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Objectives: We report a case of acutely worsening allergic fungal sinusitis in a patient receiving immunotherapy with pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor. Methods: A 53-year-old man with a history of metastatic melanoma and recent initiation of pembrolizumab therapy presented with acutely worsening headaches, left abducens nerve palsy, and neuroimaging demonstrating an erosive skull base lesion with bilateral cavernous sinus involvement. Results: Intraoperative findings were consistent with non-invasive allergic fungal sinus disease. Microbiology and histopathologic data ruled out malignancy and demonstrated Aspergillus fumigatus without concern for angioinvasion. After treatment with antifungal therapy, the patient’s symptoms and abducens nerve palsy resolved. Symptoms were well-controlled 7 months after his initial presentation. Conclusions: Inflammatory sinusitis in patients receiving anti-PD-1 therapy may be secondary to T-cell infiltration, a similar pathophysiology as immune-related adverse events, and warrants appreciation by otolaryngologists given our increasing exposure to immunotherapy and its head and neck manifestations.

Background Allergic fungal rhinosinusitis (AFRS) is characterized by higher revision endoscopic sinus surgery (ESS) rates and unique radiographic features when compared to chronic rhinosinusitis with nasal polyposis (CRSwNP) or chronic rhinosinusitis without nasal polyposis (CRSsNP). Objective We hypothesized that an increased frequency of concha bullosa in AFRS or other radiographic nuances might allow for accumulation of allergic mucin and contribute to increased ESS revision rates. Methods A retrospective cohort study was performed. Patient diagnosis (AFRS, CRSwNP, and CRSsNP), basic demographics, and prior ESS rates were collected. Results A total of 210 consecutive patients were included (AFRS = 70, CRSwNP = 70, and CRSsNP = 70). Pediatric AFRS patients had more unilateral disease (38.1% vs 4.4%; P = .007) and anterior ethmoid skull base erosion (23.8% vs 6.7%; P = .047) than adult AFRS patients. AFRS patients were more likely to be younger (24.9 ± 10.1 years vs 45.6 ± 14.4 years vs 48.7 ± 18.2 years; P Conclusion In this cohort, pediatric AFRS patients had more unilateral disease and anterior ethmoid skull base erosion. Concha bullosa prevalence was significantly higher in AFRS as compared to those with CRSwNP or CRSsNP, despite prior ESS. Surgeons should consider concha bullosa as a potential anatomical subsite to harbor recurrent or residual disease.

ObjectivesWe reviewed the phenotyping and endotyping of chronic rhinosinusitis (CRS) and treatment options.MethodsWe searched PubMed, Google, Google Scholar, and the Proquest Central Database of the Kırıkkale University Library.ResultsPhenotypes are observable properties of an organism produced by the environment acting upon the genotype, that is, patients with a particular disorder are subgrouped according to common characteristics. Currently, CRS is usually phenotyped as being with (CRSwNP) or without (CRSsNP) nasal polyps. However, this is not immutable as some individuals progress from nonpolyp to polypoid CRS over time. Phenotypes of CRS are also based on inflammatory patterns, generally CRSwNP is eosinophilic, CRSsNP neutrophilic; but there is a spectrum, rather than a clear-cut division into 2 types. An endotype is a subtype of a condition defined by a distinct functional or pathobiological mechanism. Endotypes of CRS can be (1) nontype Th2, (2) moderate type Th2, and (3) severe type Th2 immune reactions, based on cytokines and mediators such as IL4, 5, 13. CRS endotyping can also include a (1) type 2 cytokine-based approach, (2) eosinophil-mediated approach, (3) immunoglobulin E-based approach, and (4) cysteinyl leukotriene-based approach. Subdivisions of CRSwNP can be made into nonsteroidal anti-inflammatory drug-exacerbated respiratory disease, allergic fungal sinusitis, and eosinophil pauci-granulomatous arteritis by testing. General treatment for all CRS is nasal douching. The place of surgery needs careful reconsideration. Endotype-directed therapies include glucocorticosteroids, antibiotics, aspirin, antifungals, anticytokines, and immunoglobulin replacement. The recognition of united airways and the co-occurrence of CRSwNPs and severe asthma should lead to common endotyping of both upper and lower airways in order to better direct therapy.ConclusionEndotyping can allow for the identification of groups of patients with CRS with a high likelihood of successful treatment, such as patients with a moderate type 2 immune reaction or those with acquired immune deficiency.

Allergic fungal sinusitis (AFS) is a condition that has an allergic basis caused by exposure to fungi in the sinonasal tract leading to chronic inflammation. Despite standard treatment modalities, which typically include surgery and medical management of allergies, patients still have a high rate of recurrence. Subcutaneous immunotherapy (SCIT) has been used as adjuvant treatment for AFS. Evidence exists to support the use of sublingual immunotherapy (SLIT) as a safe and efficacious method of treating allergies, but no studies have assessed the utility of SLIT in the management of allergic fungal sinusitis. A record review of cases of AFS that are currently or previously treated with sublingual immunotherapy from 2007 to 2011 was performed. Parameters of interest included serum IgE levels, changes in symptoms, Lund-McKay scores, decreased sensitization to fungal allergens associated with AFS, and serum IgE levels. Ten patients with diagnosed AFS were treated with SLIT. No adverse effects related to the use of SLIT therapy were identified. Decreases in subjective complaints, exam findings, Lund-McKay scores, and serum IgE levels were observed. Thus, sublingual immunotherapy appears to be a safe adjunct to the management of AFS that may improve patient outcomes.

Background Oral itraconazole is an antifungal that has been shown to be of benefit to patients with allergic bronchopulmonary aspergillus (ABPA). It is hypothesized that itraconazole may similarly benefit patients with allergic fungal sinusitis (AFS), a disease similar to ABPA. This study was designed to evaluate the therapeutic response of itraconazole in patients with refractory chronic fungal sinusitis who have failed maximal medical and surgical therapy. Methods A retrospective chart review was performed of 23 patients with AFS and nonallergic eosinophilic fungal sinusitis treated with oral itraconazole. Charts were reviewed for patient demographics, comorbidities, allergies, fungal cultures, type of surgery performed, and amount of oral steroids used before and after itraconazole. All patients were given a 6-month dose of itraconazole (100 mg b.i.d.) when recurrence developed after surgery. Time to next recurrence, change in oral steroid use, and outcomes were noted. Liver function tests were taken at monthly intervals while on itraconazole. Results Twenty-three patients, 13 men and 10 women, were started on oral itraconazole for recurrent fungal sinusitis. Nineteen patients responded to the medication with a decrease in symptoms and fungal mucin/polyps on endoscopy. Three patients had to stop because of elevated liver enzymes. In the remaining 16 patients a decrease in oral steroid use was noted. In addition, 11 of the 16 patients are disease free to date at a mean follow-up of 15.7 months. No permanent complications occurred from the use of the medication. Conclusion Oral itraconazole may be of benefit to those patients with recalcitrant fungal sinusitis who have failed maximal medical and surgical therapy. Itraconazole may prolong the time to next recurrence and may enable the patient to significantly decrease or stop oral steroids.

Background Noninvasive fungal sinusitis is a heterogenous group of conditions including allergic fungal sinusitis (AFS) and nonallergic eosinophilic fungal sinusitis (NEFS). Th2-mediated cascades have been postulated to be the major inflammatory response in patients with AFS although other mechanisms also may be involved. The detailed mucosal Th2 cytological status of NEFS still has not been studied in great depth. Methods Using a meticulous patient selection algorithm over a 2-year period, infundibular mucosal tissue from patients with AFS, NEFS, chronic rhinosinusitis (CRS), and normal controls was studied (n = 59). Immunohistochemistry for mast cells, eosinophils, and immunoglobulin E (IgE) cells was performed and cell counts per unit area were measured. Results Mast cell, eosinophil, and IgE+ cell numbers were significantly raised in patients with AFS, NEFS, and CRS when compared with controls. There was no significant difference between cell numbers in patients with AFS and NEFS. Conclusion Patients with AFS exhibit a classic Th2 inflammatory response in nasal mucosal tissue with NEFS and CRS patients showing evidence of a similar Th2 cascade, including the presence of IgE+ cells.

Background The aim of this study was to examine the changes of orbital volumes in allergic fungal sinusitis (AFS) patients with proptosis who undergo endoscopic sinus surgery. Methods A retrospective study of operative patients with proptosis due to AFS was performed. Normative data were obtained using patients with chronic sinusitis without orbital involvement. Orbital volume measurements were obtained using digitized images and computer software to calculate volumes (cm3) of outlined regions on 1.3-mm axial computed tomography images. Orbital volumes were measured as total volumes and volumes within the bony orbit. Bony orbits were defined using two techniques: (1) the region posterior to a line from ipsilateral zygoma to contralateral zygoma and (2) the region posterior to a line from zygoma to ipsilateral lacrimal bone. Four affected orbits in three AFS patients with proptosis were evaluated. Twenty-eight unaffected orbits in 14 patients were used as normal comparisons. Results Orbital involvement by AFS resulting in proptosis decreased orbital volumes within the bony orbit to a mean of 70% of normal. After successful endoscopic sinus surgery, bony orbital volumes normalize or approach normal ranges to a mean 90% of normal with resolution of clinically apparent proptosis. Total volumes remained stable before and after surgery. Conclusion Massive AFS may affect the orbit resulting in proptosis. Spontaneous orbital remodeling with clinical resolution of proptosis and normalization of bony orbital volumes can be seen in AFS patients several months after sinus surgery and aggressive medical treatment. Surgical orbital reconstruction typically is not needed once the sinus disease is adequately addressed.

BackgroundSinonasal pathology is nearly universal in the cystic fibrosis (CF) population. The bacteriology of sinus cultures from CF patients and the implications of sinus bacterial pathogens in this group have been studied; however, sinus fungal isolates from CF patients have not been examined in the literature.MethodsWe reviewed 30 consecutive CF patients undergoing endoscopic sinus surgery at our institution for the presence of fungal isolates obtained from the sinuses at the time of surgery.ResultsThirty-three percent of fungal cultures were positive in this sample; in addition, two patients were newly diagnosed with allergic fungal sinusitis.ConclusionWe examine the possible implications of positive fungal sinus cultures in the CF population.

Background Erosion of the bony sinus walls in allergic fungal sinusitis (AFS) is an established phenomenon. Reports of the incidence of bone erosion in AFS vary widely, and definitions of bone erosion lack uniformity. Differences in bone erosion among ethnic and gender groups have not been examined previously in the literature. Methods At our institution we reviewed 47 cases of AFS for ethnic and gender differences in presentation and presence of bone erosion. Results Caucasians presented at a mean 12 years later than African-Americans (p = 0.002); however, this difference was largely carried by Caucasian females. African-Americans presented with a greater incidence of bone erosion than Caucasians (p = 0.028). In addition, there are statistically significant differences in the individual paranasal sinuses affected by bone erosion in AFS. Conclusions We examine the potential implications of ethnic and gender differences in presentation and bone erosion in AFS.

Background Since its original description in the early 1980s, our understanding of allergic fungal sinusitis (AFS) has continued to evolve. The goal of this research was to characterize the typical AFS patient and describe a treatment protocol using endoscopic sinus surgery, high-dose itraconazole, low-dose bursts of oral corticosteroids, and topical corticosteroids. Methods A 12-year retrospective chart review was conducted to extract demographic and management data on 139 patients meeting the AFS criteria of atopy, characteristic radiographic findings, eosinophilic mucin, nasal polyposis, and a positive fungal culture or stain. Results The typical AFS patient presented at 42.8 years of age, was female, and had 3.5 positive fungal cultures over an average of 31.4 months of follow-up. Although 69 patients (50.3%) experienced recurrence, reoperation was required in only 17 (20.5%) of 83 patients initially managed by our protocol. There were no serious adverse effects attributed to itraconazole over the 36,000 doses prescribed. Conclusion The use of itraconazole, short-burst low-dose oral corticosteroids, topical corticosteroids, and endoscopic surgery is a safe and clinically effective regimen in the management of AFS. Our clinical experience suggests medical management of recurrent AFS with itraconazole may avoid revision surgery.

Allergic fungal sinusitis (AFS), first described over 18 years ago and subsequently identified using established criteria, remains a challenge to treat. Our protocol has included complete functional endoscopic sinus surgery to remove the fungal load and restore physiologic mucous clearance. The patient is treated with prednisone for several months and followed monthly with total serum IgE levels and an established endoscopic mucosal staging system. A group of 11 patients first treated in 1994 and presented at the 1995 American Rhinology Society Spring meeting are being presented again to provide an update on their progress over the past four years. A great deal of experience has been gained from their treatment and has continued to modify our postoperative medical management. An overview of AFS, our evolving and current treatment protocol, and possible future trends are discussed in this paper.

Allergic fungal sinusitis is a chronic disorder that is being more frequently recognized by otolaryngologists. It is a recurrent illness characterized by frequent exacerbations, and requires aggressive medical and surgical treatment. When surgical therapy is employed, it is necessary to ensure adequate debridement and removal of edematous tissue. We have been using powered dissection as our primary method in sinus surgery over the past three years. We have treated 11 patients with allergic fungal sinusitis, and find powered instrumentation to be very effective in removing the polypoid tissue from the nose and sinuses, and in providing a clear surgical field. The procedure can be performed safely, with minimal trauma to normal tissue. We believe that the use of powered dissection greatly enhances the comprehensive treatment of allergic fungal sinusitis.

In little more than a decade, allergic fungal sinusitis has gone from a medical curiosity to one of the more perplexing problems to challenge the otorhinolaryngologist. These patients are typically immunocompetent adolescents or young adults with pansinusitis (unilateral and bilateral) and polyposis, atopy, and characteristic radiographic findings. Allergic mucin contained within the sinuses demonstrates numerous eosinophils and Charcot-Leyden crystals, and fungal stains show the presence of noninvasive hyphae. Fungal cultures may or may not be positive. We have found the following approach to allergic fungal sinusitis to be most effective: 1) Adequate preoperative evaluation and medical preparation; 2) Meticulous exenterative surgery; 3) Closely supervised immunotherapy with relevant fungal and non-fungal antigens; 4) Medical management including topical and systemic corticosteroids as needed; 5) Irrigation and self-cleansing by the patient; and 6) Close clinical follow-up with endoscopically guided debridement when necessary.

Although paranasal fungal sinusitis is rare, an increased number of Aspergillus and non-Aspergillus related cases of allergic fungal sinusitis have been described since its first report in 1983. The histopathologic findings necessary for a definitive diagnosis rest upon the detection of scattered fungal elements in a matrix of allergic mucin. The clinical spectrum and treatment of allergic fungal sinusitis are detailed within four illustrated case reports. Sinus surgery, followed by meticulous post-surgical care by an allergy and otolaryngology team using oral corticosteroids, and followed by maintenance intranasal steroids and nasal airway irrigations in conjunction with allergy immunotherapy, has resulted in excellent clinical outcomes.

Fungal sinusitis can present as one of four distinct clinicopathologic 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.

A case of Allergic Fungal Sinusitis successfully controlled with oral corticosteroids followed by endoscopic sinus surgery is presented. The clinical diagnosis of AFS is emphasized. Endoscopic sinus surgery is preferable to open sinus techniques since the underlying mucosal disease is reversible. A prospective study is needed to determine the most appropriate treatment for this unique clinical disorder.

This is the first report of AFS which caused frontal lobe symptomatology and which resolved with surgical therapy. The surgical approach used provided excellent exposure and the sinuses could be examined and thoroughly cleaned both from above and intranasally. The dural defect, which resulted from the destruction of the cribiform and fovea ethmoidalis, was easily reconstructed with a pericranial flap. This exposure facilitates debridement and reconstruction while minimizing complications such as cerebral spinal fluid leakage or brain injury which may occur with endoscopic manipulations in patients with bony destruction and loss of normal landmarks.

A case report of recalcitrant allergic fungal sinusitis (AFS) refractory to systemic corticosteroids and multiple functional endoscopic sinus surgeries (FESSs) treated with anti-IgE antibody omalizumab is reported. AFS is often classified with chronic rhinosinusitis (CRS). Although similar symptoms are among the two diseases, AFS has a unique pathophysiology. Patients with AFS demonstrate type 1 hypersensitivity to fungal allergens, increased total serum IgE, increased CD8+ T-cell prevalence, and IL-4 and IL-5 response. Omalizumab should be considered in the treatment of AFS.

Fungi in paranasal sinuses are characteristic and considered a major pathogenic factor in a subset of chronic rhinosinusitis (CRS) patients, known as allergic fungal rhinosinusitis (AFRS). CD8+ T cells are enriched in AFRS sinuses but their role in fungal-specific responses is unknown. Alternaria alternata– and Aspergillus fumigatus–specific T lymphocyte responses were investigated in 6 AFRS patients, 10 eosinophilic mucus CRS (EMCRS) patients, 10 CRS with nasal polyps (CRSwNPs) patients, 6 allergic rhinitis with fungal allergy (ARFA) patients, and five controls. Fungal-specific proliferation of human peripheral blood mononuclear cells (PBMCs) was studied prospectively. Proliferating cells were examined for CD3, CD4, CD8, and CD25 expression. Relevant clinical characteristics, fungal allergy, detection of fungi in sinuses, and CD4+ and CD8+ composition of sinus T cells were also examined. CD4+ T-cell division to fungi occurred in all samples, regardless of fungal allergy or CRS. Fungal-specific CD8+ T-cell division occurred in all ARFA and control samples and the majority of CRSwNP patients; however, CD8+ T cells failed to proliferate in AFRS and EMCRS patients. The CD8+ T cells from AFRS patients also did not up-regulate the activation marker, CD25, with fungal antigen exposure. Presence of A. alternata– and A. fumigatus–specific CD4+ and CD8+ T-cell proliferation in healthy individuals, ARFA, and CRSwNP patients suggests that both T-cell subsets may be important in immune responses to these fungi. In AFRS and EMCRS patients, only fungal-specific CD4+ T-cell proliferation occurred; hence, a lack of CD8+ T-cell proliferation and activation in the presence of sinus eosinophilic mucus in these patients, regardless of fungal allergy, is a novel finding. This raises the question whether a dysfunctional CD8+ T-cell response predisposes to ineffective clearance and accumulation of fungi in the sinuses of susceptible patients.