Braz. j. . vol.83 número2

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www.bjorl.org

OTORHINOLARYNGOLOGY

CASE

REPORT

Primary

laryngeal

aspergillosis

in

the

immunocompetent

state:

a

clinical

update

夽

Aspergilose

laríngea

primária

no

estado

imunocompetente:

atualizac

¸ão

clínica

Mainak

Dutta

∗

_,

_Arijit

_Jotdar,

_Sohag

_Kundu,

_Bhaskar

_Ghosh,

_Subrata

_Mukhopadhyay

MedicalCollegeandHospital,DepartmentofOtorhinolaryngologyandHead-NeckSurgery,Kolkata,WestBengal,India

Received9February2015;accepted4June2015 Availableonline17October2015

Introduction

Laryngealaspergillosisisknowntooccurin immunocompro-misedstates,particularlyindiabetesmellitus,tuberculosis, andhumanimmuno-deficiencyvirus (HIV)infection,andis associatedwith use of inhalational steroids and cytotoxic drugs.Primarylaryngeal aspergillosisis rare,especiallyin immunocompetentpatients, withveryfewreportedcases todate.It often mimicsthe pre-malignantandmalignant conditionsoflarynx,andrespondswelltoantifungals.This reportpresentsacaseofprimarylaryngealaspergillosisin animmunocompetentmiddle-agedwoman,andexploresthe currentpoolofevidenceregardingitspathogenesisand clin-icalaspects.Todate,thisrepresentstheonlycomprehensive reviewonthetopic.

Case

report

A45-year-oldwomanpresentedwithprogressivehoarseness fortwomonths.Itwasprecededbyanepisodeofsorethroat

夽 _Please _cite _this _article _as: _Dutta _M, _Jotdar _A, _Kundu _S,

GhoshB, Mukhopadhyay S.Primary laryngeal aspergillosisinthe immunocompetentstate:aclinicalupdate.BrazJOtorhinolaryngol. 2017;83:228---34.

∗_{Corresponding}_author.

E-mail:[email protected](M.Dutta).

PeerReviewundertheresponsibilityofAssociac¸ãoBrasileirade OtorrinolaringologiaeCirurgiaCérvico-Facial.

whichsubsidedwithmedication.Therewasnohistoryof dif-ficultyindeglutition,respiratorydistress,andvoiceabuse. Therewasnorecent-onsetlossofweightandappetite,with nocough or evening risein temperature. Neithershe nor any of herkin hadhistory ofpulmonary tuberculosis.She wasnotaddictedtotobaccooralcohol,andwasotherwise healthy.

Indirectlaryngoscopyandsubsequent fiber-optic laryn-goscopy revealed inflamed vocal cords with impaired mobility, covered withdirty-white necroticdebris resem-bling keratotic patches over areas of congestion. The vestibular folds were edematous (Fig. 1A). There wasno palpablecervicallymph-node.Stigmataofhealingoractive infection,suchasscar,sinus,orfistulawereabsentinthe neck.Chest X-rayshowednoevidenceofactiveorhealed tuberculosis.Routinehematologicinvestigationswere unre-markable; she wasnon-diabeticand seronegativefor HIV. Withaprovisionaldiagnosisofglotticmalignancy,shewas scheduledformicrolaryngealevaluationundergeneral anes-thesiawithaplanforbiopsy.Itwasrevealedatthisstage that the lesion resembling early malignancy or kerato-sis was actually areas of leukoplakic patch, which could be easily scraped off as a creamy layer, leaving a raw undersurface.Fungalstainingof scrapingsshowed branch-ingseptatehyphae,morphologicallyresemblingAspergillus. Histologyfromvocalcordtissuesamplesrevealednecrotic exudatesinstromacrowdedwithseptate‘‘spaghetti-like’’ fungalfilamentsbranchingat∼45◦,interspersedwithshreds

of squamous epithelium (Fig. 1B and C). Culture reports

http://dx.doi.org/10.1016/j.bjorl.2015.06.002

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Figure 1 (A) Fiber-opticlaryngoscopy revealed inflamed vocalcords covered with dirtywhite necrotic debris(arrows) that resembledkeratoticpatchesoverareasofcongestion.(BandC)Histopathologyrevealednecroticexudatesintissuestromacrowded withseptate‘‘spaghetti-like’’fungalfilaments branchingat∼45◦_,_interspersed_with _shreds_of_vocal_cord_squamous _epithelium (hematoxylin---eosin;400×).

corroboratedthehistologyfindings,confirming thegrowth

asAspergillusfumigatus.

A retrospective medical history based on the clinico-histologicfindingsrevealedthatthepatienthadnobronchial asthma or any sortof allergy. Furtherinvestigations were directedat anyco-morbid,contributoryfactorsthatcould have led to a transient immunodeficiency. However, she had nohistory of intakeof inhalational corticosteroids or cytotoxic drugs, nor any exposure to radiation. Thatshe wasnon-diabeticwasknownfromtheroutinepre-operative check-up. Subsequent investigations failed to show any focus of fungal infestation in the body. This included the tracheo-bronchial tree, where flexible bronchoscopy and subsequentculturefromthebroncho-alveolarlavagewere unremarkable,andtheparanasalsinuses,whichshowedno evidence of infection on diagnostic nasal endoscopy and imaging.Adiagnosisofprimarylaryngealaspergillosiswas reached, and the patient was offered oral itraconazole (300mg/day)forthreeweeks.Fiber-opticlaryngoscopy per-formedtendaysfollowing therapyshowedhervocal cords tobeedematous,butwithoutanywhitepatchesordebris. Shewasfollowedupeverytwomonths.Atsixmonths,her voicehadreturnedtonormal,withnoresiduallesion.

Discussion

Aspergillus sp. are ubiquitous, saprophytic fungi that

grow on soil and decaying matter. However, they also resultinopportunisticinfections(sinusitis,bronchitis, aller-gic bronchopulmonaryaspergillosis, aspergilloma, invasive aspergillosis) whose severity depends upon the virulence of the species (A. fumigatus, A. flavus, and A. niger) and on the host’s immunity.1 _The _inhaled _spores _deposit on the mucosa of the paranasal sinuses, larynx, and the tracheobronchial tree, and the dark airway cavities favor their growth as hyphae. There they colonize or invade deeper tissues, producing symptoms when host immunity wanes. Laryngotracheobronchial and pulmonary aspergilloses therefore represent a group of the dreaded complications of immunocompromization. They might rarely be seen in immunocompetent individuals as well.

However,primary aspergillosis restricted to the larynx in anon-immunocompromized subjectis truly rare.2 _A thor-oughsearch in the PubMed/MEDLINE, LILACS, and SciELO databasesrevealed only27 casesin the Englishliterature (Table1).

Little is known about the etiopathogenesis of pri-marylaryngealaspergillosisinimmunocompetentsubjects, primarily because of limited documentation, which are mostlysingle-casereports.Aspergillosisisessentially oppor-tunistic, and host immunity is the key in production of clinicaldiseaseratherthanthevirulenceofthe fungus,1,3 althoughit isnotclear how.4 _Besides_the _known_states_of immunocompromization(Table 2; Group A),it may affect ‘‘apparentlyhealthy’’subjects,probablybecauseaperson ‘‘asymptomatic’’ at the point of contracting the disease mightnotbefullyimmunocompetent;rather,she/hecould beinatransient phaseofwaning of immunity.Thiscould be possible in some given conditions (Table 2; Group B). Almostallofthemaresystemicfactorsalteringhost immu-nity,exceptforinhaledsteroidsinpowderform,andprior exposuretoirradiationandLASERaspartofthetreatment protocolforlaryngealcarcinoma.

Besides, there are some ‘‘local’’ or ‘‘laryngo-tropic’’ factors (Table 2; Group C) whose true role in the patho-genesis remains conjectural.Manypatients hadhistory of voiceabuse(∼14%), smoking(∼11%), andradiation

expo-sure(∼11%)(Fig.2;Table1).Ithasbeenpostulatedthatthey

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1. Presentcase;2015 45/F Hoarsenessofvoice None Malignancy

2. GangopadhyayM,

MajumdarK,

BandyopadhyayA,Ghosh A.Invasiveprimary aspergillosisofthelarynx presentingashoarseness andachronicnonhealing laryngealulcerinan immunocompetenthost: Arareentity.EarNose ThroatJ.2014;93:265---8.

42/M Hoarsenessofvoice,

fever,coughwith expectoration

Smoking,vocalabuse Malignancy

3. Al-OgailiZ,ChapeikinG,

PalmerD.Primary aspergillosisofbilateral laryngoceles.CaseRep Med.2014;2014:384271.

77a_/F _Difficulty_in swallowingand talking,hoarsenessof voice

Smoking,useof inhaled

corticosteroidsfor asthma

Lymphoma

4. DoloiPK,BaruahDK, GoswamiSC,PathakGK. Primaryaspergillosisof thelarynx:acasereport. IndianJOtolaryngol HeadNeckSurg. 2014;66(Suppl.1):326---8.

35/F Hoarsenessofvoice, cough

None Keratosis

laryngis

5. RanY,etal.20135 _23/F _Hoarseness_of_voice, severeparoxysmal cough,tachypnea

Oralsex None

6. SundarrayC,PandaS, RayR.Primaryvocalcord aspergillosisina non-immunocompromised host.JIndianMedAssoc. 2011;109:200.

NA NA NA NA

7. RanY,etal.20112 _30/F _Hoarseness_of_voice, precededbyan episodeofcommon cold(fever, headache,cough), laterassociatedwith vocalfatigue, expectoration,and occasionalvomiting

Vocalabuse,oral antibiotics (ampicillin, cefixime),repeated intra-laryngeal injectionof dexamethasone

Laryngitis

8. LiuYC,etal.20104 ₃₀a_/F _Hoarseness_of_voice _Vocal_abuse,_true vocalcordcyst

None

32/F Vocalabuse,therapy

withbroad-spectrum antibiotics

9. RanY,etal.20083 _36/F _Hoarseness_of_voice, vocalfatigue

Systemicantibiotic (penicillin, cefotaxime)and dexamethasone therapyforrhinitis andasthma

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Table1 (Continued)

Sl.no. Citations Age

(years)/sex

Presentation Associatedfactors Initialdiagnosis

10. WittkopfJ,ConnellyS,

HoffmanH,SmithR, RobinsonR.Infectionof truevocalfoldcystwith

Aspergillus.Otolaryngol HeadNeckSurg. 2006;135:660---1.

62/F Hoarsenessofvoice Truevocalfoldcyst

(?aspergilloma)

NA

11. OgawaY,etal.20021 ₇₃a_/M _Hoarseness_of_voice _History_of

radiotherapyfor laryngealsquamous cellcarcinoma; historyofdiabetesb

Malignancy

12. DeanCM,HawkshawM, SataloffRT.Laryngeal aspergillosis.EarNose ThroatJ.2001;80:300.c

17/F Hoarsenessofvoice, vocalfatigue

None NG

13. FairfaxAJ,etal.19997,c ₇₅d_/M _Hoarseness_of_voice ultimatelyleadingto aphonia

Longtermuseof inhalationalsteroid (fluticasone)through diskhaler,historyof chronicsmokingfor 40years,pasthistory ofcarcinoma prostratetreated withbilateral orchidectomy

None

14. BeustL,GodeyB,LeGallF, GrollierR,LeClechG. Primaryaspergillosisofthe larynxandsquamouscell carcinoma.AnnOtolRhinol Laryngol.1998;107(10Pt1): 851---4.

53/M Hoarsenessofvoice, respiratorydistress

Radiotherapyfor squamouscell carcinomalarynx

Nonef 64/M

15. NongD,etal.19976 _30---40f_/4M 4F

Hoarsenessofvoice leadingtoaphonia, mildsorethroat, occasionalcough(in severecases)

None Acute

laryngitis, tuberculosis, malignancy

16. Benson-MitchellR,Tolley N,CroftCB,GallimoreA. Aspergillosisofthe larynx.JLaryngolOtol. 1994;108:883---5.

62/M Hoarsenessofvoice None Malignancy

17. KheirSM,FlintA,Moss JA.Primaryaspergillosis ofthelarynxsimulating carcinoma.HumPathol. 1983;14:184---6.

50/M Hoarsenessofvoice Chronicobstructive pulmonarydisease

Malignancy

18. FerlitoA.Primary aspergillosisofthe larynx.JLaryngolOtol. 1974;88:1257---63.

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19. RaoPB.Aspergillosisof larynx.JLaryngolOtol. 1969;83:377---9.

48/M Hoarsenessofvoice None NA

Inmostcases,unlessotherwisementioned,itraconazolewasthepreferredanti-fungalagent.

a_Surgery_was_the_mainstay_of_treatment_[excision_of_laryngoceles_(serial_no._3),_excision_of_vocal_cord_cyst_(serial_no._8),_CO 2laser

cautery(serialno.11)].

b _According_to_the_authors,_prior_radiation_exposure_was_the_more_probable_contributory_factor_for_the_laryngeal_{aspergillosis}_in_this

patientratherthandiabetes.

c _These_citations_have_been_retrieved_as_{cross-references}_from_the_articles_obtained_following_the_search_strategy_described_in_the

text.

d _Treated_with_amphotericin_lozenges.

e _The_lesions_acted_as_harbingers_of_recurrence_of_the_laryngeal_cancer.

f _Treated_with_amphotericin_B_(one_patient),_ketoconazole_(three_patients),_and_itraconazole_(four_patients).

NA,notavailable;NG,notgiven;M,male;F,female.

betooearly toconclude anydefinitive roleoforal sexin primarylaryngealaspergillosis.

Interestingly, 50% of immunocompetent subjects with primary laryngeal aspergillosis had no identifiable con-tributory factors that could have somehow decreased or alteredtheprotectivelaryngealphysiology(Fig.2;Table1).

Consequently,thediagnosis isnotstraightforward.Inmost patients,includingthepresentone,theconditionhasbeen mistakenclinicallyasmalignancy(includinglymphoma)and keratosis laryngis. In the largest series published, none hadacorrectpre-operativediagnosis.6_The_current_patient presented with hoarseness and had irregular leukoplakic

Table2 Suggestedetiologicfactorsforprimarylaryngealaspergillosis.

GroupA Conditionsleadingtoan

immunocompromized state

•Acquiredimmunodeficiencysyndrome

•Uncontrolleddiabetes

•Malignancy(especiallyhematologic) •Severeaplasticanemia

•Prolongedneutropenia

•Long-termsystemicsteroidintake

•Activetuberculosis •Transplantrecipients

•Oncytotoxicdrugs •Chronicliverdisease •Chronicdebilitatingillness

•Terminalillness

•Prolongedhospitalization

•Onparenteralnutrition

GroupB Conditionsleadingto

transientsystemic/local immunodeficiencyinan individualwhocanbe otherwiseasymptomatic atthetimeof

contractingthedisease

•Humanimmunodeficiencyvirusinfection •Diabetesundercontrol

•Oralsteroidspray(powderform)andimpropermouthwash •Priorirradiation

•TreatmentwithLASER

•Pasthistoryoftuberculosis •Alcoholism

•Chronicobstructivepulmonarydisease •Ondialysis

•Futurerecurrenceoflaryngealcancer •Useofbroadspectrumantibiotics

GroupC Associatedconditions

withonlyhypothetical explanation

•Vocalabuse •Truevocalcyst

•Oralsex •Smoking

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None 50 14.29 14.29 10.71 10.71 10.71 7.14 3.57 3.57 3.57 Voice abuse Steroid intake Smoking Broad-spectrum antibiotics

Exposure to radiation

Vocal fold cyst

Oral sex

Diabetes under control

COPD

0 10 20 30

Percentage

40 50 60 70

Figure2 Proportionateinvolvementofthedifferentfactors associatedwithprimarylaryngealaspergillosisin immunocom-petentsubjects(expressedinpercentages).Notethatin50%of the patients,no contributoryfactor couldbe elicited. (Data were unavailable in one patient.)COPD, chronic obstructive pulmonarydisease.

patchesoverthevocalcords---thetypicalpresentationof primaryaspergillosislimitedtothelarynxwithvariable sub-glottic and supraglottic extensions. However, it can also manifest asulcerativeplaques, as/withinvocal cysts, and evenwithinbilaterallaryngoceles(Table1),addingtothe clinicaldilemma.

Histopathology is essential for correct diagnosis; it demonstrates the septate hyphae with characteris-tic dichotomous branching at 45◦_.2,4 _Culture _patterns (sabouraud dextrose agar at 28◦_C), _and _presently _gene extractionthroughapre-formed‘‘DNA-kit’’andsubsequent amplification by polymerase chain reaction, followed by sequencing in specialized laboratories provide for the species of Aspergillus involved.2---5 _Decision _regarding administrationof systemic antifungals is controversial, as aspergillosisischieflycolonizingratherthaninvasive. How-ever,histologicevidenceofinvasionhasbeendemonstrated inimmunocompetentsubjectspresentingwithhoarseness.

The situationis akin tofungal rhinosinusitis when sys-temicantifungalsarepreferentiallyadministeredonlywhen thereisosseo-neurovascularinvolvement.Nevertheless,in primarylaryngealaspergillosis,oralitraconazolefor three-to-four weeks has been the standard treatment in most publishedreports irrespectiveof invasion.2---5 _Use _of keto-conazoleandamphotericinBlozengeshasbeenmentioned infewearlierreports,6,7_but_{itraconazole,}_with_fewer side-effectsandsatisfactoryoutcome,ispresentlyfavored.Data onlong-termfollow-upislacking,buttodatetherehasbeen norecurrencefollowingcompletetreatmentwithsystemic antifungals.

Lackofdefiniteguidelinesforclinicaldiagnosisdueofthe rarityofthediseasemighthaveresultedinunder-reporting, but presently primary laryngeal aspergillosis in immuno-competent subjects should be considered an ‘‘emerging diseaseentity.’’ Analysisof the frequency ofcases in the five-year-wisesplitsinceitsfirstdocumentationshowsthat there has been a steep rise of the trend-line (Fig. 3). Therefore, it might not be as uncommon as generally considered.Althoughthehost-pathogeninteractionin cau-sation of the disease is still unknown, primary laryngeal aspergillosiscurrentlyrepresentsanentitythatpresent-day

15 14 13 12 11 10

Number of patients reported

Time period in groups of 5 years 9 8 7 6 5 4 3 2 1 0

1966 - 1970 1971 - 1975 1976 - 1980 1981 - 1985 1986 - 1990 1991 - 1995 1996 - 2000 2001 - 2005 2006 - 2010 201

1 - 2014

Figure 3 Time-trend of the number of cases of primary

laryngealaspergillosisreportedinimmunocompetentpatients in the last five decades. The linear black line with arrow-headrepresents thetrend-line. There hasbeen asignificant increase in reporting, especially after 1995, although eight ofthe11 patients reportedinthetime-period of1996---2000 werefromacase-seriesthatspannedtenyears.Nevertheless, theelevation ofthetrend-line withtime isremarkable. Pri-mary laryngeal aspergillosis is now a disease to look for in symptomaticimmunocompetentindividuals.(n.b.:thepresent patienthasbeenincludedinthe2011---2014group).

otolaryngologistsareexpectedtoencountermoreoftenin non-immunocompromizedindividuals.

Conclusion

Theincidenceofprimarylaryngealaspergillosisin immuno-competent individuals has been steadily rising in the last fewyears.Aneasilyremovable whitepatch(leukoplakia), asmallslough-coveredulcer,oravocalnoduleinahealthy patientpresentingwithhoarsenesswithnoapparent expo-suretoany knownimmunomodulatoryagent/environment shouldarouse suspicion of primary aspergillosis. Etiologic factorsareoftendifficulttoelicit,andimmunitymightnot playadefinitiveroleinthecausation.However,knowledge ofthesuggestedcontributory factorswitha highindexof suspicionwouldhelpcliniciansdirecttheirwork-up accord-inglytoexcludethedifferentials,therebyaidingtodetect thispotentiallycurablediseaseintime,irrespectiveofthe statusofthehost’simmunity.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgments

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AurisNasusLarynx.2002;29:73---6.

2.RanY,LiL,CaoL,DaiY,WeiB,ZhaoY,etal.Primaryvocalcord aspergillosisandscanningelectronmicroscopicalobservationof thefocusofinfection.Mycoses.2011;54:e634---7.

3.RanY,YangB,LiuS,DaiY,PangZ,FanJ,etal.Primaryvocal cordaspergillosiscausedbyAspergillusfumigatusandmolecular identificationoftheisolate.MedMycol.2008;46:475---9.

aspergillosisrelatedtooralsex?Acasereportandreviewofthe literature.MedMycolCaseRep.2013;2:1---3.

6.NongD,NongH,LiJ,HuangG,ChenZ.Aspergillosisofthelarynx: areportof8cases.ChinMedJ(Engl).1997;110:734---6. 7.Fairfax AJ, David V, Douce G. Laryngeal aspergillosis