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Objectives: Allergic fungal rhinosinusitis (AFRS) is an eosinophilic subtype of chronic rhinosinusitis with nasal polyposis (CRSwNP). This study aimed to investigate the transcriptome of AFRS nasal polyp epithelium., Methods: Sinonasal epithelial cells were harvested from healthy nasal mucosa and polyp tissue collected from participants undergoing elective sinonasal surgery. Primary epithelial cells were subsequently grown in air/liquid interface and subjected to RNA-seq analysis, RT-qPCR, immunoblotting, and immunostaining., Results: A total of 19 genes were differentially expressed between healthy and AFRS sample epithelium. The second top candidate gene, ranked by adjusted p-value, was prostaglandin E receptor 2 (PTGER2). The upregulation of PTGER2 was confirmed by RT-qPCR and immunoblot. The presence of the EP2 receptor, encoded by the PTGER2 gene, was confirmed by immunocytochemistry., Conclusion: PTGER2 is a potential novel therapeutic target for AFRS. EP2 dysregulation is associated with aspirin-exacerbated respiratory disease, potentially giving insight into common mechanisms of disease in severe CRSwNP., Level of Evidence: NA Laryngoscope, 2024., (© 2024 The Author(s). The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objective: To compare the efficacy of th2-targeted biologic medications (dupilumab, omalizumab, and mepolizumab) on absolute risk reduction (ARR) of functional endoscopic sinus surgery (FESS) in patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) and allergic fungal rhinosinusitis (AFRS)., Methods: The TriNetX Research Network database was queried for each mAb's market lifespan through March 2024. Adults with CRSwNP were propensity score matched against non-mAb controls based on age, sex, race, and asthma diagnosis. The primary outcome was rate of FESS, with secondary outcomes including inpatient admission, emergency department (ED) visit, and incidence of acute sinusitis. Subgroup analysis was performed for patients with AFRS., Results: All mAbs decreased FESS risk (dupilumab, ARR 11.48%, 95% CI 9.82%-13.15%, p < 0.001; omalizumab, ARR 12.02%, 95% CI 4.36%-19.68%, p = 0.002; mepolizumab, ARR 10.32%, 95% CI 5.24%-15.40%, p < 0.001) in CRSwNP patients. Only dupilumab also reduced risk of inpatient admission (ARR 8.59%, 95% CI 7.04%-10.15%, p < 0.001), ED visit (ARR 5.94%, 95% CI 4.28%-7.61%, p < 0.001), and acute sinusitis (ARR 2.60%, 95% CI 1.09%-4.12%, p = 0.001). In AFRS patients, only dupilumab reduced the risk of all outcomes: FESS (ARR 6.97%, 95 CI 2.86%-11.09%, p = 0.001), inpatient admission (ARR 16.93%, 95% CI 11.30%-22.57%, p < 0.001), ED visit (ARR 13.15%, 95% CI 7.15%-19.14%, p < 0.001), and acute sinusitis (ARR 7.17%, 95% CI 2.18%-12.17%, p = 0.005)., Conclusion: Although all mAbs reduced FESS risk in CRSwNP, only dupilumab reduced secondary outcomes as well. Similarly, only dupilumab improved all outcomes in AFRS patients. These data demonstrate the potential of mAbs in reducing disease burden and enhancing patient outcomes in CRSwNP and AFRS., Level of Evidence: NA Laryngoscope, 2024., (© 2024 The Author(s). The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: Structured histopathology (SHP) is a method of analyzing sinonasal tissue to characterize endotypes of chronic rhinosinusitis with nasal polyps (CRSwNP). Allergic fungal rhinosinusitis (AFRS) shares several features with certain endotypes of CRSwNP. Our objective was to compare the histopathology of AFRS and eosinophilic CRSwNP to further understand whether they are separate endotypes or disease entities altogether., Methods: A retrospective review of AFRS and CRSwNP patients undergoing endoscopic sinus surgery was performed. Data were collected on demographics, comorbidities, subjective and objective severity scores, and 13-variable SHP reports. CRSwNP patients with >10 eosinophils per high-power field (eCRSwNP) were included. Chi-squared and t-tests were used for statistical analysis., Results: A total of 29 AFRS and 108 eCRSwNP patients were identified. AFRS patients were younger and more often Black. Symptom severity scores (SNOT-22, Lund-MacKay, and Lund-Kennedy) were uniform between groups. AFRS patients had a higher rate of Charcot-Leyden crystals (41.4% vs. 10.2%; p < 0.001). Severe degree of inflammation, eosinophilic inflammatory predominance, eosinophil aggregates, subepithelial edema, and basement membrane thickening were common in both groups, and their rates were not statistically significantly different between groups. Metaplasia, ulceration, fibrosis, and hyperplastic/papillary change rates were low (<30%) and similar between groups., Conclusion: The SHP of eCRSwNP and AFRS are highly consistent, which suggests AFRS is a severe subtype of CRSwNP overall rather than a separate disease entity. This also lends credence to AFRS belonging on the endotypic spectrum of CRSwNP., Level of Evidence: 3 Laryngoscope, 134:2617-2621, 2024., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

A review of the treatment of allergic and invasive fungal sinusitis, as well as a presentation of the first recorded case of a conversion from allergic fungal sinusitis (AFS) to chronic granulomatous invasive sinusitis and the fourth case of invasive fungal sinusitis associated with Curvularia. This immunocompetent patient suffering from chronic AFS converted after repeated high-dose steroid tapers and noncompliance. AFS may present atypically and should be suspected even in immunocompetent patients with sinus disease who report new onset pain and neurologic symptoms. Clinicians should consider the potential complications associated with repeated systemic steroid administration. Laryngoscope, 129:2447-2450, 2019. [ABSTRACT FROM AUTHOR]

This review will address the current knowledge of the pathogenic mechanisms in allergic fungal sinusitis (AFS) and the basis for the current classification of a subgroup of chronic rhinosinusitis patients. Special attention is directed to the role of immunoglobulin E (IgE)-mediated fungal allergy in the pathogenesis of AFS. Concepts relating to the mucosal inflammatory response are introduced, as a knowledge of the reactions of the sinus mucosal cells can lead to a better understanding of the mechanisms perpetuating and maintaining the chronic inflammation. Laryngoscope, 2009 [ABSTRACT FROM AUTHOR]

Background: A subset of Chronic Rhinosinusitis (CRS) patients are those with eosinophilic CRS (ECRS). These patients remain the most refractory to medical and surgical intervention, and are thought to reflect an inflammatory process arising from a variety of causes. Recently the role of fungus in ECRS, defined as the presence of fungi in the eosinophilic mucin of CRS, has been proposed as causal in many cases. Other proposed causes of ECRS include bacterial superantigen induction of inflammation and aspirin sensitivity. Design: Retrospective review. Methods: Histopathology from patients with previously diagnosed ECRS was prospectively re-reviewed for bacterial and fungal presence and correlated with patients' demographic data. The study population was comprised of 55 specimens with ECRS from 34 patients, over a 3-year period from a single investigator at the University of Pittsburgh Medical Center. Results: Histologic presence of bacteria was shown in 34 of 55 (62%) of all ECRS specimens. Specimens with fungal colonization were more often associated with bacterial presence than without bacteria (17 of 22 [77%] vs. 5 of 22 [23%], P < .02). Conclusion: Bacteria were present in almost two-thirds of all specimens, and most cases of fungal presence were accompanied by bacterial presence, potentially providing support for bacteria as a source of superantigen. Other possible reasons for the high rate of bacterial and fungal colonization of ECRS include increased pathogen exposure, or failure to eliminate pathogens. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis: An immunoglobulin (Ig)E-mediated allergic pathogenesis is presumed in allergic fungal sinusitis (AFS), yet extensive polyps and eosinophilic mucus (EM) in the paranasal sinuses may also occur in the absence of allergy. Although a noninvasive fungal pathogenesis is presumed in all chronic rhinosinusitis with EM (EMCRS), fungal-specific nonallergic immune responses have not been thoroughly investigated. We tested the hypothesis that there is a fungal-specific humoral response in EMCRS and that it is not confined to IgE. Study Design: EMCRS patients were prospectively stratified into subgroups based on the presence or absence of fungi within EM and of fungal-specific systemic IgE. There were 12 AFS, 5 AFS-like, 8 nonallergic fungal eosinophilic sinusitis (NAFES), and 5 nonallergic, nonfungal eosinophilic sinusitis (NANFES) patients. Methods: Alternaria alternata and Aspergillus fumigatus-specific serum IgE, IgG, IgM, and IgA was measured by enzyme-linked immunosorbent assay and compared with strictly defined healthy and disease-control groups. Results: Fungal-specific IgG ( Alternaria alternata P = .0002; Aspergillus fumigatus P = .004), and IgA levels ( Alternaria alternata P = .0016; Aspergillus fumigatus P = .002) were higher in EMCRS compared with healthy volunteers but not with disease controls. Fungal-specific IgG3 levels were significantly elevated in all the EMCRS subgroups compared with controls for either fungal antigen ( P < .0001). Importantly, fungal-specific IgE levels were not significantly different between fungal-allergic EMCRS and disease controls. Conclusions: Fungal-specific immunity characterized by serum IgG3 and not IgE, distinguished the EMCRS subgroups from control groups regardless of the presence of fungus within EM or of systemic fungal allergy. Fungal-specific IgE responses in fungal-allergic EMCRS were no different to those in fungal-allergic controls, thus challenging the presumption of a unique pathogenic role of fungal allergy in 'allergic fungal sinusitis.' [ABSTRACT FROM AUTHOR]

Objective To compare the differences in the clinical and radiographic presentation of allergic fungal sinusitis in children and adults. Study Design Retrospective chart and computed tomography review. Methods The settings included a tertiary care children's hospital, adult academic private hospital, and academic affiliated county hospital. All patients with documented allergic fungal sinusitis who underwent computed tomography evaluation and had surgical treatment of their disease from 1988 to 1999 were included in the study. In total, 151 patients aged 5 to 75 years; 44 of these patients were less than or equal to 17 years of age (children) and 107 were greater than 17 years of age (adults). Main outcome measures included 1) the presence of obvious bony facial abnormalities on presentation, 2) bilateral or unilateral sinus disease on presentation, 3) the presence of asymmetrical disease on presentation, 4) the presence of bony extension on computed tomography scan, and 5) type of fungus present. Results Fifteen of 36 (42%) pediatric patients and 10 of 103 (10%) adult patients had obvious alteration of their facial skeleton (proptosis, telecanthus, or malar flattening) on presentation ( P <.05). Proptosis was the most common facial abnormality in both groups and was seen more often in children (8 of 36 [22%]) than in adults (9 of 103 [9%]) ( P <.05). Twenty-eight of 40 (70%) pediatric patients and 37 of 100 (37%) adult patients presented with unilateral sinus disease ( P <.05). Thirty-five of 40 (88%) pediatric patients and 58 of 100 (58%) adults presented with asymmetrical disease ( P <.05). Computed tomography scans showed that 10 of 40 (25%) pediatric patients and 23 of 100 (23%) adult patients had bony erosion with extension of disease into surrounding structures ( P >.05). Cultures from both adults and children showed mainly Bipolaris and Curvilaria species in equal amounts ( P >.05). Adults had a greater incidence of Aspergillus species. Conclusions Presentation in pediatric patients with allergic fungal sinusitis is different from that in adults, with children having obvious abnormalities of their facial skeleton, unilateral sinus disease, and asymmetrical disease more often. Findings on computed tomography scan show an equal amount of bony erosion with extension of disease. The types of fungus cultured in the sinus cavities are similar in both groups. [ABSTRACT FROM AUTHOR]

Background Allergic fungal sinusitis (AFS) was recognized in 1981. Since 1983, a form of sinusitis histologically similar to AFS except for the absence of fungal hyphae has also been noted. The designation 'eosinophilic mucin rhinosinusitis (EMRS)' is proposed. Its relationship to AFS is controversial and problematic. Objective To determine whether distinctive clinical and immunological differences exist to differentiate the histological entity of EMRS from AFS. Study Design Literature review and comparison of cases of AFS (n = 418) to EMRS (n = 40) from the literature, as well as cases of AFS (n = 13) and EMRS (n = 29) accrued in the present study. Results A total of 431 AFS patients were compared with 69 EMRS patients. The mean age of patients with AFS was significantly younger than patients with EMRS (30.7 y compared with 48.0 y, respectively; P < .001). Male-to-female ratios were 1.03:1 and 1.26:1 for AFS and EMRS, respectively, and were not significantly different. Forty-one percent of patients with AFS were asthmatic compared with 93% of patients with EMRS ( P < .0001). Thirteen percent of patients with AFS were aspirin sensitive compared with 54% of patients with EMRS ( P < .0001). Polyp occurrence was almost 100% in both groups. Eighty-four percent of patients with AFS had allergic rhinitis (AR), while only 63% of patients with EMRS had AR ( P = .004). Fifty-five percent of AFS patients had bilateral disease, in contrast to the 100% of EMRS patients with bilateral disease ( P < .0001). Although average total immunoglobulin E (IgE) was elevated in both groups, it was significantly more elevated in AFS patients (range, 12-13,084 mg/dL; mean, 1,941 mg/dL) compared with EMRS patients (range, 14-1,162 mg/dL; mean, 267 mg/dL; P < .001). Total immunoglobulin G (IgG) and IgG subclasses were seldom reported in the cases available from the literature of either AFS or EMRS. However, in the present series of EMRS, IgG1 deficiency occurred in 50% of evaluated patients (mean, 475 ± 175 mg/dL; range, 250-869 mg/dL; normal, 422 to 1,200 mg/dL) but in no cases of AFS reported in the literature. Conclusions Significant clinical and immunological differences exist to distinguish AFS from EMRS. It is postulated that AFS is an allergic response to fungi in predisposed individuals, while EMRS occurs because of a systemic dysregulation of immunological controls. Because EMRS is a systemic disease, unilateral disease is not seen. In contrast, AFS, an allergic response to fungi, may occur unilaterally or bilaterally depending on the antigenic stimulation. EMRS also has a significantly higher association with asthma, an increased incidence of aspirin sensitivity, and an increased incidence of IgG1 deficiency. Therapy with a systemic steroid, a potent and indiscriminant anti-inflammatory agent, is a useful adjunct in both disorders. Fungal immunotherapy following surgical extirpation of AFS is useful in preventing AFS recurrence. It is predicted that fungal immunotherapy and antifungal agents will be ineffective in patients with EMRS. It is important to differentiate these two similar histopathological entities in future trials assessing therapeutic efficacy. Inclusion of both entities in a study could obscure recognition of the true effectiveness of intervention, because of the possible variable response differences between the two entities. This study shows that significant clinical and immunological differences exist between EMRS and AFS. The future awaits an exploration of the pathophysiological basis of these differences. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of immunotherapy (IT) with fungal antigens on clinical outcome in patients with allergic fungal sinusitis (AFS). Study Design: Prospective case control. Methods: In this comparison study, 22 patients meeting the diagnostic criteria of allergic fungal sinusitis (AFS) were evaluated after a mean of 33 months' therapy. All received similar treatment consisting of endoscopic sinus surgery, corticosteroids, and antibiotics as needed for complicating purulent sinusitis. Eleven patients received postoperative immunotherapy (IT) with fungal and nonfungal antigens to which sensitivity had been demonstrated, while the remaining 11 received no immunotherapy. Results: The effect of IT was to significantly improve patient outcome as assessed objectively by an AFS endoscopic mucosal staging system ( P < .001) and a sinusitis-specific quality-of-life scale, the Chronic Sinusitis Survey ( P = .002). In addition, IT was shown to reduce reliance on systemic ( P < .001) and topical nasal ( P = .043) corticosteroid therapy to control disease. Follow-up was similar in the two groups and was not a determinant of differences in outcome ( P = .7). Conclusions: Results from this study indicate that specific IT with fungal antigens improves patient outcome in AFS. Laryngoscope, 108:1623-1627, 1998 [ABSTRACT FROM AUTHOR]

The objective of this study was to describe CT and MR findings in patients with allergic fungal sinusitis (AFS). CT and MR images were examined from 10 patients with histologically proven AFS. All patients demonstrated CT evidence of central sinus high attenuation and T2-weighted MR signal void corresponding to surgically proven areas of thick inspissated allergic mucin. AFS is a distinct clinical entity with a highly specific radiographic appearance based on CT and MRI. [ABSTRACT FROM AUTHOR]

Allergic fungal sinusitis (AFS) is a serious form of sinonasal fungal disease that is commonly associated with Aspergillus or Dematiaceous fungi. This study was performed to determine the incidence of Aspergillus or Penicillium in AFS by using in situ hybridization (ISH) for Aspergillus and Penicillium ribosomal RNA (rRNA). The Fontana-Masson melanin stain (FMMS) was also used to detect pigmented fungi (A. niger and Dematiaceous fungi). ISH was performed on 26 patients: 17 AFS cases with histologic evidence of fungi, 5 AFS cases without histologic evidence of fungi, 3 cases of invasive fungal sinusitis (IFS), and 1 case of fungus ball. Nine AFS specimens with histologic evidence of fungi were ISH positive. Positivity was also noted in two of three IFS cases, while no staining was seen in the fungus ball and in six AFS specimens without fungi demonstrable by silver stains. Six ISH-positive cases were FMMS positive, suggesting A. niger. Five ISH-negative AFS specimens were FMMS positive, suggesting Dematiaceous fungi. In summary, many AFS patients in our institution demonstrate Aspergillus/Penicillium organisms. Ancillary techniques may help identify fungi responsible for AFS if cultures are negative or not performed. ISH for rRNA is a useful means for rapidly speciating fungi in human tissues. [ABSTRACT FROM AUTHOR]