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Rationale: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have been shown to be vitamin D3 (VD3) deficient, which is associated with more severe disease and increased polyp size. To gain mechanistic insights into these observational studies, we examined the impact of VD3 deficiency on inflammation and VD3 metabolism in an Aspergillus fumigatus (Af) mouse model of chronic rhinosinusitis (Af-CRS)., Methods: Balb/c mice were fed control or VD3 deficient diet for 4 weeks. Mice were then sensitized with intraperitoneal Af, and one week later given Af intranasally every three days for four weeks while being maintained on control or VD3 deficient diet. Airway function, sinonasal immune cell infiltrate and sinonasal VD3 metabolism profiles were then examined., Results: Mice with VD3 deficiency had increased Penh and sRaw values as compared to controls as well as exacerbated changes in sRaw when coupled with Af-CRS. As compared to controls, VD3 deficient and Af-CRS mice had reduced sinonasal 1α-hydroxylase and the active VD3 metabolite, 1,25(OH)2D3. Differential analysis of nasal lavage samples showed that VD3 deficiency alone and in combination with Af-CRS profoundly upregulated eosinophil, neutrophil and lymphocyte numbers. VD3 deficiency exacerbated increases in monocyte-derived dendritic cell (DC) associated with Af-CRS. Conversely, T-regulatory cells were decreased in both Af-CRS mice and VD3 deficient mice, though coupling VD3 deficiency with Af-CRS did not exacerbate CD4 or T-regulatory cells numbers. Lastly, VD3 deficiency had a modifying or exacerbating impact on nasal lavage levels of IFN-γ, IL-6, IL-10 and TNF-α, but had no impact on IL-17A., Conclusions: VD3 deficiency causes changes in sinonasal immunity, which in many ways mirrors the changes observed in Af-CRS mice, while selectively exacerbating inflammation. Furthermore, both VD3 deficiency and Af-CRS were associated with altered sinonasal VD3 metabolism causing reductions in local levels of the active VD3 metabolite, 1,25(OH)2D3, even with adequate circulating levels.

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. [ABSTRACT FROM AUTHOR]

Background: Multiple hypotheses are evolving that suggest several, potentially overlapping etiologies for olfactory dysfunction (OD) in chronic rhinosinusitis (CRS). Understanding inflammatory cytokine profiles of the olfactory cleft (OC) and their association with olfactory function is foundational for future clinical care and research. Methods: This cross‐sectional, case‐control study evaluates associations among OC mucus inflammatory proteins, psychophysical olfactory testing, and computed tomography (CT) analysis of the OC and sinuses. Normative reference intervals were determined for each protein and odds ratios (ORs) were used to compare proportions of altered expression between CRS without nasal polyposis (CRSsNP) and CRS without nasal polyposis (CRSwNP). Results: Case subjects with CRS (n = 151) and controls (n = 74) were evaluated. A majority of OC proteins tested were found within detectable ranges for cases and controls. The CRS cohort had significantly higher concentrations for 23 of 26 proteins. CRS cases with abnormal levels of C‐C motif chemokine ligand 2 (CCL2), CCL3, interleukin 5 (IL5), IL10, and IL13 associated with greater olfactory deficits. The prevalence of elevated IL5 and IL13 in anosmic patients was 64.6% and 62.5%, respectively (p < 0.004). CRS cases with the highest odds of elevated expression in CRSwNP were IL5 (OR = 10.83) and IL13 (OR = 8.36). However, both IL5 and IL13 were still elevated in approximately 14% of CRSsNP patients. The highest magnitude of correlation between the total percent of OC opacification was found to be with IL5 (r = 0.543; p < 0.001), whereas other moderate correlations were noted with immunoglobulin E (IgE), IL10, and IL13. Conclusion: This study confirmed that OC inflammatory proteins vary both by disease phenotype and in their association with OD. Type 2 inflammatory mediators are increased in CRS, especially within the CRSwNP group. However, a substantial proportion of CRSsNP also express type 2 inflammatory mediators. Further research is necessary to understand the complex roles OC mucous inflammatory proteins might play in defining endotype and in impacting CRS‐related OD. ©2021 ARSAAOA, LLC. [ABSTRACT FROM AUTHOR]

Rationale: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have been shown to be vitamin D3 (VD3) deficient, which is associated with more severe disease and increased polyp size. To gain mechanistic insights into these observational studies, we examined the impact of VD3 deficiency on inflammation and VD3 metabolism in an Aspergillus fumigatus (Af) mouse model of chronic rhinosinusitis (Af-CRS). Methods: Balb/c mice were fed control or VD3 deficient diet for 4 weeks. Mice were then sensitized with intraperitoneal Af, and one week later given Af intranasally every three days for four weeks while being maintained on control or VD3 deficient diet. Airway function, sinonasal immune cell infiltrate and sinonasal VD3 metabolism profiles were then examined. Results: Mice with VD3 deficiency had increased Penh and sRaw values as compared to controls as well as exacerbated changes in sRaw when coupled with Af-CRS. As compared to controls, VD3 deficient and Af-CRS mice had reduced sinonasal 1α-hydroxylase and the active VD3 metabolite, 1,25(OH)2D3. Differential analysis of nasal lavage samples showed that VD3 deficiency alone and in combination with Af-CRS profoundly upregulated eosinophil, neutrophil and lymphocyte numbers. VD3 deficiency exacerbated increases in monocyte-derived dendritic cell (DC) associated with Af-CRS. Conversely, T-regulatory cells were decreased in both Af-CRS mice and VD3 deficient mice, though coupling VD3 deficiency with Af-CRS did not exacerbate CD4 or T-regulatory cells numbers. Lastly, VD3 deficiency had a modifying or exacerbating impact on nasal lavage levels of IFN-γ, IL-6, IL-10 and TNF-α, but had no impact on IL-17A. Conclusions: VD3 deficiency causes changes in sinonasal immunity, which in many ways mirrors the changes observed in Af-CRS mice, while selectively exacerbating inflammation. Furthermore, both VD3 deficiency and Af-CRS were associated with altered sinonasal VD3 metabolism causing reductions in local levels of the active VD3 metabolite, 1,25(OH)2D3, even with adequate circulating levels. [ABSTRACT FROM AUTHOR]

Background The objective of this work was to identify trends in chronic rhinosinusitis (CRS)-related publications for the past 3 decades. Methods Literature review was conducted using multiple terms, including sinusitis, chronic rhinosinusitis, chronic sinus disease, nasal polyposis, ethmoid sinusitis, frontal sinusitis, and maxillary sinusitis. Abstracts were divided into 3 decades: 1983 through 1992, 1993 through 2002, and 2003 through 2012. For each decade, we compared the total number of publications and journals, study design, use of validated outcome measures, quality of evidence, number of authors, country of origin, and clinical vs basic science. Results A total of 3406 abstracts were identified. There was a statistically significant increase in the number of publications with a 637% increase from 1983 through 1992 to 2003 through 2012 ( p < 0.05). Likewise, the number of journals with CRS-related publications significantly increased during the study period (117 to 350; p < 0.05). Prospective studies increased (15.30% to 28.90%, p < 0.05) and retrospective studies decreased (33.00% to 17.36%, p < 0.05). Cohort studies were the most common type of design study (18.70% to 32.46%). In studies reporting outcome measures, the use of validated measures significantly increased over time (2.56% to 49.70%, p < 0.05). Although, the quality of evidence for most clinical publications for all 3 decades were grade C, the number and percentage of grade A and grade B publications increased significantly over time (0.99% to 7.23%, p < 0.05; 6.9% to 10.44%, p < 0.05; respectively). Conclusion CRS-related publication quantity and quality have increased over the last 3 decades. [ABSTRACT FROM AUTHOR]

Background Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have deficiencies in circulating and sinonasal levels of the inactive form of vitamin D3, 25-hydroxycholecalciferol (25VD3). Moreover, CRSwNP patients have reduced epithelial cell-specific expression of 1α-hydroxylase; the enzyme responsible for the conversion of 25VD3 to its metabolically active form, 1α,25-dihydroxyvitamin D3 (1,25VD3). The objective of this work was to determine the impact of sinonasal 1α-hydroxylase levels combined from all cellular sources on subjective disease severity and to identify variables influencing its expression. Methods Blood and sinus tissue explants were collected at the time of surgery from control, chronic rhinosinusitis without nasal polyps (CRSsNP), CRSwNP, and allergic fungal rhinosinusitis (AFRS) patients. 1α-Hydroxylase was measured by immunostaining with flow cytometric analysis. Subjective disease severity was measured by the 22-item Sino-Nasal Outcomes Test (SNOT-22). 1,25VD3 and 25VD3 were measured by enzyme-linked immunosorbent assay (ELISA). Results Patients with CRSwNP or AFRS have reduced 1α-hydroxylase and 1,25VD3 compared to controls or CRSsNP. Circulating 1,25VD3 levels were the same among all groups. No differences in sinonasal 1α-hydroxylase or 1,25VD3 were found between CRSwNP and AFRS. Gender, age, race, atopy, and systemic 25VD3 had no impact on sinonasal 1α-hydroxylase levels in any group. However, CRSwNP patients with asthma had higher 1α-hydroxylase than those without asthma. Total 1α-hydroxylase levels inversely correlated with SNOT-22 in CRSwNP, but not CRSsNP. Conclusion Patients with CRSwNP and AFRS both have reduced sinonasal 1α-hydroxylase and 1,25VD3 compared to controls or CRSsNP. Reductions in intracellular 1α-hydroxylase combined from all sinonasal cell types were associated with more severe subjective disease severity in CRSwNP. [ABSTRACT FROM AUTHOR]

Background: Aspergillus fumigatus and Alternaria alternata are ubiquitous environmental fungal allergens that can exacerbate airway inflammation and contribute to the disease process in patients with chronic rhinosinusitis (CRS). These antigens have been shown to induce human sinonasal epithelial cells (HSNECs) to promote a proinflammatory response, but what is unclear is a means by which to reduce these effects. Inhaled pathogens can induce HSNECs to produce reactive oxygen species (ROS) that trigger cytokine production. Objective: This study aimed to determine whether the free radical scavenger superoxide dismutase (SOD) could reduce HSNEC-derived inflammation, as measured by interleukin (IL)-6 and IL-8 production, in response to Aspergillus or Alternaria exposure. Methods: Sinus tissue explants were collected at the time of surgery from control patients (n = 7) and patients with CRS with nasal polyps (CRSwNP) (n = 9). HSNECs were cultured from the explants and treated with Aspergillus, Alternaria, and SOD for 24 hours. Cell supernatants and lysates were collected, and IL-6 and IL-8 concentrations were measured using enzyme-linked immunosorbent assay. Results: In control and CRSwNP HSNECs, Aspergillus and Alternaria both increased cytokine production (p < 0.05), as measured by IL-6 and IL-8 concentration. SOD treatment reduced the inflammatory response to fungal antigen exposure from CRSwNP HSNECs but not control HSNECs. In CRSwNP patients, SOD significantly decreased IL-6 and IL-8 production after Alternaria exposure and IL-8 after Aspergillus exposure (p < 0.05). Conclusions: When HSNECs from CRSwNP patients are treated with SOD concurrently with Aspergillus or Alternaria, SOD treatment decreases the fungal antigen-induced inflammatory response. The ability to attenuate inflammation induced by common fungal allergens with SOD treatment could provide a novel therapeutic or preventative approach for patients with CRS or other allergic inflammatory airway diseases. [ABSTRACT FROM AUTHOR]

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Background: The complement cascade forms part of the initial innate response to pathogens in the airway. Complement activation is important in the maintenance of host homeostasis, but excessive and uncontrolled activation may lead to inflammation and disease. The role of the complement pathway in the innate response in chronic rhinosinusitis (CRS) is poorly characterized Methods: Sinus mucosa biopsy specimens from the anterior ethmoid or uncinate process of patients with allergic fungal rhinosinusitis (AFRS), CRS without NPs (CRS-NPs), and controls were harvested and gene and protein expression of C3, factor B (fB), C5, and C7 complement proteins were analyzed using quantitative polymerase chain reaction and immunohistochemical techniques. Results: fB, C3, and C5 gene expression were increased in both AFRS and CRS-NPs compared with controls (p < 0.05). Transcriptional activity for the terminal pathway protein C7 was not significantly increased when compared with controls, with C7 levels actually reduced in AFRS patients when compared with controls. Immunohistochemistry studies showed the presence of C3 and fB on the mucosal surface and in submucosa of both AFRS and CRS-NPs, but not normal controls. Terminal pathway protein C9 was not found in our specimens. Conclusion: Both AFRS and CRS-NPs display up-regulation of the complement pathway, in particular, the alternative pathway (fB) and common pathways (C3 and C5). Enhanced innate responses as shown by alterations in complement components may play a pivotal role in the inflammatory response noted in CRS and provide potential therapeutic targets in the future. [ABSTRACT FROM AUTHOR]

Background: Allergic rhinitis (AR) is characterized in part by hyperresponsiveness to nonspecific stimuli, a phenomenon that reflects the fundamental role of nasal neural pathways in chronic airway inflammation. Neurotrophins may serve pivotal roles in mediating hyperresponsiveness in allergic airway disease, although the role of such neurogenic mediators in chronic rhinosinusitis (CRS) is not well understood. This study was designed to examine the expression of two potent neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), in CRS. Methods: Inferior turbinate and sinus mucosa were obtained from CRS patients with and without nasal polyps (NPs) and from nonallergic controls. Enzyme-linked immunosorbent assay was used for quantitative determination of tissue concentrations of NGF and BDNF. Results: Ninety-four tissue samples from 48 patients were included. Mean concentration of NGF in sinus mucosa was significantly higher in CRS than controls. CRS without NPs was associated with a 60% increase in sinus NGF over controls (p < 0.05), and CRS with NPs was associated with a 140% increase (p < 0.05). Mean sinus NGF concentration was significantly elevated in allergic subjects compared with controls (p < 0.01). A similar trend was noted in subjects with nonallergic CRS, although this did not reach significance. Mean BDNF concentration was decreased in CRS compared with controls, with the most significant decrease in patients with polyps (p < 0.05). Mean turbinate concentration of both NGF and BDNF were similar in controls and CRS. Conclusion: Increased expression of NGF may contribute to neural hyperresponsiveness in CRS sinus mucosa, particularly those patients with NP and/or allergies. BDNF expression is decreased in CRS sinus mucosa. Alterations in neurogenic inflammation may contribute to the pathophysiology of CRS and provide alternative therapeutic targets. [ABSTRACT FROM AUTHOR]

Summary: Objectives: To review developmental abnormalities and iatrogenic alterations in sinus anatomy that may predispose patients with congenital craniofacial malformations to chronic rhinosinusitis. Study design: Retrospective study. Methods: Seven patients with craniofacial malformations who were surgically treated by the senior author were included in the study. All were diagnosed with chronic rhinosinusitis refractory to medical management. Four patients had undergone previous corrective craniofacial surgery, and three of these patients developed iatrogenic sinus disease. Demographic data, diagnoses and anatomical abnormalities were included. Results: Abnormal sinus anatomy was present in all patients, most commonly skull base abnormalities and dehiscent lamina papyracea. All patients underwent successful endoscopic surgical management (n =7) for their chronic rhinosinusitis. Two patients had adjuvant external procedures. There were no complications and no recurrences after a mean follow up time of 15 months. Conclusions: Otolaryngologists should be aware of the possibility of chronic rhinosinusitis in patients with craniofacial malformations. Careful preoperative evaluation of radiographic studies should be performed as most of these patients will have abnormal sinus anatomy. In addition, patients who undergo surgery to correct their craniofacial malformations are susceptible to altered sinus anatomy that may predispose them to the development of iatrogenic chronic rhinosinusitis. [Copyright &y& Elsevier]

Background: Both obesity and chronic rhinosinusitis (CRS) are characterized by inflammation. Furthermore, both disease processes are independently associated with decreases in quality-of-life (QOL). We sought to investigate the role of comorbid obesity in QOL outcomes in CRS patients undergoing endoscopic sinus surgery (ESS). Methods: Adult patients with medically refractory CRS (n = 241) were prospectively enrolled into a multiinstitutional treatment outcomes investigation. Body mass index (BMI) calculations were used to differentiate patient weight groups (normal weight: 18.5 to 24.9, overweight: 25.0 to 29.9; and obese:≥30.0). Preoperative and postoperative QOL(RhinosinusitisDisability Index [RSDI] and the 22-item Sino-Nasal Outcome Test [SNOT-22]) were evaluated compared across BMI groups and obesity subclasses. Results: The prevalence of comorbid obesity was 41% (n=99). Higher prevalence of comorbid disease was found across increasing BMI groups including diabetes mellitus, asthma, and depression. No significant differences were found in mean preoperative QOL measures between any BMI groups. Significant improvement between preoperative and postoperative QOL mean scores (p ≤ 0.050) was found for all BMI groups. Despite no significant difference in mean QOL improvement between BMI groups (p ≤ 0.142), overweight and obese patients reported reduced relative mean percentage (%) improvement compared to normal weight participants on the RSDI total score (33% and 37% vs 55%, respectively) and SNOT-22 total score (29% and 40% vs 48%, respectively). Conclusion: Patients with comorbid obesity experience significant improvement in average QOL gains following ESS though the percentage of relative improvement in QOL may be decreased in patients with comorbid obesity andCRS as compared to those without. [ABSTRACT FROM AUTHOR]

Background Evidence comparing the impact of medical and surgical management of chronic rhinosinusitis on olfactory function is limited. This study evaluates olfactory outcomes in patients who failed initial medical management and elect either continued medical management or endoscopic sinus surgery (ESS) followed by medical management. Methods Adult subjects were prospectively enrolled into a nonrandomized, multi-institutional cohort. Baseline characteristics, quality-of-life and objective clinical findings were collected along with 2 quality-of-life disease-specific measures, the Rhinosinusitis Disability Index (RSDI) and Sinonasal Outcome Test (SNOT-22). The primary outcome measure was the posttreatment change (≥6 months) in the Brief Smell Identification Test (B-SIT). Bivariate and multivariate analyses compared B-SIT changes by treatment type while controlling for baseline cofactors. Results Subjects (n = 280) were enrolled between March 2011 and May 2013. Baseline B-SIT scores (mean ± standard deviation) were comparable between medical and surgical treatment groups (8.8 ± 3.2 vs 9.0 ± 3.2; p = 0.703). Subjects with baseline impaired olfaction (n = 83; 29.6%) experienced B-SIT improvement in both the medical (n = 17; 2.3 ± 2.8; p = 0.005) and surgical (n = 66; 2.1 ± 3.0; p < 0.001) cohort. A total of 38.6% of subjects with impaired olfaction return to normal olfaction at follow-up with no difference identified between treatment modalities ( p = 0.803). Multivariate analyses identified prior surgery as a predictor of less improvement regardless of treatment modality in patients with baseline impaired olfaction. Average changes in B-SIT scores were comparable between treatment groups ( p > 0.050). Conclusion Subjects electing ESS experienced gains in olfaction comparable to subjects electing continued medical management. Further study with larger sample size and more sensitive measures of olfaction are needed to determine differences between treatment groups. [ABSTRACT FROM AUTHOR]