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Page 1: Fungal Rhinosinusitis: A Categorization and Definitional ... fungal... · Fungal Rhinosinusitis: A Categorization and Definitional Schema Addressing Current Controversies ... (rhino-)

The LaryngoscopeVC 2009 The American Laryngological,Rhinological and Otological Society, Inc.

Contemporary Review

Fungal Rhinosinusitis: A Categorizationand Definitional Schema AddressingCurrent Controversies

Arunaloke Chakrabarti, MD; David W. Denning, FRCP, FRCPATH; Berrylin J. Ferguson, MD;

Jens Ponikau, MD; Walter Buzina, PhD; Hirohito Kita, MD; Bradley Marple, MD;

Naresh Panda, MS; Stephan Vlaminck, MD; Catherine Kauffmann-Lacroix, M. Pharm; Ashim Das, MD;

Paramjeet Singh, MD; Saad J. Taj-Aldeen, PhD; A. Serda Kantarcioglu, PhD; Kumud K. Handa, MS;

Ashok Gupta, MS; M. Thungabathra, PhD; Mandya R. Shivaprakash, MD; Amanjit Bal, MD;

Annette Fothergill, BS, MBA; Bishan D. Radotra, MD

Background: Fungal (rhino-) sinusitis encom-passes a wide spectrum of immune and pathologicalresponses, including invasive, chronic, granuloma-tous, and allergic disease. However, consensus on ter-minology, pathogenesis, and optimal management islacking. The International Society for Human andAnimal Mycology convened a working group toattempt consensus on terminology and diseaseclassification.

Discussion: Key conclusions reached were: rhi-nosinusitis is preferred to sinusitis; acute invasivefungal rhinosinusitis is preferred to fulminant, ornecrotizing and should refer to disease of <4 weeksduration in immunocompromised patients; bothchronic invasive rhinosinusitis and granulomatousrhinosinusitis were useful terms encompassing locallyinvasive disease over at least 3 months duration,with differing pathology and clinical settings; fungalball of the sinus is preferred to either mycetoma oraspergilloma of the sinuses; localized fungal coloniza-tion of nasal or paranasal mucosa should be intro-duced to refer to localized infection visualized endo-scopically; eosinophilic mucin is preferred to allergicmucin; and allergic fungal rhinosinusitis (AFRS),eosinophilic fungal rhinosinusitis, and eosinophilicmucin rhinosinusitis (EMRS) are imprecise andrequire better definition. In particular, to implicatefungi (as in AFRS and EMRS), hyphae must bevisualized in eosinophilic mucin, but this is often notprocessed or examined carefully enough by histolo-gists, reducing the universality of the disease classifi-cation. A schema for subclassifying these entities,including aspirin-exacerbated rhinosinusitis, is pro-posed allowing an overlap in histopathological fea-tures, and with granulomatous, chronic invasive, andother forms of rhinosinusitis. Recommendations forfuture research avenues were also identified.

Additional Supporting Information may be found in the online ver-sion of this article.

FromtheDepartment ofMedicalMicrobiology,Postgraduate Institute ofMedical Education and Research, Chandigarh, India (A.C.); NationalAspergillosis Centre, Education and Research Centre, University Hospital ofSouth Manchester, Manchester, UK (D.W.D); Department of Otolaryngology,University of Pittsburgh School ofMedicine, Pittsburgh, Pennsylvania, U.S.A.(B.J.F.); Otolaryngology Research, State University of New York at Buffalo,Buffalo, New York, U.S.A. (J.P.); Medical Mycology, Institute of Hygiene,Microbiology& Environmental Medicine, Medical University of Graz, Austria(W.B.); Department of Allergic Diseases andMedicine, Mayo Clinic, Rochester,Minnesota, U.S.A. (H.K.); Department of Otolaryngology–Head and NeckSurgery, University of Texas Southwestern Medical Center, Dallas, Texas,U.S.A. (B.M.); Department ofOtolaryngology, Postgraduate Institute ofMedicalEducation and Research, Chandigarh, India (N.P.); Department of Rhinology,ENT, AZ, St. JeanHospital, Bruges, Belgium (S.V.); Parasitology andMycologyLaboratory, University Hospital Centre, Poitiers, France (C.K.-L.); Departmentof Histopathology, Postgraduate Institute of Medical Education and Research,Chandigarh, India (A.D.); Department of Radiodiagnosis and Imaging,Postgraduate Institute of Medical Education and Research, Chandigarh,India (P.S.); Laboratory of Medicine and Pathology, Hamad MedicalCorporation, Doha, Qatar (S.J.T.-A.); Deep Mycosis Laboratory, Department ofMicrobiologyandClinicalMicrobiology, CerrahpasaMedical Faculty, Istanbul,Turkey (A.S.K.); Department of ENT, All India Institute of Medical Sciences,New Delhi, India (K.K.H.); Department of Otolaryngology, PostgraduateInstitute of Medical Education and Research, Chandigarh, India (A.G.);Department of Biochemistry, Postgraduate Institute of Medical Educationand Research, Chandigarh, India (M.T.); Department of Medical Microbiology,Postgraduate Institute ofMedical Education andResearch,Chandigarh, India(M.R.S.); Department of Histopathology, Postgraduate Institute of MedicalEducation and Research, Chandigarh, India (A.K.); Department of Pathology,The University of Texas Health Science Center, San Antonio, Texas, U.S.A.(A.F.); Department of Histopathology, Postgraduate Institute of MedicalEducation and Research, Chandigarh, India (B.D.R.).

Editor’s Note: This Manuscript was accepted for publication onApril 7, 2009.

This work is a summary of the panel discussion during the Workshopon Fungal Sinusitis, Chandigarh, India, February 9–11, 2008. Themajor spon-sors of the workshop were the International Society for Human and AnimalMycology, Lifecare Innovations, India, Pfizer Inc., andMerek Sharp &Dohme.

Send correspondence to Arunaloke Chakrabarti, MD, Departmentof Medical Microbiology, Postgraduate Institute of Medical Educationand Research, Chandigarh, Chandigarh 160012, India.E-mail: [email protected]

DOI: 10.1002/lary.20520

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Key Words: Fungal sinusitis, Aspergillus,zygomycetes, allergy, dematiaceous fungi.

Laryngoscope, 000:000–000, 2009

INTRODUCTIONSinusitis, or more accurately rhinosinusitis (RS), is

a common disorder affecting approximately 20% ofthe population.1 Acute rhinosinusitis (ARS) is well cat-egorized. However, controversies surround chronicrhinosinusitis (CRS) and the role of fungi in this condi-tion. CRS accounts for >90% of all cases of rhinosinusitis,and the correct diagnosis of each category of CRS is im-portant for optimum therapy and predicting the course.Recognizing the importance of resolving the many contro-versies concerning CRS, and to develop a systematicmanagement protocol of fungal rhinosinusitis (FRS), theInternational Society for Human and Animal Mycologyformed a working group on fungal rhinosinusitis. Thegroup participated in a workshop in February 2008 inChandigarh, India, and deliberated on their clinical expe-riences of patients with FRS and the research in thisarea. From this workshop a consensus document was pre-pared through panel discussions.

The first published attempt to classify FRS came in1965, when Hora recognized two categories: one wasnoninvasive, behaving clinically like chronic bacterialsinusitis, and the other invasive, in which the infectionresults in a mass that behaves like malignant neoplasm,eroding bone and spreading into adjacent tissue.2 Theinvasive nature of the disease was further confirmed onhistopathology.3,4 McGill et al., in 1980, reported a thirdtype of FRS in immunocompromised patients: a fulmi-nant form with rapid and malignant course.5 In 1976,Safirstein noted a combination of nasal polyposis, crustformation, and sinus cultures yielding Aspergillus spe-cies, and observed the clinical similarity that thisconstellation of findings shared with allergic bronchopul-monary aspergillosis (ABPA).6 Similarly, in 1981, Milleret al.,7 and in 1983, Katzenstein et al.,8 independentlyrecognized a pathophysiologic resemblance among a fewcases of CRS associated with a mucosal plug in thesinuses of patients with ABPA, which led to a descrip-tion of a fourth type of FRS, namely allergic Aspergillussinusitis. Later, it became apparent that melanized fungiare common etiological agents of this allergic type ofsinusitis, which led to the renaming of this type of FRSas allergic fungal sinusitis or rhinosinusitis (AFS orAFRS).9–11 In recent years, the definition of AFRS hasfaced a greater challenge with the demonstration offungi in eosinophilic mucin independently from type Ihypersensitivity in most cases of CRS.12,13 Ponikau et al.proposed a new term for this condition, namely eosino-philic fungal rhinosinusitis (EFRS), to reflect thestriking role of eosinophils.12

FRS can be broadly divided into two categoriesbased on histopathological findings: invasive and nonin-vasive, depending on invasion of the mucosal layer. Inthe late 1990s, deShazo et al. proposed a new classifi-

cation for tissue invasive FRS based on the clinicalcondition, immune status, histopathology, and fungusinfection: acute (fulminant) invasive, granulomatousinvasive, and chronic invasive types.14 The granuloma-tous invasive type is mainly described in chronic FRScases from Sudan, India, and Pakistan, where thepatients are immunocompetent, almost exclusivelyidentified with Aspergillus flavus, and present as nonca-seating granuloma with proptosis. These cases havebeen distinguished from chronic invasive FRS, whichhas a chronic course, often in subtly immunocompro-mised patients, such as those with diabetes mellitus andcorticosteroid treatment, with dense accumulation ofhyphae invading tissue, sometimes in association withthe orbital apex syndrome. The described noninvasiveFRS disorders are of three types: saprophytic fungal in-festation, fungal ball, and fungus-related eosinophilicrhinosinusitis including AFRS. Although a sinus fungalball is more or less a clear-cut entity, substantial confu-sion surrounds fungus-related eosinophilic rhinosinusitisand the definition of AFRS. As originally described, thedetection of fungi in allergic mucin is considered impor-tant in the diagnosis of AFRS, although occasionallyhyphae are sparse in the sinus contents. This leads toconfusion and potential overlap with eosinophilic mucinrhinosinusitis (EMRS), as described by Ferguson in2000.15 Ferguson speculated that EMRS is a systemicdisease with dysregulation of immunological controlwhere eosinophilic mucin could be present without thepresence of fungi.15

Present Classification of Fungal RhinosinusitisAlthough much confusion exists regarding classifi-

cation, the most commonly accepted system dividesfungal rhinosinusitis (FRS) into invasive and noninva-sive diseases based on histopathological evidence oftissue invasion by fungi. The invasive diseases include1) acute invasive (fulminant) FRS, 2) granulomatousinvasive FRS, and 3) chronic invasive FRS. The noninva-sive diseases include 1) saprophytic fungal infestation,2) fungal ball, and 3) fungus-related eosinophilic FRSthat includes AFRS.

Acute invasive (fulminant) FRS. The disease isdescribed by a time course of <4 weeks with predomi-nant vascular invasion occurring in patients withimmunocompromised status. The histopathology demon-strates hyphal invasion of blood vessels, which mayinclude the carotid arteries and cavernous sinuses, vas-culitis with thrombosis, hemorrhage, tissue infarction,and acute neutrophilic infiltrates (Fig. 1).14 The diseasehas also been termed acute necrotizing FRS, as a necrot-izing pathological reaction may be seen in some patientswith only minimal inflammation, with plenty of fungi inthe necrotic tissue.16 Patients with neutrophil dysfunc-tion or neutropenia, such as hematological malignancies,aplastic anemia, uncontrolled diabetes mellitus, andhemochromatosis, or those undergoing antineoplasticchemotherapy or following transplantation, are espe-cially susceptible to acute invasive FRS,17–19 althoughthis type of infection is reported occasionally in

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apparently immunocompetent hosts. Aspergillus species,or members of the class zygomycetes are the most fre-quent etiological agents.16–22

Granulomatous invasive FRS. The disease isdescribed by a time course of >12 weeks with an enlarg-ing mass in the cheek, orbit, nose, and paranasalsinuses in immunocompetent hosts. Proptosis is often aprominent feature. Histopathologically, a granulomatous

response is seen with considerable fibrosis. Noncaseatinggranuloma with foreign body or Langhans-type giantcells may be seen, sometimes with vasculitis, vascularproliferation, and perivascular fibrosis (Fig. 2). Hyphaeare usually scanty and A. flavus is the primary agentisolated. The presence or absence of precipitating anti-bodies against antigens from the etiological fungicorrelates well with disease progression.23 The disease

Fig. 1. (A) Acute invasive fungalsinusitis with bland infarcted area(�400). (B) Necrotizing inflammationwith fibrin thrombi (�100). (C)Numerous hyphae of zygomyceteson hematoxylin and eosin stain(�100). (D) Fungal hyphae on Gomorimethenamine-silver stain (�200).

Fig. 2. (A) Computed tomographyscan of patient with chronic granu-lomatous fungal rhinosinusitisinvolving the right nasal cavity in achronic invasive granulomatous fun-gal rhinosinusitis with bony destruc-tion of paranasal sinuses extendinginto right orbit. (B) Extensive granu-lomatous process in a fibrotic back-ground on hematoxylin and eosinstain (�100). (C) Fungal hyphaeinside giant cells on periodic acid-Schiff stain (�400). (D ) Fungalhyphae inside giant cells on Gomorimethenamine-silver stain (�400).

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has primarily been seen in Sudan, India, Pakistan, andSaudi Arabia.14,24,25

Chronic invasive FRS. Chronic invasive FRS is aslowly destructive process that most commonly affectsthe ethmoid and sphenoid sinuses, but may involve anyparanasal sinus. The disease typically has a time courseof >12 weeks. However, in contrast to granulomatousinvasive FRS, the entity is characterized as dense accu-mulation of hyphae, occasional presence of vascularinvasion, and sparse inflammatory reaction in associa-tion with involvement of local structures (Fig. 3). Theentity is usually seen in the context of AIDS, diabetesmellitus, and corticosteroid treatment.14,24,26 Cultures oftissue are positive in >50% of cases and Aspergillusfumigatus is the most common agent isolated.

Saprophytic fungal infestation. Asymptomaticcolonization of mucous crusts within the nasal cavity, of-ten in patients who had previous sinus surgery, hasbeen described as saprophytic fungal infestation. Thepossibility of extension of this growth leading to the for-mation of fungal ball has been predicted.27

Fungal ball. Fungal ball is described as thepresence of noninvasive accumulation of dense conglom-eration of fungal hyphae in one sinus cavity, usually themaxillary sinus, although the disease may affect othersinuses or rarely multiple sinuses.28 Various terms, suchas mycetoma, aspergilloma, and chronic noninvasivegranuloma have been used interchangeably in the litera-ture to designate sinus fungal ball.27 The disease isdefined by the following criteria: radiological evidence ofsinus opacification with or without radiographic hetero-geneity, mucopurulent cheesy or clay-like materialswithin the sinus, a dense conglomeration of hyphae sep-arate from the sinus mucosa, nonspecific chronic

inflammation of the mucosa, no predominance ofeosinophils or granuloma or allergic mucin, and no histo-pathological evidence of fungal invasion of mucosa(Fig. 4).29 Interestingly, the disease has been found morecommonly in middle-aged and elderly females, in con-trast to all forms of invasive and chronic aspergillosis,which are more common in males.30 Fungi remain non-invasive in the context of a fungal ball, however, andrarely could become invasive after substantial immu-nosuppression, such as renal transplantation.31 Inaddition, some patients develop allergic mucin surround-ing the fungal balls when corticosteroids aretapered.27,32 Dhong et al. showed that all fungal ballshave a characteristic gritty matted gross appearance tothe surgeon, whereas the majority, but not all, had com-puted tomography (CT) characteristics that includedradiographic heterogeneity.33 Likewise, such heterogene-ity can sometimes be seen in nonfungal sinusitis. Inapproximately 70% of fungal balls, the diagnosis is madeexclusively by histology or microscopy, and cultures arenegative. Implication of Aspergillus species as the causa-tive agent may be aided by the use of galactomannandetection in the sinus material.

Eosinophil related FRS including AFRS. It isbelieved that fungal allergens elicit immunoglobulin E(IgE)-mediated allergic and possibly type III (immunecomplex)-mediated mucosal inflammation in the absenceof invasion in an atopic host.34,35 Moreover, when thesensitized individuals are exposed to an environment ofhigh fungal content, symptoms of upper and/or lowerairway hyper-responsiveness increase significantly.36

Generalized sinonasal inflammation in combination withviscid allergic mucin effectively obstructs the normaldrainage pathway. Fungi persist locally, stimulating

Fig. 3. (A) Coronal computed to-mography scan of immunosup-pressed patient with amyloidosisand chronic invasive mucormycosisin chronic invasive fungal rhinosinu-sitis. Right ethmoid and pterygopa-latine space involvement. (B)Nongranulomatous chronic inflam-matory infiltrate with transverse sec-tion of fungal hyphae eosinophilicSplendore-Hoeppli phenomenon onhematoxylin and eosin stain (�200).(C) Periodic acid-Schiff stain (�400).(D) Gomori methenamine-silver stain(�200).

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locally destructive immune responses. The process thenmay expand to involve adjacent sinuses and mayproduce sinus expansion and bony erosion.37,38 Accumu-lation of eosinophilic mucin in the expanded sinusesleads to elevation of inflammatory mediators, such asmajor basic protein, eosinophil peroxidase, eosinophil-derived neurotoxin, tumor necrosis factor b, andinterleukins (IL)-4, 5, 10, and 13.39,40 Although the pre-sentation of the disease is subtle, occasional dramaticpresentations of the disease in the form of acute visualloss, gross facial dysmorphia, or complete nasal obstruc-tions have been observed.10,41,42 Why only some patientsbehave in this acute fashion is not known.

To diagnose AFRS, Bent and Kuhn11 proposed fivediagnostic criteria: type I hypersensitivity, nasal polypo-sis, characteristic findings on CT scan, presence of fungion direct microscopy or culture, and allergic mucin con-taining fungal elements without tissue invasion (Fig. 5).These early observations were based on <20 patientscapturing the usual clinical findings of AFRS, althoughthere are exceptions to several of the criteria, particu-larly the presence of nasal polyps. Patients withrecurrent AFRS, who have had prior surgery, frequentlylack nasal polyps, although their sinuses contain eosino-philic mucin with hyphae. One diagnostic requirementput forth by the guidelines for clinical research in CRSwas to consider AFRS a distinct entity, categorized by atype I hypersensitivity to fungi cultured from eosino-philic mucin containing hyphae, harvested from thepatient’s nose or sinus cavities, and without evidence oftissue invasion by fungus.42 Although the detection offungi in allergic mucin is considered important, hyphaemay be sparse in sinus content and take considerabletime to visualize with the currently used stains. This

has led to confusion in categorization of this entity, espe-cially with the description of EMRS.15 However, the useof much more sensitive diagnostic techniques, such aschitin staining43 or polymerase chain reaction amplifica-tion,44–46 but not Aspergillus antigen,47 to detect thepresence of fungi in the majority cases of chronic rhino-sinusitis may reveal that EMRS is predominantly orcompletely related to a response to one or more fungi. InEMRS cases, disease was uniformly bilateral, combinedwith a significantly higher frequency of asthma and anincreased incidence of aspirin sensitivity, and frequentlyan immunoglobulin G1 deficiency.15 In a prospectivestudy from India, considerable overlap in findingsbetween AFRS and EMRS were observed, although typeI hypersensitivity, Charcot-Leyden crystals, bony ero-sion, and heterogeneous opacity with sinus expansion onCT scan were found to be significantly associated withAFRS, whereas asthma was significantly associated withEMRS.48 It is possible that EMRS and AFRS are differ-ing manifestations of the same pathological process,with considerable overlap.

Current understanding of the pathophysiology ofAFRS would suggest that the initiation of the inflamma-tory cascade is a multifunctional event, requiring thesimultaneous occurrence of IgE-mediated sensitivity, spe-cific T-cell HLA receptor expression, and exposure tospecific fungi.26,34 The fungi causing AFRS are diverse,and in a review of the English literature, Manning andHolman in 1998 reported 168 positive cultures, 87% ofthe cases due to dematiaceous fungi, and 13% yieldedAspergillus species49 Interestingly, in the Indian scenarioA. flavus was isolated in more than 80% of the cases ofAFRS.23,48,50–52 A. flavus was also isolated from 50% ofpatients diagnosed with AFRS in the Middle East.53

Fig. 4. (A) Computed tomographyscan showing a fungus ball in theleft maxillary sinus on coronal viewwith hyperdense secretions. (B)Gross photo of a fungal ball. (C)Fungal hyphae on periodic acid-Schiff stain (�200). (D) Gomori me-thenamine-silver stain (�200).

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Contrary to the prevailing belief that fungi wereresponsible for CRS in only a selected group of patientswith distinct pathophysiology, Ponikau et al. in 1999demonstrated the presence of fungi in nasal mucus from96% of patients with CRS and found type I hypersensi-tivity to be present in <25% of their study group. Theydetected fungi along with eosinophil and eosinophildegraded products in mucus.12 Often the eosinophilsdetected in the mucus were in clusters along with a fewCharcot-Leyden crystals, but sometimes they found theeosinophils in the form of cellular debris and crystals.They termed this mucin eosinophilic mucin and coinedthe term eosinophilic fungal rhinosinusitis (EFRS). How-ever, they also cultured a diverse array of airborne fungifrom the nose of 100% of healthy volunteers. Later, theyfurther improved the detection technique in eosinophilicmucin by using a fluorescein-labeled chitinase stainingtechnique (Fig. 6).43 From Europe, Braun et al., in 2003,made a similar observation using sensitive techniques todetect fungi.13 Ponikau et al. further progressed theirhypothesis by demonstrating high levels of toxic majorbasic protein (MBP) from eosinophils in the mucus ofpatients with CRS, and postulated that MBP damagesthe nasal epithelium from the luminal side, permittingsecondary bacterial infection on the damaged epithe-lium.54 Increasingly the role of bacteria in CRS isquestioned. Ponikau proposed that certain fungi couldelicit eosinophilic inflammation in the absence of type Ihypersensitivity reactions in patients with CRS.12,54

This concept of nonatopic eosinophilia from fungi is sup-ported by studies that demonstrate that peripheral bloodmononuclear cells (PBMCs) from patients with CRSshow exaggerated humoral and cellular responses, bothTh1 and Th2 types, after exposure to common airborne

fungi, particularly of the Alternaria species, which areabsent in PBMCs from healthy control subjects. Theauthors claimed that the anomalous immune andinflammatory responses to ubiquitous fungi mightexplain the chronic eosinophilic inflammation of CRS.55

These findings raise several questions: 1) Is AFRS a sep-arate distinct entity under CRS that requires not onlythe presence of eosinophilic mucin with hyphae, but alsothe presence of atopy? 2) Is EFRS a nonallergic fungaleosinophilic inflammation that exists as a separate CRSentity? 3) Do secondary bacterial infections exist in alarge group of patients with CRS? 4) If secondary bacte-rial infection is present, is this promoted by damage tothe nasal and sinus epithelium from fungal inducedeosinophilia in many of the patients with CRS? Alterna-tively, do AFRS and EFRS represent the limits of arange of fungal eosinophilic inflammation?

With the confusion in discrete definitions of AFRS,EFRS and EMRS, another possibility is that fungi maybe bystanders or one of several contributors to the wholeprocess. In the analysis of pathophysiology of eosinophilrelated FRS, it has been suggested that fungal elementstrapped in the mucus in sinuses are the source of anti-genic material that stimulates IgE, IgG, and IgAproduction.8,56 Numerous stimuli, other than fungi, or inaddition to fungi, may be responsible for the pathophysi-ology of this disorder, including the putative role ofallergens, bacteria, and bacterial-derived superanti-gens.57 A role has been proposed for Staphylococcal-derived superantigens in the pathogenesis of CRS associ-ated with nasal polyps.58 All of these studies indicatethat until there is definite evidence of T cell activitywithin the sinuses that responds to fungal antigens,together with further demonstration that removal of

Fig. 5. (A) Computed tomographycoronal scan showing recurrence ofallergic fungal rhinosinusitis follow-ing prior surgery. Hyperdensity ofmucin within right ethmoid andmaxillary sinuses. (B) Allergic fungalsinusitis with allergic mucin (�100).(C) Fungal hyphae inside allergicmucin on periodic acid-Schiff stain(�400). (D) Gomori methenamine-sil-ver stain showing hyphae within themucin (�100).

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fungal antigens ameliorates the disease, the case againstfungal involvement remains only circumstantial. Theconfusion in this area was further complicated with thewell-documented but rare reports of histologic tissueinvasion in possible cases of AFRS.59 It may be due totwo separate pathogenic processes, allergic disease andinfection by the fungus in the same host. Extending thehypersensitivity process in the causation of AFRS, someresearchers claimed the consistent presence of AFRSand ABPA in the same patients, and termed the processas sino-bronchial allergic mycosis syndrome.60

All these controversies in the definition of thecategories of FRS have emphasized the need for collabo-rative work and exchange of findings among doctors andscientists interested in this field.

In the workshop the following consensus opinionsand definitions were made through panel discussion:

IS THE OPTIMAL TERMINOLOGY FUNGAL RHINOSINUSITIS

OR FUNGAL SINUSITIS? It is essential to clarify the termi-nology because there are other sinuses in the bodybesides the paranasal sinuses. As most cases of nasalfungal sinusitis have a proceeding or concomitantinvolvement of the nasal cavity, except with isolated fun-gal ball lesions, fungal rhinosinusitis was the termconsidered most appropriate. However, the terms rhini-tis and rhinosinusitis are two different entities andshould not be confused.

IS THE OPTIMAL TERMINOLOGY ACUTE INVASIVE, FULMI-

NANT, OR NECROTIZING FUNGAL RHINOSINUSITIS? The keycharacteristics of this life-threatening category of fungalrhinosinusitis in immunosuppressed patients are inva-

sion of tissue and duration of illness <4 weeks. In somepatients, a necrotizing reaction may be seen histopatho-logically with minimal inflammation, but necrotizinglesions are not seen in all patients in this group. Theextent and nature of lesions also depends on the degreeof immunosuppression. The term fulminant conveys therapid destruction and often fatal outcome that occurs inpatients with severe immunosuppression or when leftuntreated. However, illness usually takes a more pro-tracted course when the treatment is started early orwith reversal of immunosuppression. Therefore, the con-sensus was to use the term acute invasive fungalrhinosinusitis, with the etiological agent substituted, ifknown (i.e., acute invasive Mucorales rhinosinusitis).

DISTINCTION BETWEEN ACUTE AND CHRONIC FRS. Acutedisease is when the duration of illness is <1 month, andthat of chronic disease is >3 months, although other fac-tors, such as host immune status and vascular invasion,may also distinguish the two forms of disease. In theacute variety, a neutrophilic tissue reaction, and in thechronic course an eosinophilic reaction, is usually seen.Questions were raised as to whether it is required toinclude a subacute category to cover the transition timebetween acute and chronic form, and whether introduc-tion of the new term subacute would change themanagement strategies. The introduction of a new term,or the change of the term, may affect the clinicians’ con-siderations of seriousness of the disease. Afterdeliberation, it was unanimously decided that the newterm subacute might be used in the rare situation whenthe duration of illness is within 1 to 3 months and the

Fig. 6. Histological images of eosinophilic mucin taken from two patients (top and bottom). The left panels show the mucin stained withGomori methenamine-silver (GMS), and no hyphae or fungal elements are visible in these sections. The right panels are serial sections andshow alternative ways of visualizing fungi. At the top a chitinase stain, which detects chitin present in all fungal cell walls, but not bacteria(note the septate hyphae) (�400). The bottom right shows a serial section of the right side GMS stain, but instead stained with an anti-Alternaria polyclonal antibody. Note again the lack of fungal visualization on GMS, which is in contrast to anti-Alternaria staining, and dem-onstrates not only the presence of intact fungi but also its remnants and fungal antigens. These images question the sensitivity of GMSstaining to rule the presence of fungal matter, including hyphae (�200).

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pathology is of mixed cellular reaction (both neutrophilicand eosinophilic).

ARE GRANULOMATOUS AND CHRONIC FRS SEPARATE

ENTITIES? This was one of the unresolved issues. In thegranulomatous type, a histopathologic granulomatousresponse with considerable fibrosis, typified by nonca-seating granuloma with foreign body or Langhans-typegiant cells, occasional vasculitis, vascular proliferation,and perivascular fibrosis, hyphae are usually sparse andA. flavus is consistently isolated. It may be a geographi-cally or ethnicity-related entity, as it is most commonlyseen in Sudan, India, Pakistan, and Saudi Arabia. Incontrast, the chronic invasive type is characterized bydense accumulation of hyphae, sometimes with vascularinvasion, chronic or sparse inflammatory reaction, andisolation of A. fumigatus with direct destruction of adja-cent tissues. It is not clear whether fibrosis is presentconsistently in the chronic invasive form. The clinico-pathological distinction between these two types is notsharp. Both have a chronic course and frequently promi-nent orbital involvement. Moreover, no difference inprognosis or therapy is yet apparent based on thisdistinction. However, in the panel discussion, the partici-pants agreed that chronic invasive and granulomatousFRS should be differentiated, primarily on pathologicalgrounds, until more data are forthcoming.

IS THE OPTIMAL TERMINOLOGY FUNGAL BALL, MYCETOMA,OR ASPERGILLOMA? These terms have been used inter-changeably in the literature to designate the sinusfungal ball. The disease is defined as the presence ofnoninvasive dense accumulation of fungi in sinus cav-ities. The use of the term mycetoma is technically notcorrect, as mycetoma is a chronic local invasion of subcu-taneous tissue by bacteria or fungi with the formation ofsinus tract, swelling, and granule. The term aspergil-loma is also not appropriate, because the disease is notalways due to Aspergillus species. Therefore, the sinusfungal ball seems to be the most appropriate term.

Because the presence of a fungal ball in the sphe-noid sinus is potentially much more serious than that inthe maxillary sinus due to the proximity to the brain,the consensus view was that it is desirable to describewhich sinus is involved. The treatment of sinus fungalball requires removal of the mass but fatal invasiveaspergillosis has been reported following surgery ofsphenoid sinus fungal balls. Thus it was decided tore-examine the management of fungal balls to find outwhether mucosal biopsy to document lack of invasion isrequired when the preoperative scan and operative find-ings suggest a sinus fungal ball. Regarding thedescription of each condition the consensus was todescribe it as localization þ fungal ball � causative fun-gus (e.g., maxillary sinus fungal ball due to A. flavus).

IS THERE AN ENTITY SAPROPHYTIC FUNGAL INFESTATION

OF NASAL MUCOSA? Simple colonization of nasal or para-nasal sinuses without any symptoms has been describedas saprophytic fungal infestation.27 The colonizationoccurs often over mucous crusts in patients who had ahistory of previous sinus surgery, and is detected uponendoscopic examination. It remains silent until it isdetected or presents with foul odor. Further extension of

the growth may lead to fungal ball formation. Afterdeliberation, the consensus was to describe the conditionas localized fungal colonization of nasal or paranasalmucosa.

WHAT IS THE DISTINCTION AMONG AFRS/EFRS/EMRS? Much discussion focused on finding commonalityamong the different forms of eosinophilic diseases of rhi-nosinusitis. In AFRS, there is so called allergic mucinwith many eosinophils and the presence of noninvasivefungi with raised fungal specific IgE. The EFRS andEMRS (EFRS-like) cases do not have specific IgE andthey differ in the presence (EFRS) or absence of fungusvisualized microscopically (EMRS). One specific problemwas that the presence or absence of fungal hyphaedepends on the thoroughness of the histopathologicalexamination of the mucous. Sometimes the mucous isnot provided to pathology, especially with the use ofmicrodebriders, which suction away removed tissue andmucus. The possibility of another AFRS-like group was,therefore, evoked in which the presence of fungus is notdemonstrated, although there is a positive fungal-spe-cific IgE response demonstrable.

The first consensus reached was to call the mucusin such conditions as eosinophilic mucin rather thanallergic mucin, irrespective of presence or absence ofatopy, as eosinophilic mucin describes the presence ofeosinophil or eosinophil degraded products in mucus,which is present in all described conditions. The diseaseswith eosinophilic mucin may be broadly divided intononfungal and fungal categories. The nonfungal sideincludes the AFRS-like group with fungal specific IgE,the EMRS (EFRS-like) category, and aspirin-exacerbatedRS (previously known as aspirin-sensitive RS). The fun-gal side includes AFRS, EFRS, and a limited number ofcases of aspirin-exacerbated RS, which also have fungalhyphae demonstrable (Fig. 7).

There was a vigorous discussion by the panel onwhether it is essential to demonstrate the presence of

Fig. 7. The inter-relationships of various forms of chronic rhinosi-nusitis derived by consensus discussion. AFRS ¼ allergic fungalrhinosinusitis; EMRS ¼ eosinophilic mucin rhinosinusitis; EFRS ¼eosinophilic fungal rhinosinusitis; RS ¼ rhinosinusitis.

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fungal hyphae in eosinophilic mucin, or is it enough todemonstrate the presence of fungal antigen or nucleicacid in the mucus to differentiate the two broad groups.There was agreement that there is no evidence whetherantifungal treatment is useful for eosinophilic diseaseswith fungus demonstrable, and further, that there is noclear information as to whether any fungus that is seenis the cause of eosinophilic infiltration or contributing tothe disease process. There was also discussion on thedefinition of eosinophilic mucin/nasal exudates and thepercentage of occurrence of nasal polyps. In most cases,there are clusters of eosinophils and eosinophil degradedproducts present in mucus with or without Charcot Ley-den crystals. Sometimes there is sensitivity to one ormore specific fungi (as detectable IgE in AFRS), andsometimes there is presence of IgG antibodies to specificfungi. It is also not known whether unilateral diseaserepresents a precursor stage to bilateral disease in anyof the eosinophilic diseases.

The role of fungi in AFRS, EFRS, and EMRSremains unclear. Fungal and nonfungal entities withassociated eosinophilia are shown in the consensus dia-gram of Figure 7, whereas outside the eosinophilichistopathology box lie invasive fungal entities and fun-gal balls with little overlap with eosinophilic patterns.

The consensus developed during the panel discus-sion is summarized and tabulated in Table I.

BIBLIOGRAPHY

1. International Rhinosinusitis Advisory Board. Infectious rhi-nosinusitis in adults: classification, etiology and manage-ment. Ear Nose Throat J 1997;76:5–22.

2. Hora JF. Primary aspergillosis of the paranasal sinuses andassociated areas. Laryngoscope 1965;75:768–773.

3. Jahrsdoerfer RA, Ejercito VS, Johns MME, Contrell RW,Sydnor JB. Aspergillosis of the nose and paranasalsinuses. Am J Otol 1979;1:6–14.

4. Lowe J, Bradley J. Cerebral and orbital Aspergillus infec-tion due to invasive aspergillosis of ethmoid sinus. J ClinPathol 1986;39:774–778.

5. McGill TJ, Simpson G, Healy GB. Fulminant aspergillosisof the nose and paranasal sinuses: a new clinical entity.Laryngoscope 1980;90:748–754.

6. Safirstein B. Allergic broncho-pulmonary aspergillosis withobstruction of the upper respiratory tract. Chest 1976;70:788–790.

7. Millar JN, Johnston A, Lamb D. Allergic aspergillosis of themaxillary sinuses. Thorax 1981;36:710.

8. Katzenstein AA, Sole SR, Greenberger PA. Allergic Asper-gillus sinusitis: a newly recognized form of sinusitis.J Allergy Clin Immunol 1983;72:82–93.

9. Allphin AL, Strauss M, Abdul Karim FW. Allergic fungal si-nusitis: problems in diagnosis and treatment. Laryngo-scope 1991;101:815–820.

10. Manning SC, Schaefer SD, Close LG, Vuitch F. Culture pos-itive allergic fungal sinusitis. Arch Otolaryngol 1991;117:174–178.

11. Bent JP, Kuhn FA. Diagnosis of allergic fungal sinusitis.Otolaryngol Head Neck Surg 1994;111:580–588.

12. Ponikau JU, Sherris DA, Kern EB, et al. The diagnosis andincidence of allergic fungal sinusitis. Mayo Clin Proc1999;74:877–884.

13. Braun H, Buzina W, Freudenschuss K, Beham A, Stamm-berger H. ‘‘Eosinophilic fungal rhinosinusitis’’: a commondisorder in Europe? Laryngoscope 2003;113:264–269.

14. deShazo RD, Chapin K, Swain R. Fungal sinusitis. N Eng JMed 1997;337:254–259.

15. Ferguson BJ. Eosinophilic mucin rhinosinusitis: a distinctclinicopathological entity. Laryngoscope 2000;110:799–813.

16. Gowing NFC, Hamlin IME. Tissue reaction to Aspergillusin cases of Hodgkin’s disease and leukemia. J Clin Pathol1960;13:396–413.

17. deShazo RD. Fungal sinusitis. Am J Med Sci 1998;316:39–45.

18. Ferguson BJ. Mucormycosis of the nose and paranasalsinuses. Otolaryngol Clin North Am 2000;33:349–365.

19. Adelson RT, Marple BF. Fungal rhinosinusitis: state-of-artdiagnosis and treatment. J Otolaryngol 2005;34(suppl 1):S18–S23.

20. Zapico ADV, Suarez AR, Encinas PM, Angulo CM, PozueloEC. Mucormycosis of the sphenoid sinus in an otherwisehealthy patient. Case report and literature review.J Layngol Otol 1996;110:471–473.

21. Sridhara SR, Paragache G, Panda NK, Chakrabarti A.Mucormycosis in immunocompetent individuals: anincreasing trend. J Otolaryngol 2005;34:402–406.

22. Chakrabarti A, Das A, Mandal J, et al. The rising trend ofinvasive zygomycosis in patients with uncontrolled diabe-tes mellitus. Med Mycol 2006;44:335–342.

23. Chakrabarti A, Sharma SC, Chander J. Epidemiology andpathogenesis of paranasal sinus mycoses. OtolaryngolHead Neck Surg 1992;107:745–750.

TABLE I.Consensus Developed During Panel Discussion About the Controversies.

Sl No. Controversy Consensus

1 Fungal rhinosinusitis or fungal sinusitis? Fungal rhinosinusitis

2 Acute invasive, fulminant, or necrotizing fungal rhinosinusitis? Acute invasive fungal rhinosinusitis (when etiological agent isknown, e.g., acute invasive Aspergillus rhinosinusitis)

3 Distinction between acute and chronic FRS Acute when duration is <1 month

Chronic when duration is >3 months

Subacute when duration 1–3 months

4 Are granulomatous and chronic FRS separate entities? Keep the entities separate until more data clarify the facts

5 Fungal ball, mycetoma, or aspergilloma? Fungal ball with the description localization þ fungal ball �causative fungus (e.g., maxillary sinus fungal ball due toAspergillus flavus)

6 Saprophytic fungal infestation of nasal mucosa? Localized fungal colonization of nasal or paranasal sinus mucosa

7 Allergic mucin or eosinophilic mucin? Eosinophilic mucin

8 Distinction between AFRS/EFRS/EMRS? See Fig. 7

FRS ¼ fungal rhinosinusitis; AFRS ¼ allergic fungal rhinosinusitis; EFRS ¼ eosinophilic fungal rhinosinusitis; EMRS ¼ eosinophilic mucin rhinosinusitis.

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24. Veress B, Malik OA, el-Tayeb AA, el-Daoud S, Mahgoub ES,el-Hassan AM. Further observations on primary para-nasal Aspergillus granuloma in the Sudan. A morphologi-cal study of 46 cases. Am J Trop Med Hyg 1973;2:765–772.

25. deShazo RD, O’Brien M, Chapin K, Soto-Aguilar M, Gard-ner L, Swain R. A new classification and diagnostic crite-ria for invasive fungal sinusitis. Arch Otolaryngol HeadNeck Surg 1997;123:1181–1188.

26. Milroy CM, Blanshard JD, Lucas S, Michaels L. Aspergillo-sis of the nose and paranasal sinuses. J Clin Pathol1989;42:123–127.

27. Ferguson BJ. Definitions of fungal rhinosinusitis. Otolaryn-gol Clin North Am 2000;33:227–235.

28. Grosjean P, Weber R. Fungus balls of the paranasal sinuses:a review. Eur Arch Otorhinolaryngol 2007;264:461–470.

29. deShazo RD, O’Brien M, Chapin K, et al. Criteria for the di-agnosis of sinus mycetoma. J Allergy Clin Immunol 1997;99:475–485.

30. Dufour X, Kauffmann-Lacroix C, Ferrie JC, Goujon JM,Rodier MH, Klossek JM. Paranasal sinus fungal ball epi-demiology, clinical features and diagnosis. A retrospectiveanalysis of 173 cases from a single center in France,1989-2002. Med Mycol 2006;44:61–67.

31. Gungor A, Adusumilli V. Fungal sinusitis: progression ofdiseases in immunosuppression—a case report. Ear NoseThroat J 1998;77:207–215.

32. Graham SM, Ballas ZK. Postoperative steroids confuse thediagnosis of allergic fungal sinusitis. J Allergy ClinImmunol 1998;101:139–140.

33. Dhong HJ, Jung JY, Park JH. Diagnostic accuracy in sinusfungus balls: CT scan and operative findings. Am J Rhi-nol 2000;14:227–231.

34. Horst M, Hejjaoni A, Horst V, Michel FB, Bonsquent J.Double-blind, placebo controlled rush immunotherapywith a standardized Alternaria extract. J Allergy ClinImmunol 1990;85:460–472.

35. Marple BF. Allergic fungal rhinosinusitis: current theoriesand management strategies. Laryngoscope 2001;111:1006–1019.

36. Downs S, Mitkakis T, Marks G, et al. Clinical importance ofAlternaria exposure in children. Am J Respir Crit CareMed 2001;164:455–459.

37. Honser SM, Corey JP. Allergic fungal rhinosinusitis: patho-physiology, epidemiology, and diagnosis. Otolaryngol ClinNorth Am 2000;33:399–408.

38. Ghegan MD, Lee FS, Schlosser RJ. Incidence of skull baseand orbital erosion in allergic fungal rhinosinusitis(AFRS) and non-AFRS. Otolaryngol Head Neck Surg2006;134:592–595.

39. Nussenbaum B, Marple BF, Schwade ND. Characteristics ofbony erosion in allergic fungal rhinosinusitis. OtolaryngolHead Neck Surg 2001;124:150–154.

40. Kuhn FA, Swan R. Allergic fungal sinusitis: diagnosis andtreatment. Curr Opin Otolarynogol Head Neck Surg2003;11:1–5.

41. Marple BF, Gibbs SR, Newcomer MT, Mabry RL. Allergicfungal sinusitis-induced visual loss. Am J Rhinol 1999;13:191–195.

42. Meltzer E, Hamilos D, Hadley J, et al. Rhinosinusitis:establishing definitions for clinical research and patientcare. J Allergy Clin Immunol 2004:114(suppl):S155–S212.

43. Taylor MJ, Ponikau JU, Sherris DA, et al. Detection of fun-gal organisms in eosinophilic mucin using a fluorescein-labeled chitin-specific binding protein. Otolaryngol HeadNeck Surg 2002;127:377–383.

44. Rao AK, Mathers PH, Ramadan HH. Detection of fungi inthe sinus mucosa using polymerase chain reaction. Oto-laryngol Head Neck Surg 2006;134:581–585.

45. Kim ST, Choi JH, Jeon HG, Cha HE, Hwang YJ, ChungYS. Comparison between polymerase chain reaction andfungal culture for the detection of fungi in patients withchronic sinusitis and normal controls. Acta Otolaryngol2005;125:72–75.

46. Polzehl D, Weschta M, Podbielski A, Riechelmann H, RimekD. Fungus culture and PCR in nasal lavage samples ofpatients with chronic rhinosinusitis. J Med Microbiol2005;54:31–37.

47. Kostamo K, Richardson M, Eerola E, et al. Negative impactof Aspergillus galactomannan and DNA detection in thediagnosis of fungal rhinosinusitis. J Med Microbiol 2007;56:1322–1327.

48. Saravanan K, Panda NK, Chakrabarti A, Bapuraj RJ. Aller-gic fungal rhinosinusitis: an attempt to resolve the diag-nostic dilemma. Arch Otolaryngol Head Neck Surg 2006;132:173–178.

49. Manning SC, Holman M. Further evidence for allergicpathophysiology in allergic fungal sinusitis. Laryngoscope1998;108:1485–1496.

50. Chhabra A, Handa KK, Chakrabarti A, Mann SBS, PandaN. Allergic fungal sinusitis: clinicopathological character-istics. Mycoses 1996;39:437–441.

51. Panda NK, Sharma SC, Chakrabarti A, Mann SBS. Para-nasal sinus mycoses in north India. Mycoses 1998;41:281–286.

52. Dhiwakar M, Thakar A, Bahadur S, et al. Pre-operative di-agnosis of allergic fungal sinusitis. Laryngoscope 2003;113:688–694.

53. Taj-Aldeen SJ, Hilal AA, Schell WA. Allergic fungal rhinosi-nusitis: a report of 8 cases. Am J Otolaryngol 2004;25;213–218.

54. Ponikau JU, Sherris DA, Kephart GM, et al. Striking depo-sition of toxic eosinophil major basic protein in mucus:implications for chronic rhinosinusitis. J Allergy ClinImmunol 2005;116:362–369.

55. Shin SH, Ponikau JU, Sherris DA, et al. Chronic rhinosinusi-tis: an advanced immune response to ubiquitous airbornefungi. J Allergy Clin Immunol 2004;114:1369–1375.

56. Manning SC, Vuitch F, Weinberg AG, Brown OE. Allergicaspergillosis: a newly recognized form of sinusitis in thepediatric population. Laryngoscope 1989;99:681–685.

57. Borish L, Rosenwasser L, Steinke JW. Fungi in chronichyperplastic eosinophilic sinusitis. Clin Rev AllergyImmunol 2006;30:1–9.

58. Bachert C, Gevaert P, Holtappels G, Johansson SG, VanCauwenberge P. Total and specific IgE in the nasal polypsin related to local eosinophilic inflammation. J AllergyClin Immunol 2001;107:607–614.

59. Thakar A, Sarkar C, Dhiwakar M, Bahadur S, Dahiya S.Allergic fungal sinusitis: expanding the clinicopathologi-cal spectrum. Otolaryngol Head Neck Surg 2004;130:209–216.

60. Venarske DL, deShazo RD. Sinobronchial allergic mycosis:the SAM Syndrome. Chest 2002;121:1670–1676.

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