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Following the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) treatment algorithm for chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), patients suffering from severe uncontrolled CRSwNP are recommended to receive oral corticosteroids, (revision) sinus surgery, systemic biologicals and/or aspirin treatment after desensitization (ATAD). Given the major differences in indications, outcomes, practical considerations, risks and costs of these key pillars of treatment, there is a growing need to define criteria for each treatment option and list the clinically relevant and major considerations for them. This EUFOREA document therefore provides an expert panel overview of the expected outcomes, specific considerations and (contra)indications of the five major treatment arms of severe uncontrolled CRSwNP: oral corticosteroids, primary and revision sinus surgery, biological treatment and ATAD. This overview of treatment considerations is needed to allow physicians and patients to consider the different options in the context of providing optimal and personalized care for severe uncontrolled CRSwNP. In conclusion, the five major treatment options for severe uncontrolled CRSwNP have intrinsic advantages, specific indications and considerations that are of importance to the patient, the physician and the society. This EUFOREA statement supports the unmet need to define criteria for the indication of every treatment pillar of CRSwNP., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Allergic fungal rhinosinusitis (AFRS) is a unique clinical entity that falls under the broader umbrella of chronic rhinosinusitis with nasal polyps with type 2 inflammation. It is characterized by nasal polyposis, production of characteristic thick eosinophilic mucin, and expansile change of involved sinus cavities. The diagnosis is classically made using the Bent and Kuhn criteria. However, recent studies have indicated the lack of specificity of some major criteria. The need to fulfill all 5 criteria before diagnosing AFRS partially mitigates this but renders the criteria cumbersome to use, and highlights the need to develop more specific criteria. Our understanding of AFRS pathophysiology has advanced significantly and has helped elucidate the lack of histatins contributing to the inability to clear fungal spores, consequently leading to fungi-induced disruption of the epithelial barrier and stimulation of sinonasal epithelial cells. These trigger a cascade of type 2 inflammatory cytokines driven by both the adaptive and innate immune system. Although more research is needed, these findings could hypothetically point to a limited type 3 immune response at the sinus mucosa, resulting in a compensatory overstimulation of type 2 inflammatory processes. Treatment for AFRS remains centered on surgery and topical corticosteroids. Short courses of systemic corticosteroids may be used with caution, and fungal-specific immunotherapy and systemic antifungals are options in recalcitrant disease. Biologics show early promise, as we await data from randomized controlled trials under way. Finally, new insights into AFRS pathology provide opportunities for novel therapeutic strategies., (Copyright © 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The unified airway hypothesis proposes that upper and lower airway diseases reflect a single pathological process manifesting in different locations within the airway. Functional, epidemiological, and pathological evidence has supported this well-established hypothesis for some time. However, literature on the pathobiologic roles/therapeutic targeting of eosinophils and IL-5 in upper and lower airway diseases (including asthma, chronic rhinosinusitis with nasal polyps [CRSwNP], and nonsteroidal anti-inflammatory drug-exacerbated respiratory disease) has recently emerged. This narrative review revisits the unified airway hypothesis by searching the scientific literature for recent learnings and clinical trial/real-world data that provide a novel perspective on its relevance for clinicians. According to the available literature, eosinophils and IL-5 have important pathophysiological roles in both the upper and lower airways, although the impact of eosinophils and IL-5 may vary in asthma and CRSwNP. Some differential effects of anti-IL-5 and anti-IL-5-receptor therapies in CRSwNP have been observed, requiring further investigation. However, pharmaceutical targeting of eosinophils and IL-5 in patients with upper, lower, and comorbid upper and lower airway inflammation has led to clinical benefit, supporting the hypothesis that these are linked conditions manifesting in different locations. Consideration of this approach may improve patient care and aid clinical decision making., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Allergic fungal rhinosinusitis (AFRS) is an endotype of chronic rhinosinusitis (CRS) with nasal polyps characterized by eosinophilic mucin laden with fungal hyphae entrapped in expanded sinus cavities with an exaggerated hypersensitivity to fungal elements. The last decade has elucidated fungi-driven inflammatory pathways contributing to the pathophysiology of chronic inflammatory respiratory diseases. In addition, novel therapeutic biologic options have become available for CRS over the last several years., Objective: To review the current literature examining AFRS, focusing on recent developments in our understanding of its pathophysiology and implications for treatment options., Methods: Review article., Results: Fungi-driven respiratory inflammation has been linked to fungal proteinases and toxin activity. In addition, AFRS patients demonstrate a local sinonasal immunodeficiency in antimicrobial peptides and hence limited antifungal activity, along with an exaggerated type 2 inflammatory response, highlighting a possible imbalanced type 1, type 2, and type 3 profile. The elucidation of these dysregulated molecular pathways has highlighted novel potential therapeutic targets. As such, the clinical management of AFRS, which once included surgery and extended courses of oral corticosteroids, is transitioning away from long courses of oral corticosteroids to incorporate novel delivery mechanisms of topical therapeutic targets and biologics for recalcitrant disease., Conclusion: AFRS is an endotype of CRS with nasal polyps (CRSwNP) for which the molecular pathways leading to its inflammatory dysfunction are beginning to be illuminated. In addition to affecting treatment options, these understandings may shape necessary changes to diagnostic criteria and the extrapolated effects of environmental changes on AFRS. More critically, a better appreciation of fungi-driven inflammatory pathways may have implications for the understanding of broader CRS inflammation.

These evidence-based guidelines support patients, clinicians, and other stakeholders in decisions about the use of intranasal corticosteroids (INCS), biologics, and aspirin therapy after desensitization (ATAD) for the management of chronic rhinosinusitis with nasal polyposis (CRSwNP). It is important to note that the current evidence on surgery for CRSwNP was not assessed for this guideline nor were management options other than INCS, biologics, and ATAD. The Allergy-Immunology Joint Task Force on Practice Parameters formed a multidisciplinary guideline panel balanced to include the views of multiple stakeholders and to minimize potential biases. Systematic reviews for each management option informed the guideline. The guideline panel used the Grading of Recommendations Assessment, Development and Evaluation approach to inform and develop recommendations. The guideline panel reached consensus on the following statements: (1) In people with CRSwNP, the guideline panel suggests INCS rather than no INCS (conditional recommendation, low certainty of evidence). (2) In people with CRSwNP, the guideline panel suggests biologics rather than no biologics (conditional recommendation, moderate certainty of evidence). (3) In people with aspirin (nonsteroidal anti-inflammatory drug)-exacerbated respiratory disease, the guideline panel suggests ATAD rather than no ATAD (conditional recommendation, moderate certainty of evidence). The conditions for each recommendation are discussed in the guideline., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Allergic fungal rhinosinusitis (AFRS) is a noninvasive subtype of chronic rhinosinusitis with nasal polyps (CRSwNP) that usually develops in immunocompetent atopic individuals and is more common in geographic regions characterized by warm temperatures and high humidity, conducive to higher environmental fungal presence. Allergic fungal rhinosinusitis usually presents with unique computed tomography findings and significant polyp burden, yet patients often report minimal sinus symptoms. Patients with AFRS often have extremely elevated serum total and fungal-specific IgE levels. Treatment almost always requires surgery, in which adjuvant medical therapy is critical to success. However, until recently the choice of adjuvant therapy has consisted primarily of either oral and/or topical steroids. Although oral corticosteroids decrease recurrence after surgery, data for the effectiveness of other adjunctive pharmacologic agents, including topical and oral antifungal agents and immunotherapy, have remained unclear and hence are not recommended in recent guidelines including the International Consensus of Allergy and Rhinology. Three biologics, omalizumab, dupilumab, and mepolizumab, have recently been approved for treating CRSwNP in general, but clinical trials to date with these biologics did not involve AFRS patients. Recently published case reports and smaller prospective studies have shown good efficacy of these biologics on the AFRS subgroup of patients. This article provides an overview of the understanding of the pathophysiology of AFRS, implications of this understanding on the possible role of biologics, and clinical reports on the use of biologics in treating AFRS. Because biologics are indicated for treating CRSwNP, follow up real-world evidence studies are needed for AFRS., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS), latest version EPOS2020, and the International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR-RS), latest version ICAR-RS-2021, assimilate thousands of articles on the topic of rhinosinusitis. Encompassing scores of subtopics and relying on the perspectives of many international experts, EPOS2020 and ICAR-RS-2021 reduce the existing data into consumable formats and create evidence-based recommendations. The approaches and findings are similar in many respects but have significant differences. This clinical commentary, authored by some of the principal authors of these documents, compares and contrasts EPOS2020 and ICAR-RS-2021, examining methodology, diagnostic and treatment recommendations, and each document's emphases. This commentary demonstrates that, through somewhat differing methodologies, the 2 documents arrive at largely similar conclusions. Those who care for patients suffering from rhinosinusitis will find the documents complementary and valuable in their differences as much as in their similarities., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

In the last two decades, the development of culture-independent genomic techniques has facilitated an increased appreciation of the microbiota-immunity interactions and their role in a multitude of chronic inflammatory diseases such as chronic rhinosinusitis (CRS), asthma, inflammatory bowel disease and dermatitis. While the pathologic role of bacteria in chronic inflammatory diseases is generally accepted, the understanding of the role of fungi remains controversial. Chronic rhinosinusitis, specifically the phenotype linked to nasal polyps, represents a spectrum of chronic inflammatory diseases typically characterized by a type 2 immune response. Studies on the microbiota within sinus cavities from healthy and diseased patients have focused on the bacterial community, mainly highlighting the loss of diversity associated with sinus inflammation. Within the various CRS with nasal polyps (CRSwNP) phenotypes, allergic fungal rhinosinusitis presents an opportunity to investigate the role of fungi in chronic type 2 immune responses as well as the antifungal immune pathways designed to prevent invasive fungal diseases. In this review, we examine the spectrum of fungi-associated sinus diseases highlighting the interaction between fungal species and host immune status on disease presentation. With a focus on fungi and type 2 immune response, we highlight the current knowledge and its limitations of the sinus mycobiota along with cellular interactions and activated molecular pathways linked to fungi., (© 2021 ARS-AAOA, LLC.)

Biologics have recently been approved for use in chronic rhinosinusitis with nasal polyps patients. While effective in controlling disease on subjective and objective short-term outcome measures, limited data suggest that biologics have the potential to be used long term. The current wholesale acquisition costs for biologics are quite high. Widespread, prolonged use of these medications may create a large burden to our healthcare system. Cost-effectiveness analyses, particularly for specific patient cohorts, are needed to determine appropriate use of these medications. The ethics of patient preference of various treatment options, counseling regarding side effect profiles, and healthcare economics also need to be addressed., (© 2021 ARS-AAOA, LLC.)

Background: Biologic medications are emerging as options for treating chronic rhinosinusitis with nasal polyps (CRSwNP). Several questions remain regarding patient selection, indications, clinical efficacy, and cost effectiveness., Methods: In November 2019, a group of physicians and scientists gathered to consider strategies for future studies regarding biologics. During the discussion, gaps in knowledge highlighted a need for a consensus on the present day use of biologics in polyp patients., Results: The goal of this guideline is to propose recommendations for the current use of biologics in CRSwNP as new evidence continues to emerge and inform practice., Conclusion: We suggest that physicians evaluate patients on an individual basis and closely monitor for improvement due to the high cost and unknown long-term effects of biologics., (© 2020 ARS-AAOA, LLC.)

Allergic fungal rhinosinusitis (AFRS) represents a subtype of chronic rhinosinusitis with nasal polyposis that exhibits a unique, often striking clinical presentation. Since its initial description more than a quarter century ago, a more sophisticated understanding of the pathophysiology of AFRS has been achieved and significant advancements in improving clinical outcomes made. This review focuses on the latest developments involving the pathophysiology and clinical management of this fascinating disease., Competing Interests: Disclosure A.U. Luong serves as a consultant for Aerin Medical (Sunnyvale, California), Arrinex (Redwood City, California), Lyra Therapeutics (Watertown, Massachusetts), and Stryker (Kalamazoo, Michigan). She is on the advisory board for ENTvantage (Austin, Texas), Sanofi (Paris, France), and Novartis (Basel, Switzerland)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: In the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP), Aspergillus fumigatus (A. fumigatus) can upregulate IL-33 from human sinonasal epithelial cells (SNECs), which then activates innate lymphoid cells causing release of IL-13, an important driver of allergic inflammation. However, the mechanism by which A. fumigatus mediates the induction of IL-33 expression remains to be elucidated. The objectives of this study were to determine the specific fungal component(s) and the receptor responsible for mediating the A. fumigatus induced increase in IL-33 expression in SNECs from patients with CRSwNP., Methods: SNECs from CRSwNP patients were cultured and stimulated with various fungal components in the absence or presence of 4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride, an irreversible serine protease inhibitor, or GB83, a reversible protease activated receptor 2 (PAR2) inhibitor. IL-33 expression was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). PAR2 expression was examined in inflamed mucosa from nonatopic control and CRSwNP patients., Results: Elevation of IL-33 expression in primary SNECs was found in response to fungal protease but not fungal cell wall components. PAR2 expression was elevated in inflamed mucosa from CRSwNP patients in comparison to controls. The A. fumigatus fungal protease-mediated elevation in IL-33 expression by human SNECs was serine protease- and PAR2-dependent., Conclusion: These data suggest that serine protease activity of A. fumigatus is capable of inducing IL-33 expression in CRSwNP SNECs via PAR2, a potential therapeutic target in the treatment of CRSwNP., Level of Evidence: NA Laryngoscope, 129:2230-2235, 2019., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Bioabsorbable steroid-releasing implants (mometasone furoate, 370 μg) are effective for improving postsurgical outcomes in the frontal sinus ostia (FSO). In this study we evaluated the effect of these implants on frontal outcomes in various patient subgroups with chronic rhinosinusitis (CRS) using pooled data from 2 randomized, controlled trials (RCTs)., Methods: A total of 160 subjects were enrolled in 2 RCTs. After surgery, subjects were randomized to receive an implant in 1 FSO with the contralateral side as control. Data through day 90 from the 2 studies were pooled and subgroup analyses were performed., Results: At day 30, relative to controls, steroid-releasing implants significantly reduced the need for postoperative interventions by 46.8% (95% confidence interval [CI], -60.7 to -27.9), for surgical interventions by 51.2% (95% CI, -68.2 to -25.2), and for oral steroid interventions by 37.2% (95% CI, -54.6 to -13.1) in the pooled data set. At day 90, statistically significant reductions (p < 0.05) in the need for postoperative interventions (relative reduction [RR], 30.2%), restenosis/occlusion rate (RR, 31.7%), and inflammation score (absolute difference, -6.0), and increase in estimated FSO diameter (absolute difference, 1 mm), favoring the treated side, were observed. Subgroup analyses of the pooled data showed statistically significant improvements (p < 0.05) at day 90 in restenosis/occlusion rate, and estimated FSO diameter, favoring the treated side across subgroups, with no statistically significant subgroup-by-treatment interactions., Conclusion: Bioabsorbable steroid-releasing sinus implants improve outcomes of frontal sinus surgery through 90 days, irrespective of asthma status, previous endoscopic sinus surgery, extent of surgery, extent of polyps, or Lund-Mackay computed tomography stage in the FSO., (© 2018 The Authors International Forum of Allergy & Rhinology, published by ARSAAOA, LLC.)

Objective Allergic fungal rhinosinusitis (AFRS) is a clinical subtype of chronic rhinosinusitis with nasal polyps (CRSwNP), characterized by eosinophilic mucin, evidence of fungal elements within the mucin, fungal-specific type I hypersensitivity, and characteristic computed tomography findings. It remains controversial whether AFRS represents a disease with a unique pathophysiology from chronic rhinosinusitis or is merely a severe form of CRSwNP. The goal of this study was to identify molecular features unique to AFRS. Study Design Cross-sectional case-control. Setting Single academic tertiary referral institution. Subjects and Methods Subjects included 86 patients undergoing endoscopic sinus surgery: CRSwNP (n = 34), AFRS (n = 37), and healthy controls (n = 15). Pathway and correlation analyses were performed with whole-genome microarray data for study patients undergoing surgery for recalcitrant chronic rhinosinusitis. Our findings were confirmed with quantitative polymerase chain reaction and immunohistochemical studies. Results AFRS was uniquely characterized by a pronounced association with adaptive T helper 2-associated immune gene expression. AFRS exhibited altered expression of proteins associated with secretory salivary peptides-namely, histatin, a peptide with known antifungal activity in the oral cavity. Furthermore, the expression of histatins correlated negatively with that of type 2 inflammatory mediators. We confirm the decreased expression of histatins in AFRS when compared with CRSwNP by quantitative polymerase chain reaction and localized its expression to a submucosal cell population. Conclusion There exist clear molecular profiles that distinguish AFRS from CRSwNP. This divergence translates into an altered ability to control fungal growth and may in part explain some of the phenotypical differences between CRSwNP and AFRS.

Background: Chronic rhinosinusitis (CRS) and asthma describe inflammation of the upper and lower airway, respectively. Not surprisingly, the prevalence of CRS and asthma has been linked, with up to 50% asthma prevalence in CRS with nasal polyposis (CRSwNP) patients. However, these prevalence rates do not address subtypes of CRSwNP including allergic fungal rhinosinusitis (AFRS). This study sets out to objectively determine asthma prevalence in CRS subtypes prospectively., Methods: A prospective prevalence study of adult CRS patients was conducted over a 1-year period at a tertiary care center. Patients were grouped into CRSwNP, CRS without nasal polyposis (CRSsNP), or AFRS. Patients were administered the Asthma Screening Questionnaire (ASQ) and asthma was confirmed by pulmonary function testing (PFT) if positive on the ASQ. Chi square analysis was performed to compare the asthma prevalence among the CRS subtypes., Results: A total of 410 patients (age 48.1 ± 16.4; 53.5% male) were included. Of these, 178 (43.4%) had CRSwNP, 166 (40.5%) had CRSsNP, and 66 (16.1%) met criteria for AFRS. Analysis revealed that 48.3% of CRSwNP patients, 16.5% of CRSsNP patients, and 23.6% of AFRS patients had asthma confirmed by PFTs. Chi square analysis showed a significant difference in asthma prevalence between CRSwNP and AFRS (p = 0.0016) and CRSwNP and CRSsNP (p = 0.0000), but no significant difference between CRSsNP and AFRS (p = 0.2380)., Conclusion: There is a significant difference in the prevalence of asthma between CRSwNP and AFRS, suggesting a fundamental distinction in their etiologies despite similar immunologic profiles. Further efforts to delineate these biological disparities are underway., (© 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: Environmental fungi have been linked to TH2 cell-related airway inflammation and the TH2-associated chronic airway diseases asthma, chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), and allergic fungal rhinosinusitis (AFRS), but whether these organisms participate directly or indirectly in disease pathology remains unknown., Objective: To determine the frequency of fungus isolation and fungus-specific immunity in patients with TH2-associated and non-TH2-associated airway disease., Methods: Sinus lavage fluid and blood were collected from sinus surgery patients (n = 118) including patients with CRSwNP, patients with CRS without nasal polyps, patients with AFRS, and non-CRS/nonasthmatic control patients. Asthma status was determined from medical history. Sinus lavage fluids were cultured and directly examined for evidence of viable fungi. PBMCs were restimulated with fungal antigens in an enzyme-linked immunocell spot assay to determine total memory fungus-specific IL-4-secreting cells. These data were compared with fungus-specific IgE levels measured from plasma by ELISA., Results: Filamentous fungi were significantly more commonly cultured in patients with TH2-associated airway disease (asthma, CRSwNP, or AFRS: n = 68) than in control patients with non-TH2-associated disease (n = 31): 74% vs 16%, respectively (P < .001). Both fungus-specific IL-4 enzyme-linked immunocell spot (n = 48) and specific IgE (n = 70) data correlated with TH2-associated diseases (sensitivity 73% and specificity 100% vs 50% and 77%, respectively)., Conclusions: The frequent isolation of fungi growing directly within the airways accompanied by specific immunity to these organisms only in patients with TH2-associated chronic airway diseases suggests that fungi participate directly in the pathogenesis of these conditions. Efforts to eradicate airway fungi from the airways should be considered in selected patients., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: The pathogenesis of allergic fungal rhinosinusitis (AFRS) is thought to represent an immunological reaction to fungal antigens. Recent studies have implicated superantigens and non-immunoglobulin E (IgE)-mediated mechanisms in the development of AFRS. The objective of this study is to assess the prevalence of Staphylococcus aureus in AFRS vs other subsets of chronic rhinosinusitis with polyps (CRSwNP, also termed non-AFRS)., Methods: A case series with retrospective review of 19 patients with AFRS and 21 patients with CRSwNP was performed at a tertiary referral center. The diagnosis of AFRS required the presence of defined criteria described by Bent and Kuhn. Bacterial cultures and fungal cultures were analyzed for each group., Results: S. aureus was significantly more prevalent in the AFRS group compared with the non-AFRS group (63.2% vs 24.1%, p = 0.005)., Conclusion: S. aureus has been implicated as a disease modifier in CRSwNP through superantigen-mediated mechanisms. This study demonstrates a higher prevalence of S. aureus in patients with AFRS vs patients with other subsets of CRSwNP (non-AFRS). These results support a potential role for S. aureus in the pathogenesis of AFRS., (© 2013 ARS-AAOA, LLC.)

Background: Initial attention on the pathophysiology of chronic rhinosinusitis (CRS) has focused on eosinophils. Other immune cells such as mast cells (MCs) have been identified and appear to be elevated in CRS with nasal polyp (NP) patients. MCs are commonly linked to immunoglobulin E (IgE)-mediated inflammatory changes characterized by elevated T helper 2 cytokines. Although atopy is a common comorbid condition with CRS, the objective of this study was to determine if elevated MCs are linked primarily to atopic status in CRS patients and to understand the significance of MCs in the pathophysiology of CRS., Methods: Ethmoid sinonasal mucosa from patients undergoing endoscopic sinus surgery was harvested from 3 groups: healthy control (HC), CRS without NP (CRSsNP), and CRS with NP (CRSwNP) and analyzed by flow cytometry to quantify CD117(+) /CD203c(+) MCs and CRTH2(+) CD4(+) T cells. Relative expression of prostaglandin D(2) synthase in ethmoid mucosa was determined by quantitative real-time polymerase chain reaction (PCR)., Results: MCs were significantly elevated in CRSwNP patients as compared to CRSsNP patients and HCs. This elevation was not solely dependent on the presence of IgE-mediated hypersensitivity. Relative expression of prostaglandin D(2) synthase was also increased in CRSwNP patients along with an associated presence of a CRTH2(+) memory CD4(+) T cell population., Conclusion: Elevated percentages of MCs are found in the sinonasal mucosa of CRSwNP patients, regardless of atopic status. Secreted by MCs, elevated prostaglandin D(2) may play a role in the recruitment of CRTH2(+) cells to the inflamed mucosa of CRSwNP patients., (Copyright © 2012 American Rhinologic Society-American Academy of Otolaryngic Allergy, LLC.)

Background: Recent data has implicated Staphylococcus aureus (SA) superantigen as a potential disease modifier in patients with chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP). The objective of this work was to compare total serum immunoglobulin E (IgE) and serum eosinophils in patients with CRSwNP and CRS without nasal polyps (CRSsNP) based on culture results of the 3 most commonly isolated bacteria., Methods: Retrospective review at a tertiary rhinology referral center of patients with CRS over a 4-year period., Results: Bacterial cultures and immunologic data were obtained from 62 patients with CRSwNP and 34 patients with CRSsNP. SA was the most prevalent bacteria in the CRSwNP group, isolated in 19 patients (31%). Patients with elevated total serum IgE (>114 IU/mL) were more likely to have SA on culture (p = 0.04) in this population. The percent serum eosinophil levels in the SA+ group compared with the SA- group was not significant (6.0 vs 5.1, p = 0.17). Lund-Mackay computed tomography (CT) scores, but not Sino-Nasal Outcome Test 20 (SNOT-20) scores were significantly higher in the SA+ vs SA- group (p = 0.03) in patients with CRSwNP. The CRSsNP group demonstrated no difference in IgE or serum eosinophils between different bacterial groups., Conclusion: Our findings suggest that there is an association between SA sinonasal presence and elevated total serum IgE in patients with CRSwNP. In addition, SA+ patients had higher Lund-Mackay CT scores, indicating a higher objective burden of disease in this group of patients., (Copyright © 2011 American Rhinologic Society-American Academy of Otolaryngic Allergy, LLC.)

The immunologic reaction to fungal stimuli has long been thought to be a contributor to the development of sinonasal disease. We aim to review the role of fungi in upper and lower airway inflammatory diseases. The immune response to fungi in the pathogenicity of specific respiratory inflammatory diseases such as allergic bronchopulmonary aspergillosis and a subtype of CRS known as allergic fungal rhinosinusitis has been relatively well described. Fungi are thought to serve both as immunogenic antigens and as adjuncts to inflammation through protease activity. Development of a recent murine mouse model of asthma bypassing the pre-sensitization of allergen further suggests a broader role for fungi in allergic asthma. The literature is lacking in defining a clear presence of fungi within the inflamed sinus cavity of CRS patients and its potential immunologic effects, as well as the utility of antifungal therapy for CRS management. We will review these data and potential common molecular mechanisms activated by fungi in the common pathway toward upper and lower airway inflammatory pathology.

Background: There is clear evidence that the prevalence of primary antibody deficiency (PAD) is higher in patients with recurrent and chronic rhinosinusitis (CRS) than in the general population. The purpose of this multi‐institutional and multidisciplinary evidence‐based review with recommendations (EBRR) is to thoroughly review the literature on rhinosinusitis with PAD, summarize the existing evidence, and provide recommendations on the evaluation and management of rhinosinusitis in patients with PAD. Methods: The PubMed, EMBASE, and Cochrane databases were systematically reviewed from inception through August 2022. Studies on the evaluation and management of rhinosinusitis in PAD patients were included. An iterative review process was utilized in accordance with EBRR guidelines. Levels of evidence and recommendations on the evaluation and management principles for PAD were generated. Results: A total of 42 studies were included in this evidence‐based review. These studies were evaluated on incidence of PAD in rhinosinusitis patients, incidence of rhinosinusitis in PAD patients, and on the different treatment modalities used and their outcome. The aggregate quality of evidence was varied across reviewed domains. Conclusion: Based on the currently available evidence, PAD can occur in up to 50% of patients with recalcitrant CRS. Despite the presence of multiple studies addressing rhinosinusitis and PAD, the level of evidence supporting different treatment options continues to be lacking. Optimal management requires a multidisciplinary approach through collaboration with clinical immunology. There is need for higher‐level studies that compare different treatments in patients with PAD and rhinosinusitis. [ABSTRACT FROM AUTHOR]

Unified airway disease, including concurrent asthma and chronic rhinosinusitis (CRS), is a common, but poorly understood disorder with no curative treatment options. To establish a murine model of chronic unified eosinophilic airway inflammation, mice were challenged with Aspergillus niger , and sinonasal mucosa and lung tissue were evaluated by immunohistochemistry, flow cytometry, and gene expression. Inhalation of A niger conidia resulted in a Th2-biased lung and sinus inflammation that typifies allergic asthma and CRS. Gene network and pathway analysis correlated with human disease with upregulation of not only the JAK-STAT and helper T-cell pathways, but also less expected pathways governing the spliceosome, osteoclast differentiation, and coagulation pathways. Utilizing a specific inhibitor and gene-deficient mice, we demonstrate that STAT6 is required for mycosis-induced sinus inflammation. These findings confirm the relevance of this new model and portend future studies that further extend our understanding of the immunopathologic basis of airway mycosis and unified airway disease. [ABSTRACT FROM AUTHOR]

The sinonasal microbiome remains poorly defined, with our current knowledge based on a few cohort studies whose findings are inconsistent. Furthermore, the variability of the sinus microbiome across geographical divides remains unexplored. We characterize the sinonasal microbiome and its geographical variations in both health and disease using 16S rRNA gene sequencing of 410 individuals from across the world. Although the sinus microbial ecology is highly variable between individuals, we identify a core microbiome comprised of Corynebacterium, Staphylococcus, Streptococcus, Haemophilus and Moraxella species in both healthy and chronic rhinosinusitis (CRS) cohorts. Corynebacterium (mean relative abundance = 44.02%) and Staphylococcus (mean relative abundance = 27.34%) appear particularly dominant in the majority of patients sampled. Amongst patients suffering from CRS with nasal polyps, a statistically significant reduction in relative abundance of Corynebacterium (40.29% vs 50.43%; P =.02) was identified. Despite some measured differences in microbiome composition and diversity between some of the participating centres in our cohort, these differences would not alter the general pattern of core organisms described. Nevertheless, atypical or unusual organisms reported in short‐read amplicon sequencing studies and that are not part of the core microbiome should be interpreted with caution. The delineation of the sinonasal microbiome and standardized methodology described within our study will enable further characterization and translational application of the sinus microbiota. [ABSTRACT FROM AUTHOR]

Objective The recent development of endotypes to categorize disease variants of chronic rhinosinusitis (CRS) reflects an evolving understanding of the various pathophysiologic and pathogenetic mechanisms that contribute to the clinical heterogeneity of CRS manifestations. This review highlights popular endotype-based criteria used to define different CRS with nasal polyposis (CRSwNP) subtypes and further discusses the emerging therapeutic advances for each classificatory approach. Data Sources PubMed literature review. Methods A review of the current literature was conducted to determine present-day uses of immunologic and molecular profiles in the CRSwNP disease spectrum to identify specific endotypes. Results Four distinct but overlapping classification schemes have emerged to define endotypes within the CRSwNP phenotype: 1) type 2 cytokine-based approach, 2) eosinophil-based approach, 3) immunoglobulin (Ig)E-based approach, and 4) cysteinyl based approach. The identification of key inflammatory biomarkers related to these CRSwNP endotypes has broadened the classification of CRS beyond common phenotypic expressions. Furthermore, CRSwNP endotypes may improve the selection of CRSwNP patients who are suitable candidates for biomarker-specific treatment options, such as anti-interleukin-5; anti-IgE; and platelet-directed therapies. Conclusion Chronic rhinosinusitis endotyping with key biomarker patterns of inflammation allows for improved diagnostic and potentially therapeutic classifications of CRSwNP variants. [ABSTRACT FROM AUTHOR]

Background: The escalating negative impact of climate change on our environment has the potential to result in significant morbidity of rhinologic diseases. Methods: Evidence based review of examples of rhinologic diseases including allergic and nonallergic rhinitis, chronic rhinosinusitis, and allergic fungal rhinosinusitis was performed. Results: The lower socioeconomic population, including historically oppressed groups, will be disproportionately affected. Conclusions: We need a systematic approach to improve healthcare database infrastructure and funding to promote diverse scientific collaboration to address these healthcare needs. [ABSTRACT FROM AUTHOR]

Background Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory condition of the sinonasal mucosa consisting of poorly defined subtypes and characterized by variable clinical manifestations, responses to therapy, and underlying pathophysiologies. In the related disorder of asthma, progress has been made in defining disease subtypes on both clinical and pathophysiologic levels, facilitating the development of targeted biologic pharmacotherapy. The potential role of these drugs for the management of CRS will be reviewed. The objective of this work is to highlight the emerging therapeutic targets in CRS in light of evolving treatment options for asthma and enhanced understandings of the clinical manifestations and pathophysiology of CRS. Methods This article is a review of recent studies regarding current and future advances in biomarker-directed therapies in the medical treatment of CRS. Results Various biologic therapies used in the management of asthma have demonstrated clinical promise for CRS, particularly within the CRS with nasal polyposis (CRSwNP) phenotype. Several randomized, double-blind, placebo-controlled studies increasingly support the targeting of immunoglobulin E (IgE) and interleukin (IL)-5 pathways to improve outcome measures in CRSwNP patients. The IL-4/IL-13 pathway and other type 2 inflammatory pathways have also shown potential as targets for CRSwNP, but all pathways require further investigation. Conclusion Recalcitrant CRS in the United States and Europe is most commonly associated with nasal polyposis and a type 2 cytokine skewing in the tissue, resulting in tissue infiltration of eosinophils, mast cells, and basophils. Targeting biomarkers of the associated type 2 pathways may be a practical treatment option for recalcitrant CRSwNP in the future. [ABSTRACT FROM AUTHOR]

As many as 30% of AFRS patients exhibit extrasinus expansion into intracranial and orbital compartments without tissue invasion.3 AFRS patients commonly report nasal congestion, thick nasal drainage, and loss of sense of smell, but visual disturbances or facial deformity may result in severe cases.4 AFRS is a challenging CRSwNP subtype to treat given the frequently advanced presentation of disease with extensive, difficult to clear, sticky eosinophilic mucin laden with fungal hyphae. The classic diagnosis of AFRS requires strictly meeting all components of these criteria.8 However, limited reports have suggested that AFRS can progress to an invasive form of fungal sinusitis in certain clinical scenarios.9 As to whether this represents a distinct subtype of AFRS observed in immunocompromised hosts remains unclear. Six of the 32 patients with negative serum fungal-specific IgE had fungal-specific IgE levels within the mucin.13 Although the importance of local IgE reactivity in the absence of systemic IgE elevation is not clear, this phenomenon emphasizes the limits of the current diagnostic criteria for AFRS, especially because these patients would not meet current criteria. [Extracted from the article]

Background: Balloon sinus dilation (BSD) is a commonly performed sinus procedure in the United States. Several cadaveric studies have evaluated BSD accuracy and the maxillary sinus has consistently been shown to be the most challenging to cannulate. We designed an independent study to evaluate the intraoperative accuracy of maxillary sinus BSD. Methods: A prospective, single‐blinded trial evaluating the accuracy of maxillary sinus BSD was performed using 2 commercially available BSD systems (guidewire‐ and probe‐based systems) randomly assigned to patients undergoing endoscopic surgery for chronic rhinosinusitus without nasal polyps (CRSsNP) or a skullbase approach in patients without sinus disease. All patients underwent maxillary BSD followed by uncinectomy to reveal dilation of the natural maxillary sinus ostia. The recorded procedures were reviewed by 3 fellowship‐trained rhinologists from different institutions blinded to the BSD system utilized. The primary endpoint compared accuracy of maxillary BSD attempts. The secondary endpoint compared accuracy between the 2 systems. Results: Twenty‐nine maxillary BSD procedures were performed in 18 patients (age range, 20‐79 years; mean, 51 years) without nasal polyposis undergoing maxillary antrostomy as part of a more extensive procedure. BSD was successful in 18 of 29 (62%) attempts and unsuccessful in 9 of 29 (31%) attempts, with statistically "almost perfect" interrater agreement (kappa = 0.86). There was no statistical difference between the 2 BSD systems (p = 0.81). Conclusion: Maxillary BSD appeared to be less accurate in living patients when compared with findings from previously published cadaver studies. There were no differences in accuracy between the probe‐ and guidewire‐based systems. This is the first non‒industry‐sponsored study evaluating maxillary sinus BSD in living patients. Further studies are needed to investigate the clinical implications of our findings. [ABSTRACT FROM AUTHOR]