Medical treatment of allergic fungal sinusitis.

LEARNING OBJECTIVES: This review of allergic fungal sinusitis (AFS) will enable the reader to (1) differentiate AFS from the other forms of fungal sinusitis, (2) understand AFS pathophysiology, (3) recognize AFS clinical presentation, (4) prepare an effective treatment and follow-up strategy, and (5) avoid diagnostic and treatment pitfalls. DATA SOURCES: All English language MEDLINE articles that cross-referenced allergy, fungal, and sinusitis from 1983-present. Other MESH words referenced included: antibodies, fungal; fungus diseases; IgE; spores, fungal; rhinosinusitis. Additional referenced articles, published abstracts, and conference proceedings were also utilized. STUDY SELECTION: All case reports, studies, and review articles. RESULTS: Allergic fungal sinusitis is a distinct form of non-invasive fungal sinusitis. It is under-diagnosed, and incidence varies by region. Dematiaceous fungi predominate. In the southwestern United States, Bipolaris spicifera is the most common cause. Patients present with nasal polyps, rhinosinusitis, and occasionally proptosis. CT scans show hypertrophic sinusitis and often hyperattenuating allergic mucin within the sinus cavities. Extra-sinus extension of disease is common. Surgical histopathology shows eosinophilic-lymphocytic mucosal inflammation and inspissated allergic mucin containing non-invasive fungal hyphae. All patients are atopic and have positive allergy skin tests to the AFS organism. Total serum IgE levels are usually elevated. AFS immunopathophysiology is analogous to allergic bronchopulmonary aspergillosis. Treatment requires surgery, postoperative oral corticosteroids (OCS), and aggressive allergy management including allergen immunotherapy. Oral corticosteroids reduce disease activity and forestall the need for recurrent sinus surgery. Postoperative changes in total serum IgE mirror the clinical status and may predict disease recurrence. Patients should be cooperatively followed by the medical specialist and surgeon because early sinus surgery for recurrence, together with aggressive medical management, gives the best outcome. CONCLUSIONS: Allergic fungal sinusitis is a new allergic disorder with recognizable clinical and histopathologic findings. Treatment requires aggressive allergy management, postoperative OCS, monitoring of total serum IgE, and medical/surgical co-management.     

Sensitization to recombinant Aspergillus fumigatus allergens in allergic fungal sinusitis.

BACKGROUND: Allergic bronchopulmonary mycosis is primarily caused by Aspergillus fumigatus. Despite similarities, allergic fungal sinusitis (AFS) is thought to be caused by various fungi. OBJECTIVE: Identify fungal elements in AFS allergic mucin and determine the prevalence of specific immunoglobulin (Ig)E to recombinant A. fumigatus allergens (rAsp) in AFS patients. METHODS: Allergic mucin from 17 definitive and 10 probable AFS patients were histologically examined for fungal elements. Sera from 18 definitive AFS patients, 10 probable AFS patients, 6 chronic sinusitis patients, and 5 A. fumigatus-allergic patients were tested for specific IgE to A. fumigatus and five rAsps. RESULTS: Ten of the 17 definitive cases had hyphae morphologically resembling Aspergillus or Fusarium spp. One probable AFS patient had similar findings. Of definitive patients, 94% (17 of 18) showed A. fumigatus-specific IgE (> or = 0.35 kUa/L), and 67% were positive to one or more rAsp. Four of 10 probable patients demonstrated A. fumigatus-specific IgE, and 2 had IgE to one or more rAsp. The definitive group had greater mean A. fumigatus IgE (P < 0.05) versus the probable and chronic sinusitis groups. The definitive group's rate of IgE to the rAsps was statistically greater. All definitive patients with Aspergillus or Fusarium spp. in situ had A. fumigatus-specific IgE, and 7 of 10 had IgE to at least one rAsp. CONCLUSIONS: Most definitive AFS patients have A. fumigatus-specific IgE and many have specific IgE to rAsps. Many also demonstrate Aspergillus spp. or Fusarium spp. in situ. Findings suggests that A. fumigatus is an important causative agent in AFS in the southeast United States.     

变应性真菌性鼻窦炎临床病理分析

目的 探讨变应性真菌性鼻窦炎(AFS)的临床病理特征,提高对AFS的认识和病理诊断水平.方法 回顾并分析首都医科大学附属北京同仁医院2002-2006年36例AFS的临床病理和影像学资料,应用阿尔辛蓝-过碘酸雪夫(AB-PAS)、环六亚甲基四胺银(GMS)特殊染色及黏蛋白5B(MUC5B)免疫组织化学(SP法)染色标记真菌,同时选取AFS新鲜活检组织lO例进行透射电镜观察.结果 36例AFS中,男21例,女15例,发病年龄11～53岁.多具有变应性疾病病史.CT平扫示受累的鼻窦充满软组织影,伴斑片状高密度影,窦壁骨质可出现压力性骨破坏.实验室检查:一种或多种真菌抗原皮试阳性(31/36);血清学检查总IgE和(或)真菌特异性lgE增高(20/36);外周血嗜酸性粒细胞数增多(23/36).真菌培养10例阳性.组织病理学:大体典型病变为黏稠的"油灰样"分泌物,镜下为特征性的"嗜酸性黏蛋白",AB-PAS及GMS染色、MUC5B免疫组织化学染色真菌均着色.透射电镜可见嗜酸性粒细胞脱颗粒现象.结论 "嗜酸性黏蛋白"是AFS最具特征性的病理学表现,建议采用AB-PAS、GMS特殊染色及MUCSB免疫组织化学染色等多种方法 联合标记真菌;需对临床症状、影像学特点、实验室检查及病理学表现等多个方面进行综合判断以得出正确诊断.     

Unusual aspects of allergic bronchopulmonary fungal disease: report of two cases due to Curvularia organisms associated with allergic fungal sinusitis.

We report two cases of allergic bronchopulmonary fungal disease (ABPFD) caused by Curvularia sp and associated with allergic fungal sinusitis (AFS). Curvularia lunata was cultured in one case and Curvularia senegalensis was cultured in the other. Based on these cases and a review of the literature, we discuss unusual clinical and pathologic features that can occur in ABPFD. Unusual clinical aspects of ABPFD include associated AFS, absence of asthma, progression to Churg-Strauss angiitis and granulomatosis, concomitant hypersensitivity pneumonitis, and underlying cystic fibrosis. Atypical pathologic features that may occur in ABPFD include follicular bronchiolitis, xanthomatous bronchiolitis, limited tissue invasion, fungus balls, and association with unusual fungi. Prominent follicular bronchiolitis and xanthomatous bronchiolitis were misleading histologic features in one of our cases and led to a delay in recognition of the diagnosis. Both patients presented primarily with AFS; ABPFD was detected subsequently. This suggests that a small subset of patients with AFS may be at risk for ABPFD. The goal of this review is to increase awareness of unusual clinical and pathologic manifestations of ABPFD. It is hoped that this will result in accurate diagnosis and proper therapy, especially for patients who present with atypical features. Unusual fungal species should be considered in patients who have clinical findings compatible with ABPFD but who do not demonstrate immunologic reactivity to Aspergillus sp, especially Aspergillus fumigatus. In addition, ABPFD should be considered in patients with AFS who develop new pulmonary lesions.     

A case of allergic fungal sinusitis caused by Bipolaris spicifera]

We describe a case of allergic fungal sinusitis (AFS) caused by Bipolaris spicifera, the first case reported in Japan. A 70-year-old man was admitted to our hospital because of diplopia following bilateral nasal obstruction and discharge. Radiological studies using computed tomographic scan showed a large soft tissue mass occupying the right frontal, bilateral ethmoid and sphenoid sinuses. He underwent drainage surgery and histopathological examination of the contents of the paranasal sinuses revealed scattered fungal hyphae within "allergic mucin". By cytological examination, these hyphae showed septation at irregular intervals, and were swollen to various sizes. Microbiological studies identified the fungus as Bipolaris spicifera. The presence of allergic mucin and scattered fungal hyphae were very important findings in making a diagnosis of AFS histopathologically, so squash cytology of the contents of the paranasal sinuses was quite useful to observe fungal elements and identify the strain in this case.     

Allergic fungal sinusitis in children.

BACKGROUND: Allergic fungal sinusitis (AFS) has been characterized in adults presenting with chronic sinusitis. Rare reports allude to a similar disease in children. OBJECTIVE: To characterize the features of AFS in children. METHODS: Children referred to otolaryngology clinics at Arkansas and LeBonheur Children's Hospitals for chronic sinusitis during a 12-year period were studied. This retrospective analysis reviews the following: clinical presentation, laboratory evaluations, radiographic and pathologic findings, and surgical intervention. Twenty patients (age range, 7-18 years; mean age, 12.5 years; median age, 16 years) met previously published criteria for AFS. Thirteen patients were male and 7 were female. Thirteen were African American and 7 were white. RESULTS: Presentation at diagnosis included the following: atopy (n = 20), nasal symptoms (n = 20), recurrent sinusitis (n = 18), nasal polyps (n = 18), recurrent headaches (n = 12), asthma (n = 11), proptosis (n = 10), and ocular symptoms (n = 10). All had radiographic evidence of sinusitis and allergy to fungal organisms. IgE levels were elevated in 8 of 9 patients, and 10 of 15 patients had eosinophilia. Surgical specimens demonstrated allergic mucin (n = 11), Charcot-Leyden crystals (n = 2), hyphae or fungal debris (n = 9), and fungal growth (n = 17). All patients underwent endoscopic sinus surgery, with 11 requiring multiple surgical procedures. Postoperatively, 19 patients received intranasal and oral steroids, and all had nasal saline washes. Eleven patients (9 who had undergone multiple surgical procedures) were treated with immunotherapy. Relapse was seen in 55% of patients at 1 year of follow-up. CONCLUSION: AFS presents with a higher incidence of proptosis in children when compared with adults. Typically, AFS occurs in atopic children with refractory sinus disease, requiring a high index of suspicion for evaluation and aggressive treatment.     

Allergic fungal sinusitis

Many common chronic inflammatory rhinosinusitis conditions (hypertrophic sinus disease [HSD]) have the histopathological profile of allergic or asthmatic inflammation. Allergic fungal sinusitis (AFS) is both a type of noninvasive fungal rhinosinusitis and a type of HSD. AFS has clinicopathological features that make it similar, but not identical, to allergic bronchopulmonary aspergillosis (ABPA). Allergic mucin is a defined pathological entity occurring in ABPA, AFS, and in the HSD "eosinophilic mucin rhinosinusitis (EMRS)." Diagnosis of AFS requires a careful review of surgical reports, histopathology, and culture results. Treatment includes surgery and aggressive postoperative medical management of allergic inflammatory disease. Prognosis is good with integrated medical-surgical follow-up, but recurrence remains problematic. The association of ABPA, AFS, and HSD with class II genes of the major histocompatibility complex places the initiation of these inflammatory diseases within the context of antigen presentation and the acquired immune response. Pathological immunomanipulation of this response by local microbial superantigens may be a common mechanism for disease pathogenesis. Future research into the molecular biology of these related conditions may offer insight into the pathogenesis of other chronic inflammatory diseases.     

HLA-DQB1 *03 in allergic fungal sinusitis and other chronic hypertrophic rhinosinusitis disorders

BACKGROUND: Many common chronic inflammatory disorders have strong HLA gene associations, particularly with MHC class II. Allergic fungal rhinosinusitis (AFS) and hypertrophic sinus disease (HSD) are chronic sinonasal mucosal inflammatory disorders. Allergic bronchopulmonary aspergillosis, a disorder analogous to AFS, was recently reported to have HLA-MHC class II associations. OBJECTIVE: We sought to determine whether MHC class II is also associated with AFS and HSD. METHODS: HLA DNA genotyping was obtained on 44 patients with AFS and 30 patients with HSD (of which 21 were atopic). RESULTS: Sixty-six percent of patients with AFS carried at least one HLA-DQB1 *03 allele; DQB1 *0301 and DQB1 *0302 were the most frequent allelic variants (odds ratio [OR] vs healthy subjects = 8.22; 95% CI, 4.30-15.73; P < .001; OR vs all patients with HSD = 1.93; 95% CI, 1.09-3.41; P < .01; OR vs atopic patients with HSD = 2.57; 95% CI, 1.46-4.53; P < .001). Of the 31 patients with AFS and positive Bipolaris spicifera cultures, 68% had DQB1 *03, with DQB1 *0301 and DQB1 *0302 being most frequent (OR vs healthy subjects = 8.93; 95% CI, 4.65-17.15; P < .001; OR vs patients with HSD = 2.10; 95% CI, 1.18-3.73; P < .001). Of the 30 patients with HSD, 50% carried DQB1 *03 (OR vs healthy subjects = 4.25; 95% CI, 2.25-8.02; P < .001) but differed in frequencies of DQB1 *03 allelic variants compared with patients with AFS ( P = .0004). For HSD, nonatopic subjects had the highest DQB1 *03 association (OR vs healthy subjects = 8.63; 95% CI, 4.50-16.54; P < .001). DQB1 *03 allelic variants did not correlate with allergy skin test results, atopic status, total serum IgE levels, culture results, asthma, or aspirin-nonsteroidal anti-inflammatory drug hypersensitivity. CONCLUSION: Patients with AFS and HSD have HLA-DQB1 *03 alleles as a risk factor for disease, with AFS having the highest association. However, they differ in DQB1 *03 allelic variant frequencies, suggesting several potential roles for MHC class II in their immunopathogenesis.     

Unusual aspects of allergic bronchopulmonary fungal disease: Report of two cases due to Curularia organisms associated with allergic fungal sinusitis

We report two cases of allergic bronchopulmonary fungal disease (ABPFD) caused by Curvularia sp and associated with allergic fungal sinusitis (AFS). Curvularia lunata was cultured in one case and Curvularia senegalensis was cultured in the other. Based on these cases and a review of the literature, we discuss unusual clinical and pathologic features that can occur in ABPFD. Unusual clinical aspects of ABPFD include associated AFS, absence of asthma, progression to Churg-Strauss angiitis and granulomatosis, concomitant hypersensitivity pneumonitis, and underlying cystic fibrosis. Atypical pathologic features that may occur in ABPFD include follicular bronchiolitis, xanthomatous bronchiolitis, limited tissue invasion, fungus balls, and association with unusual fungi. Prominent follicular bronchiolitis and xanthomatous bronchiolitis were misleading histologic features in one of our cases and led to a delay in recognition of the diagnosis. Both patients presented primarily with AFS; ABPFD was detected subsequently. This suggests that a small subset of patients with AFS may be at risk for ABPFD. The goal of this review is to increase awareness of unusual clinical and pathologic manifestations of ABPFD. It is hoped that this will result in accurate diagnosis and proper therapy, especially for patients who present with atypical features. Unusual fungal species should be considered in patients who have clinical findings compatible with ABPFD but who do not demonstrate immunologic reactivity to Aspergillus sp, especially Aspergillus fumigatus. In addition, ABPFD should be considered in patients with AFS who develop new pulmonary lesions.     

A superantigen hypothesis for the pathogenesis of chronic hypertrophic rhinosinusitis, allergic fungal sinusitis, and related disorders.

BACKGROUND: Chronic eosinophilic-lymphocytic respiratory mucosal inflammatory disorders include hypertrophic sinus disease, allergic fungal sinusitis, allergic bronchopulmonary aspergillosis, and chronic severe asthma. They have many analogous or shared aspects of pathology at molecular, cellular, and clinical levels of analysis. OBJECTIVE: To propose a theory, and supporting data through comprehensive literature review, that unifies these diseases' pathogenesis. METHODS AND DATA SOURCES: Current medical literature was used as supportive background information. Reinterpretation of existing studies and reasoned speculation were used when necessary and identified where used. English language MEDLINE articles that referenced sinusitis, rhinosinusitis, allergic fungal sinusitis, asthma, allergic bronchopulmonary aspergillosis, nasal polyp, superantigen, and T cell receptor from 1983 to present were potentially used as background or supportive information. Additional referenced articles, published abstracts, and National Center for Biotechnology Information Entrez protein database searches were used. Case reports, studies, review articles, and textbooks were included. RESULTS: Multiple lines of evidence support the proposed hypothesis that microbial T cell superantigen production, persistence, and host-responsiveness are the fundamental components that unify the pathogenesis of all common chronic eosinophilic-lymphocytic respiratory mucosal inflammatory disorders. Superantigen amplification of preexisting immunopathology is the proposed mechanism for disease induction and maintenance. Preexisting immunopathology is created in the individual by a potential heterogeneity of immunopathologic signals that can include type I immediate hypersensitivity, other antigen-specific immune responses, cytokine dysregulation, eicosanoid dysregulation, various genetic mutations, and other molecular pathology. Although the ability to develop chronic severe inflammatory disease is dependent upon this immunopathology, host T cell receptor V beta genetics and persistent superantigen production/exposure at the respiratory mucosa by relevant superantigen-producing extra- or intracellular microbes are postulated to be required. This mechanism for disease pathogenesis may also apply to other disorders. Approaches to prove this theory and its predictions are presented. CONCLUSIONS: The pathogenesis of all the disorders discussed can be unified through the superantigen hypothesis proposed. Multiple lines of evidence support this hypothesis. How we view these common conditions will change, and new research into pathogenesis and treatment will occur if this proves true.     

Immunotherapy for allergic diseases

Conclusions Immunotherapy continues to be an important component in the treatment of allergic diseases. It remains the only mode of treatment that has exhibited the potential for modifying the natural history of allergic diseases and possibly for preventing them from occurring at all. Though many aspects of its administration still need to be studied in a scientifically rigorous manner, it has proven to be effective even when given with nonstandardized methods. As a result, it continues to be important for physicians to learn the art of giving effective immunotherapy in addition to the ever-expanding science.     

霉菌性鼻窦炎诊断与治疗

目的探讨霉菌性鼻窦炎的诊断与治疗方法。方法对48例经手术病理证实为霉菌性鼻窦炎的临床表现、体征影像学及手术、病例资料、治疗效果进行总结分析。结果32例术前经临床表现、结合CT即明确诊断,16例为术后经病理检查才明确诊断,48例均行鼻窦病灶清理术,术后用抗真菌药物冲洗窦腔,全部病例均治愈。结论该病大多有典型的临床表现,CT有明确的特征性,手术彻底清除病灶,通畅引流,抗真菌药物冲洗窦腔是有效的治疗方法。     

Contemporaneous occurrence of allergic bronchopulmonary aspergillosis, allergic Aspergillus sinusitis, and aspergilloma.

BACKGROUND: The clinical categories of Aspergillus-related respiratory disorders usually remain mutually exclusive. The coexistence of allergic bronchopulmonary aspergillosis (ABPA) with aspergilloma is uncommon, whereas concurrent ABPA and allergic Aspergillus sinusitis (AAS) is rare. The association of these 3 clinical entities has previously been documented only once in a patient who had earlier been operated on for an aspergilloma before the diagnoses of ABPA and AAS were established. OBJECTIVE: To describe an adult in whom ABPA, AAS, and aspergilloma were diagnosed simultaneously. METHODS: Spirometry, radiography, computed tomography, skin allergy testing with Aspergillus antigens, serum precipitins against Aspergillus, total and specific IgE, functional endoscopic sinus surgery, and fungal culture were performed. RESULTS: A 26-year-old man who had asthma and rhinitis since childhood presented with hemoptysis. Serial chest radiographs revealed transient pulmonary infiltrates and an aspergilloma. Computed tomography of the thorax confirmed the aspergilloma and showed bilateral central bronchiectasis along with patchy infiltrates. Strong bands of precipitins were detected against Aspergillus fumigatus, and intradermal testing with Aspergillus antigens elicited strong type I and III hypersensitivity reactions. Specific IgE and IgG antibodies against A fumigatus were positive, and total IgE levels were significantly elevated. Peripheral blood eosinophilia was also detected. Sinus involvement was confirmed on computed tomography, and pathologic material obtained by functional endoscopic sinus surgery demonstrated allergic mucin that contained fungal elements. In addition, A fumigatus was cultured. CONCLUSIONS: ABPA, AAS, and aspergilloma can occur simultaneously in the same patient.