Allergic Fungal SinusitisAllergic Fungal SinusitisWilliam Reisacher, MD FACS FAAOAWilliam Reisacher, MD FACS FAAOA

Assistant ProfessorAssistant ProfessorWeill Cornell Medical CollegeWeill Cornell Medical College

NewYorkNewYork--Presbyterian HospitalPresbyterian Hospital

BackgroundBackground

Chronic Chronic rhinosinusitisrhinosinusitis (CRS) is reported by (CRS) is reported by approximately 35 million Americansapproximately 35 million Americans11

Direct cost of CRS in the USA is $4.3 billion Direct cost of CRS in the USA is $4.3 billion annuallyannually22

2525--30% of CRS patients have nasal polyps (NP)30% of CRS patients have nasal polyps (NP)33

NP are found in 1NP are found in 1--4% of the general population4% of the general population44

Incidence slightly higher in males and elderlyIncidence slightly higher in males and elderly55

Classification of NPClassification of NP66

CRS w/o NP AFS

CRS w NP

CRS

Background of AFSBackground of AFS

Similarities with allergic Similarities with allergic bronchopulmonarybronchopulmonaryaspergillosisaspergillosis (ABPA)(ABPA)Combination of Combination of GellGell and Coombs types 1 and 3 and Coombs types 1 and 3 hypersensitivitieshypersensitivities77

Bent and Kuhn diagnostic criteria (1994)Bent and Kuhn diagnostic criteria (1994)88

–– Type I hypersensitivityType I hypersensitivity–– Nasal polypsNasal polyps–– Characteristic radiologic findingsCharacteristic radiologic findings–– EosinophilicEosinophilic mucus without fungal invasion into sinus mucus without fungal invasion into sinus

tissuetissue–– Positive fungal stain of sinus contents removed at Positive fungal stain of sinus contents removed at

surgerysurgery

Demographic Features of AFSDemographic Features of AFSYoung, atopic and Young, atopic and immunocompetentimmunocompetentMean age of presentation is 28.9Mean age of presentation is 28.9Lower socioeconomic statusLower socioeconomic statusMore common in southeastern United StatesMore common in southeastern United States77

55--10% of all patient undergoing surgery for CRS10% of all patient undergoing surgery for CRS77

Present in 51% of patients in Northern India with CRSPresent in 51% of patients in Northern India with CRS1010

Wise et al. Wise et al. –– African Americans with AFS presented with African Americans with AFS presented with mean age 11.7 years younger than Caucasiansmean age 11.7 years younger than Caucasians1111

GheganGhegan et al. et al. –– African American males were 15x more African American males were 15x more likely to have bone erosion than Caucasians and African likely to have bone erosion than Caucasians and African American females combinedAmerican females combined1212

Clinical Presentation of AFSClinical Presentation of AFS

HeadacheHeadacheUnilateral nasal Unilateral nasal congestioncongestionDiminished sense of Diminished sense of smell and tastesmell and tastePostnasal dripPostnasal dripRefractory sinusitisRefractory sinusitisProptosisProptosis, , telecanthustelecanthusHistory of sinus History of sinus surgerysurgery

Differential Diagnosis of AFSDifferential Diagnosis of AFSCRS with nasal CRS with nasal polyposispolyposisEMCRSEMCRSInvasive fungal sinusitisInvasive fungal sinusitisMycetomaMycetoma ((““Fungus ballFungus ball””))AntrochoanalAntrochoanal polyppolypNeoplasmNeoplasm–– Inverting Inverting papillomapapilloma–– CarcinomaCarcinoma–– NasolacrimalNasolacrimal duct cystduct cyst–– GliomaGlioma, , dermoiddermoid lesions, lesions, encephalocelesencephaloceles

Inflammatory / AutoimmuneInflammatory / Autoimmune–– WegenerWegener’’s s granulomatosisgranulomatosis–– SarcoidosisSarcoidosis

PolypoidPolypoid mucosal changesmucosal changes

Radiologic Findings of AFSRadiologic Findings of AFS

CT scan T1 - MRI

Gross and Gross and HistologicHistologic Appearance of Appearance of AFSAFS

Thick, dark, tenacious Thick, dark, tenacious mucusmucusSheets of necrotic and Sheets of necrotic and degranulatingdegranulatingeosinophilseosinophilsCharcotCharcot--Leyden Leyden crystalscrystalsScant fungal Scant fungal hyphaehyphae

Management of AFSManagement of AFS

Medical managementMedical management–– AntiAnti--inflammatory medicationinflammatory medication–– AntiAnti--fungal therapyfungal therapy

SurgerySurgeryImmunotherapyImmunotherapy

Medical ManagementMedical Management

AntiAnti--inflammatoryinflammatory–– Systemic corticosteroids (preSystemic corticosteroids (pre--op/postop/post--op)op)–– Topical corticosteroidsTopical corticosteroids–– LeukotrieneLeukotriene receptor antagonistsreceptor antagonists–– MacrolideMacrolide antibioticsantibiotics

AntiAnti--fungalfungal–– SystemicSystemic–– Topical (Jen, Topical (Jen, KackerKacker, Huang et al. 2004), Huang et al. 2004)1313

Surgical ManagementSurgical ManagementPrior radical procedures replaced by complete, but Prior radical procedures replaced by complete, but conservative endoscopic surgery.conservative endoscopic surgery.Follow the polyps to the Follow the polyps to the mucinmucinImageImage--guidance if availableguidance if availableDonDon’’t forget to send the t forget to send the mucinmucin for fungal stainingfor fungal stainingPostPost--operative debridement and irrigationoperative debridement and irrigationKupferbergKupferberg staging systemstaging system–– Stage 0: NEDStage 0: NED–– Stage 1: Edematous mucosa/allergic Stage 1: Edematous mucosa/allergic mucinmucin–– Stage 2: Stage 2: PolypoidPolypoid mucosa/allergic mucosa/allergic mucinmucin–– Stage 3: Polyps and fungal debrisStage 3: Polyps and fungal debris

Need for revision surgery is about 30%Need for revision surgery is about 30%1414

Immunotherapy for AFSImmunotherapy for AFS

Mabry, et al. 1995 Mabry, et al. 1995 –– 9 AFS patients with no 9 AFS patients with no controls. Less crust formation and post controls. Less crust formation and post operative operative mucinmucin and no adverse effects.and no adverse effects.1515

BassichisBassichis, et al. 2006, et al. 20061414

–– 60 patient with AFS60 patient with AFS–– 24 patients, no IT. 36 patients, IT24 patients, no IT. 36 patients, IT–– Average followAverage follow--up was 48.5 monthsup was 48.5 months–– Significant reduction of office visitsSignificant reduction of office visits–– Decrease in need for reDecrease in need for re--operation from 33% to 11%operation from 33% to 11%

DematiaceousDematiaceous FungiFungi

““Darkly pigmentedDarkly pigmented””Present in 87% of Present in 87% of culture positiveculture positive--cases cases of AFSof AFS1616

–– AlternariaAlternaria–– BipolarisBipolaris–– CurvulariaCurvularia–– HelminthosporiumHelminthosporium–– FusariumFusarium

13% were 13% were aspergillusaspergillus

Fungus and NPFungus and NPPonikauPonikau et al. from Mayo Clinic suggested that NP may arise from et al. from Mayo Clinic suggested that NP may arise from immune hyper responsiveness to fungi that commonly colonize the immune hyper responsiveness to fungi that commonly colonize the nose of patients with CRSnose of patients with CRS1717

GosepathGosepath et al. demonstrated et al. demonstrated AlternariaAlternaria DNA in 100% of surgical DNA in 100% of surgical polyp specimens from CRS patientspolyp specimens from CRS patients1818

SabirovSabirov et al. studied the role of local et al. studied the role of local IgEIgE specific for Alternariaspecific for Alternaria1919

–– CRS w NP (N=21) vs. CRS w/o NP (N=13) and healthy controls (N=8)CRS w NP (N=21) vs. CRS w/o NP (N=13) and healthy controls (N=8)–– Serum levels of Serum levels of AlternariaAlternaria--specific specific IgEIgE were no different between were no different between

groupsgroups–– AlternariaAlternaria--specific specific IgEIgE in polyps was significantly higher than in the in polyps was significantly higher than in the

nasal tissues of the other two groupsnasal tissues of the other two groupsAn association was present between An association was present between alternariaalternaria--specific specific IgEIgE and and increased ECP and increased ECP and eosinophileosinophil levels in patients with nasal polypslevels in patients with nasal polyps1919

Is AFS really Is AFS really ““AllergicAllergic””??Stewart and Stewart and HunsakerHunsaker, 2002, 20022020

–– 13 AFS, 11 AFS13 AFS, 11 AFS--like, 27 nonlike, 27 non--AFS AFS polypoidpolypoid CRSCRS–– 9 mold RAST panel9 mold RAST panel–– Elevated Elevated IgGIgG in all groupsin all groups–– Elevated Elevated IgEIgE in AFS group to average of 5 molds vs. 0.1 in the in AFS group to average of 5 molds vs. 0.1 in the

AFSAFS--like grouplike group

Wise, et al., 2008Wise, et al., 200821 21

–– Sinus mucosa homogenates from AFS (11), Sinus mucosa homogenates from AFS (11), CRSsNPCRSsNP (8) and non(8) and non--CRS patients (9)CRS patients (9)

–– ImmunoCAPImmunoCAP for 14 common antigensfor 14 common antigens–– AFS group had significantly higher levels of AFS group had significantly higher levels of IgEIgE for for

CladosporiumCladosporium, , AspergillusAspergillus, Timothy grass, red maple, cockroach, , Timothy grass, red maple, cockroach, ragweed and cockleburragweed and cocklebur

Can nonCan non--allergic patients develop allergic patients develop Allergic Fungal Sinusitis?Allergic Fungal Sinusitis?

NonNon--AFRS EMCRSAFRS EMCRS2222

–– Fungus not identified Fungus not identified histologicallyhistologically–– Higher incidence of asthma, ASA sensitivityHigher incidence of asthma, ASA sensitivity–– Lower incidence of allergiesLower incidence of allergies–– Always bilateralAlways bilateral

Collins, et al., 2004Collins, et al., 200423 23

–– Comparison of AFRS with nonComparison of AFRS with non--AFRS EMCRS (negative AFRS EMCRS (negative for allergy and no fungus identified in the for allergy and no fungus identified in the mucinmucin))

–– 17/24 AFRS had fungal specific 17/24 AFRS had fungal specific IgEIgE in in mucinmucincompared to 20% in noncompared to 20% in non--AFRS EMCRSAFRS EMCRS

–– Possibly a local Possibly a local IgEIgE--mediated immune responsemediated immune response

ReferencesReferences11 Current Estimates from the National Health Interview Survey, 199Current Estimates from the National Health Interview Survey, 1994. 4.

National Center for Health Statistics. Vital and Health StatistiNational Center for Health Statistics. Vital and Health Statistics 1995; cs 1995; Series 10.Series 10.

22 Murphy MP, Fishman P, Short SO, et al. Health care utilization aMurphy MP, Fishman P, Short SO, et al. Health care utilization and cost nd cost among adults with chronic among adults with chronic rhinosinusitisrhinosinusitis enrolled in a health maintenance enrolled in a health maintenance organization. organization. OtolaryngolOtolaryngol Head Neck Head Neck SurgSurg 2002;127:3672002;127:367--76.76.

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44 Van Van ZeleZele T, T, GevaertGevaert P, P, HoltappelsHoltappels G, et al. Local immunoglobulin G, et al. Local immunoglobulin production in nasal production in nasal polyposispolyposis is modulated by is modulated by superantigenssuperantigens. . ClinClin Exp All Exp All 2007;37:18402007;37:1840--7.7.

55 Deal RT, Deal RT, KountakisKountakis SE. Significance of nasal polyps in chronic SE. Significance of nasal polyps in chronic rhinosinusitisrhinosinusitis: symptoms and surgical outcomes. Laryngoscope : symptoms and surgical outcomes. Laryngoscope 2004;114:19322004;114:1932--35.35.

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ReferencesReferences77 Schubert MS. Allergic fungal sinusitis pathogenesis and Schubert MS. Allergic fungal sinusitis pathogenesis and

management strategies. Drugs 2004;64:363management strategies. Drugs 2004;64:363--374.374.88 Bent JP, Kuhn FA. Diagnosis of allergic fungal sinusitis. Bent JP, Kuhn FA. Diagnosis of allergic fungal sinusitis.

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1111 Wise S, Wise S, VenkatramanVenkatraman G, Wise J, et al. Ethnic and gender G, Wise J, et al. Ethnic and gender differences in bone erosion in allergic fungal sinusitis. Am J differences in bone erosion in allergic fungal sinusitis. Am J RhinolRhinol2004;18:3972004;18:397--404.404.

1212 GheganGhegan M, Lee, F, Schlosser R. Incidence of skull base and M, Lee, F, Schlosser R. Incidence of skull base and orbital erosion in allergic fungal orbital erosion in allergic fungal rhinosinusitisrhinosinusitis (AFRS) and non(AFRS) and non--AFRS. AFRS. OtolaryngolOtolaryngol Head Neck Head Neck SurgSurg 2006;134:5922006;134:592--5.5.

ReferencesReferences1313 Jen A, Jen A, KackerKacker A, Huang C, et al. A, Huang C, et al. FluconazoleFluconazole nasal spray in the nasal spray in the

treatment of allergic fungal sinusitis: a pilot study. Ear Nose treatment of allergic fungal sinusitis: a pilot study. Ear Nose Throat J 2004;83:692Throat J 2004;83:692--695.695.

1414 BassichisBassichis BA, BA, MarpleMarple BF, Mabry RL. Use of immunotherapy in BF, Mabry RL. Use of immunotherapy in previously treated patients with allergic fungal sinusitis. previously treated patients with allergic fungal sinusitis. OtolaryngolOtolaryngol Head Neck Head Neck SurgSurg 2001;125(5):4872001;125(5):487--490.490.

1515 Mabry RL, Manning SC, Mabry CS, et al. Immunotherapy in the Mabry RL, Manning SC, Mabry CS, et al. Immunotherapy in the treatment of allergic fungal sinusitis. treatment of allergic fungal sinusitis. OtolaryngolOtolaryngol Head Neck Head Neck SurgSurg1997;116:311997;116:31--35.35.

1616 Manning SC, Schaefer SD, Close LG, et al. CultureManning SC, Schaefer SD, Close LG, et al. Culture--positive positive allergic fungal sinusitis. Arch allergic fungal sinusitis. Arch OtolaryngolOtolaryngol Head Neck Head Neck SurgSurg1991;117:1741991;117:174--178.178.

1717 PonikauPonikau JU, JU, SherrisSherris DA, Kern EB, et al. The diagnosis and DA, Kern EB, et al. The diagnosis and incidence of allergic fungal sinusitis. Mayo incidence of allergic fungal sinusitis. Mayo ClinClin Proc 1999;74:844Proc 1999;74:844--77. 77.

1818 GosepathGosepath J, J, BriegerBrieger J, J, VlachtsisVlachtsis K, et al. Fungal DNA is present in K, et al. Fungal DNA is present in tissue specimens of patients with chronic tissue specimens of patients with chronic rhinosinusitisrhinosinusitis. Am J . Am J RhinolRhinol 2004;18:92004;18:9--13.13.

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E specific for E specific for alternariaalternaria alternataalternata in the pathogenesis of nasal in the pathogenesis of nasal polyposispolyposis. Laryngoscope 2007;118:4. Laryngoscope 2007;118:4--9.9.

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2323 Collins M, Nair S, Smith W, et al. Role of local immunoglobulin Collins M, Nair S, Smith W, et al. Role of local immunoglobulin E E production in the production in the pathophysiologypathophysiology of noninvasive fungal sinusitis. of noninvasive fungal sinusitis. Laryngoscope 2004;114:1242Laryngoscope 2004;114:1242--1246.1246.