Five-year EuroQol 5-Dimension Outcomes After Endoscopic Sinus Surgery.

OBJECTIVE: The EuroQol 5-Dimension (EQ-5D) is a general health survey that is quick to administer, widely used, and directly convertible to health utility values (HUV). We aim to describe the five-year EQ-5D outcomes among patients who undergo surgical treatment for chronic rhinosinusitis (CRS). STUDY DESIGN: Prospective observational cohort study. METHODS: Patients with CRS completed the EQ-5D questionnaire preoperatively and annually for five years following endoscopic sinus surgery. Paired t-tests and McNemar's tests were used to compare preoperative and postoperative scores. Mixed-effects modeling was used for multivariate analysis. RESULTS: Among 1296 patients enrolled in our study, 812 (74.7%) completed the postoperative survey at one year and 336 (38.9%) completed it at five years. There was a significant and sustained reduction of patients reporting pain/discomfort (74.9% vs. 58.0%, p < 0.001) and anxiety/depression (49.6% vs. 38.1%, p = 0.01) out to five years. Frequency of problems reported in the usual activity domain decreased at one year and was sustained through year four (30.6% vs 19.7%, p = 0.003). After multivariable modeling, female gender (p = 0.02), prior sinus surgery (p = 0.01), tobacco use (p = 0.038), headaches (p = 0.013), allergies (p = 0.001), diabetes (p = 0.022), hypertension (p = 0.036), higher preoperative SNOT-22 score (p < 0.001), and a lower preoperative Lund-Mackay score (p < 0.001) were associated with significantly worse EQ-5D HUV over time. Similarly, a worse EQ-5D Visual Analog Scale (VAS) over time was associated with allergies (p = 0.03), diabetes (p < 0.001), hypertension (p = 0.04), higher preoperative SNOT-22 score (p < 0.001), and prior sinus surgery (p < 0.001). CONCLUSION: Patients with chronic rhinosinusitis experience significant sustained improvements in health-related quality of life up to five years after ESS as measured by the EQ-5D instrument. LEVEL OF EVIDENCE: Level 2 Laryngoscope, 134:2592-2601, 2024.

The Impact of Gender on Long-Term Quality of Life After Sinus Surgery for Chronic Rhinosinusitis.

OBJECTIVE: To identify the impact of gender on the clinical outcomes of endoscopic sinus surgery (ESS) through the comparison of quality of life measures in female and male patients who undergo surgical treatment for chronic rhinosinusitis (CRS). STUDY DESIGN: Prospective observational cohort study. METHODS: Patients with CRS completed the 22-item Sino-Nasal Outcome Test (SNOT-22) and EuroQol 5-Dimension Survey (EQ-5D) preoperatively and annually for 5 years following ESS. Health utility values (HUV) were calculated from EQ-5D scores. Comparisons of cohort characteristics were performed with chi-square and t-tests. A multivariable linear mixed effects model evaluated changes in SNOT-22 and HUV over time by gender. RESULTS: Among the 1268 patients (54% female) enrolled, 789 and 343 completed postoperative surveys at one and 5 years, respectively. Preoperatively, females experienced more severe symptoms: mean SNOT-22 score (51.1 ± 20.9 female vs. 44.7 ± 20.0 male, p < 0.001) and HUV (0.80 ± 0.14 female vs. 0.84 ± 0.11 male, p < 0.001). These gender differences were resolved by year one postoperatively (SNOT-22: p = 0.083; HUV: p = 0.465). Two years after surgery, however, females reported more severe symptoms (SNOT-22: 25.6 ± 20.7 female vs. 21.5 ± 17.4 male, p = 0.005; HUV: 0.88 ± 0.12 female vs. 0.90 ± 0.11 male, p = 0.018), a difference that persisted at year five. These gender-related differences remained after adjusting for age, race, ethnicity, nasal polyps, history of prior ESS, and smoking status (p < 0.001). Within-subject improvement was comparable between genders (SNOT-22: p = 0.869; HUV: p = 0.611). CONCLUSION: Females with CRS reported more severe symptoms both before and 5 years after surgery compared to their male counterparts. Understanding the mechanism behind these gender-related differences is important for optimizing CRS treatment. LEVEL OF EVIDENCE: 2 Laryngoscope, 133:3319-3326, 2023.

Specialized pro-resolving mediator lipidome and 16S rRNA bacterial microbiome data associated with human chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a clinical syndrome defined by symptoms including nasal congestion, facial pain and pressure, anosmia, and rhinorrhea lasting more than 12 weeks. Several mechanistically distinct processes lead to the development of clinical symptoms in CRS including innate immune dysfunction, dysregulated eicosanoid metabolism and perturbations in host-microbiome interactions [1]. We developed a database comprised of patient demographic information, lipid mediator metabolomic profiles, and 16S bacterial rRNA gene sequence data from 66 patients undergoing endoscopic sinus surgery. Briefly, ethmoid sinus tissue and middle meatal swabs were collected from patients, including non-CRS controls, CRS with polyps (CRSwNP), and CRS without polyps (CRSsNP). Lipid mediator pathways from arachidonic acid (AA) and docosahexanoic acid (DHA) were analyzed by liquid chromatography/tandem mass spectrometry. Bacterial taxa were profiled in parallel by 16S rRNA gene sequencing. This database provides a useful compendium of AA/DHA metabolomic profiles and associated bacterial microbiota in patients with varying disease subtypes, demographics, and risk factors/comorbidities.

Altered tissue specialized pro-resolving mediators in chronic rhinosinusitis.

Current literature implicates arachidonic acid-derived leukotrienes and prostaglandins in the pathogenesis of chronic rhinosinusitis. However, other omega-3 and omega-6 derived lipid mediators, such as specialized pro-resolving mediators (SPMs), may also be important in chronic inflammatory disorders of the upper airway. We hypothesize that SPMs differ among CRS subtypes compared to controls and in relation to sinonasal microbiota. Ethmoid sinus tissue and middle meatal swabs were collected from a convenience sample of 66 subjects, including non-CRS controls, CRS with polyps (CRSwNP), and CRS without polyps (CRSsNP). Lipid mediator pathways were analyzed by liquid chromatography/tandem mass spectrometry. Bacterial taxa were profiled in parallel by 16S rRNA gene sequencing. Resolvin D2 was elevated in both CRSwNP (p = 0.00076) and CRSsNP (p = 0.030) compared with non-CRS controls. Lipoxin A4 was significantly increased in CRSwNP compared with CRSsNP (p = 0.000033) and controls (p = 0.044). Cigarette smoking was associated with significantly lower concentrations of several 15-lipoxygenase metabolites including resolvin D1 (p = 0.0091) and resolvin D2 (p = 0.0097), compared with never-smokers. Several of the lipid compounds also correlated with components of the sinonasal mucosal microbiota, including bacterial pathogens such as Pseudomonas aeruginosa. These data suggest that dysfunctional lipid mediator pathways in CRS extend beyond the traditional descriptions of leukotrienes and prostaglandins and include SPMs. Furthermore, dysregulated SPM signaling may contribute to persistent inflammation and bacterial colonization in CRS.

Differential Expression of Mucins in Murine Olfactory Versus Respiratory Epithelium.

Mucins are a key component of the surface mucus overlying airway epithelium. Given the different functions of the olfactory and respiratory epithelia, we hypothesized that mucins would be differentially expressed between these 2 areas. Secondarily, we evaluated for potential changes in mucin expression with radiation exposure, given the clinical observations of nasal dryness, altered mucus rheology, and smell loss in radiated patients. Immunofluorescence staining was performed to evaluate expression of mucins 1, 2, 5AC, and 5B in nasal respiratory and olfactory epithelia of control mice and 1 week after exposure to 8 Gy of radiation. Mucins 1, 5AC, and 5B exhibited differential expression patterns between olfactory and respiratory epithelium (RE) while mucin 2 showed no difference. In the olfactory epithelium (OE), mucin 1 was located in a lattice-like pattern around gaps corresponding to dendritic knobs of olfactory sensory neurons, whereas in RE it was intermittently expressed by surface goblet cells. Mucin 5AC was expressed by subepithelial glands in both epithelial types but to a higher degree in the OE. Mucin 5B was expressed by submucosal glands in OE and by surface epithelial cells in RE. At 1-week after exposure to single-dose 8 Gy of radiation, no qualitative effects were seen on mucin expression. Our findings demonstrate that murine OE and RE express mucins differently, and characteristic patterns of mucins 1, 5AC, and 5B can be used to define the underlying epithelium. Radiation (8 Gy) does not appear to affect mucin expression at 1 week. LEVEL OF EVIDENCE: N/A (Basic Science Research).IACUC-approved study [Protocol 200065].

Oral vitamin B12 supplement is delivered to the distal gut, altering the corrinoid profile and selectively depleting Bacteroides in C57BL/6 mice.

Vitamin B12 is a critical nutrient for humans as well as microbes. Due to saturable uptake, high dose oral B12 supplements are largely unabsorbed and reach the distal gut where they are available to interact with the microbiota. The aim of this study was to determine if oral B12 supplementation in mice alters 1) the concentration of B12 and related corrinoids in the distal gut, 2) the fecal microbiome, 3) short chain fatty acids (SCFA), and 4) susceptibility to experimental colitis. C57BL/6 mice (up to 24 animals/group) were supplemented with oral 3.94 µg/ml cyanocobalamin (B12), a dose selected to approximate a single 5 mg supplement for a human. Active vitamin B12 (cobalamin), and four B12-analogues ([ADE]CN-Cba, [2Me-ADE]CN-Cba, [2MeS-ADE]CN-Cba, CN-Cbi) were analyzed in cecal and fecal contents using liquid chromatography/mass spectrometry (LC/MS), in parallel with evaluation of fecal microbiota, cecal SCFA, and susceptibility to dextran sodium sulfate (DSS) colitis. At baseline, active B12 was a minor constituent of overall cecal (0.86%) and fecal (0.44%) corrinoid. Oral B12 supplementation increased active B12 at distal sites by >130-fold (cecal B12 increased from 0.08 to 10.60 ng/mg, fecal B12 increased from 0.06 to 7.81 ng/ml) and reduced microbe-derived fecal corrinoid analogues ([ADE]CN-Cba, [2Me-ADE]CN-Cba, [2MeS-ADE]CN-Cba). Oral B12 had no effect on cecal SCFA. Microbial diversity was unaffected by this intervention, however a selective decrease in Bacteroides was observed with B12 treatment. Lastly, no difference in markers of DSS-induced colitis were detected with B12 treatment.

The Role of Staphylococcus aureus in Patients with Chronic Sinusitis and Nasal Polyposis.

PURPOSE OF REVIEW: Staphylococcus aureus (S. aureus) is correlated with the development of persistent severe inflammatory disease of the upper airway including chronic rhinosinusitis with nasal polyps (CRSwNP). The presence of S. aureus is associated with atopic disease including allergic rhinitis and atopic dermatitis and is associated with poor outcomes. RECENT FINDINGS: Several different strains of S. aureus generate different toxins and gene products that can account for organism pathogenicity. S. aureus bacteria and its antigens shape the bacterial and fungal microbiome and the mucosal niche which generates host responses that can account for inflammation. The multiple disease phenotypes and molecular endotypes seen in CRSwNP can be characterized by T-helper cell environment within the inflammatory milieu, the presence of epithelial barrier dysfunction, aberrant eicosanoid metabolism, poor wound healing, and dysfunctional host-bacteria interactions which lead to recalcitrant disease and worse surgical outcomes. Understanding the pathomechanisms that S. aureus utilizes to promote nasal polyp formation, prolonged tissue inflammation, and bacterial dysbiosis are essential in our efforts to identify new therapeutic approaches to resolve this chronic inflammatory process.

Characterization of Sinus Microbiota by 16S Sequencing from Swabs.

New culture-independent microbiology methods are leading to a paradigm shift in our understanding of how the microbial community at the mucosal surface impacts sinonasal health and disease. Whereas traditional culture-based protocols were designed to identify specific pathogens in order to direct antibiotic therapies and eradicate bacteria, newer molecular techniques allow for the identification of both culturable and nonculturable bacteria in diverse communities. As a result of the recent explosion in the use of molecular techniques, we are gaining an understanding of how commensal bacteria may help modulate the host immune response and promote homeostasis. Here, we describe the general workflow of microbiome sequencing including the detailed methods for extracting mixed-community genomic DNA from sinonasal swabs, amplifying bacterial 16S rRNA genes using quantitative PCR, and preparing the samples for next-generation sequencing on the most commonly used sequencing platforms.

Bacterial Pathogens and the Microbiome.

Bacterial pathogens and microbiome alterations can contribute to the initiation and propagation of mucosal inflammation in chronic rhinosinusitis (CRS). In this article, the authors review the clinical and research implications of key pathogens, discuss the role of the microbiome, and connect bacteria to mechanisms of mucosal immunity relevant in CRS.

Geographic distribution of otolaryngologists in the United States.

We conducted a study to determine the demographic traits, training characteristics, and geographic distribution of otolaryngologists in the United States using publicly available data. We then correlated our findings with U.S. census data. Univariate analysis was performed to analyze results, with a p value of <0.05 determined as significant. We used data from the American Board of Otolaryngology's list of 18,587 board-certified allopathic otolaryngologists through 2013 and the American Osteopathic Colleges of Ophthalmology & Otolaryngology-Head & Neck Surgery's list of 428 osteopathic otolaryngologists. From these two databases, 9,642 otolaryngologists met inclusion criteria, which included an active practice in the United States and an age of 70 years and younger. This group was made up of 8,185 men (84.9%) and 1,449 women (15.0%); we were not able to identify the sex of 8 otolaryngologists (0.1%). The median age of the women was significantly lower than that of the men (54 vs. 48 yr; p < 0.001). A total of 8,510 otolaryngologists (88.3%) graduated from a U.S. allopathic medical school, and 8,520 (88.4%) graduated from a U.S. allopathic residency program. We determined that 25.9% of otolaryngologists established their practice in the same metropolitan statistical area where they completed their residency training. Older practitioners (p < 0.001) and women (p < 0.001) were significantly more likely to stay in the same area than younger physicians and men. In terms of population, 61.8% of the otolaryngologists practiced in metropolitan areas with more than 1 million residents; by comparison, these areas represent only 55.3% of the total U.S. population, indicating that otolaryngologists are over-represented in larger U.S. cities.

Toll-like receptor 7 stimulates production of specialized pro-resolving lipid mediators and promotes resolution of airway inflammation.

Although specialized pro-resolving mediators (SPMs) biosynthesized from polyunsaturated fatty acids are critical for the resolution of acute inflammation, the molecules and pathways that induce their production remain elusive. Here, we show that TLR7, a receptor recognizing viral ssRNA and damaged self-RNA, mobilizes the docosahexaenoic acid (DHA)-derived biosynthetic pathways that lead to the generation of D-series SPMs. In mouse macrophages and human monocytes, TLR7 activation triggered production of DHA-derived monohydroxy metabolome markers and generation of protectin D1 (PD1) and resolvin D1 (RvD1). In mouse allergic airway inflammation, TLR7 activation enhanced production of DHA-derived SPMs including PD1 and accelerated the catabasis of Th2-mediated inflammation. D-series SPMs were critical for TLR7-mediated resolution of airway inflammation as this effect was lost in Alox15(-/-) mice, while resolution was enhanced after local administration of PD1 or RvD1. Together, our findings reveal a new previously unsuspected role of TLR7 in the generation of D-series SPMs and the resolution of allergic airway inflammation. They also identify TLR stimulation as a new approach to drive SPMs and resolution of inflammatory diseases.

Infection regulates pro-resolving mediators that lower antibiotic requirements.

Underlying mechanisms for how bacterial infections contribute to active resolution of acute inflammation are unknown. Here, we performed exudate leukocyte trafficking and mediator-metabololipidomics of murine peritoneal Escherichia coli infections with temporal identification of pro-inflammatory (prostaglandins and leukotrienes) and specialized pro-resolving mediators (SPMs). In self-resolving E. coli exudates (10(5) colony forming units, c.f.u.), the dominant SPMs identified were resolvin (Rv) D5 and protectin D1 (PD1), which at 12 h were at significantly greater levels than in exudates from higher titre E. coli (10(7) c.f.u.)-challenged mice. Germ-free mice had endogenous RvD1 and PD1 levels higher than in conventional mice. RvD1 and RvD5 (nanograms per mouse) each reduced bacterial titres in blood and exudates, E. coli-induced hypothermia and increased survival, demonstrating the first actions of RvD5. With human polymorphonuclear neutrophils and macrophages, RvD1, RvD5 and PD1 each directly enhanced phagocytosis of E. coli, and RvD5 counter-regulated a panel of pro-inflammatory genes, including NF-κB and TNF-α. RvD5 activated the RvD1 receptor, GPR32, to enhance phagocytosis. With self-limited E. coli infections, RvD1 and the antibiotic ciprofloxacin accelerated resolution, each shortening resolution intervals (R(i)). Host-directed RvD1 actions enhanced ciprofloxacin's therapeutic actions. In 10(7) c.f.u. E. coli infections, SPMs (RvD1, RvD5, PD1) together with ciprofloxacin also heightened host antimicrobial responses. In skin infections, SPMs enhanced vancomycin clearance of Staphylococcus aureus. These results demonstrate that specific SPMs are temporally and differentially regulated during infections and that they are anti-phlogistic, enhance containment and lower antibiotic requirements for bacterial clearance.

Diabetes promotes an inflammatory macrophage phenotype and atherosclerosis through acyl-CoA synthetase 1.

The mechanisms that promote an inflammatory environment and accelerated atherosclerosis in diabetes are poorly understood. We show that macrophages isolated from two different mouse models of type 1 diabetes exhibit an inflammatory phenotype. This inflammatory phenotype associates with increased expression of long-chain acyl-CoA synthetase 1 (ACSL1), an enzyme that catalyzes the thioesterification of fatty acids. Monocytes from humans and mice with type 1 diabetes also exhibit increased ACSL1. Furthermore, myeloid-selective deletion of ACSL1 protects monocytes and macrophages from the inflammatory effects of diabetes. Strikingly, myeloid-selective deletion of ACSL1 also prevents accelerated atherosclerosis in diabetic mice without affecting lesions in nondiabetic mice. Our observations indicate that ACSL1 plays a critical role by promoting the inflammatory phenotype of macrophages associated with type 1 diabetes; they also raise the possibilities that diabetic atherosclerosis has an etiology that is, at least in part, distinct from the etiology of nondiabetic vascular disease and that this difference is because of increased monocyte and macrophage ACSL1 expression.

Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections.

Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A(4) hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B(4). We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation.

Chiral lipidomics of E-series resolvins: aspirin and the biosynthesis of novel mediators.

Control of the inflammatory response is of wide interest given its important role in many diseases. In recent years we identified novel mechanisms and lipid mediators that play an active role in stimulating the resolution of self-limited acute inflammation. These novel pro-resolving mediators include the essential fatty acid-derived lipoxins, resolvins, protectins and maresins. Members of each possess a unique pro-resolving mechanism of action; each limits neutrophilic infiltration, regulates local mediators (chemokines, cytokines) as well as stimulates macrophage-enhanced clearance of apoptotic PMN, cellular debris and microbes. Given this unique mechanism of action, resolvins have already been shown to play pivotal roles in regulating key events in a wide range of experimental inflammatory diseases. These pro-resolving mediators also provide a molecular link between omega-3 essential fatty acids (e.g. EPA, DHA) and the resolution process of inflammation and tissue homeostasis. Here, we review recent evidence obtained using chiral LC-MS-MS-based lipidomics to identify a novel 18S-series of resolvins derived from EPA. Resolvin E1 possesses potent actions in vivo and in vitro demonstrated now in many laboratories, and herein we review comparisons in E-series resolvin biosynthesis and action of 18S-resolvin E1 and 18S-resolvin E2. The biosynthesis and formation of both 18S and 18R-series are enhanced with aspirin treatment and involve the utilization of dietary EPA as well as recombinant human 5-lipoxygenase and LTA(4) hydrolase in their stereospecific biosynthesis. Herein we also demonstrate the utility of LC-MS-MS-based lipidomics in identifying resolvins, protectins and related products in marine organisms such as Engraulis (Peruvian anchovy). These new findings emphasize the utility of chiral LC-MS-MS lipidomics and the potential for identifying new resolution circuits with chiral LC-MS-MS-based lipidomics and metabolomics.