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Objective and Design: Staphylococcus aureus (S. aureus) is one of the leading causes of human respiratory tract infections. The function of Staphylococcal protein A (SpA), expressed on the S. aureus bacterial membrane and released in the environment, on human nasal epithelial cells (HNECs) have not been fully elucidated. In this study, we tested the SpA expression in S. aureus from chronic rhinosinusitis patients and investigated the effects of SpA on HNECs inflammation through Interferon Gamma Receptor 1(IFNGR1)/phosphorylated Janus Kinase 2 (p-JAK2) pathway., Methods: RNA profiling was performed to investigate inflammatory activation in a S. aureus chronic rhinosinusitis (CRS) mouse model. SpA release by S. aureus clinical isolates was determined using ELISA. The effect of purified SpA and SpA enriched conditioned media from S. aureus clinical isolates on HNECs cytotoxicity, apoptosis and release of inflammatory cytokines was evaluated using lactate dehydrogenase assays, and flow cytometry. SpA dependent IFNGR1 and p-JAK2 expression were assessed by qPCR, immunofluorescence and western blot in HNECs., Results: 49 genes were significantly induced in S. aureus CRS mice indicative of activation of interferon signaling. SpA release was significantly higher in S. aureus clinical isolates from chronic rhinosinusitis with nasal polyps (CRSwNP) patients. Purified SpA significantly increased IFNGR1 mRNA and protein expression in HNECs. SpA induced cytotoxic effects and induced the release of Interleukin-6 (IL-6) and IL-8 in an IFNGR1 dependent way., Conclusion: SpA induces interferon signaling through activation of the IFNGR1-JAK-2 pathway, which provides an understanding of how S. aureus SpA affects the inflammatory process in the upper airways., (© 2022. The Author(s).)

Prophages affect bacterial fitness on multiple levels. These include bacterial infectivity, toxin secretion, virulence regulation, surface modification, immune stimulation and evasion and microbiome competition. Lysogenic conversion arms bacteria with novel accessory functions thereby increasing bacterial fitness, host adaptation and persistence, and antibiotic resistance. These properties allow the bacteria to occupy a niche long term and can contribute to chronic infections and inflammation such as chronic rhinosinusitis (CRS). In this study, we aimed to identify and characterize prophages present in Staphylococcus aureus from patients suffering from CRS in relation to CRS disease phenotype and severity. Prophage regions were identified using PHASTER. Various in silico tools like ResFinder and VF Analyzer were used to detect virulence genes and antibiotic resistance genes respectively. Progressive MAUVE and maximum likelihood were used for multiple sequence alignment and phylogenetics of prophages respectively. Disease severity of CRS patients was measured using computed tomography Lund-Mackay scores. Fifty-eight S. aureus clinical isolates (CIs) were obtained from 28 CRS patients without nasal polyp (CRSsNP) and 30 CRS patients with nasal polyp (CRSwNP). All CIs carried at least one prophage (average=3.6) and prophages contributed up to 7.7 % of the bacterial genome. Phage integrase genes were found in 55/58 (~95 %) S. aureus strains and 97/211 (~46 %) prophages. Prophages belonging to Sa3int integrase group (phiNM3, JS01, phiN315) (39/97, 40%) and Sa2int (phi2958PVL) (14/97, 14%) were the most prevalent prophages and harboured multiple virulence genes such as sak, scn, chp, luk E/D, sea . Intact prophages were more frequently identified in CRSwNP than in CRSsNP ( P =0.0021). Intact prophages belonging to the Sa3int group were more frequent in CRSwNP than in CRSsNP ( P =0.0008) and intact phiNM3 were exclusively found in CRSwNP patients ( P =0.007). Our results expand the knowledge of prophages in S. aureus isolated from CRS patients and their possible role in disease development. These findings provide a platform for future investigations into potential tripartite associations between bacteria-prophage-human immune system, S. aureus evolution and CRS disease pathophysiology.

Objective: Recently, depleted tissue zinc levels were found in nasal mucosa from patients with chronic rhinosinusitis (CRS) in correlation with tissue eosinophilia, however, no clinical biomarkers for tissue zinc levels have been identified. Metallothionein-3 (MT3) is an intracellular zinc chelator and previous data showed MT3 mRNA levels to be reduced in CRS patients with nasal polyps (CRSwNP). In this study, we examined the correlation between MT3 expression and zinc levels in nasal mucosa and primary human nasal epithelial cells (HNECs) to investigate whether MT3 could be a clinical biomarker for tissue zinc levels., Method: Tissue was harvested from 36 patients and mounted on tissue micro-array (TMA) slides. MT3 expression and tissue zinc fluorescence intensity were measured at different areas within the mucosa (surface epithelium and lamina propria) and compared between controls, CRSwNP and CRS without nasal polyps (CRSsNP) patients. MT3 mRNA and protein expression were examined in zinc-depleted HNECs by qPCR and immunofluorescence microscopy., Results: MT3 expression in CRSwNP was significantly decreased in both surface epithelium (p<0.001 to controls) and lamina propria (p = 0.0491 to controls). There was a significant positive correlation between tissue zinc levels and MT3 expression in nasal mucosa (r = 0.45, p = 0.007). In zinc-deplete HNECs, MT3 expression was significantly decreased at mRNA (p = 0.02) and protein level (p<0.01). There was a significant positive correlation between tissue zinc levels and MT3 expression within individual HNECs (r = 0.59, p<0.001)., Conclusions: MT3 expression reflects intramucosal zinc levels in both nasal mucosa and HNECs indicating MT3 could be used as a clinical biomarker for monitoring intracellular zinc levels in the nasal mucosa., (Copyright © 2021. Published by Elsevier B.V.)

Background: Recent studies demonstrated that B cells and their chemoattractants are elevated in the nasal mucosa of patients with chronic rhinosinusitis (CRS) with nasal polyposis (CRSwNP). However, the presence of naive B cells and of plasmablasts and memory B-cell subsets in the mucosa and periphery of the same patient with CRS is yet to be characterized., Objective: Here we sought to quantify naive, plasmablasts, and memory B cells in mucosal tissue and peripheral blood of patients with CRSwNP, patients with CRS without nasal polyps (CRSsNP), and control patients., Methods: Polyps, mucosa, and peripheral blood samples were prospectively collected from the patients with CRS and from the non-CRS controls. We used flow cytometry to distinguish among naive, plasmablast, and memory B cells in sinus tissue and peripheral blood., Results: A total of 45 patients were recruited for the study. The patients with CRSwNP had significantly increased mucosal B-cell numbers versus the controls (3.39 ± 4.05% versus 0.39 ± 1.05% of live cells; p < 0.01, Kruskal-Wallis test), which included naive B cells (0.61 ± 0.94 versus 0.11 ± 0.24% of live cells; p < 0.03, Kruskal-Wallis test), plasmablasts (0.06 ± 0.26 versus 0.00 ± 0.00% of live cells; p < 0.055, Kruskal-Wallis test), and memory B cells (0.62 ± 1.26 versus 0.05 ± 0.15% of live cells; p < 0.02, Kruskal-Wallis test)., Conclusion: Our study identified increased frequencies of different B-cell subtypes in the mucosa of patients with CRSwNP but not in the peripheral blood. We also found that patients with CRSwNP had significantly increased B-cell subtypes compared with the patients with CRSsNP and the controls. These results implied a potential role for mucosal B cells in the ongoing inflammation in patients with CRSwNP.

Background: The unconventional toll-like receptor (TLR) CD180 is implicated in chronic inflammatory diseases; however, its role in chronic rhinosinusitis (CRS) has yet to be investigated. Here we study the expression of CD180, its homologue TLR4 and myeloid differentiation factor 1 (MD1) on mucosal and systemic immune cell populations in relation to serum immunoglobulin G (IgG) levels., Methods: A total of 70 patients were recruited to the study. Mucosal and peripheral blood samples were prospectively collected from CRS patients and non-CRS controls without evidence of sinus disease. The expression of TLR4, MD1, and CD180 was investigated using qualitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry, and flow cytometry. Serum IgG levels were determined using enzyme-linked immunosorbent assay (ELISA)., Results: CRS with nasal polyps (CRSwNP) patients had significantly increased messenger RNA (mRNA) expression of CD180 and MD1 compared to controls (5.54-fold and 2.1-fold, respectively, p < 0.01). B cells lacking CD180 were lower in CRSwNP tissue compared to CRS without nasal polyps (CRSsNP) and controls (21.07 ± 6.41 vs 41.61 ± 7.82 vs 40.06 ± 8.06; p < 0.01) but higher in blood (39.18 ± 8.3 vs 17.95 ± 7.82 and 12.49 ± 4.92; p ≤ 0.05)., Conclusion: Changes in mucosal and peripheral CD180-expressing B cells were identified in CRSwNP patients compared to CRSsNP and controls. This suggests a role for these cells in the dysregulated immune response in these patients., (© 2017 ARS-AAOA, LLC.)

Background: Patients with aspirin-exacerbated respiratory disease (AERD) and chronic rhinosinusitis with nasal polyps (CRSwNP) are often reported to be recalcitrant to standard medical and surgical intervention. Failure rates of standard endoscopic sinus surgery in these patients are reported to be as high as 90%. We review the outcomes for our cohort of AERD patients undergoing endoscopic sinus surgery and endoscopic modified Lothrop procedure (EMLP)., Methods: Data was collected prospectively between January 2001 and December 2013. Information including demographics, asthma status, aspirin sensitivity, 22-item Sino-Nasal Outcome Test (SNOT-22), Lund-Mackay scores, and endoscopic ostium assessment were collected for up to 5 years. Minimum follow-up was 6 months., Results: A total of 31 AERD patients underwent complete sphenoethmoidectomy, maxillary antrostomy and EMLP during the study period with an average follow-up of 36 months. Polyp recurrence was seen in a total of 18 patients (58%). Seven patients required revision EMLP following initial surgery demonstrating a failure rate of 22.5%. AERD patients had a statistically significant increased risk of both nasal polyps recurrence and need for revision surgery. Revision EMLP was needed due to recurrence of nasal polyps in 6 cases and frontal ostium stenosis in a single case. Time to revision EMLP was similar between the groups., Conclusion: Complete sphenoethmoidectomy, maxillary antrostomy, and EMLP is successful in a significant majority of patients with AERD and CRSwNP. It is well tolerated with a low complication rate and facilitates successful ongoing medical management of the condition in patients with AERD., (© 2016 ARS-AAOA, LLC.)

Background: Chronic rhinosinusitis (CRS) is categorized into 2 types based on the absence (CRSsNP) and presence of nasal polyps (CRSwNP). Although CRSsNP patients lack nasal polyps, the mucosa may show variable degrees of polypoid change. This raises the question of whether or not the classification system is an over simplification and that CRSsNP and CRSwNP only represent 2 phenotypic extremes along a broader spectrum of immunologically different disease processes. To investigate this, adaptive and innate immune cells were compared in the different tissue types within CRSsNP and CRSwNP patients., Methods: Tissue from 15 CRSwNP, 6 CRSsNP, and 8 healthy control patients was obtained prospectively. Nonpolypoid mucosa, polypoid tissues, and polyps were obtained at the time of endoscopic sinus surgery and analyzed using flow cytometry for various adaptive and innate immune cell subsets., Results: In the polyps from CRSwNP patients there were significantly more T regulatory (Treg) cells (12.86 ± 12.60 vs 2.83 ± 4.68) and Th17 cells (16.12 ± 11.75 vs 2.31 ± 2.13) compared to the polypoid tissue from CRSsNP patients. Cellular infiltrates in the nonpolypoid or polypoid mucosa of the different patient categories showed no difference in CRSwNP, CRSsNP and control groups., Conclusion: This observational study identified an increase in Treg and Th17 cells in CRSwNP patients implying that these cells may be implicated in polyp development. Importantly it also identified a similar inflammatory infiltrate in nonpolyp or polypoid mucosa across control, CRSsNP, and CRSwNP groups inferring that polyps should be sampled when studying CRSwNP., (© 2016 ARS-AAOA, LLC.)

Background: Staphylococcus aureus (S. aureus) has been shown to exist within nasal epithelial cells in chronic rhinosinusitis (CRS) patients. This study investigates the localization of intracellular S. aureus (ICSA) in CRS patients, the associated histopathology changes, and their effect on long-term postoperative outcomes., Methods: A prospective study of patients with CRS with and without polyps and control patients (n = 25, 15, and 8, respectively) undergoing endoscopic sinus surgery was performed. Validated patient reported symptom scores and objective endoscopic scores were collected preoperatively and 12 months postoperatively. Mucosal tissue samples were collected and examined for the presence of ICSA using immunohistochemical analysis. Tissue also underwent routine hematoxylin and eosin and Sirius Red staining to evaluate the inflammatory cell load and extent of fibrosis., Results: ICSA appeared to localize to the perinuclear region of the pseudostratified columnar respiratory epithelium. ICSA was more prevalent in CRS without nasal polyps (CRSsNP) than in CRS with nasal polyps (CRSwNP) or controls (80% vs 56% vs 38%, respectively). ICSA positive status did not appear to influence symptom or endoscopic scores at the time of surgery nor 12 months postoperatively. Lymphocytes and total inflammatory cells were significantly increased in ICSA(+) group than ICSA(-) groups (36.4 vs 22.4 cells/area and 53.8 vs 29.1 cells/area, respectively). There was no difference found in fibrosis., Conclusion: This study indicated that ICSA was most prevalent in CRSsNP patients and was associated with increased lymphocytia and total inflammatory cells but not with worse symptomatology, endoscopy results, or basement membrane (BM) thickening., (© 2016 ARS-AAOA, LLC.)

Background: Endoscopic modified Lothrop procedure (EMLP) is used to treat patients who fail conventional sinus surgery. The failure rate of a primary EMLP is reported to be between 5% and 32%. The failure rate of revision EMLP has not been reported. We present our institutions data regarding the outcome of patients requiring revision EMLP., Methods: Data was collected prospectively. Patients undergoing primary EMLP between January 2001 and December 2013 with a minimum follow-up of 6 months were included. Information related to demographics, asthma status, aspirin sensitivity, 22-item Sino-Nasal Outcome Test (SNOT-22) score, Lund-Mackay scores, intraoperative findings, and endoscopic ostium assessment were collected., Results: There were 213 primary EMLPs completed with average follow-up of 36 months. The failure rate of primary EMLP was 8.9% (19/213), whereas the failure rate of revision EMLP was 21% (4/19). Risk factors for failure of primary EMLP included the presence of intraoperative pus, more than 5 previous sinus operations and aspirin-exacerbated respiratory disease (AERD). Revision of EMLP was undertaken primarily due to recurrence of nasal polyps or ostium stenosis. Those patients who underwent revision EMLP experienced symptomatic improvement and no major complications following the procedure., Conclusion: The failure rate of revision EMLP is 21% in our series. The majority of revisions were for nasal polyp recurrence. Revision EMLP is a safe and well-tolerated procedure in the small group of patients that require further surgery. Patients with intraoperative pus present at their initial EMLP, more than 5 previous sinus operations, or AERD are at increased risk of failure., (© 2016 ARS-AAOA, LLC.)

Background: A subgroup of chronic rhinosinusitis with nasal polyps (CRSwNP) patients is refractory to optimal surgical therapy and requires multiple revision sinus operations. Studies have shown that mucosal eosinophilia correlates with disease severity. We hypothesized that a high-grade tissue inflammatory load is associated with these refractory patients., Methods: A single-surgeon, retrospective case-control study comparing 20 CRSwNP patients requiring a second surgery during follow-up (refractory group) vs a matched cohort of 20 CRSwNP patients without needing further revision surgery (control group). Hematoxylin and eosin (H&E)-stained tissue harvested intraoperatively (×2 for the refractory group) were recalled for histopathological examination of subepithelial inflammation and basement membrane (BM) thickness., Results: The refractory group had a significantly higher average eosinophil count (49 vs 18), relative eosinophilia (55% vs 32%) as well as total inflammatory cell count (86 vs 49) than the control group (p < 0.05). However within the refractory group, the eosinophil-lymphocyte ratio was reduced from their first to their second (revision) surgeries whereas the total averaged inflammatory cell count remained unchanged. No significant difference in BM thickness was found between the groups., Conclusion: These findings suggest that a higher inflammatory and eosinophilic load is associated with refractory disease and thus may be useful in predicting need for future revision surgery in CRSwNP., (© 2015 ARS-AAOA, LLC.)

Background: The body of knowledge regarding rhinosinusitis(RS) continues to expand, with rapid growth in number of publications, yet substantial variability in the quality of those presentations. In an effort to both consolidate and critically appraise this information, rhinologic experts from around the world have produced the International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR:RS)., Methods: Evidence-based reviews with recommendations(EBRRs) were developed for scores of topics, using previously reported methodology. Where existing evidence was insufficient for an EBRR, an evidence-based review (EBR)was produced. The sections were then synthesized and the entire manuscript was then reviewed by all authors for consensus., Results: The resulting ICAR:RS document addresses multiple topics in RS, including acute RS (ARS), chronic RS (CRS)with and without nasal polyps (CRSwNP and CRSsNP), recurrent acute RS (RARS), acute exacerbation of CRS (AECRS), and pediatric RS., Conclusion: As a critical review of the RS literature, ICAR:RS provides a thorough review of pathophysiology and evidence-based recommendations for medical and surgical treatment. It also demonstrates the significant gaps in our understanding of the pathophysiology and optimal management of RS. Too often the foundation upon which these recommendations are based is comprised of lower level evidence. It is our hope that this summary of the evidence in RS will point out where additional research efforts may be directed., (© 2016 ARS-AAOA, LLC.)

Background: Patients who suffer from hyposmia and anosmia report a negative effect on their overall quality of life. Smell disturbance of patients with chronic rhinosinusitis (CRS) can improve after endoscopic sinus surgery (ESS). Although several studies have shown that 50-83% of patients may notice an improvement in olfactory function after ESS, the olfactory improvement after revision ESS (RESS), especially by objective measurements, is still lacking., Methods: Olfactory function was assessed by the traditional Chinese version of the University of Pennsylvania Smell Identification Test (UPSIT-TC) preoperatively and postoperatively, recorded as smell identification test (SIT) score. Olfactory outcomes from anosmia to hyposmia/normosmia, or from hyposmia to normosmia, were considered as "improvement." Postoperative assessments were divided into two periods: period 1 (P1) is defined as >6 but <12 months postoperatively; period 2 (P2) is defined as >12 but <24 months postoperatively., Results: Thirty-two patients with smell disturbance preoperatively (period 0 [P0]) and confirmed by UPSIT-TC were enrolled into this study. Mean SIT score at P0 was 13.3; mean SIT score at P1 was 18.6; mean SIT score at P2 was 20.4. The presence of nasal polyps blocking the olfactory cleft were associated with better olfaction improvements (p < 0.05) as was the degree of mucosal swelling. The overall improvement rates were 44.8 and 47.8% at P1 and P2, respectively., Conclusion: RESS resulted in objective evidence of olfactory improvement in approximately one-half of our cohort over 16 months of follow-up and offers a treatment option for an otherwise poor prognosis condition.

Background: The purpose of this level 4, retrospective cohort study was to detail the outcomes of primary, revision, and endoscopic modified Lothrop procedure (EMLP) (Draf III) frontal sinus surgery and evaluate whether risk factors would help determine which patients would benefit from which procedures., Methods: The study used a retrospective chart review. Endoscopic assessment of frontal ostium patency and patient reported symptoms were prospectively collected on patients who underwent frontal sinusotomy between January 2003 and December 2009. High-risk cohorts were studied to assess their response to standard endoscopic sinus surgery (ESS) compared with EMLP., Results: A total of 339 patients who met the inclusion and exclusion criteria underwent either primary or revision endoscopic frontal sinus surgery. The average ± standard deviation (SD) length of follow-up was 20.8 ± 18.7 (95% confidence interval [CI], 18.0-22.9) months. Postsurgical recurrence of disease with persistence of symptoms requiring an EMLP occurred in 9 patients in the primary group and 38 in the revision group. The highest risk groups for failure of standard frontal sinusotomy were patients with nasal polyps, asthma, Lund-Mackay score >16, and frontal ostium size <4 mm (relative risk = 9.9, p < 0.0001)., Conclusion: Patients with underlying asthma and polyposis as well as narrow frontal ostia and extensive radiological disease have a high failure rate from standard endoscopic frontal sinusotomy. In this patient group consideration should be given to offering the patient a primary EMLP procedure, which has excellent success rates with low risks and low morbidity., (© 2013 ARS-AAOA, LLC.)

Background: The complex interplay between host, environment, and microbe in the etiopathogenesis of chronic rhinosinusitis (CRS) remains unclear. This study focuses on the host-microbe interaction, specifically the regulation of nitric oxide (NO) and reactive oxygen species (ROS) against the pathogenic organism Staphylococcus aureus (S. aureus). NO and ROS play crucial roles in innate immunity and in the first-line defense against microbial invasion., Methods: Sinonasal tissue samples were harvested from CRS and control patients during surgery. CRS patients were classified S. aureus biofilm-positive (B+) or biofilm-negative (B-) using fluorescence in situ hybridization and clinically as polyp-positive (P+) or polyp-negative (P-). Samples were assessed using an NO polymerase chain reaction (PCR) array containing 84 genes involved in NO and ROS regulation, and gene expression of all subgroups were compared to each other., Results: Twenty-three samples were analyzed with 31 genes significantly changed, the greatest seen in the B+P+ CRS patients. Four genes consistently displayed differential expression between the groups including the cytoprotective oxidation resistance 1 (OXR1) and peroxiredoxin 6 (PRDX6), neutrophil cytosolic factor 2 (NCF2), and the prion protein (PRNP) genes., Conclusion: Alteration in gene expression points to impaired innate immune responses differing among CRS subgroups based on S. aureus biofilm and polyp status. The consistent alteration of 4 genes among distinct groups demonstrates that S. aureus biofilms and polyps are associated with specific changes in gene expression. Further studies are required to validate these findings in a wider cohort of patients and correlate this to protein expression and disease manifestation., (© 2013 ARS-AAOA, LLC.)

Objectives/hypothesis: Patients with aggressive nasal polyp recurrence form an important subgroup of patients with refractory sinus disease. The objectives of this study were to establish patterns of polyp recurrence and evaluate the effect of frontal sinus surgery (Draf 2a vs. Draf 3) on polyp recurrence., Study Design: Retrospective cohort study reviewing 338 consecutive operations., Methods: Polyp recurrence was defined according to the Lund-Kennedy mucosal edema score. Survival analysis methods were used for statistics., Results: After complete sphenoethmoidectomies, Draf 2a frontal sinusotomies, and middle meatal antrostomies persistent polyp recurrence occurred in 19.8% of patients after 6 months and increased to 22.7% of patients after 12 months. Polyps first recurred in the area of the frontal sinus/ostium (55%) followed by the ethmoids (38%). Asthma and aspirin sensitivity were the most important variables affecting recurrence (hazard ratios, 1.71, 1.79, respectively; P < .05) The Draf 3 procedure was a significant factor in reducing recurrence, especially in asthma and aspirin intolerant patients. The overall revision rate was 18% (follow-up duration >12 months, median = 29 months), with a 37% revision rate in the FESS group versus 7% in the Draf 3 group (P < .001). Survival analysis showed that the Draf 3 significantly reduced the risk of revision (hazard ratio = 0.258, P = .0026)., Conclusions: Nasal polyposis is characterized by a high rate of recurrence. The presence of asthma or aspirin intolerance leads to more aggressive recurrence, and in these patients the Draf 3 drillout procedure becomes a good option for improved long-term outcomes and reducing the need for revision surgery., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

The European Position Paper on Rhinosinusitis and Nasal Polyps 2012 is the update of similar evidence based position papers published in 2005 and 2007.The document contains chapters on definitions and classification, we now also proposed definitions for difficult to treat rhinosinusitis, control of disease and better definitions for rhinosinusitis in children. More emphasis is placed on the diagnosis and treatment of acute rhinosinusitis. Throughout the document the terms chronic rhinosinusitis without nasal polyps and chronic rhinosinusitis with nasal polyps are used to further point out differences in pathophysiology and treatment of these two entities. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. Last but not least all available evidence for management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is analyzed and presented and management schemes based on the evidence are proposed.

The European Position Paper on Rhinosinusitis and Nasal Polyps 2012 is the update of similar evidence based position papers published in 2005 and 2007. The document contains chapters on definitions and classification, we now also proposed definitions for difficult to treat rhinosinusitis, control of disease and better definitions for rhinosinusitis in children. More emphasis is placed on the diagnosis and treatment of acute rhinosinusitis. Throughout the document the terms chronic rhinosinusitis without nasal polyps (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP) are used to further point out differences in pathophysiology and treatment of these two entities. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. Last but not least all available evidence for management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is analyzed and presented and management schemes based on the evidence are proposed. This executive summary for otorhinolaryngologists focuses on the most important changes and issues for otorhinolaryngologists. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.

Background: There is little scientific evidence to support the current practice of using oral glucocorticosteroids and antibiotics to treat patients with chronic rhinosinusitis and nasal polyps., Objective: We evaluated the effects of oral glucocorticoids and doxycycline on symptoms and objective clinical and biological parameters in patients with chronic rhinosinusitis and nasal polyps., Methods: In a double-blind, placebo-controlled, multicenter trial, we randomly assigned 47 participants with bilateral nasal polyps to receive either methylprednisolone in decreasing doses (32-8 mg once daily), doxycycline (200 mg on the first day, followed by 100 mg once daily), or placebo for 20 days. Participants were followed for 12 weeks. Patients were assessed for nasal peak inspiratory flow and symptoms and by nasal endoscopy. Markers of inflammation such as eosinophilic cationic protein (ECP), IL-5, myeloperoxidase, matrix metalloproteinase 9, and IgE were measured in nasal secretions. Concentrations of eosinophils, ECP, and soluble IL-5 receptor alpha were measured in peripheral blood samples., Results: Methylprednisolone and doxycycline each significantly decreased nasal polyp size compared with placebo. The effect of methylprednisolone was maximal at week 3 and lasted until week 8, whereas the effect of doxycycline was moderate but present for 12 weeks. Methylprednisolone significantly reduced levels of ECP, IL-5, and IgE in nasal secretions, whereas doxycycline significantly reduced levels of myeloperoxidase, ECP, and matrix metalloproteinase 9 in nasal secretions., Conclusion: This is the first double-blind, placebo-controlled study to show a significant effect of oral methylprednisolone and doxycycline on size of nasal polyps, nasal symptoms, and mucosal and systemic markers of inflammation., (Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: The aim of this study was to determine the expression of cell cycle regulation genes in patients with inverted papilloma (IP) and compare this with expression in patients with nasal polyps (NPs)., Methods: Tissue from 18 patients with IP and 5 patients with NPs were stained by immunohistochemistry techniques for p53 and p27. Measurement of the gene expression was performed by three assessors, who we blinded with respect to the specimens., Results: The mean score for p53 expression (3.33) was significantly higher in the IP group than the NP group (1.46). The mean difference between IP and NPs was 1.80 (CI, 1.15-2.46; p = 0.003). Additionally, we showed in a number of individuals variation in the p53 expression within the same specimen. There was no difference in the mean scores for p27, with the mean difference 0.79 (CI, 0.30-1.89; p = 0.147)., Conclusion: Our study established a significantly increased expression of p53 in IP when compared with NPs. Additionally, there appear to be two different cell populations identified within the same specimens, which exhibited variation in their p53 expression.

Chronic rhinosinusitis (CRS) represents chronic inflammation of the sinus mucosa characterised by dysfunction of the sinuses' natural defence mechanisms and induction of different inflammatory pathways ranging from a Th1 to a Th2 predominant polarisation. Recalcitrant CRS is associated with Staphylococcus aureus dominant mucosal biofilms; however, S. aureus colonisation of the sinonasal mucosa has also been observed in healthy individuals challenging the significance of S. aureus in CRS pathogenesis. We aimed to investigate the relationship between CRS key inflammatory markers, S. aureus biofilm properties/virulence genes and the severity of the disease. Tissue samples were collected during endoscopic sinus surgery from the ethmoid sinuses of CRS patients with (CRSwNP) and without (CRSsNP) nasal polyps and controls (n = 59). CD3+ T‐cell subset frequencies and key inflammatory markers of CD4+ helper T cells were determined using FACS analysis. Sinonasal S. aureus clinical isolates were isolated (n = 26), sequenced and grown into biofilm in vitro, followed by determining their properties, including metabolic activity, biomass, colony‐forming units and exoprotein production. Disease severity was assessed using Lund–Mackay radiologic scores, Lund–Kennedy endoscopic scores and SNOT22 quality of life scores. Our results showed that S. aureus biofilm properties and CRS severity scores correlated positively with total CD4+ T‐cell frequencies but looking into CD4+ T‐cell subsets showed an inverse correlation with Th1 and Th17 cell frequencies. CD4+ T‐cell frequencies were higher in patients harbouring lukF.PV‐positive S. aureus while its regulatory and Th17 cell subset frequencies were lower in patients carrying sea− and sarT/U‐positive S. aureus. Recalcitrant CRS is characterised by increased S. aureus biofilm properties in relation to increased total CD4+ helper T‐cell frequencies and reduced frequencies of its Th1, Th17 and regulatory T‐cell subsets. These findings offer insights into the pathophysiology of CRS and could lead to the development of more targeted therapies. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis (CRS) is a persistent inflammation of the nasal cavity and paranasal sinuses associated with tissue remodelling, dysfunction of the sinuses' natural defence mechanisms, and induction of different inflammatory clusters. The etiopathogenesis of CRS remains elusive, and both environmental factors, such as bacterial biofilms and the host's general condition, are thought to play a role. Bacterial biofilms have significant clinical relevance due to their potential to cause resistance to antimicrobial therapy and host defenses. Despite substantial medical advances, some CRS patients suffer from recalcitrant disease that is unresponsive to medical and surgical treatments. Those patients often have nasal polyps with tissue eosinophilia, S. aureus-dominant mucosal biofilm, comorbid asthma, and a severely compromised quality of life. This review aims to summarise the contemporary knowledge of inflammatory cells/pathways in CRS, the role of bacterial biofilm, and their impact on the severity of the disease. Here, an emphasis is placed on S. aureus biofilm and its secreted products. A better understanding of these factors might offer important diagnostic and therapeutic perceptions for recalcitrant disease. [ABSTRACT FROM AUTHOR]

I aeruginosa i clinical isolates from recalcitrant CRS patients in their planktonic and biofilm stages and to investigate I in vitro i safety application of acriflavine on human nasal epithelial cells (HNECs). The minimum biofilm eradication concentration (MBEC) was determined (320 µg/ml) using AlamarBlue (Figure S1C,D) and crystal violet assays (Figure S1E,F), which resulted in the significant killing of biofilms and reduction in biofilm biomass of matured biofilm ( I p i < .05, Figure S1). Novel anti-biofilm drugs that could be topically applied to the nasal mucosa safely and without promoting antibiotic resistance could address multiple current unmet needs. [Extracted from the article]

Chronic rhinosinusitis (CRS) has a complex and multifactorial pathogenesis with a heterogeneous inflammatory profile. Proteomic analysis of nasal mucus may enable further understanding of protein abundances and biologic processes present in CRS and its endotypes compared with in healthy patients. Our aim was to determine differences in the nasal mucus proteome of healthy patients and patients with CRS. Nasal mucus was obtained from healthy patients, patients with CRS without nasal polyps (CRSsNP), and patients with CRS with nasal polyps (CRSwNP) before surgery. Gel electrophoresis was performed to fractionate the complex protein extracts before mass spectrometry analysis. Gene set enrichment analysis was performed on differentially expressed proteins. A total of 33 patients were included in this study (12 healthy, 10 with CRSsNP, and 11 with CRSwNP). In all, 1142 proteins were identified in mucus samples from healthy patients, 761 in mucus samples from patients with CRSsNP, and 998 in mucus samples from patients with CRSwNP. Dysfunction in immunologic pathways, reduced cellular signaling, and increased cellular metabolism with associated tissue remodeling pathways were present in patients with CRS compared with in healthy patients. Significant downregulation of mucosal immunity and antioxidant pathways with increased tissue modeling processes may account for the clinical manifestations of CRS. Ultimately, the differing proteome and biologic processes provide further insight into CRS pathogenesis and its endotypes. [ABSTRACT FROM AUTHOR]

B, CRS HNEC-ALI demonstrated significantly reduced TER compared with control HNEC-ALI when healthy mucus and CRSsNP mucus was applied. Similarly, mucus from CRSsNP patients induced an increased release of IL-6 by HNEC-ALI cells compared with mucus from healthy control patients (0.759 vs 0.174 pg/mL, I P i = .008) (Figure D). In fact, CRSwNP mucus samples had cytotoxic effects on HNEC-ALI cultures and both CRSsNP and CRSwNP mucus induced increased IL-8 and IL-6 cytokine release by the cells compared with negative control. [Extracted from the article]

Matrix metalloproteinase (MMP)-9 is thought to be involved in the etiopathogenesis of chronic rhinosinusitis (CRS) with nasal polyps and cleaves collagen IV, causing hyperpermeability of the basement membrane within mucosal tissue. It is known that MMP-9 expression is negatively affected by sirtuin (SIRT)-1 in human monocytotic cells, retinal endothelial cells, and epithelial carcinoma cells. However, it is unknown which factors affect MMP-9 expression and activity in human nasal epithelial cells (HNECs). To examine factors affecting MMP-9 expression and activity in HNECs, HNECs were stimulated with Toll-like receptor (TLR) agonists, followed by quantitative PCR, immunofluorescence, and zymography to examine MMP-9 expression and activity. MMP-9 expression was evaluated in sinonasal tissue of control subjects without CRS, and patients with CRS without nasal polyps and those with CRS with nasal polyps, in relation to the expression of SIRT1 using a tissue microarray. The effect of SIRT1 stimulation/inhibition on MMP-9 expression in HNECs was also tested. TLR3 agonists increased MMP-9 mRNA expression (473 fold, P = 0.0198) and activity (20.4-fold, P < 0.05). SIRT1 activation or inhibition reciprocally affected MMP-9 expression in the presence of TLR3 agonists. MMP-9 and SIRT1 expression within the epithelial layer of sinonasal tissue was inversely correlated only in patients with CRS but not in control subjects. TLR3 agonists increased MMP-9 expression and activity in HNECs, and the effect was abolished in the presence of SIRT1 activation. SIRT1 and MMP-9 expression was inversely correlated in CRS tissue, supporting SIRT1 as a possible therapeutic target for nasal polyp formation. [ABSTRACT FROM AUTHOR]

Background: The appropriate surgical approach to the severely diseased maxillary sinus is still debatable. Some advocate creating a wide maxillary antrostomy to allow for increased ventilation and improved delivery of postoperative medication. Others, however, recommend more aggressive surgery with complete clearance of all diseased tissue. The aim of this study was to evaluate the outcome of canine fossa puncture and canine fossa trephine (CFT) for the severely diseased maxillary sinus. Methods: A retrospective chart review was performed on 97 patients who underwent a CFT as a part of endoscopic sinus surgery or modified Lothrop procedure. Outcomes were measured in terms of the maxillary sinus endoscopy grade at last follow-up and need for revision surgery. Two groups were formed: those who experienced recurrence of disease and those who were disease free at last follow-up. A comparison was made between the two groups and differences were noted. Results: A CFT was performed in 97 patients with nasal polyposis (NP) who had an average number of 2.38 previous sinus surgeries. At an average follow-up of 27.8 months, 80 of the patients were disease free. In 17 patients disease recurred, and 11 of those required revision surgery with a CFT. Those patients who had recurrence of disease tended to be more allergic, have higher Lund-Mackay score, and had an increased number of prior sinus surgeries. In addition, allergic fungal sinusitis was associated with a poorer prognosis after CFT. Conclusion: CFT allows for complete clearance of all gross disease in the maxillary sinus. CFT decreases the chance of disease recurrence in patients with severe NP. [ABSTRACT FROM AUTHOR]

Background: This study reviews the role of frontal sinus minitrephination in today's era of endoscopic sinus surgery. Retrospective chart review was performed of 163 patients undergoing a total of 149 bilateral and 39 unilateral frontal sinus minitrephinations. Methods: Charts were reviewed for patient demographics and outcomes. Details obtained from the chart included type of surgery performed, reason for minitrephine placement, pathology, Lund score, complications, and endoscopic patency. Results: One hundred eighty-eight minitrephines were placed during 80 modified Lothrop and 108 frontal sinusotomies. Trephines were placed when there was difficulty finding the frontal recess, severe edema/polyps, obstructing frontal cells (type 3/type 4 frontoethmoidal cells and intersinus septum cell), and to aid the dissection and postoperative irrigation during the modified Lothrop. Twelve complications occurred with infection at the trephine site being the most common. Follow-up ranged from 2 to 122 months (average, 25.5 months) with 92% showing endoscopic patency at last visit. Conclusion: Frontal sinus trephination is a safe useful procedure that can be extremely helpful in identifying the pathway to the frontal sinus. Fluorescein flushes through the trephine help guide the dissection in a modified Lothrop. Lastly, it may be used in the postoperative period to flush the sinus with saline and steroids to promote patency of the frontal sinus. [ABSTRACT FROM AUTHOR]

Chronic Rhinosinusitis (CRS) is a multifactorial disease where microorganisms' innate and adaptive immunity can play a role. This study assessed the total IgG, IgG subclasses, IgE and IgA levels in serum samples from CRS and non-CRS control patients in relation to the disease severity, phenotype, histopathology and comorbidities. Total serum IgG, IgG1, IgG2, IgG3, IgG4 and IgE was determined from 10 non-CRS controls, 10 CRS without nasal polyp (CRSsNP) and 26 CRS with nasal polyp (CRSwNP) patients using ImmunoCap assays. Tissue lysates were analyzed for IgG levels by ELISA. Immunohistochemical analysis was used to measure the expression of IgE and IgG4 in tissue sections. The presence of anti-nuclear antigens (ANAs) against 12 autoantigens in sera and tissue lysates was determined by immunoblot assays. Total serum IgG/IgG1/IgG2 levels were higher in CRS patients vs. controls (p < 0.001), but were not different between CRSwNP and CRSsNP patients (p = 0.57). Serum IgG4/IgE levels were increased in CRSwNP patients compared to controls (p = 0.006), however, this relationship was attenuated by the inclusion of covariates. Serum IgG4 levels were more strongly associated with asthma (p = 0.038, exact median test) and tissue eosinophilia (Spearman's rank rho = 0.51, p = 0.016) than IgE levels. No systemic ANAs were detected in any of the subjects tested. There was a polyclonal increase in serum immunoglobulins in CRS patients with elevated IgG4/IgE levels in CRSwNP patients having tissue eosinophilia and asthma. [ABSTRACT FROM AUTHOR]

Background: Staphylococcus aureus has a high prevalence in chronic rhinosinusitis (CRS) patients and is suggested to play a more etiopathogenic role in CRS patients with nasal polyps (CRSwNP), a severe form of the CRS spectrum with poorer surgical outcomes. We performed a microbial genome-wide association study (mGWAS) to investigate whether S. aureus isolates from CRS patients have particular genetic markers associated with CRS with nasal polyps (CRSwNP) or CRS without nasal polyps (CRSsNP). Methods: Whole genome sequencing was performed on S. aureus isolates collected from 28 CRSsNP and 30 CRSwNP patients. A mGWAS approach was employed using large-scale comparative genomics to identify genetic variation within our dataset. Results: Considerable genetic variation was observed, with > 90,000 single nucleotide polymorphisms (SNPs) sites identified. There was little correlation with CRS subtype based on SNPs and Insertion/Delection (Indels). One indel was found to significantly correlate with CRSwNP and occurred in the promoter region of a bacitracin transport system ATP-binding protein. Additionally, two variants of the highly variable superantigen-like (SSL) proteins were found to significantly correlate with each CRS phenotype. No significant association with other virulence or antibiotic resistance genes were observed, consistent with previous studies. Conclusion: To our knowledge this study is the first to use mGWAS to investigate the contribution of microbial genetic variation to CRS presentations. Utilising the most comprehensive genome-wide analysis methods available, our results suggest that CRS phenotype may be influenced by genetic factors other than specific virulence mechanisms within the S. aureus genome. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis (CRS) is a persistent inflammation of the sinus mucosa. Recalcitrant CRS patients are unresponsive to medical and surgical interventions and often present with nasal polyps, tissue eosinophilia, and Staphylococcus aureus dominant mucosal biofilms. However, S. aureus sinonasal mucosal colonisation occurs in the absence of inflammation, questioning the role of S. aureus in CRS pathogenesis. Here, we aimed to investigate the relationship between S. aureus biofilm metabolic activity and virulence genes, innate immune cells, and disease severity in CRS. Biospecimens, including sinonasal tissue and nasal swabs, and clinical datasets, including disease severity scores, were obtained from CRS patients and non-CRS controls. S. aureus isolates were grown into biofilms in vitro , characterised, and sequenced. The patients' innate immune response was evaluated using flow cytometry. S. aureus was isolated in 6/19 (31.58%) controls and 23/53 (43.40%) CRS patients of 72 recruited patients. We found increased S. aureus biofilm metabolic activity in relation to increased eosinophil cell frequencies and disease severity in recalcitrant CRS cases. Mast cell frequencies were higher in tissue samples of patients carrying S. aureus harbouring lukF.PV , sea, and fnbB genes. Patients with S. aureus harbouring lukF.PV and sdrE genes had more severe disease. This offers insights into the pathophysiology of CRS and could lead to the development of more targeted therapies. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: The treatment of the middle turbinate (MT) during endoscopic sinus surgery (ESS) for chronic rhinosinusitis (CRS) remains a contentious issue with arguments both for and against its resection. The purpose of this study was to examine the clinical impact of partial MT resection (PMTR) during ESS, paying particular attention to the risk of developing empty nose syndrome (ENS) and alteration to olfaction. Methods: This cohort study was performed on prospectively collected data. A total of 177 patients underwent ESS for CRS; 93 had PMTR and 84 MT preservation (MTP). Preoperative data collection included subjective symptom scores as per the Adelaide Disease Severity Score (ADSS), Lund‐Mackay scores, and nasal polyp status. The Empty Nose Syndrome 6‐Item Questionnaire (ENS6Q) was administered by telephone consultation and analyzed alongside postoperative symptom scores. Results: There was no difference in ENS6Q scores in patients who underwent PMTR vs those who had MTP. Patients who underwent PMTR had a higher baseline disease on Lund‐Mackay scoring, and were more likely to be nasal polyp patients and be undergoing revision surgery. ADSS scores demonstrated significant improvements in all rhinologic symptoms, with no difference between the cohorts. Conclusion: PMTR is an adjunctive procedure to ESS. This study has established that PMTR as performed by the senior author carries no additional risk of developing ENS symptoms as defined by the ENS6Q, and that it carries no additional risk to olfaction or other rhinologic symptoms. PMTR can be safely considered at time of ESS, especially in patients at risk of lateralization of the MT. [ABSTRACT FROM AUTHOR]