Sinonasal Disease Severity Research Articles

Inflammatory heterogeneity in aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease (AERD) is a mechanistically distinct subtype of chronic rhinosinusitis with nasal polyps (CRSwNP). Although frequently associated with type 2 inflammation, literature characterizing the milieu of inflammatory cytokines and lipid mediators in AERD has been conflicting. We sought to identify differences in the upper airway inflammatory signature between CRSwNP and AERD and determine whether endotypic subtypes of AERD may exist. Levels of 7 cytokines representative of type 1, type 2, and type 3 inflammation, and 21 lipid mediators were measured in nasal mucus from 109 patients with CRSwNP, 30 patients with AERD, and 64 non-CRS controls. Differences in inflammatory mediators were identified between groups, and patterns of inflammation among patients with AERD were determined by hierarchical cluster analysis. AERD could be distinguished from CRSwNP by profound elevations in IL-5, IL-6, IL-13, and IFN-γ; however, significant heterogeneity existed between patients. Hierarchical cluster analysis identified 3 inflammatory subendotypes of AERD characterized by (1) low inflammatory burden, (2) high type 2 cytokines, and (3) comparatively low type 2 cytokines and high levels of type 1 and type 3 cytokines. Several lipid mediators were associated with asthma and sinonasal disease severity; however, lipid mediators showed less variability than cytokines. AERD is associated with elevations in type 2 cytokines (IL-5 and IL-13) and the type 1 cytokine, IFN-γ. Among patients with AERD, the inflammatory signature is heterogeneous, supporting subendotypes of the disease. Variability in AERD immune signatures should be further clarified because this may predict clinical response to biologic medications that target type 2 inflammation.

Activation of the 15-lipoxygenase pathway in aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and an intolerance of medications that inhibit cyclooxygenase-1. Patients with AERD have more severe upper and lower respiratory tract disease than do aspirin-tolerant patients with CRSwNP. Adysregulation in arachidonic acid metabolism is thought to contribute to the enhanced sinonasal inflammation in AERD. Our aim was to utilize an unbiased approach investigating arachidonic acid metabolic pathways in AERD. Single-cell RNA sequencing (10× Genomics, Pleasanton, Calif) was utilized to compare the transcriptional profile of nasal polyp (NP) cells from patients with AERD and patients with CRSwNP and map differences in the expression of select genes among identified cell types. Findings were confirmed by traditional real-time PCR. Lipid mediators in sinonasal tissue were measured by mass spectrometry. Localization of various proteins within NPs was assessed by immunofluorescence. The gene encoding for 15-lipooxygenase (15-LO), ALOX15, was significantly elevated in NPs of patients with AERD compared to NPs of patients with CRSwNP (P< .05) or controls (P< .001). ALOX15 was predominantly expressed by epithelial cells. Expression levels significantly correlated with radiographic sinus disease severity (r= 0.56; P< .001) and were associated with asthma. The level of 15-oxo-eicosatetraenoic acid (15-Oxo-ETE), a downstream product of 15-LO, was significantly elevated in NPs from patients with CRSwNP (27.93 pg/mg of tissue) and NPs from patients with AERD (61.03 pg/mg of tissue) compared to inferior turbinate tissue from controls (7.17 pg/mg of tissue [P< .001]). Hydroxyprostaglandin dehydrogenase, an enzyme required for 15-Oxo-ETE synthesis, was predominantly expressed in mast cells and localized near 15-LO+ epithelium in NPs from patients with AERD. Epithelial and mast cell interactions, leading to the synthesis of 15-Oxo-ETE, may contribute to the dysregulation of arachidonic acid metabolism via the 15-LO pathway and to the enhanced sinonasal disease severity observed in AERD.

TAS2R38 is a novel modifier gene in patients with cystic fibrosis

The clinical manifestation of cystic fibrosis (CF) is heterogeneous also in patients with the same cystic fibrosis transmembrane regulator (CFTR) genotype and in affected sibling pairs. Other genes, inherited independently of CFTR, may modulate the clinical manifestation and complications of patients with CF, including the severity of chronic sinonasal disease and the occurrence of chronic Pseudomonas aeruginosa colonization. The T2R38 gene encodes a taste receptor and recently its functionality was related to the occurrence of sinonasal diseases and upper respiratory infections. We assessed the T2R38 genotype in 210 patients with CF and in 95 controls, relating the genotype to the severity of sinonasal disease and to the occurrence of P. aeruginosa pulmonary colonization. The frequency of the PAV allele i.e., the allele associated with the high functionality of the T2R38 protein, was significantly lower in i) CF patients with nasal polyposis requiring surgery, especially in patients who developed the complication before 14 years of age; and ii) in CF patients with chronic pulmonary colonization by P. aeruginosa, especially in patients who were colonized before 14 years of age, than in control subjects. These data suggest a role for T2R38 as a novel modifier gene of sinonasal disease severity and of pulmonary P. aeruginosa colonization in patients with CF.

A Novel Role for 15-Lipoxygenase Metabolites in Aspirin Exacerbated Respiratory Disease

Aspirin Exacerbated Respiratory Disease (AERD) is defined by the triad of asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and an intolerance to cyclooxygenase-1 inhibitors. AERD patients tend to have more severe respiratory disease than aspirin-tolerant patients with CRSwNP. The underlying mechanisms contributing to enhanced disease in AERD are not understood, but a dysregulation in arachidonic acid metabolism is important. We investigated the 15-lipoxygenase (15-LO) pathway in AERD pathogenesis. We examined expression levels of genes important for the synthesis and function of arachidonic acid metabolites in AERD and CRSwNP NP by single-cell RNA sequencing using the 10X Genomics platform and by traditional RT-PCR. Lipid mediators were measured in sinonasal tissue by mass spectrometry. Immunofluorescence was used to examine localization of specific enzymes within NP. ALOX15 expression was significantly elevated in AERD compared to CRSwNP NP (p<0.05) and control tissue (p<0.001) and was predominantly expressed in epithelial cells. ALOX15expression significantly correlated with radiographic sinus disease severity (r=0.56, p<0.001) and was associated with comorbid asthma in CRSwNP. 15-oxo-ETE, a downstream product of 15-LO, was significantly elevated in CRSwNP (27.93 pg/mg tissue) and AERD (61.03 pg/mg tissue) NP compared to control (7.17 pg/mg tissue, p<0.001). Hydroxyprostaglandin dehydrogenase, an enzyme required for 15-oxo-ETE synthesis, was predominantly expressed in mast cells and, by immunofluorescence, localized near 15-LO+epithelium in AERD NP. Epithelial and mast cell interactions, leading to the synthesis of 15-oxo-ETE, may contribute to the dysregulation of arachidonic acid metabolism via the 15-LO pathway as well as to the enhanced sinonasal disease severity observed in AERD.

Update on sinus disease in children with cystic fibrosis: advances in treatment modalities, microbiology, and health-related quality-of-life instruments.

There is a lack of consensus with regards to the diagnosis and treatment of sinus disease in children with cystic fibrosis. Here, we review literature from the past 18 months in order to highlight the way forward in this contentious field. Most of the literature (from the past 18 months) on sinus disease in pediatric cystic fibrosis focused on treatment approaches, bacteriology and immunology, and health-related quality-of-life (HRQOL) instruments. Quality studies have demonstrated that functional endoscopic sinus surgery (FESS) is as safe in children with or without cystic fibrosis; that the microbiology of the paranasal sinus in children with cystic fibrosis is different than that of their lungs; and, that HRQOL instruments may prove useful in determining sinonasal disease severity in children with cystic fibrosis. Medical and surgical approaches appear to be viable in the treatment of sinonasal disease in pediatric cystic fibrosis; the microbiology and immunology of pediatric cystic fibrosis is proving more complex and nuanced than initially believed; and, HRQOL instruments show promise in reconciling differences between observable and clinically relevant sinus disease in pediatric cystic fibrosis patients.

Clinical Characteristics of Patients with Chronic Rhinosinusitis without Nasal Polyps in an Academic Setting

Although patients with chronic rhinosinusitis without nasal polyps (CRSsNP) represent a majority of the chronic rhinosinusitis (CRS) population, they have not been completely characterized phenotypically. To perform a comprehensive phenotypic characterization of subjects with CRSsNP, using CRS with nasal polyps (CRSwNP) as a comparator. Patients with a history of CRS with positive sinus computed tomography (>18 years old) evaluated in the allergy/immunology or otolaryngology clinics of an academic center between 2002 and 2012 were identified via International Classification of Diseases, Ninth Revision codes. A retrospective chart review was performed on a subset of 507 patients with CRSsNP and 874 with CRSwNP. Characteristics analyzed included demographics, comorbid conditions, and radiologic sinus severity. Of the total CRS population, approximately 82% had CRSsNP and 18% had CRSwNP. Of the 507 patients in the CRSsNP group, 319 (63%) were female compared with 393 of 847 (45%) in the CRSwNP group. The prevalence of atopy was 52% in CRSsNP versus 76% in CRSwNP (P < .0001). In CRSsNP, atopic patients had more severe radiographic disease compared with nonatopic patients (P < .005). The prevalence of asthma was 36% in CRSsNP versus 56% in CRSwNP (P < .0001). Comorbid asthma was not associated with radiographic sinus disease severity in CRSsNP but was associated with severity in CRSwNP (P < .0001). The relative prevalence of CRS phenotypes in the western population is approximately 80% CRSsNP and 20% CRSwNP. Patients with CRSsNP were predominantly female, whereas patients with CRSwNP were predominantly male. The prevalence of asthma was higher in our cohort of patients with CRSsNP than previously described. Atopy was associated with more severe radiographic sinonasal disease in CRSsNP, whereas asthma was not associated with radiographic sinonasal disease severity.

Correlations between cystic fibrosis genotype and sinus disease severity in chronic rhinosinusitis.

Cystic fibrosis (CF) patients commonly develop chronic rhinosinusitis (CRS). The impact of the most common cystic fibrosis transmembrane conductance regulator (CFTR) mutation, F508del, on the severity of sinonasal disease remains inconclusive. The objective of this study is to evaluate the impact of CFTR genotype functional classification on sinonasal disease severity in patients with CRS. Retrospective chart review of patients with CF who underwent endoscopic sinus surgery for chronic rhinosinusitis from 1998 to 2015. Patients were divided into high- or low-risk genotypes based on standardized CFTR gene functional classification. The primary outcome was the 22-item Sino-Nasal Outcome Test (SNOT-22) score. Secondary outcomes included endoscopic scores, extent of surgery performed, presence of polyposis, number of revision surgeries, and Lund-MacKay computed tomography scores. Thirty-eight patients harbored a high-risk CFTR genotype, and 11 had a low-risk genotype. On bivariate analysis, there was no association between CFTR genotype risk stratification and measures of preoperative disease severity or postoperative outcomes. There were no associations between genotype risk stratification and outcome variables on multivariate linear regression, adjusted for age and gender. There were significant improvements in several SNOT-22 subdomains before and after endoscopic sinus surgery (P < 0.05), but the magnitude of improvement was not significantly different on the basis of CFTR genotype risk stratification. High-risk CFTR genotypes are not associated with worse sinonasal disease severity or postoperative symptom control than low-risk CFTR genotypes after adjusting for confounding factors. Level 4. Laryngoscope, 1752-1758, 2018.

Effect of obesity on sinonasal disease in asthma

ABSTRACTObjective: Sinonasal disease can contribute to poor asthma control. There are reports that link obesity with an increased prevalence of sinonasal disease, but no studies evaluating the severity of sinonasal disease in obese asthmatics, and how this impacts asthma control. The purpose of the current study was to determine if obesity is associated with increased severity of sinonasal disease, and/or affects response to nasal corticosteroid treatment in asthma. Methods: This study included 236 adults participating in a 24-week randomized, double-masked, placebo-controlled study of nasal mometasone for the treatment of poorly controlled asthma. Sinonasal disease severity was assessed using validated questionnaires, and compared in participants of differing BMIs. Eosinophilic inflammation was assessed using markers in nasal lavage, serum and exhaled nitric oxide. Response to treatment was compared in different BMI groups. Results: Obesity had no effect on the severity of sinonasal disease symptoms in asthmatics (Sino-Nasal Outcome Test 22 (SNOT 22) score [mean ± SD] 35.4 ± 18.5, 40.2 ± 22.8, and 39.1 ± 21.7, p = 0.43, in lean, overweight and obese participants), nor on nasal, bronchial or systemic markers of allergic inflammation. Nasal steroids had some limited effects on symptoms, lung function and inflammatory markers in lean participants, but no detectable effect was found in obese patients. Conclusions: Obesity does not affect severity of sinonasal disease in patients with asthma; the association of sinonasal disease symptoms with increased asthma severity and markers of Type 2 inflammation are consistent across all BMI groups. The response of obese patients to nasal corticosteroids requires further study.

Respiratory viral detection in the paranasal sinuses of patients with cystic fibrosis.

Pulmonary colonization with antibiotic-resistant organisms in patients with cystic fibrosis (CF) is often preceded by upper-airway infections. Although there is a well-described relationship between pulmonary respiratory viral infections and overall disease progression of CF, the pathogenicity of respiratory viral infections in the paranasal sinuses of patients with CF remains unknown. With recent advances in respiratory virus detection techniques, this study sought to detect the presence of respiratory viruses in the paranasal sinuses of patients with CF in comparison with healthy controls and to correlate the viral presence with clinical measures of sinonasal disease. This prospective individual cohort study compared 24 patients with CF with 14 healthy controls. Basic demographics, clinical measures of disease and respiratory viral screens (commercial multiplex) obtained directly from the paranasal sinuses were compared between the two groups. Respiratory viruses were detected in 33% of patients with CF (8/24) compared with 0% of the healthy controls (0/14) (p = 0.017). Respiratory viruses were only detected during the winter months, and the most commonly identified were influenza A and human rhinovirus strains. There was no statistical difference in the 22-Item Sino-Nasal Outcome Test (SNOT-22) scores (p = 0.93) or modified Lund-Kennedy scores (p = 0.74) between patients with CF with a positive viral test and those without a positive result. Respiratory viral detection is more commonly detected in the paranasal sinuses of patients with CF compared with healthy controls. Although respiratory viral presence did not correlate with a worse clinical severity of sinonasal disease, these findings may provide insight into the pathophysiology of CF and open new avenues for potential targeted therapy.

Effect of the F508del genotype on outcomes of endoscopic sinus surgery in children with cystic fibrosis

ObjectiveNumerous authors have sought to describe genotype–phenotype correlations in cystic fibrosis (CF), notably to pancreatic insufficiency and lung disease. However, few studies have focused on the association between the F508del genotype and response to sinus surgery. The objective of this study is to assess the effect of the F508del genotype on sinonasal disease severity and outcomes following functional endoscopic sinus surgery (FESS) in a pediatric population. MethodsA retrospective chart review of 153 children with CF seen at a tertiary care pediatric hospital from 1995 to 2008 was performed. Patients were classified into one of three groups according to F508del genotype, either as homozygous, heterozygous or not carrying a F508del mutation. The sinonasal disease phenotype of the three groups was compared based on clinical and radiological findings, extent of endoscopic sinus surgery and rate of revision surgery. ResultsThe relationship between the F508del genotype and pancreatic insufficiency was confirmed (p<0.05). There was no association between the F508del genotype and increased need for FESS (p=0.75). Moreover, no association was established between F508del homozygosity and presence of nasal polyps, Lund–Mackay score, extent of surgery or length of postoperative hospitalization. The rates of revision surgery did not differ significantly among the three genotypes analyzed (p=0.59). ConclusionThere is no clear association between the F508del genotype and an increased need for FESS, extent of surgery, or revision surgery. Given the phenotypic variability of sinonasal disease in patients with CF, a prospective study is needed to better understand outcomes following FESS and the contribution of gene modifiers to this effect.

Diagnostic tools in Rhinology EAACI position paper

This EAACI Task Force document aims at providing the readers with a comprehensive and complete overview of the currently available tools for diagnosis of nasal and sino-nasal disease. We have tried to logically order the different important issues related to history taking, clinical examination and additional investigative tools for evaluation of the severity of sinonasal disease into a consensus document. A panel of European experts in the field of Rhinology has contributed to this consensus document on Diagnostic Tools in Rhinology.

The Effect of Deliberate Hypercapnia and Hypocapnia on Intraoperative Blood Loss and Quality of Surgical Field During Functional Endoscopic Sinus Surgery

Anesthetic management during functional endoscopic sinus surgery is aimed at minimizing bleeding and establishing a near-perfect surgical field. We investigated whether deliberate intraoperative hypercapnia and hypocapnia may affect blood loss and quality of surgical field through a proposed modulating effect of different carbon dioxide (CO2) tension levels on nasal vasculature. One hundred and eighty patients were randomly assigned to normocapnia (end-tidal CO2 [ETco2] 37 +/- 2 mm Hg), hypercapnia (ETco2 60 +/- 2 mm Hg), and hypocapnia (ETco2 27 +/- 2 mm Hg) groups. Anesthetic management was with propofol and remifentanil infusions, nitrous oxide, and moderate controlled hypotension. Blood loss and operating conditions were assessed by the surgeon who was blinded to group assignment. Differences among the study groups, the effect of the study group and time on ETco2 levels and hemodynamic variables, and the association of blood loss with surgical covariates were analyzed. There were no differences in blood loss and quality of surgical field among the study groups. Patients in the hypocapnia group demonstrated the highest, and in the hypercapnia group, the lowest, requirements for remifentanil, labetalol, and administration of the antihypertensive medications in general. The computed tomography-graded severity of sinonasal disease and duration of surgery were the only independent predictors of intraoperative blood loss. CO2 management during functional endoscopic sinus surgery does not influence operating conditions or blood loss.