Therapeutic Antibodies for Nasal Polyposis Treatment: Where Are We Headed?

This review article aims to outline what is known in the pathophysiology of chronic rhinosinusitis with nasal polyposis (CRSwNP) and describe the mechanism of the biologic agents being investigated for this disease. Chronic rhinosinusitis with nasal polyposis is an inflammatory disease of the nasal and paranasal mucosa, which causes symptoms of nasal obstruction, hyposmia, and rhinorrhea. Conventional therapy for CRSwNP includes intranasal corticosteroids (INCS) and polypectomy, but INCS offer only modest benefits, and recurrence after surgery is common. Therefore, effective pharmacologic therapies for CRSwNP are being actively sought. Monoclonal antibodies have been successful in other chronic diseases involving eosinophilic inflammation, such as chronic urticaria and asthma. Thus, researchers have begun expanding their scope and investigating the efficacy of these drugs in the treatment of nasal polyposis. The monoclonal antibodies under investigation (omalizumab (anti IgE), dupilumab (anti IL-4/IL-13), and reslizumab and mepolizumab (both anti IL-5), benralizumab (anti IL-5Rα), and etokimab (anti IL-33)) target key players in the pathophysiology of nasal polyposis (NP). Dupilumab has just completed phase III trials for CRSwNP with positive results, while omalizumab, mepolizumab, and benralizumab are currently in phase III trials for this indication. At this time, while there are no FDA-approved biologics for use in NP, research has highlighted the contributions of IL-4, IL-5, IL-13, and IgE as disease mediators in the pathogenesis of NP. The current FDA-approved treatment of intranasal steroids does not provide significant relief for many patients; therefore, these phase III trials of monoclonal antibodies bring hope for an exciting new treatment option.

The Anterior Ethmoidal "Genu": A Newly Appreciated Anatomic Landmark for Endoscopic Sinus Surgery.

Human sinonasal anatomy varies widely between patients, challenging surgeons operating in the sinuses. Ethmoid sinus anatomy is so variable it has been referred to as a labyrinth. Accordingly, reliable, consistent anatomic landmarks aid surgeons operating in this region. The goal of this investigation was to explore our observations and hypothesis that the ethmoidal bulla and the uncinate process are not entirely separate structures but rather attach, and the attachment could potentially provide a landmark for surgeons performing ethmoid and frontal recess surgery. Ethmoid sinus anatomy was studied in 57 sinonasal complexes through a variety of methods including gross anatomic dissection, endoscopic dissection and 3D CT stereoscopic imaging. The uncinate process and ethmoidal bulla were noted to fuse at the superior aspect of the hiatus semilunaris in 57/57 cases, forming a genu-like feature in the anterior ethmoid. This consistent anatomic feature related closely to the frontal sinus drainage pathway, which drained medial to it in 44/57 (77%) cases. The anterior ethmoidal "genu" appears to be an excellent anatomic feature that surgeons can use during ethmoid and frontal recess surgery. High resolution 3D stereoscopic CT scan is capable of demonstrating sinonasal anatomy in a detailed fashion previously only achieved by cadaveric dissection. This technology can potentially allow for a virtual dissection of a patient's anatomy prior to surgery and could improve minimally invasive procedures and reduce complications. Clin. Anat. 32:534-540, 2019. © 2019 Wiley Periodicals, Inc.

Correlation of Symptoms, Clinical Signs, and Biomarkers of Inflammation in Postsurgical Chronic Rhinosinusitis.

OBJECTIVE: The study aimed to evaluate symptoms described by patients with chronic rhinosinusitis with polypoid changes/nasal polyps and their correlation with computed tomography (CT), nasal endoscopy, and intranasal biomarkers. STUDY DESIGN: Prospective multicenter study symptom data from postsurgical adult chronic rhinosinusitis study participants with recurrent disease refractory to medical therapy were analyzed in comparison with objective data. METHODS: Using logistic regression analysis, participant-rated 16-question surveys from 258 participants were assessed for correlation with nasal endoscopy scores, CT percentage of sinus occlusion, and intranasal biomarkers of fungal antigens (Alternaria and Aspergillus), eosinophilic inflammation (eosinophil-derived neurotoxin [EDN] and major basic protein [MBP]), and inflammatory cytokines (interleukins 5 and 13). RESULTS: Study participant assessments revealed increased CT occlusion in participants presenting with greater inability to smell ( P < .019). Mucosal inflammation identified on nasal endoscopy was positively correlated with congestion ( P < .028), runny nose ( P < .002), and ear pain ( P < .007). Elevated EDN was positively correlated in patients with bothersome congestion ( P < .031) and runny nose ( P < .011). Sneezing was positively correlated with multiple markers: Alternaria ( P < .024), interleukin-13 ( P < .027), MBP ( P < .034), and interleukin-5 ( P < .019). CONCLUSION: Nasal endoscopy, not CT imaging, has the strongest correlation with the 2 cardinal symptoms of congestion and runny nose in CRS patients; these correlate with biomarkers of eosinophilic inflammation.

An immunologic test for chronic rhinosinusitis based on free intranasal eosinophilic major basic protein.

BACKGROUND: A histologic hallmark of chronic rhinosinusitis (CRS) is an eosinophilic inflammation, present with and without nasal polyposis and independent of atopy. Eosinophils migrate through nasal tissue including the epithelium into the nasal airway mucus, where they form clusters and degranulate, releasing granule proteins including the toxic major basic protein (MBP). Specific biomarkers for CRS, which could be used as a diagnostic test for CRS with a high sensitivity and specificity, are presently lacking. Recently, an enzyme-linked immunosorbent assay (ELISA)-based test for MBP in nasal airway mucus received regulatory approval. METHODS: A new assay was specifically developed to detect released MBP in airway mucus. MBP levels in nasal mucus of 85 randomly selected CRS patients diagnosed by endoscopy, computed tomography (CT) scans and symptoms were compared to 13 healthy controls and 5 disease controls (allergic rhinitis). RESULTS: Overall, 92% (78/85) of CRS patients' mucus were positive for MBP (mean 7722 ng/mL) vs none of 13 healthy controls and none of 5 allergic rhinitis patients (<7.8 ng/mL; p < 0.000000000002). In this study, the MBP ELISA had a 92% sensitivity and 100% specificity for CRS. CONCLUSION: Free MBP in nasal mucus can be used as a biomarker to diagnose CRS. The MBP ELISA represents the first immunologically-based test to potentially distinguish CRS from the eosinophilic inflammation in allergic rhinitis.

Computed tomography scans as an objective measure of disease severity in chronic rhinosinusitis.

OBJECTIVES: A truly objective method of measuring disease severity in chronic rhinosinusitis (CRS) has only recently existed. We evaluated computed tomography (CT) scans of CRS patients using this novel objective 3D computerized system and compared results with a novel 2D computerized analysis of a single coronal slice through the osteomeatal complex (OMC) and subjective methods including Lund-Mackay and Zinreich's modified Lund-Mackay. STUDY DESIGN: Prospective multicenter study. SETTING: Two academic tertiary referral centers. SUBJECTS AND METHODS: Forty-six adults with a diagnosis of CRS underwent CT examination and received an intramuscular triamcinolone injection, dosage weight dependent, followed by CT scan 4 to 5 weeks later. Recruitment lasted 21 months. Scans were evaluated with all 4 scoring methods over 5 months. RESULTS: The Lin's concordance class correlation (CCC) of the OMC method revealed the best correlation to the 3D volumetric computerized values (0.915), followed by the Zinreich (0.904) and Lund-Mackay methods (0.824). Posttreatment results demonstrated that both the OMC (0.824) and Zinreich's (0.778) methods had strong agreement with the 3D volumetric methods and were very sensitive to change, whereas the Lund-Mackay (0.545) had only moderate agreement. CONCLUSION: Computerized CT analysis provides the most comprehensive, objective, and reproducible method of measuring disease severity and is very sensitive to change induced by treatment intervention. A 2D coronal image through the OMC provides a valid, user-friendly method of assessing CRS and is representative of CRS severity in all sinuses. Zinreich's subjective method correlated well overall, but the Lund-Mackay method lagged behind in disease representation and sensitivity to change.

Three-dimensional volumetric computed tomographic scoring as an objective outcome measure for chronic rhinosinusitis: clinical correlations and comparison to Lund-Mackay scoring.

BACKGROUND: We aimed to test the hypothesis that three-dimensional (3D) volume-based scoring of computed tomography (CT) images of the paranasal sinuses was superior to Lund-Mackay CT scoring of disease severity in chronic rhinosinusitis (CRS). We determined correlation between changes in CT scores (using each scoring system) with changes in other measures of disease severity (symptoms, endoscopic scoring, and quality of life) in patients with CRS treated with triamcinolone. METHODS: The study group comprised 48 adult subjects with CRS. Baseline symptoms and quality of life were assessed. Endoscopy and CT scans were performed. Patients received a single systemic dose of intramuscular triamcinolone and were reevaluated 1 month later. Strengths of the correlations between changes in CT scores and changes in CRS signs and symptoms and quality of life were determined. RESULTS: We observed some variability in degree of improvement for the different symptom, endoscopic, and quality-of-life parameters after treatment. Improvement of parameters was significantly correlated with improvement in CT disease score using both CT scoring methods. However, volumetric CT scoring had greater correlation with these parameters than Lund-Mackay scoring. CONCLUSION: Volumetric scoring exhibited higher degree of correlation than Lund-Mackay scoring when comparing improvement in CT score with improvement in score for symptoms, endoscopic exam, and quality of life in this group of patients who received beneficial medical treatment for CRS.

An exploratory trial of Cyclamen europaeum extract for acute rhinosinusitis.

OBJECTIVES/HYPOTHESIS: An exploratory US trial in patients with acute rhinosinusitis was conducted to evaluate the efficacy and safety of Cyclamen europeaum extract, a product marketed in Europe that causes reflex nasal discharge and subsequent decongestion. STUDY DESIGN: Prospective, randomized, placebo-controlled, double-blind, and parallel group. METHODS: Outpatients (n = 29) with cardinal symptoms of acute rhinosinusitis and both endoscopic and radiographic (computed tomography [CT] scan) evidence at 25 US centers were randomized to receive intranasal, lyophilized, reconstituted Cyclamen europeaum extract (Cyclamen) or placebo spray for 7 days. Primary outcomes were reduction in percent sinus opacification on CT scans and reduction in PM predose instantaneous total symptom scores measured on a six-point scale. Secondary outcomes included other measures of symptom score change and endoscopic signs of mucopurulence and inflammation. RESULTS: Cyclamen treatment significantly reduced sinus opacification compared with placebo treatment (P < .045). Although Cyclamen treatment reduced total symptom scores from baseline more than placebo treatment (-2.4 vs. -1.4), there were no significant treatment group differences (P = .312). Cyclamen treatment was well tolerated. CONCLUSIONS: Cyclamen treatment significantly reduced sinus opacification in patients with acute rhinosinusitis. Further exploration of Cyclamen treatment in larger patient populations is warranted.

Improving the detection of fungi in eosinophilic mucin: seeing what we could not see before.

OBJECTIVE: To investigate the improvement in histologic detection of fungi with Gomori methenamine silver (GMS) stain by trypsin predigestion in the mucus of patients with chronic rhinosinusitis (CRS). STUDY DESIGN: Prospective, single group, descriptive analysis. SETTING: Multi-institutional. SUBJECTS AND METHODS: Thirty-four sinus specimens from 12 surgical patients with CRS were stained with hematoxylin and eosin, GMS stain, GMS with trypsin digestion, immunofluorescence stains for chitinase, and anti-Alternaria. All patients received skin testing, total IgE serology, and radioallergosorbent tests (RAST) for 23 fungal-specific IgE antibodies. RESULTS: The conventional GMS stain detected fungi in only 9 of 34 (27%) specimens. Predigesting the specimen with trypsin dramatically improved the visualization of fungi (31/34, 91%). The chitinase immunofluorescence visualized fungi in 32 of 34 (94%), and anti-Alternaria visualized 33 of 34 specimens (97%). Only 8 of 12 (75%) patients had detectable allergies. CONCLUSIONS: This report describes a simple modification of the conventional GMS stain that can significantly improve the visualization of fungi on histology and explains the lack of detection in previous studies. These novel, more sensitive histologic methods reveal the presence of fungi within the eosinophilic mucin in allergic and also nonallergic CRS patients, further questioning a crucial role of an IgE-mediated pathophysiology.

Immunologic response to fungus is not universally associated with chronic rhinosinusitis.

In the December 2009 issue of this journal, Orlandi et al presented a study in which peripheral blood mononuclear cells (PBMCs) from chronic rhinosinusitis (CRS) patients (5 from Texas, 5 from Utah) and seven nonhealthy controls were stimulated with fungal extracts. Despite the small numbers, they confirmed important aspects of previous studies: 1) CRS patients' PBMCs react to certain fungal stimuli by producing significantly (P < 0.05) higher amounts of interleukin (IL)-5 and IL-13 when compared to controls; 2) CRS patients have an enhanced humoral response (significantly elevated immunoglobulin [Ig] G levels to Alternaria); and 3) CRS patients react independently from an IgE-mediated allergy, as evidenced by that fact that nonallergic CRS patients also produced IL-5 in response to fungal stimuli. Unfortunately, the authors chose not to highlight their positive results. They emphasized what they failed to demonstrate, specifically an immune response to fungi above a certain threshold in some patients (Utah) with milder CRS. However, these results are potentially explained by the different methods used, and care should be applied when interpreting their results.

Recognition of fungal protease activities induces cellular activation and eosinophil-derived neurotoxin release in human eosinophils.

Eosinophils are multifunctional leukocytes implicated in the pathogenesis of asthma and in immunity to certain organisms. Associations between exposure to an environmental fungus, such as Alternaria, and asthma have been recognized clinically. Protease-activated receptors (PARs) are G protein-coupled receptors that are cleaved and activated by serine proteases, but their roles in innate immunity remain unknown. We previously found that human eosinophils respond vigorously to Alternaria organisms and to the secretory product(s) of Alternaria with eosinophils releasing their proinflammatory mediators. In this study, we investigated the roles of protease(s) produced by Alternaria and of PARs expressed on eosinophils in their immune responses against fungal organisms. We found that Alternaria alternata produces aspartate protease(s) and that human peripheral blood eosinophils degranulate in response to the cell-free extract of A. alternata. Eosinophils showed an increased intracellular calcium concentration in response to Alternaria that was desensitized by peptide and protease ligands for PAR-2 and inhibited by a PAR-2 antagonistic peptide. Alternaria-derived aspartate protease(s) cleaved PAR-2 to expose neo-ligands; these neo-ligands activated eosinophil degranulation in the absence of proteases. Finally, treatment of Alternaria extract with aspartate protease inhibitors, which are conventionally used for HIV-1 and other microbes, attenuated the eosinophils' responses to Alternaria. Thus, fungal aspartate protease and eosinophil PAR-2 appear critical for the eosinophils' innate immune response to certain fungi, suggesting a novel mechanism for pathologic inflammation in asthma and for host-pathogen interaction.

Fungal rhinosinusitis: a categorization and definitional schema addressing current controversies.

BACKGROUND: Fungal (rhino-) sinusitis encompasses a wide spectrum of immune and pathological responses, including invasive, chronic, granulomatous, and allergic disease. However, consensus on terminology, pathogenesis, and optimal management is lacking. The International Society for Human and Animal Mycology convened a working group to attempt consensus on terminology and disease classification. DISCUSSION: Key conclusions reached were: rhinosinusitis is preferred to sinusitis; acute invasive fungal rhinosinusitis is preferred to fulminant, or necrotizing and should refer to disease of <4 weeks duration in immunocompromised patients; both chronic invasive rhinosinusitis and granulomatous rhinosinusitis were useful terms encompassing locally invasive disease over at least 3 months duration, with differing pathology and clinical settings; fungal ball of the sinus is preferred to either mycetoma or aspergilloma of the sinuses; localized fungal colonization of nasal or paranasal mucosa should be introduced to refer to localized infection visualized endoscopically; eosinophilic mucin is preferred to allergic mucin; and allergic fungal rhinosinusitis (AFRS), eosinophilic fungal rhinosinusitis, and eosinophilic mucin rhinosinusitis (EMRS) are imprecise and require better definition. In particular, to implicate fungi (as in AFRS and EMRS), hyphae must be visualized in eosinophilic mucin, but this is often not processed or examined carefully enough by histologists, reducing the universality of the disease classification. A schema for subclassifying these entities, including aspirin-exacerbated rhinosinusitis, is proposed allowing an overlap in histopathological features, and with granulomatous, chronic invasive, and other forms of rhinosinusitis. Recommendations for future research avenues were also identified.

Innate antifungal immunity of human eosinophils mediated by a beta 2 integrin, CD11b.

Eosinophils produce and release various proinflammatory mediators and also show immunomodulatory and tissue remodeling functions; thus, eosinophils may be involved in the pathophysiology of asthma and other eosinophilic disorders as well as host defense. Several major questions still remain. For example, how do human eosinophils become activated in diseased tissues or at the site of an immune response? What types of host immunity might potentially involve eosinophils? Herein, we found that human eosinophils react vigorously to a common environmental fungus, Alternaria alternata, which is implicated in the development and/or exacerbation of human asthma. Eosinophils release their cytotoxic granule proteins, such as eosinophil-derived neurotoxin and major basic protein, into the extracellular milieu and onto the surface of fungal organisms and kill the fungus in a contact-dependent manner. Eosinophils use their versatile beta(2) integrin molecule, CD11b, to adhere to a major cell wall component, beta-glucan, but eosinophils do not express other common fungal receptors, such as dectin-1 and lactosylceramide. The I-domain of CD11b is distinctively involved in the eosinophils' interaction with beta-glucan. Eosinophils do not react with another fungal cell wall component, chitin. Because human eosinophils respond to and kill certain fungal organisms, our findings identify a previously unrecognized innate immune function for eosinophils. This immune response by eosinophils may benefit the host, but, in turn, it may also play a role in the development and/or exacerbation of eosinophil-related allergic human diseases, such as asthma.

Diagnosis and treatment of chronic rhinosinusitis: focus on intranasal Amphotericin B.

Chronic rhinosinusitis (CRS) is a chronic disease that affects 14.2% of the US adult population. Despite being widespread, little is known about the etiology of CRS. Treatment has been symptomatic and focused on relieving symptoms. Recent investigations into causes of CRS have revealed that most CRS patients have an eosinophilic infiltration of their nasal tissue (mucosa), regardless of atopy and elevated immunoglobulin E levels. Although fungi are ubiquitous and in the nasal mucus of both healthy people and patients, it is only in the patients that the eosinophils (part of the inflammatory response) are found. Fungi in the nasal mucus are harmless, yet in CRS patients these same fungi stimulate an inflammatory response, inducing the eosinophils to leave the blood vessels and enter the nasal and sinus tissue and ultimately enter the nasal airway mucus. In the nasal mucus these eosinophils attack the fungi and destroy the fungi by the release of a toxic substance called major basic protein (MBP) from the granules in the eosinophils. This degranulation and release of the toxic MBP not only destroys fungi, but also produces collateral damage injuring the nasal and sinus mucosal lining tissue. The injury to the mucosal lining makes the nasal and sinus mucosa susceptible to penetration and potential infection by bacteria. When this tissue inflammation and damage is persistent and prolonged we call it CRS. The diagnosis of CRS is based largely on symptomatic criteria, with anterior rhinoscopy or endoscopy, and, if there is any doubt about the diagnosis, computed tomography imaging is employed to confirm the presence of diseased sinus mucosa. Treatment of CRS, whether medical (intranasal corticosteroids, saline irrigations) or surgical, is aimed at decreasing inflammation and obstruction in the sinonasal passages. Antibiotics, although commonly used in CRS, should not be administered unless there is suspicion of an acute bacterial infection. The theory behind the fungal and eosinophilic etiology of CRS has led to use of an antifungal compound, intranasal Amphotericin B. In clinical studies, topical irrigation with Amphotericin B has been shown to be both a safe and effective treatment for CRS.

Rhinosinusitis: Developing guidance for clinical trials.

The Rhinosinusitis Initiative was developed by 5 national societies. The current guidance document is an expansion of the 2004 publication, "Rhinosinusitis: Establishing definitions for clinical research and patient care" and provides templates for clinical trials in antimicrobial, anti-inflammatory, and symptom-relieving therapies for the following: (1) acute presumed bacterial rhinosinusitis, (2) chronic rhinosinusitis (CRS) without nasal polyps, (3) CRS with nasal polyps, and (4) classic allergic fungal rhinosinusitis. In addition to the templates for clinical trials and proposed study designs, the Rhinosinusitis Initiative has developed 6 appendices, which address (1) health outcomes, (2) nasal endoscopy and staging of CRS, (3) radiologic imaging, (4) microbiology, (5) laboratory measures, and (6) biostatistical methods.

Rhinosinusitis: developing guidance for clinical trials.

The Rhinosinusitis Initiative was developed by 5 national societies. The current guidance document is an expansion of the 2004 publication "Rhinosinusitis: Establishing definitions for clinical research and patient care" and provides templates for clinical trials in antimicrobial, anti-inflammatory, and symptom-relieving therapies for the following: (1) acute presumed bacterial rhinosinusitis, (2) chronic rhinosinusitis (CRS) without nasal polyps, (3) CRS with nasal polyps, and (4) classic allergic fungal rhinosinusitis. In addition to the templates for clinical trials and proposed study designs, the Rhinosinusitis Initiative has developed 6 appendices, which address (1) health outcomes, (2) nasal endoscopy and staging of CRS, (3) radiologic imaging, (4) microbiology, (5) laboratory measures, and (6) biostatistical methods.

Airway manifestations of pediatric eosinophilic esophagitis: a clinical and histopathologic report of an emerging association.

OBJECTIVES: Pediatric eosinophilic esophagitis (EE) typically presents with dysphagia, vomiting, dyspepsia, or food impaction. The purpose of this study was to highlight the emerging association of pediatric EE and airway disease. An additional goal of this study was to describe the unique histopathologic findings found in EE and specifically explore the potential role of the cytotoxic protein called eosinophil major basic protein (MBP) in the pathophysiology of the disease. METHODS: A retrospective review of 3 children with EE and airway symptoms included symptom presentation, aerodigestive tract endoscopic findings, ambulatory 24-hour dual pH-metry, allergy tests, treatment modalities, and treatment response. Esophageal tissue obtained from biopsies of each patient was evaluated by hematoxylin and eosin to determine the number of eosinophils per high-power field, by immunofluorescent anti-MBP staining to determine the presence of MBP, and by standard light and transmission electron microscopy to evaluate eosinophil migration patterns. RESULTS: All patients had airway inflammation that included nonspecific laryngeal edema and grade I or II subglottic stenosis. Allergy testing was positive in the 2 patients who were tested. All patients had symptoms refractory to standard reflux therapy. Ambulatory pH-metry findings were normal in 2 patients and abnormal in 1 patient despite maximum treatment. Two patients had visual abnormalities seen during esophageal examination. The number of eosinophils ranged from 20 to 45 per high-power field. Intracellular and extracellular MBP deposition was found in all esophageal biopsy specimens. All patients were treated with swallowed fluticasone, and 2 had symptom relapses that required repeat treatment. CONCLUSIONS: The spectrum of pediatric EE can include upper airway disease. Intracellular and extracellular MBP deposition is present in EE, which potentially releases cytotoxic mediators that explain the esophageal and airway clinical symptoms seen in those with the disease. Eosinophilic esophagitis should be considered in patients with a history of atopic diseases and unexplained upper airway findings refractory to reflux treatment. Treatment with swallowed fluticasone is successful; however, relapses are common and require repeat treatment and close follow-up.

The role of ubiquitous airborne fungi in chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a confusing disease for both allergists and otorhinolaryngologists, partly because of its poorly understood pathophysiology and partly because of its limited treatment options. Several recent reports have provided evidence for a better understanding of the etiology and the relationship of CRS to airborne fungi-especially to Alternaria. First, the development of novel methods enables detection of certain fungi in mucus from the nasal and paranasal sinus cavities. Second, a non-IgE-mediated immunological mechanism for reactivity of patients with CRS to certain common fungi has been described. Third, these fungi are surrounded by eosinophils in vivo, suggesting that they are targeted by eosinophils. Finally, the preliminary results of studies using antifungal agents to treat patients with CRS are promising. Overall, these recent discoveries provide a logical mechanism for the pathophysiology of CRS, and they also suggest promising avenues for treatment of CRS with antifungal agents.

The role of ubiquitous airborne fungi in chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a confusing disease for both allergists and otorhinolaryngologists, partially due to its poorly understood pathophysiology and partially due to its limited treatment options. Several recent reports now provide evidence for a better understanding of the etiology and the relationship of CRS to airborne fungi, especially to Alternaria. First, the development of novel methods enables detection of certain fungi in mucus from the nasal and paranasal sinus cavities. Second, a non-immunoglobulin E-mediated immunologic mechanism for reactivity of CRS patients to certain common fungi has been described. Third, these fungi are surrounded by eosinophils in vivo, suggesting that they are targeted by eosinophils. Fourth, the preliminary results of studies using antifungal agents to treat patients with CRS are promising. Overall, these recent discoveries provide a logical mechanism for the pathophysiology of CRS, and they also suggest promising avenues for treatment of CRS with antifungal agents.