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Abstract

To reevaluate the current criteria for diagnosing allergic fungal sinusitis (AFS) and determine the incidence of AFS in patients with chronic rhinosinusitis (CRS). This prospective study evaluated the incidence of AFS in 210 consecutive patients with CRS with or without polyposis, of whom 101 were treated surgically. Collecting and culturing fungi from nasal mucus require special handling, and novel methods are described. Surgical specimen handling emphasizes histologic examination to visualize fungi and eosinophils in the mucin. The value of allergy testing in the diagnosis of AFS is examined. Fungal cultures of nasal secretions were positive in 202 (96%) of 210 consecutive CRS patients. Allergic mucin was found in 97 (96%) of 101 consecutive surgical cases of CRS. Allergic fungal sinusitis was diagnosed in 94 (93%) of 101 consecutive surgical cases with CRS, based on histopathologic findings and culture results. Immunoglobulin E-mediated hypersensitivity to fungal allergens was not evident in the majority of AFS patients. The data presented indicate that the diagnostic criteria for AFS are present in the majority of patients with CRS with or without polyposis. Since the presence of eosinophils in the allergic mucin, and not a type I hypersensitivity, is likely the common denominator in the pathophysiology of AFS, we propose a change in terminology from AFS to eosinophilic fungal rhinosinusitis.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
... The involvement of microorganisms, particularly fungi and Staphylococcus aureus, in the pathogenesis of CRSwNP has been widely debated. The fungal hypothesis, initially proposed by Ponikau et al., suggests that common airborne fungi may elicit a strong eosinophilic immune response in predisposed individuals, leading to CRS [21][22][23][24]. This theory was extensively discussed in international forums; however, it remains controversial as subsequent studies failed to reproduce consistent results. ...
... These guidelines recommend vitamin D supplementation to achieve and maintain a target 25(OH)D3 concentration between 30 and 50 ng/mL (75 to 125 nmol/L) [103]. The American Endocrine Society recommends maintaining serum 25(OH)D3 concentrations greater than 30 ng/mL (>75 nmol/L), with a preferred range of 40 to 60 ng/mL (100 to 150 nmol/L) [21]. The 2025 expert consensus and review also suggest maintaining serum concentrations above 40 ng/mL to fully benefit from the extra- ...
... These guidelines recommend vitamin D supplementation to achieve and maintain a target 25(OH)D3 concentration between 30 and 50 ng/mL (75 to 125 nmol/L) [103]. The American Endocrine Society recommends maintaining serum 25(OH)D3 concentrations greater than 30 ng/mL (>75 nmol/L), with a preferred range of 40 to 60 ng/mL (100 to 150 nmol/L) [21]. The 2025 expert consensus and review also suggest maintaining serum concentrations above 40 ng/mL to fully benefit from the extraskeletal effects of vitamin D, with an upper threshold of 70 ng/mL [102]. ...
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Chronic rhinosinusitis with nasal polyps (CRSwNP) is a subtype of chronic rhinosinusitis (CRS) characterized by bilateral nasal polyps, primarily affecting adults. It is often associated with hyposmia and asthma and driven by persistent Th2 inflammation, particularly in Caucasian patients. The disease is recurrent and significantly impacts quality of life, yet its pathophysiology remains poorly understood. Management includes intranasal steroids, short courses of systemic corticosteroids, surgery for refractory cases, and biologics. However, despite these treatment options, disease control remains challenging. Low vitamin D levels have been associated with worse clinical outcomes, while supplementation studies show promise in improving symptoms in deficient patients. Emerging research suggests that vitamin D modulates immunity, fibroblast activity, and epithelial integrity, potentially contributing to CRSwNP pathogenesis, though the exact mechanisms remain unclear. This review synthesizes current research on vitamin D’s role in systemic and local inflammation in CRSwNP. By highlighting its potential therapeutic implications, this work aims to guide future research and inform clinical practice. Additionally, it may serve as a foundation for understanding the broader impact of vitamin D deficiency in sinonasal diseases and other atopic conditions.
... A variety of fungal organisms, exhibiting geographic variations in frequency, have been identified within nasal mucin in patients with acute or chronic sinusitis, as well as in healthy individuals without sinusitis [1][2][3]. In contrast to invasive fungal sinusitis (FS)-an acute, life-threatening condition primarily affecting highly immunocompromised patientsfungal ball (sinus mycetoma) and allergic fungal sinusitis (AFS) are chronic, indolent conditions occurring in immunocompetent individuals [1,[4][5][6][7][8][9]. ...
... A variety of fungal organisms, exhibiting geographic variations in frequency, have been identified within nasal mucin in patients with acute or chronic sinusitis, as well as in healthy individuals without sinusitis [1][2][3]. In contrast to invasive fungal sinusitis (FS)-an acute, life-threatening condition primarily affecting highly immunocompromised patientsfungal ball (sinus mycetoma) and allergic fungal sinusitis (AFS) are chronic, indolent conditions occurring in immunocompetent individuals [1,[4][5][6][7][8][9]. These non-invasive forms of FS generally have a favorable prognosis, as the fungus ball typically consists of wellorganized mycelium without tissue invasion. ...
... Fungal sinus diseases, once considered rare, have become increasingly reported over the last two decades [1,3,8,9,82]. Possible reasons for this rise include greater awareness, improved diagnostic methods, and higher prevalence of immunosuppressive conditions such as diabetes mellitus, cancer therapies, HIV, post-transplant therapies, and antibiotic overuse. ...
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Chronic fungal sinusitis (FS) can cause bone erosion and extend to the sellar region, often misdiagnosed as pituitary tumors or malignancies. We report a 56-year-old immunocompetent female with sphenoid FS presenting as a giant sellar mass compressing the optic chiasm, with normal pituitary function. The surgery successfully resolved her symptoms, and a histological examination confirmed the presence of a fungal hyphal mass. We conducted a literature review of 52 publications on FS cases with bone erosion and inflammatory extension to the sellar region, which included analyses of 67 patients (35 females, mean age 49.6 years, half immunocompetent). The most common symptom was headache (73.1%), followed by visual complaints (71.7%), visual deterioration (40.3%), ophthalmoplegia (38.8%), and visual field defects (13.4%). Symptom duration averaged 4.5 months in 65.7% of cases. Aspergillus was the most frequent (71.6%). Hormonal abnormalities included hypopituitarism (25.4%) and hyperprolactinemia (13.4%). Surgery was performed in 92.5% of patients. Common diagnoses included pituitary abscess (41.8%), fungal granuloma (16.4%), aspergillosis (16.4%) and allergic FS (14.9%). Antifungal therapy was administered in 53.7% of cases. Cure was achieved in 67.2%, while the mortality rate was 10.4%. Early recognition of fungal involvement, supported by a multidisciplinary approach, is essential for the accurate diagnosis and effective treatment. This highlights the need for vigilance to improve the outcomes in similar cases.
... On the other hand, eosinophilic mucin, while present, lacks specificity, as it is also found in AERD. Positive fungal culture, as a criterion, is deemed unreliable, as demonstrated by Ponikau et al. [27], who showed that fungal components can be present in healthy controls, rendering it nonspecific. ...
... • Positive fungal culture can occur in healthy controls, and is nonspecific [27] Epidemiology of AFRS ...
Article
Allergic fungal rhinosinusitis (AFRS) is a unique endotype of chronic rhinosinusitis with nasal polyps (CRSwNP). Despite high recurrence rates and often more severe presenting signs compared with other subtypes of CRSwNP, research dedicated to AFRS has been lacking. Diagnostic criteria are outdated, the mechanistic relationship of AFRS to other associated diseases is unclear, and the pathophysiology of disease and risk factors for recurrence have not been well studied. In December 2023, a multidisciplinary group of rhinologists, otolaryngologists, pulmonologists, allergists, immunologists, scientists, and infectious disease experts met at the National Institute of Health to discuss unmet needs for future AFRS research and care, including patient management, diagnostic criteria, severity, pathophysiology, and related conditions. A summary of these clinical and associated research discussions is included below.
... Tagetes erecta Linn (marigold) and Similax zeylanica are two herbal extracts known for their antioxidant and anti-inflammatory properties (B.H. Safirstein, 1976). These extracts have the potential to alleviate allergic rhinitis symptoms by reducing inflammation and modulating immune responses (Ponikau et al., 1999). ...
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In situ gel formulations such as Tagetes erecta Linn and Similax zeylanica were created and optimized for the administration of herbal medications. The study underscores the potential of in-situ nasal gels as a promising approach for enhancing drug delivery to treat allergic rhinitis, offering sustained drug release and prolonged therapeutic action. The estimate and compare different formulation of in-situ nasal gel formulations for the administration of herbal medications such as Similax zeylanica and Tagetes to treat allergic rhinitis. The in-situ gel was prepared by a cold method, and different concentrations of polymers were used, such as HPMC K4M (0.5- 1.5 %), PEG 4000 (1.5-3% w/v), and Carbopol 934 (0.5-1.5%) The optimized formulation, batch F-6, exhibited excellent properties in terms of physical appearance, pH range, drug content, and viscosity, making it a stable and effective formulation for nasal drug delivery. The morphology, size, and shape of the optimized formulation were investigated using Transmission Electron Microscopy (TEM). The analysis of variance (ANOVA) and the response surface models confirmed the significance and suitability of the developed formulations. The study concluded by demonstrating the effective creation and enhancement of in-situ nasal gel formulations for the administration of herbal medications such as Similax zeylanica and Tagetes erecta Linn. Promising outcomes in terms of extended therapeutic effect, enhanced bioavailability, and sustained drug release were demonstrated by the in-situ gels. Drug absorption and therapeutic effects were improved by the formulations’ usage of mucoadhesive polymers, which extended the drug’s residence duration on the nasal mucosa.
... However, the optimal imaging technique for detecting acute invasive fungal sinusitis (AFIFS) in immunocompromised patients remains uncertain, and further research is needed to determine the most reliable modality [12-13-14]. MRI has previously been evaluated as a screening tool for invasive fungal sinusitis (IFS), with reported sensitivity ranging from 64% to 87% in different studies [17,18]. In the present study, the prevalence of invasive fungal sinusitis confirmed by histopathology was 16.3%. ...
Article
OBJECTIVE: To determine the diagnostic accuracy of MRI in detecting fungal sinusitis using histopathology as the gold standard. MATERIALS AND METHODS: A cross-sectional study was done at the Department of Radiology, General Hospital, Lahore. The duration of the study was six months. For sample, Non-Probability Consecutive Sampling technique was used. A sample of 97 cases was calculated using 95% confidence limit, percentage of fungal sinusitis as 30%, and sensitivity and specificity of MRI as 85% and 83% with 13% margin of error. Inclusion criteria included patients of suspected fungal sinusitis referred from ENT department for MRI face to investigate possible sinus pathology, patients’ age 20 to 60 years and patients of either gender. Data analysis was done using Software SPSS. Data was stratified on age, gender, BMI, duration of symptoms and post-stratification test was used to assess statistical significance with p<0.05 as statistical significant. RESULTS: This study demonstrated that MRI is a highly sensitive tool for detecting fungal sinusitis, with a sensitivity of 93.59%. However, its specificity was moderate at 52.63%, meaning some cases identified as positive on MRI were later found to be negative on histopathology. The most commonly involved sinus was the maxillary sinus (58 cases), and MRI was particularly effective in detecting bone erosion and intraorbital spread. CONCLUSION: MRI is a valuable non-invasive imaging tool with high sensitivity for diagnosing fungal sinusitis. However, its moderate specificity suggests that histopathology remains the gold standard for definitive diagnosis. Future studies with larger sample sizes and advanced imaging techniques may further improve diagnostic accuracy.
... Histologically, fungal balls exhibit entangled masses of fungal organisms or fungi embedded in fibrinous, necrotic exudate with minimal mucosal inflammatory response. Typically, this condition is unilateral, affecting only one sinus in most cases (up to 90%-99%), with the maxillary sinus being the most commonly affected [4,5]. The second most common location for this disorder is the sphenoid sinus. ...
... An unused mask from each type was considered as a control. Subsequently, nasal lavage fluid of the employees was collected according to the method of Ponikau et al. (1999). The nasal cavity was rinsed with 3 ml of normal saline solution using a sterile glass syringe. ...
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Face masks serve as protective measures against pathogens and environmental pollutants. However, microplastic and phthalate pollutants present in the structure of masks may enter the nasal passages, potentially leading to health issues. In this study, we quantified microplastics and phthalate acid esters in masks used by hospital employees in various departments and in the nasal lavage fluid of these personnel before and after mask use. There were 200 participants, and the number of used masks was 160. The results indicated that the highest levels of microplastics (861.21 MP/mask) and Σ phthalate acid esters (3578.99ng/mL) were found in used masks from the laboratory. The amount of microplastics and phthalate acid esters in both masks and nasal lavage samples in the hospital departments were ranked as Laboratory > Physiotherapy > Emergency > Endoscopy. In nasal lavage samples, the amounts of these two pollutants decreased after mask use compared to the no-mask condition. Among the target phthalate acid esters, DEHP was the most prevalent in all mask and nasal lavage samples. These findings can be used for health risk assessment purposes.
... When we look at the microbiology results of other studies, there are large regional differences where Aspergillus spp. isolation ranges from 13 to 94.2% [5][6]28,29 . Treatment options of AFRS are debated since the discovery of this form of disease. ...
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Objective. The objective of this study was to analyse the aetiology, clinical presentations, histopathology and microbiological aspects of fungal rhinosinusitis (FRS) in patients undergoing endoscopic surgery. Methods. The descriptive study was carried out over a 4-year period in two Serbian ENT Clinics and included patients with sinonasal pathology who underwent endoscopic surgery. Results. The study included 26 patients. The most common forms of FRS treated by endoscopic sinus surgery was allergic FRS (AFRS). The fungus identification rate varied between entities, and was 72.2% in AFRS and 33.3% in fungal ball specimens. The common species seen in AFRS isolates were Cladosporium spp. (38.5% of isolated) and dematiaceous molds in the same percentage, while the remainder of the cultures were hyaline moulds. CT scan can be very helpful in diagnosing FRS and sometimes even in differentiating between different entities. Treatment of FRS should be tailored for each entity. Postoperative medical treatment in AFRS should consider potential advancements described in the literature. Conclusions. This study emphasises the need to combine all types of clinical, radiology, pathohistological and microbiological methods to obtain the best diagnostic and treatment strategies and should be the basis for further research.
Chapter
Chronic rhinosinusitis (CRS) is characterized by inflammation in the nose and paranasal sinuses lasting a minimum of 12 weeks. Depending on whether nasal polyps are present, CRS can be categorized into two types: CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). CRSwNP is marked by high tissue eosinophilia and an increase in T helper (Th)-2 cytokine expression. In contrast, CRSsNP is typified by Th-1 polarization and less eosinophilic infiltration. The EPOS2020 steering has decided to examine CRS from the perspective of primary and secondary classifications, further subdividing each based on the anatomical spread of the disease into localized and diffuse categories. In the case of primary CRS, the disease is categorized based on the predominance of endotypes, specifically type 2 or non-type 2. Key symptoms of CRS encompass anterior and/or posterior mucopurulent nasal discharge, nasal blockage, facial discomfort/pressure/fullness, and a diminished sense of smell (hyposmia or anosmia). Certain alarming symptoms, such as unilateral symptoms, blood-tinged rhinorrhea, orbital symptoms, swelling of the forehead, and specific neurological signs, call for immediate medical attention. As per prevailing clinical guidelines, the primary treatment for CRS involves intranasal corticosteroids. For patients who do not respond adequately to conservative treatment, endoscopic sinus surgery is suggested. Lately, biologics have emerged as a potential treatment option for CRSwNP patients who have a recalcitrant disease.
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Pathologic examination of the sinus mucosa and titration of inflammatory mediators in the sinus fluid were carried out to characterize inflammation in chronic sinusitis and determine whether patients with chronic allergic rhinitis (CAR) and sinusitis differ from patients with chronic nonallergic rhinitis (CNAR) and sinusitis. Nine control subjects (patients requiring ear, nose, and throat surgery not related to sinusitis), 12 patients with CAR and sinusitis, and 13 patients with CNAR and sinusitis were investigated. Eosinophil cationic protein, tryptase, myeloperoxidase, histamine, and prostaglandin D2 were measured in the sinus lavage fluids, and cells were enumerated. The cellular infiltrate was studied by immunohistochemistry with monoclonal antibodies against eosinophil cationic protein (eosinophils), tryptase (mast cells), neutrophil elastase (neutrophils), CD3 (lymphocytes), CD68 (macrophages), and proliferating cell nuclear antigens. Neutrophils were not increased in sinusitis. In comparison with control subjects, patients with CAR and CNAR with sinusitis showed significant increases in eosinophils and macrophages in biopsy specimens and in eosinophil cationic protein in sinus lavage fluids. In comparison with patients with CNAR, patients with CAR had an increased number of intraepithelial mast cells and lymphocytes. These findings suggest that patients with CNAR and sinusitis can be distinguished from patients with CAR and sinusitis, which resembles nonallergic rhinitis with eosinophilia syndrome.
Article
Fungal sinusitis can present as one of four distinct clinico-pathologic entities: 1) fulminant or acute; and three types of chronic, 2) indolent, 3) mycetoma, and 4) allergic fungal sinusitis (AFS). The first three forms differ both clinically and pathologically from AFS. The first reported cases of AFS were associated with the fungus Aspergillus, but recently other fungal organisms have been implicated. Five different fungal organisms have been found to cause AFS in 14 patients. The prevalence of AFS among patients with chronic sinusitis may be as high as 7%. The diagnosis is made on the histologic findings of inspissated allergic mucin containing 1) numerous eosinophils, 2) scattered noninvasive fungal hyphae, and 3) Charcot-Leyden crystals. In addition, AFS patients have a characteristic clinical and immunologic profile. The clinical presentation, diagnosis, and management of AFS are discussed. Uniformity of the classification of fungal sinusitis is proposed.
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Immunohistological investigations were performed on a series of samples from 37 patients with nasal polyps, 22 with chronic sinusitis, and 15 controls with healthy nasal and sinusal mucosa. Mean numbers of plasma- and mast cells were not different in the various groups. Immunoglobulin isotypes were always predominantly IgA and IgM; IgE were scarce. Deposited immune complexes were always absent. A statistically significant difference, however, was observed in the number of eosinophils within the mucosa. Patients with nasal polyps had up to ten times more eosinophils per surface unit than patients with sinusitis or healthy mucosa.
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Allergic fungal rhinosinusitis is a rare complication of atopic upper airways disease which may present initially as an expansive tumour of the paranasal sinuses. This reported case was caused by the rare fungal pathogen Bipolaris hawiiensis and illustrates typical clinical and laboratory features of this disorder. Although the optimum management of allergic fungal sinusitis is controversial, combined therapy with surgical clearance, antifungal agents and corticosteroids produced a favourable outcome.
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The clinical and pathologic features of seven cases of a newly recognized form of chronic sinusitis are described. Most patients were young adults with a history of asthma, and all had chronic nasal polyps. Radiographically, there was opacification of multiple sinuses. Recurrent sinusitis was common, and several patients underwent numerous surgical drainage procedures. Histologically, a distinct mucinous material containing eosinophils, Charcot-Leyden crystals, and fungal hyphae was found in tissue resected from the sinuses. We believe that these findings constitute a distinct clinicopathologic entity that we term allergic Aspergillus sinusitis. This condition shares similar histopathologic features with allergic bronchopulmonary aspergillosis (ABPA) but affects the paranasal sinuses rather than the lung. Implications for therapy of this form of sinusitis and its possible relationship to allergic lung diseases are discussed.
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To better determine the role of allergy in rhinitis and nasal polyposis, we assessed the prevalence of nasal mucosal allergy in the absence of systemic allergy. After a thorough literature search we compiled and analyzed data from nine studies (287 patients) that tested for specific immunoglobulin E both intranasally and systemically. When meta-analysis was applied to the different populations, 19% of those who demonstrated specific immunoglobulin E manifested nasal mucosal allergy but no systemic allergy. We suggest that there is an important segment of rhinitis and nasal polyp patients who have nasal mucosal allergy.
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Despite documentation of specific immunologic hypersensitivity in a few case reports, controversy continues as to the role of allergy versus true infection in the clinical entity of allergic fungal sinusitis (AFS). Using a modified radioallergosorbent test (RAST) to multiple fungal antigens, 16 patients meeting the histologic criteria of AFS and with positive fungal cultures were compared to 5 control patients with similar preoperative clinical findings but without histologic or culture evidence of AFS. All patients were immunocompetent and none demonstrated histologic evidence of tissue invasion. All AFS patients were RAST-positive to at least one fungal antigen in the family of their cultured organism with positive defined as class 2 or greater. No control patient was RAST-positive to either dematiaceous or Aspergillus fungal antigens. Thus, modified RAST testing can aid in the routine clinical diagnosis of AFS, and it provides further serologic evidence for a type I hypersensitivity in the pathogenesis of AFS.