794 | 20 | −.004 | .980 | 34 |
| CXCL1 | .065 | .615 | 62 | −.117 | .579 | 25 | .139 | .412 | 37 |
| EGF | .022 | .867 | 62 | −.064 | .759 | 25 | .031 | .856 | 37 |
| bFGF | −.004 | .976 | 62 | −.033 | .875 | 25 | −.119 | .485 | 37 |
Table 5.
Correlations of Threshold, Discrimination, and Identification with olfactory cleft proteins found to be significantly correlated with composite TDI
| Threshold | Discrimination | Identification | |||||||
|---|---|---|---|---|---|---|---|---|---|
| r | p | n | r | p | n | r | p | n | |
| CCL2 | −.465 | <.001 | 62 | −.594 | <.001 | 62 | −.381 | .002 | 62 |
| CCL3 | −.405 | .001 | 62 | −.543 | <.001 | 62 | −.379 | .002 | 62 |
| IL5 | −.350 | .009 | 54 | −.474 | <.001 | 54 | −.361 | .007 | 54 |
| IL6 | −.402 | .003 | 54 | −.465 | <.001 | 54 | −.389 | .004 | 54 |
| IL13 | −.340 | .012 | 54 | −.484 | <.001 | 54 | −.349 | .010 | 54 |
| IL10 | −.382 | .004 | 54 | −.424 | .001 | 54 | −.361 | .007 | 54 |
| IL9 | −.289 | .034 | 54 | −.397 | .003 | 54 | −.350 | .009 | 54 |
| IgE | −.261 | .050 | 57 | −.364 | .005 | 57 | −.191 | .154 | 57 |
| IL23 | −.204 | .138 | 54 | −.308 | .023 | 54 | −.339 | .012 | 54 |
| VEGF-A | .216 | .092 | 62 | .276 | .030 | 62 | .198 | .122 | 62 |
| TNFα | −.158 | .254 | 54 | −.331 | .014 | 54 | −.229 | .095 | 54 |
| CXCL5 | .197 | .125 | 62 | .073 | .575 | 62 | .224 | .080 | 62 |
| CCL11 | .131 | .310 | 62 | .072 | .580 | 62 | .200 | .120 | 62 |
| CCL5 | −.163 | .207 | 62 | −.186 | .147 | 62 | −.104 | .419 | 62 |
The relationship between individual OC mucus proteins and averaged opacification of the OC on CT scan is described in Table 6, ranked by strength of association. Once again, the same 10 OC mucus proteins were significantly correlated with OC opacification on CT scan. The majority of this group had a direct correlation, such that higher OC mucus protein levels were associated with greater opacification of the OC on CT scan. Once again, VEGF-A had the opposite relationship, wherein higher levels were associated with less OC opacification.
Table 6.
Correlations between overall olfactory cleft opacification and olfactory cleft protein concentrations
| All Patients | CRSsNP | CRSwNP | |||||||
|---|---|---|---|---|---|---|---|---|---|
| r | p | n | r | p | n | r | p | n | |
| IL5 | .668 | <.001 | 37 | .243 | .424 | 13 | .386 | .063 | 24 |
| IL10 | .621 | <.001 | 37 | .220 | .470 | 13 | .455 | .025 | 24 |
| VEGF-A | −.508 | .001 | 43 | .168 | .535 | 16 | −.446 | .020 | 27 |
| IL13 | .507 | .001 | 37 | .212 | .486 | 13 | .257 | .226 | 24 |
| IL6 | .515 | .001 | 37 | .143 | .642 | 13 | .600 | .002 | 24 |
| IL17A | .503 | .001 | 37 | .157 | .608 | 13 | .263 | .215 | 24 |
| CCL2 | .425 | .005 | 43 | .147 | .587 | 16 | .255 | .199 | 27 |
| CCL3 | .421 | .005 | 43 | .000 | 1.000 | 16 | .252 | .204 | 27 |
| IL9 | .442 | .006 | 37 | .264 | .384 | 13 | .188 | .380 | 24 |
| IgE | .427 | .007 | 39 | −.095 | .735 | 15 | .424 | .039 | 24 |
| CCL5 | .284 | .065 | 43 | .281 | .292 | 16 | .319 | .105 | 27 |
| TNFα | .260 | .120 | 37 | −.138 | .654 | 13 | .186 | .383 | 24 |
| CXCL11 | −.198 | .203 | 43 | .032 | .905 | 16 | −.033 | .872 | 27 |
| IL23 | .202 | .230 | 37 | −.028 | .928 | 13 | −.017 | .937 | 24 |
| EGF | −.166 | .287 | 43 | −.280 | .294 | 16 | −.067 | .741 | 27 |
| IL17F | .139 | .412 | 37 | −.114 | .711 | 13 | .153 | .475 | 24 |
| IL33 | −.107 | .528 | 37 | −.159 | .603 | 13 | −.096 | .657 | 24 |
| IL8 | .105 | .538 | 37 | .473 | .102 | 13 | −.066 | .760 | 24 |
| IL2 | .075 | .659 | 37 | .207 | .497 | 13 | −.208 | .329 | 24 |
| CXCL5 | −.064 | .682 | 43 | −.540 | .031 | 16 | −.135 | .503 | 27 |
| CCL11 | −.047 | .767 | 43 | −.032 | .905 | 16 | .197 | .324 | 27 |
| IL4 | .039 | .818 | 37 | .288 | .339 | 13 | −.144 | .503 | 24 |
| bFGF | .024 | .877 | 43 | .215 | .425 | 16 | .006 | .976 | 27 |
| CXCL9 | −.023 | .883 | 43 | .188 | .485 | 16 | −.061 | .763 | 27 |
| CCL20 | .009 | .957 | 43 | −.227 | .398 | 16 | .007 | .973 | 27 |
| CXCL1 | .001 | .994 | 43 | .181 | .502 | 16 | −.103 | .608 | 27 |
Next, we explored the difference in OC mucus proteins between CRSsNP and CRSwNP subgroups (Table 7). As expected, significant differences were seen between groups for 11 of 26 proteins. The vast majority of proteins were found to be higher in the CRSwNP group compared to CRSsNP (CCL2, CCL3, CXCL11, IL5, IL13, IL9, IL6, IL10, IL17A, IgE), with the exception of VEGF-A which was lower in CRSwNP. No significant difference in overall proteins was seen across groups.
Table 7.
Comparison of olfactory cleft mucus protein concentrations between chronic rhinosinusitis with and without polyps
| P Value | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Mean | Standard Deviation | Median | Min | Max | Mean | Standard Deviation | Median | Min | Max | ||
| CCL11 | 592.4 | 502.1 | 401.9 | 43.6 | 2140.5 | 493.6 | 575.6 | 304.7 | 24.1 | 3010.8 | .123 |
| CCL2 | 1591.4 | 1203.9 | 1266.2 | 392.4 | 5763.0 | 4201.6 | 4775.8 | 2231.4 | 479.7 | 21950.6 | .003 |
| CCL20 | 3512.9 | 6216.4 | 975.5 | 33.1 | 29066.1 | 5676.2 | 9536.5 | 503.4 | 33.1 | 29066.1 | .897 |
| CCL3 | 78.0 | 123.8 | 31.2 | 3.4 | 482.3 | 620.4 | 1608.5 | 155.5 | 3.4 | 7313.7 | .002 |
| CCL5 | 392.8 | 1067.5 | 57.8 | 8.1 | 4345.2 | 319.6 | 1276.9 | 34.7 | 8.1 | 7778.4 | .701 |
| CXCL1 | 9963 | 5322.2 | 10053 | 3337.7 | 22069.1 | 9799.7 | 6063.3 | 7360.7 | 2165.8 | 22069.1 | .667 |
| CXCL11 | 314.8 | 428.5 | 176.3 | 11.8 | 2054.4 | 983.6 | 5001.9 | 72.6 | 11.8 | 30507.5 | .022 |
| CXCL5 | 4251.6 | 3961.7 | 2563.1 | 131.5 | 11224.5 | 5128.5 | 3895.2 | 4029.3 | 109.5 | 11224.5 | .281 |
| CXCL9 | 4795.5 | 4518.1 | 3188.5 | 84.5 | 16371.7 | 4109.3 | 3821.5 | 3009.1 | 111.2 | 14351.3 | .561 |
| EGF | 957.4 | 980.0 | 590.3 | 178.5 | 4280.1 | 966.1 | 1561.6 | 534.4 | 93.3 | 9349.5 | .532 |
| bFGF | 2365.0 | 3385.0 | 768.1 | 99.6 | 12153.2 | 2450.0 | 4087.5 | 413.0 | 55.8 | 18027.1 | .222 |
| IgE | 241.9 | 437.7 | 92.2 | 0.0 | 1691.4 | 1510.2 | 2572.2 | 188.6 | 0.0 | 10023.4 | .033 |
| IL2 | 17.8 | 21.6 | 10 | 4.0 | 104.5 | 22.3 | 21.3 | 10.2 | 4.0 | 92.3 | .326 |
| IL4 | 12.6 | 22.7 | 5.8 | 5.8 | 102.4 | 11.5 | 14.1 | 5.8 | 3.4 | 75.1 | .359 |
| IL5 | 171.8 | 502.9 | 13.2 | 2.8 | 2242.7 | 2084.5 | 4284.2 | 477.3 | 2.8 | 22197.8 | <.001 |
| IL6 | 306.6 | 372.2 | 124.3 | 20.7 | 1259.3 | 1253.8 | 2758.7 | 324.3 | 10.6 | 15311.2 | .036 |
| IL8 | 11138.4 | 3537.7 | 11195.2 | 2600.6 | 18414.1 | 11026.1 | 3482.6 | 11995.7 | 4378 | 18094.0 | .964 |
| IL9 | 16.1 | 31.2 | 2.6 | 2.6 | 131.9 | 56.1 | 138.8 | 9.3 | 2.6 | 764.7 | .042 |
| IL10 | 6.7 | 8.7 | 3.7 | 1.5 | 40.8 | 71.9 | 351.3 | 9.1 | 1.5 | 2059.4 | .030 |
| IL13 | 70.2 | 149.7 | 10.5 | 6.4 | 653.9 | 369.7 | 564.2 | 127.7 | 8.9 | 2814.0 | <.001 |
| IL17A | 18.7 | 26.1 | 12.4 | 7.8 | 128.5 | 19.2 | 18.7 | 12.4 | 12.4 | 117.0 | .032 |
| IL17F | 15.2 | 29.1 | 4.2 | 4.2 | 127.3 | 16.5 | 30.0 | 4.2 | 4.1 | 139.6 | .811 |
| IL23 | 19.6 | 30.7 | 8.6 | 5.5 | 142.7 | 29.0 | 53.8 | 13.6 | 5.3 | 280.8 | .127 |
| IL33 | 4411.6 | 8070.6 | 1135.3 | 173 | 35278.3 | 11595.4 | 31640.0 | 963.0 | 29.2 | 140501.1 | .325 |
| TNFα | 20.6 | 29.9 | 8.7 | 3.1 | 108.1 | 170.4 | 638.3 | 13.5 | 2.5 | 3703.5 | .170 |
| VEGF-A | 5442.2 | 2144 | 5113.8 | 1591.0 | 10730.2 | 4049.9 | 1420.2 | 3757.7 | 2062.3 | 7548.7 | .005 |
A subgroup analysis was then performed within CRSsNP and CRSwNP groups in order to determine whether associations between OC mucus proteins and TDI persist when stratified by polyp status (Table 4). Within the CRSwNP group, 9 OC mucus proteins correlated with TDI score, including CCL2, IL5, IL6, IL13, IL10, IL9, TNFα, CCL5, and CCL11, each having an inverse relationship such that higher levels of protein were associated with worse olfaction. In the CRSsNP group, only CXCL5 was associated with TDI (r=0.465; p=0.019), such that higher levels were associated with better olfaction. Correlation between OC mucus proteins and OC opacification on CT scan was also determined, stratifying by polyp status (Table 6). Within CRSwNP, 4 proteins significantly correlated with OC opacification (IL6, IL10, VEGF-A, IgE). In the CRSsNP group, only CXCL5 correlated with OC opacification (R=0.540; p=0.031). Lastly, the correlation between OC mucus protein and overall Lund-Mackay score was determined, stratified by polyp status (Table 8) for those proteins previously found to be associated with TDI. Interestingly, within the CRSwNP group no correlation was seen between overall Lund-Mackay score and OC mucus cytokine level. For CRSsNP, CXCL5 was inversely correlated with overall Lund-Mackay score (R=0.699; p<0.001), whereas IL5, IL13, and IgE were all directly correlated with overall Lund-Mackay score.
Table 8.
Correlation between Lund-Mackay Score and olfactory cleft mucus protein concentration
| All Patients | CRSsNP | CRSwNP | |||||||
|---|---|---|---|---|---|---|---|---|---|
| r | p | n | r | p | n | r | p | n | |
| IL5 | .582 | <.001 | 45 | .611 | .007 | 18 | .180 | .369 | 27 |
| IL13 | .623 | <.001 | 45 | .657 | .003 | 18 | .330 | .093 | 27 |
| VEGF-A | −.458 | .001 | 53 | −.336 | .117 | 23 | −.257 | .170 | 30 |
| IL10 | .426 | .003 | 45 | .147 | .560 | 18 | .276 | .163 | 27 |
| IgE | .418 | .003 | 48 | .584 | .004 | 22 | .009 | .964 | 26 |
| IL6 | .362 | .015 | 45 | −.067 | .793 | 18 | .322 | .102 | 27 |
| CCL2 | .315 | .022 | 53 | −.230 | .291 | 23 | .273 | .145 | 30 |
| CXCL11 | −.299 | .030 | 53 | .061 | .782 | 23 | −.245 | .192 | 30 |
| IL23 | .310 | .038 | 45 | .168 | .505 | 18 | .129 | .520 | 27 |
| CXCL9 | −.279 | .043 | 53 | −.320 | .137 | 23 | −.392 | .032 | 30 |
| CCL3 | .271 | .050 | 53 | .096 | .663 | 23 | −.092 | .627 | 30 |
| IL17A | .290 | .053 | 45 | .462 | .053 | 18 | −.065 | .749 | 27 |
| CCL11 | −.220 | .113 | 53 | −.348 | .104 | 23 | .058 | .761 | 30 |
| IL9 | .239 | .114 | 45 | .289 | .246 | 18 | −.219 | .274 | 27 |
| IL2 | .174 | .254 | 45 | .285 | .251 | 18 | .000 | .999 | 27 |
| CXCL5 | −.153 | .273 | 53 | −.699 | <.001 | 23 | −.227 | .228 | 30 |
| TNFα | .132 | .387 | 45 | −.272 | .274 | 18 | .074 | .714 | 27 |
| EGF | −.105 | .453 | 53 | .118 | .593 | 23 | −.177 | .349 | 30 |
| CCL20 | −.068 | .628 | 53 | −.043 | .844 | 23 | −.117 | .538 | 30 |
| IL17F | .073 | .635 | 45 | .185 | .461 | 18 | .080 | .691 | 27 |
| IL8 | −.052 | .736 | 45 | .149 | .554 | 18 | −.140 | .486 | 27 |
| bFGF | .041 | .771 | 53 | −.020 | .928 | 23 | .167 | .379 | 30 |
| IL4 | .039 | .800 | 45 | .202 | .421 | 18 | −.117 | .562 | 27 |
| CCL5 | .033 | .812 | 53 | −.326 | .129 | 23 | .300 | .107 | 30 |
| CXCL1 | −.032 | .822 | 53 | .234 | .282 | 23 | −.102 | .591 | 30 |
| IL33 | .020 | .896 | 45 | −.115 | .648 | 18 | .124 | .539 | 27 |
Discussion
All patients with CRS share common symptomatology and the presence of sinonasal inflammation, but it is well accepted that different phenotypes exist likely representing variations in underlying pathobiology.19,20 When it comes to olfaction specifically, notable variability exists and patients can span the range between normosmia and complete anosmia. Our findings confirm that inflammatory proteins are present in mucus collected from the olfactory cleft, the quantity of proteins varies across individuals, the profile of proteins differs between CRSsNP and CRSwNP subgroups, and that individual proteins significantly correlate with both the degree of OC opacification on CT and an individual’s olfactory function as assessed by psychophysical testing.
Findings from this study support a growing body of evidence showing correlation between OC inflammatory protein levels and olfactory function.11,16,21–23 Previously, we reported a pilot study in CRS patients in which OC levels of IL5 (inversely) and VEGF-A (directly) significantly correlated with olfaction.16 Following this, Wu et al. published work showing correlations between OC and middle meatal inflammatory cytokines (IL2, IL5, IL6, IL10, IL13) and olfaction as measured by identification testing.22 A follow-up cluster study from this same group using middle meatus cytokine levels indicated IL2 was independently associated with smell identification.23 Within our cohort, including both CRSsNP and CRSwNP groups, we did not identify a relationship between OC IL2 and objective olfaction. However, taken together, there is now evidence across multiple independent cohorts to support associations between a number of different mucus proteins and olfaction. Additionally, our data shows that these correlations persist after stratifying by polyp status, suggesting that the relationship between mucus proteins and olfaction is not solely a marker of overall nasal polyp status.
Data from this study supports the hypothesis that olfactory dysfunction in some patients with CRSwNP is driven by direct inflammation of the OC mucosa, as opposed to simply alterations in nasal airflow from nasal cavity polyps/edema. Type 2 inflammation is present diffusely throughout the sinus mucosa, resulting in the edema and visible polyp formation characteristic of the CRSwNP phenotype. In some patients, this same inflammation may be present in the specialized OC mucosa, as suggested by elevations in IL5, IL6, IL10, IL13, IgE found in the mucus from the OC. When these inflammatory proteins are present in the OC, the OC is opacified on imaging, possibly a result of edema and polyp formation in the olfactory cleft. The higher these inflammatory proteins, the greater the opacification of the OC and lower the olfactory function, including both threshold and suprathreshold measures. Interestingly, OC mucus cytokines did not correlate with the degree of sinus opacification seen on Lund-Mackay CT score. Why some CRSwNP patients have OC inflammation and others do not is unclear; but one might expect that treatments which target olfactory cleft inflammation specifically would be advantageous in the setting of olfactory dysfunction. Currently available topical treatments for CRSwNP are designed to directly deliver medications to the sinus cavities, including steroid nasal sprays, steroid irrigations, and steroid eluting implants, with the goal of shrinking sinonasal polyps. If direct OC mucosal inflammation is driving olfactory loss, then the efficacy of these medications will vary in part based on their ability to adequately reach the OC mucosa. Devices or techniques which can deliver anti-inflammatory medications effectively into the olfactory cleft could offer therapeutic advantage from an olfactory standpoint.6,24–28
Anti-inflammatory medications delivered systemically would theoretically reach the inflamed OC mucosa directly via the bloodstream. The ability of systemic corticosteroids to improve olfaction in CRSwNP has been known for decades and is recommended as a treatment option in evidence-based reviews.29 It is possible that these medications may be working, at least in part, by impacting inflammatory mediators in the OC, as opposed to simply shrinking nasal cavity polyp and allowing improved nasal airflow. These concepts also have implications with regard to newer biologic medications. Monoclonal antibodies against IL5, IL4/13, and IgE currently exist and many are in Phase 3 clinical trials for treatment of CRSwNP. With regard to olfaction, in a double-blind, placebo-controlled clinical trial using dupilimab to inhibit IL4 and IL13 in patients with CRSwNP, Bachert et al found significant improvement in smell identification scores after 16 weeks (LS mean difference, 14.8 [95% CI, 10.9 to 18.7]; P<.001).30 Taken together, this data suggests the possibility that biologics targeted to IL5, IL4/13, or IgE may directly treat OC inflammation, resulting in improvement in olfactory function. Certainly, olfactory data from these ongoing clinical trials will be enlightening.
Findings from the CRSsNP subgroup is notable in that only a single protein (CXCL5) was found to significantly correlate with objective olfaction and OC opacification. CXCL5 is a chemokine expressed by a number of cell types including monocytes/macrophages, epithelial cells, and eosinophils which attract leukocytes and can play a role in angiogenesis, neuroinflammation, and remodeling of connective tissue.31,32 In our data, an inverse relationship existed such that the higher the CXCL5 the better olfaction. The role CXCL5 plays in CRSsNP or the olfactory mucosa is unknown. Although further inquiry into this chemokine seems warranted, one should keep in mind that it remains possible the association is spurious and simply the product of type 1 error.
The other notable finding from the CRSsNP subgroup is really the lack of correlation between most OC mucus proteins and olfactory function or OC opacification. The implication of this data is that direct inflammation of the OC mucosa seems less prominent in most patients with CRSsNP, at least with respect to the 26 proteins assayed in this study. Interestingly, we have previously reported that the degree of sinus opacification seen on CT correlates better with olfaction than opacification of the OC in patients with CRSsNP.33 In the current study, none of the 26 proteins assayed in the OC mucus positively correlated with OC opacification on CT scan; however, several inflammatory cytokines directly correlated with Lund-Mackay CT scores. One possibility is that these cytokines are being expressed by sinus mucosa and trafficked to the OC via sinus mucus where they were absorbed on the sponge rather than being produced directly in the OC, but this is purely speculative. In many ways, the results from the CRSsNP group generate more questions than answers with regard to underlying mechanisms of olfactory dysfunction in those without polyps.
The above discussion suggests possible mechanisms of disease and speculates regarding clinical and treatment implications, but it should be kept in mind that this data is cross-sectional and therefore does not prove causality. Although it is quite attractive to suggest that inflammatory cytokines such as IL5 and IL13 are directly causing mucosal inflammation in the OC as visible on CT and resulting in olfactory loss, this cannot be proven simply by observing an association. It is certainly possible that other mechanisms are involved and these inflammatory proteins are simply biomarkers of disease. However, data from RCTs investigating monoclonal antibodies against IL5, IL4/13, and IgE will go a long way towards proving causality, as would longitudinal studies showing OC mucosal proteins before and after targeted treatments. Certainly, future experiments would need to determine the precise mechanisms through which olfactory dysfunction occurs, as this could involve any number of steps including odorant airflow at the OC, olfactory mucus composition and odorant binding, and olfactory neuron transmission.
Strengths of the study include its prospective design, explicit inclusion/exclusion criteria, and enrollment from 5 different centers across North America, which enhance the internal validity and generalizability of findings. The array of chemokines and inflammatory cytokines includes both Type 1 and Type 2 inflammatory factors commonly implicated in CRS. Importantly, stratifying by polyp status ensured that results were not simply a product of confounding by the presence of visible nasal polyps. However, considering 26 proteins were assayed, one should be alert to the possibility of type 1 error. Although most of our statistically significant findings are strong enough to survive strict multiple comparisons adjustment (i.e. Bonferroni correction), we chose not to adjust considering the preliminary nature of these findings and our hope that they be hypothesis generating. The flip side of this argument is also worth considering. Given the variability in OC mucus levels across many proteins and modest sample size, the possibility of type II error exists as well. Therefore, some mucus proteins from the OC which were non-significant may truly correlate with objective olfaction, but we simply did not have the power to demonstrate that relationship definitively. Lastly, proteins were sampled only from the olfactory cleft location without simultaneous middle meatal mucus collection. This was done in attempt to sample the location in closest proximity to olfactory epithelium. However, without simultaneous middle meatal collection one cannot determine the degree to which these two locations correlate, which would have been insightful. Lastly, proteins that remain intracellularly may not be appropriately sampled simply with mucus collection.
Conclusion
Findings from this study demonstrate that an array of proteins can be detected in OC mucus from patients with CRS including cytokines, chemokines, growth factors, and IgE. The profile of mucus proteins differs between CRSsNP and CRSwNP subgroups, suggesting different underlying mechanisms of disease within these groups. A number of individual proteins significantly correlate with both the degree of OC opacification on CT and an individual’s olfactory function as assessed by psychophysical testing, particularly in the CRSwNP subgroup. This suggests, but does not prove, that direct inflammation of the OC may be contributing to olfactory dysfunction in many patients with CRS and that targeted treatment of this inflammation may prove efficacious. Further investigation would be required to prove causality with regard to any specific protein and olfactory loss.
Footnotes
Financial Disclosures/Conflicts of Interest: Z.M.S., R.J.S., J.M., V.R.R., J.A.A., and T.L.S. were supported for this investigation by a grant from the National Institute on Deafness and Other Communication Disorders (NIDCD), one of the National Institutes of Health, Bethesda, MD., USA (R01 DC005805; Co-PI: T.L.S./Z.M.S.). Public clinical trial registration (www.clinicaltrials.gov) ID# NCT02720653. This funding organization did not contribute to the design or conduct of this study; preparation, review, approval or decision to submit this manuscript for publication. Z.M.S. is a consultant for Olympus, Novartis, Regeneron, Optinose, and Healthy Humming which are not affiliated with this manuscript. R.J.S. is a consultant for Olympus, Arrinex, Optinose, Sanofi, and Healthy Humming, which are not affiliated with this study. V.R.R. is a consultant for Medtronic and Optinose, which are not affiliated with this study. J.A.A. is a consultant for Medtronic, Optinose, Intersect ENT, and GlycoMira Therapeutics, which are not affiliated with this study. J.L.M. is a consultant for Sanofi, which is not affiliated with this manuscript. S.C.P is a consultant for Cook Medical, which is not affiliated with this study.
Presented at the 2019 ARS 65th ANNUAL MEETING, September 13–14, NEW ORLEANS, LA
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