Distinctions between allergic fungal rhinosinusitis and chronic rhinosinusitis.

BACKGROUND: Recent reports have attempted to redefine the accepted diagnostic criteria for allergic fungal rhinosinusitis (AFRS), a form of chronic rhinosinusitis (CRS) with nasal polyps. As a result, the existence of AFRS as a distinct entity has been questioned, suggesting that allergy has no role in CRS with sinonasal eosinophilia, and the condition should be referred to as eosinophilic fungal rhinosinusitis. The purpose of the study was to differentiate between AFRS and CRS by studying antibody responses in these two clearly defined patient groups. METHODS: Ninety-nine patients were enrolled and classified as AFRS or CRS (without AFRS). Serum total IgE, IgG anti-Alternaria-specific antibodies (UniCAP 100), and IgE antifungal antibodies (immunoblotting) were compared between the groups. RESULTS: Sixty-four patients fit the traditional criteria for AFRS, with 35 as CRS. Mean serum total IgE and mean IgG anti-Alternaria-specific antibodies were statistically significantly increased in AFRS over CRS patients. There was also a statistically significant increase in the mean number of IgE antifungal bands from AFRS compared with CRS patients. CONCLUSION: We have shown a clear immunologic difference between AFRS and CRS patients. The overwhelming evidence of increased total IgE and fungal-specific IgE in AFRS supports an allergic component in AFRS. IgG anti-Alternaria-specific antibodies also point to an exaggerated fungal immune response in these patients. These results support the existence of AFRS as a separate, distinct entity of CRS. It is important to recognize AFRS to ensure proper treatment in these patients.

Allergic fungal sinusitis: pathophysiology, diagnosis and management.

Allergic fungal sinusitis (AFS) is a noninvasive form of fungal rhinosinusitis with an incidence of between 6 and 9% of all rhinosinusitis requiring surgery. Regional variation in incidence has been reported, with the southern and southwestern US particularly endemic. Patients with AFS commonly present with chronic rhinosinusitis with nasal polyps, inhalant atopy, elevated total serum immunoglobulin E (IgE), and sinus-obstructing inspissates of a characteristic extramucosal 'peanut buttery' visco-elastic eosinophil-rich material called 'allergic mucin' that contains sparse numbers of fungal hyphae. Sinus CT is always abnormal, showing findings of chronic rhinosinusitis that often include central areas of increased contrast ('hyperattenuation') within abnormal paranasal sinuses that represent the presence of fungal-containing allergic mucin. AFS has been found to be analogous in several ways to allergic bronchopulmonary aspergillosis (ABPA). Both are chronic inflammatory respiratory tract disorders that are driven by hypersensitivity responses to the presence of small numbers of extramucosal fungi found growing within airway-impacting allergic mucin. AFS allergic mucin typically cultures positive for either dematiaceous fungi such as Bipolaris spicifera or Curvularia lunata, or Aspergillus species such as A. fumigatus, A. flavus or A. niger. As with ABPA, patients have type I immediate hypersensitivity to the etiologic mold in AFS. Further, both AFS and ABPA have been found to have association with specific class II major histocompatibility alleles. Proper diagnosis of AFS and differentiation from the other forms of both noninvasive and invasive fungal rhinosinusitis requires strict adherence to published diagnostic criteria. Medical treatment of AFS has been modeled to an extent after treatment approaches for ABPA that includes the use of postoperative oral corticosteroids and aggressive antiallergic inflammation therapy. The use of follow-up measurements of total serum IgE during treatment of both AFS and ABPA patients can help to monitor disease activity. Future AFS research will lead to further insights into pathogenesis, improved treatments, and ultimately decreases in surgical recurrence rates for this highly recurrent hypertrophic rhinosinusitis disorder.

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.

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.

Allergic fungal sinusitis.

AFS is an increasingly recognized form of HSD, now reported throughout the world. It is probably the most frequently occurring fungal rhinosinusitis disorder. The term fungal sinusitis is no longer appropriate because the five categories of fungal rhinosinusitis can now be differentiated. Each category of fungal rhinosinusitis disorder carries different treatment approaches and prognosis. Diagnostic error can be minimized by adhering to strict diagnostic criteria. The analogy (but not identity) of AFS to ABPA has been supported by histopathology, immunopathology, and the clinical response to OCS treatment. AFS represents a true medical surgical disorder in which both surgery and postoperative medical treatment, if properly coordinated between medical and surgical specialists, leads to the best patient outcomes. Continued advances in the understanding of the immunogenetics and immunopathogenesis of AFS may provide fundamental insights into molecular mechanisms operant in other chronic inflammatory disorders, including other chronic eosinophilic-lymphocytic respiratory mucosal disorders such as common forms of HSD and chronic severe asthma.

Allergic fungal sinusitis: pathogenesis and management strategies.

Allergic fungal sinusitis (AFS) is a noninvasive form of highly recurrent chronic allergic hypertrophic rhinosinusitis that can be distinguished clinically, histopathologically and prognostically from the other forms of chronic fungal rhinosinusitis. There are three invasive (acute necrotising, chronic invasive and granulomatous invasive) and two noninvasive (fungal ball and allergic fungal) forms of fungal rhinosinusitis currently recognised. Confusion in differentiating between the various forms of fungal rhinosinusitis and between other forms of chronic hypertrophic sinus disease (HSD) can be eliminated by adhering to strict diagnostic criteria. Although there are characteristic presenting clinical history and physical examination findings, laboratory test results, including elevated total serum IgE and positive inhalant allergy skin tests, and sinus computed tomography scans showing chronic rhinosinusitis (often with the presence of hyperattenuating sinus contents) diagnosis of AFS is essentially based on histopathology obtained from sinus surgery. Histopathology shows the presence of eosinophilic-lymphocytic sinus mucosal inflammation, extramucosal allergic mucin (that is also seen grossly at surgery as a characteristic 'peanut-buttery' material), and scattered silver stain positive fungal hyphae within the allergic mucin but not in the mucosa. Treatment and follow up of AFS has been based on its immunopathological analogy to allergic bronchopulmonary aspergillosis, a similar noninvasive fungal hypersensitivity disorder of the lung, and its clinical and pathophysiological relationship to other forms of HSD and asthma. Treatment involves aggressive sinus surgery followed by medical management that includes allergen immunotherapy, topical and systemic corticosteroids, antihistamines and antileukotrienes. Total serum IgE levels should be followed postoperatively as they can be prognostic for recurrent disease. Close follow up and coordination of treatment by both medical and surgical physicians as a team leads to the best clinical outcomes. Ongoing studies are being directed at furthering our understanding of the pathophysiological relationships and treatment options for AFS, and other common forms of chronic hypertrophic rhinosinusitis disorders.