Braz. j. . vol.80 número4

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Brazilian

Journal

of

OTORHINOLARYNGOLOGY

www.bjorl.org

ORIGINAL

ARTICLE

Sinonasal

disorders

in

hematopoietic

stem

cell

transplantation

夽

,

夽夽

Lucas

Ricci

Bento

a

_,

_Erica

_Ortiz

a,∗

,

Ester

Maria

Danieli

Nicola

a

,

Afonso

C. Vigorito

b

,

Eulalia

Sakano

a

a_Discipline_of_{Otorhinolaryngology,}_Faculdade_de_Ciências_Médicas,_Universidade_Estadual_de_Campinas_(UNICAMP),_Campinas,_SP,

Brazil

b_Hemocentro,_Universidade_Estadual_de_Campinas_(UNICAMP),_Campinas,_SP,_Brazil

Received17January2013;accepted16February2014 Availableonline11June2014

KEYWORDS Sinusitis;

Hematopoieticstem celltransplantation; Therapeutic conducts;

Graftvs.hostdisease

Abstract

Introduction:hematopoieticstemcelltransplantation(HSCT)isassociatedwithmore respira-toryinfectionsduetoimmunosuppression.

Objective: this study aimed to verify the frequency of rhinosinusitis after HSCT, and the associationbetweenrhinosinusitisandchronicgraftvs.hostdisease(GVHD)andtypeof trans-plantation,clinicaltreatment,surgicaltreatment,andsurvival.

Methods:thiswasaretrospectivestudyinatertiaryuniversityhospital.Atotalof95patients withhematologicaldiseasesundergoingHSCTbetween1996and2011wereselected.

Results:chronicmyeloidleukemiawasthemostprevalentdisease.Thetypeoftransplantmost oftenperformedwastheallogenictype(85.26%).Thefrequencyofrhinosinusitiswas36%,with nodifferencebetweentheautologousandtheallogenictypes.ChronicGVHDoccurredin30% ofpatients.Patients withGVHDhadahigherfrequencyandrecurrence ofrhinosinusitis, in additiontomorefrequentneedforendoscopicsinusectomyanddecreasedoverallsurvival.

Conclusion: therewas ahigher frequencyof rhinosinusitis inHSCT andGVHD. The type of transplantdoesnotappeartopredisposetotheoccurrenceofrhinosinusitis.GVHDseemstobe anaggravatingfactorandrequiresamorestringenttreatment.

夽 _Please_cite_this_article_as:_Bento_LR,_Ortiz_E,_Nicola_EM,_Vigorito_AC,_Sakano_E._Sinonasal_disorders_in_{hematopoietic}_stem_cell

transplan-tation.BrazJOtorhinolaryngol.2014;80:285---9.

夽夽

Institution:DisciplineofOtorhinolaryngology,HeadandNeckUnit,RhinologySectorofHospitaldasClínicas---UNICAMP,Campinas,SP,

Brazil.

∗_{Corresponding}_author.

E-mail:erica.ortiz@terra.com.br(E.Ortiz). http://dx.doi.org/10.1016/j.bjorl.2014.05.009

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PALAVRAS-CHAVE Sinusite;

Transplantede células-tronco hematopoéticas; Condutas terapêuticas; Doenc¸a

enxerto-hospedeiro

Afecc¸õesnasossinusaisempacientestransplantadosdecélulas-tronco hematopoiéticas

Resumo

Introduc¸ão:O transplante de células troncas hematopoiéticas (TCTH) associa-se a mais infecc¸õesrespiratóriasdevidoaimunossupressão.

Objetivo:Estetrabalhotemoobjetivodeverificarafrequênciadasrinossinusitespós-TCTH, aassociac¸ãoentrearinossinusiteeadoenc¸adoenxertocontrahospedeiro(DECH)crônicoeo tipodetransplanteeotratamentoclinicoeotratamentocirúrgicoeasobrevida.

Método: Estudo retrospectivo em hospital universitário terciário. Foram selecionados 95 pacientescomdoenc¸ahematológicasubmetidosaTCTHentre1996a2011.

Resultados: Aleucemiamieloidecrônicafoiadoençamaisprevalente.Otipodetransplante maisrealizadofoioalogênico(85,26%).Afrequênciaderinossinusitefoide36%,semdiferença entre os tipos de transplante autólogo e alogênico. A DECH crônica ocorreu em 30% dos pacientes.OspacientescomDECH tiverammaiorfrequênciaerecorrênciade rinossinusite, alémdemaisnecessidadedesinusectomiaendoscópicaedediminuiçãodasobrevidaglobal.

Conclusão:HouvemaiorfrequênciaderinossinusitenoTCTHeDECH. Otipodetransplante nãoparecepredisporaocorrênciadarinossinusite.ADECH pareceserumfatoragravantee necessitadetratamentomaisrigoroso.

Introduction

Currently,hematopoieticstemcelltransplantation(HSCT)is usedinmosttertiaryhospitalsfortreatmentofhematologic malignantandnon-malignantdiseases,immunodeficiencies, andsolidtumors.1---5_The_number_of_{transplantations}

progres-sivelyincreaseswiththeimprovementandmodernizationof techniquesanddrugsused.InBrazil,approximately12,287 transplantationswereperformedinthelatterhalfof2012.6

In spite of advances in the transplantation process, patients are still predisposed to multiple upper airway infectionsandtheircomplications.1---5,7,8_{Immunosuppressive}

drugs,chemotherapy, radiation therapy, prolonged antibi-otic therapy, graft vs. host disease (GVHD), and long periodsof hospitalizationarepredisposing factorsfor air-wayinfections describedin theliteratureandobservedin theeverydaylifeofthesepatients.1---5,7,8

It is believed that immunosuppression is obviously the main triggering factor of such infections, since the air-wayisthe locationmostexposed totheenvironmentand itsmicroorganisms.However,studieshavedemonstrateda higherprevalenceandrecurrenceofrhinosinusitisin trans-planted patients with GVHD.5,7,8 _There _is _evidence _that

alterationsintheultrastructureandonthesurfaceofthe respiratoryepitheliumoccur,aswellasimmunosuppression. Therefore,inadditiontotheabsenceofimmuneprotection, thereisanalterationonthesurfaceandinthemucociliary clearance,increasingthevulnerabilitytoairwayinfections inthesepatients.9,10

Supplementaryexaminationsgreatlyassistinthe diagno-sisofrhinosinusitisintransplantedpatients,especiallynasal endoscopy.4,5,7,8_Computed_tomography_is_used_primarily_to

planthesurgicaltreatment;however,itdoesnotappearto beuseful topredict theoccurrenceof rhinosinusitisafter transplantation.11---14

Isolation of the infectious microorganism through cul-turesorbydirectscreeningisimportanttodeterminethe drugtherapy andeventhesurgical treatment, duetothe existenceofmorediversifiedandresistantmicroorganisms, includingfungi.4,5,7

Thetreatmentofrhinosinusitisintransplanted patients mustbeestablishedmorepromptlyandshouldinvolvethe useofbroad-spectrumantibioticsforalongperiod.2---5,7,8,10

More predisposed patients, such as those with GVHD, are candidates to endoscopic sinusectomy in recurrent rhinosinusitis.4,5,7,15

Thisstudyaimedtoanalyze,firstly,theprofileofpatients treated in this department by assessing the frequency of rhinosinusitis afterHSCT, andsecondly, theassociation betweenrhinosinusitis,GVHD,thetypeoftransplantation, aswellastheclinicalandsurgicaltreatmentofsuch rhinos-inusitis.

Materials

and

methods

This was a retrospective study performed in a tertiary university hospital. A total of 95 patients with hemato-logicdiseasessubmittedtoHSCTwereselected.Theywere treatedattheOtorhinolaryngology-HeadandNeckSurgery OutpatientClinicfrom1996to2011.Inclusioncriteriawere alltypesofHSTC,adultpatients,andany otorhinolaryngo-logycomplaint.Pediatricpatientsandthosewhowerenot submittedtoatransplantwereexcluded.

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Table1 Frequencyofhematologicdiseasesoftheselected patients.

Hematologicdisease Frequency Percentage CML 45 48.4%

AML 12 13%

ALL 8 8.6%

AA 6 6.5%

NHL 6 6.5%

MM 6 6.5%

Myelodysplasia 4 4.3%

HL 3 3.23%

MS 1 1.08%

PNH 1 1.08%

CLL 1 1.08%

Nefet 93 100%

CML,chronicmyeloidleukemia;AML,acutemyeloidleukemia;

ALL,acutelymphoblasticleukemia;AA,aplasticanemia;NHL,

non-Hodgkin’slymphoma;MM,multiplemyeloma;HL,Hodgkin’s

lymphoma;MS,multiplesclerosis;PNH,paroxysmal nocturnal

hemoglobinuria;CLL,chroniclymphocyticleukemia; Nefet,N

effective.

examinationsperformed at theservice. Recordsthat con-tained incomplete data for the statistical analysis were excluded.Missingdatawereremovedfromthecalculation duringthestatistical analysisof eachvariable.Therefore, thetotalofsomevariableswaslessthanthetotalsample number(95).

Thediagnosisofrhinosinusitiswasestablishedaccording tothesymptomsandsignsonphysicalexamination,in addi-tiontonasalendoscopyresults,accordingtotheGuidelines onRhinosinusitisofABORL-CCFandEPOS.10

The Research Ethics Committee of UNICAMP approved thestudy,andaninformedconsentwasobtainedfromall patients(088/2001).

Comparisons were performed between the variables, type of transplantation, and GVHD with rhinosinusi-tis occurrence, treatment, and survival. These variables werestatisticallyanalyzedthroughfrequencydistribution, Fisher’sexacttest,Kaplan---Meiercurves,andCoxmodels.

Results

Regardinghematologicaldisease,chronicmyeloidleukemia wasthemostprevalentdisease,followedbyacutemyeloid leukemiaandacutelymphocyticleukemia.Table1showsthe distributionofhematologicmalignanciesinthe95patients. The type of transplantation mostoften performed was the allogenic type(85.26%). Acute rhinosinusitisoccurred in 34 patients, which corresponds to a rate of 36.17%. Therewasnosignificantdifferenceintheoccurrenceof rhi-nosinusitisin differentautologous(30%)orallogenic (37%) transplantations.ThetypeofHSCTwasnotassociatedwith ahigherincidenceofsinusitis(Table2).

Nasal endoscopy wasperformed in 98.95% of patients. This examination showedresults within the normal range in29% ofcases.Themost frequentalteration(20%)found waspurulentrhinorrhea(Table3).Alterationssuggestiveof fungal infection were observed in little more than 5% of patients,suchasbrownishorgrayishmucosaoftheanterior

Table2 Rhinosinusitis(RS)vs.typeofautologousand allo-genichematopoieticstemcelltransplantation(HSCT).

WithRS WithoutRS Total Allogenic 30 51 81 Autologous 4 9 13 Total 34 60 94

p=0.764; diagnostic odds ratio=1.32; confidence interval

(95%)=0.33---6.38.

nasalseptumandmiddleandlowerturbinates,inadditionto necrosisofthenasalfossastructures,mainlyofthemiddle turbinatein1%ofpatients.

The CTscanofthe paranasalsinuses wasperformed in 48.42%of patients.The homogeneousopacificationofthe paranasalsinuswithoutbonestructuralalterations, regard-lessoftheaffectedsinus,wasthemostfrequentalteration (approximately40%),followedbymucosaledemain10%of theCTs(Table4).

Approximately70%ofthepatientswerealiveatthetime ofthestudy(Table5).ThemeantimeofHSCTwas8.9years (4months---16years).

ThedevelopmentofGVHDaftertransplantationoccurred in 30.53% of patients. The occurrence of GVHD was not associatedwithhighermortality (p=0.228).However,the frequency (72%) and the number of rhinosinusites were significantlyhigherinpatientswithGVHD(Table6). Approx-imately 28% of patients with GVHD had more than two episodes of rhinosinusitis, whereas no patients without GVHDhadrhinosinusitisrecurrence(Table7).

The patients whohad GVHD had greater need for sur-gical treatment (p<0.001) and decreased overall survival (Table8andFig.1).Thesurgicaltreatmentperformedwas endoscopicsinusectomyundergeneralanesthesia.

Endoscopicsinusectomywasperformedin58%(20/34)of patientswithrhinosinusitis,andapproximately48%ofthese patientshadGVHD;only9%didnothaveGVHD.

Table3 Nasalendoscopyalterations.

Endoscopicfindings Frequency Percentage Normal 29 31%

PR 19 20%

SD 11 12%

ME 11 12%

MR 10 11%

Fungal 5 5%

SD/MR 2 2%

ME/SD 2 2%

PR/ME 2 2%

ME/MR 1 1%

Necrosis 1 1%

SP 1 1%

Total 94 100%

PR, purulent rhinorrhea; SD, septal deviation; ME, mucosal

edema; MR,mucoidrhinorrhea;SP,septalperforation;

Necro-sis,signsofnecrosisofthemucosaandsignsoffungalinfection

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Table 4 Computed tomography (CT) of the paranasal sinusesfindings.

Frequency Percentage

CToftheparanasalsinuses

Normal 15 32%

HO 18 39%

ME 5 11%

AV 3 7%

SD 1 2%

AV/SD 1 2%

AV/ME 1 2%

HO/AV 1 2%

HETO/ME/SD 1 2% Total 46 100%

HO, homogeneous opacification; ME, mucosal edema; AV,

anatomicvariation;SD,septaldeviation;HETO,heterogeneous

opacification.

Table5 Frequencyofdeathsinallpatientssubmittedto hematopoieticstemcelltransplantation.

Number Percent Alive 66 69%

Dead 29 31%

Total 95 100%

Table6 Associationofgraftvs.hostdisease(GVHD)with rhinosinusitis(RS).

WithRS WithoutRS Total WithGVHD 21 8 29 WithoutGVHD 13 52 65 Total 34 60 94

p<0.001; odds ratio=10.17; confidence interval

(95%)=3.43---33.28.

Table7 Frequencybetweenrhinosinusitis(RS)recurrence andgraftvs.hostdisease(GVHD).

NoRS 1RS 2RS 3RS 4RS Total WithGVHD 8 15 2 3 1 29 WithoutGVHD 52 13 0 0 0 65 Total 60 28 2 3 1 94

Table8 Associationbetweensinonasalsurgicaltreatment andgraftvs.hostdisease(GVHD).

Withsurgery Withoutsurgery Total WithGVHD 14 15 29 WithoutGVHD 6 60 66 Total 20 75 95

p<0.001; odds ratio=9.05; confidence interval

(95%)=2.73---33.98.

Discussion

The increasednumberof immunosuppressedpatients asa result of advancements in medicine in the treatment of malignant neoplasms, and degenerative and autoimmune diseaseshassimultaneouslyprovidedgreaterexperiencein themanagementofthesecases.

Patients undergoing transplantations suffer several preparatory organicmodificationsandremain immunosup-pressedduringthisprocessforavariableperiodoftime.1---5,7

TheallogenicHSCTmayormaynotbemyeloablative,which causes increased immunosuppression in patients.1 _In _this

study,therewasahighernumberofallogenic transplanta-tions;however,thepercentageofmyeloablativeprocedures wasnotobtained.

Thefrequencyofrhinosinusitiscoincidedwiththe post-HSCTestimatedescribedintheliterature(36.7%),butwas slightly lower than that in the previous study (42%) per-formed in this same service.2,3,5,8 _This _can _be _explained

0%

17 20%

40% 60% 80% 100%

Overall survival vs. GVHD

P = 0,033

Years of TMO

Cox proportional hazard model Likelihood ratio test

Without GVHD

With GVHD RR = 0,40(0,18 + 0,99) -P = 0,047

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by the greater care given tothese patients before trans-plantation,orlowermyeloablationduringthecurrentHSCT process.Asnodatawereobtainedregardingmyeloablation, the latter association cannot be explained. However, the frequencyof rhinosinusitisremainshigherwhencompared toimmunocompetentpatients(5---15%).10

Anterior rhinoscopy is inadequate for the appropriate sinonasalassessmentofthesetransplanted patients.Nasal endoscopyistheidealandessentialexaminationtoattaina correctandearlydiagnosisofrhinosinusitis,bothpre-and post-HSCT. Endoscopic assessment can evaluate the char-acteristics of secretion and the mucosa. Thus, it better suggeststheetiologicfactor(bacterial,viral,orfungal)and allowsforearlytreatmentofsinonasaldisease.Itis notewor-thythatthesignofnecrosisorbrownishorgrayishmucosa, mainlyinthemiddleturbinateandanteriornasalseptum, suggestsinvasivefungalinfection.4,5,7,10,15

Computed tomography (CT)of the paranasalsinuses is aspecific examination,in spiteof itslowsensitivity, asit does not differentiate the type of secretion (purulent or mucoid).Italsodoesnotshowspecificsignsofinvasive fun-gal sinusitis in the initial stage of the disease. However, in immunosuppressed patients, CT assists in the manage-mentofunfavorablecasesandiscrucialintheassessment ofrhinosinusitiscomplications.11---14

Theliteratureshowscontroversialopinionsregardingthe performance of CT pre-HSCT. Billings showed that CT of theparanasalsinusesbeforetransplantationmaybeuseful forthepreventionofrhinosinusitispost-HSCTinchildren.14

However, Arulrajah argued that the symptoms of rhinor-rhea,cough,andnasalcongestionhavesimilarimportance totheCTresults,withnoneedforCTwhenthesesymptoms exist.12_Kasow_suggested_the_performance_of_preventive_CT

oftheparanasalsinusesbeforeHSCTinchildrenduetothe alterationsfoundintheexaminations,althoughthesewere notdirectlyrelatedtothechild’ssymptoms.13

Ortiz showedthatCTpre-HSCT inadultsdoes not pre-dict post-HSCTsinusitis;and anatomicalvariationsdo not predispose to rhinosinusitis after HSCT, but contribute to post-HSCT rhinosinusitis severity.11 _Therefore, _performing

CToftheparanasalsinusespriortoHSCTissuggestedonly whenthepatienthaschronicsinonasalsymptomsoracute rhinosinusitis withunfavorable evolution. After the HSCT, thisexaminationwouldbeeffective incasesrefractoryto medical treatment or suspected cases of complications, either fungal or bacterial, in order to highlight specific causes blocking ostial drainage, anatomical variations, or invasionofadjacentstructures.

The frequency of GVHD found in the study (30%) was lowerthan that reportedin the literature(50%).5,8 _These

patients were more susceptible to the development and recurrenceofrhinosinusitis,whichisinagreementwiththe literature.2---5,8,9

A previous study showed that in addition to immuno-suppression,thereisachange intheultrastructureof the respiratoryciliatedpseudo-stratifiedepitheliumand micro-scopicchangesontheepithelialsurface,suchassquamous metaplasiaandfibrosis.Therefore,theremustbeachange in mucociliary clearance that would predispose to recur-renceoftherhinosinusitis.9_Thus,_these_patients_with_GVHD

haveagreaterneedofsurgicaltreatmentforrecurrent rhi-nosinusitiscontrol.8,9

Conclusion

Patients who received HSCT have a higher incidence of sinusitiswhencomparedtoimmunocompetentpatients.

The typeof transplantationdoes notinfluence the fre-quencyofrhinosinusitis;however,chronicGVHDappearsto actuallybeanaggravatingfactor.

Chronic GVHD was associated with a greater need for sinus surgery to control rhinosinusitis. Additionally, these patientswithchronicGVHDshoweddecreasedoverall sur-vival.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

References

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3.SavageDG,TaylorP,BlackwellJ,ChenF,SzydloRM,RuleSA, etal.Paranasalsinusitisfollowingallogenicbonemarrow trans-plant.BoneMarrowTransplant.1997;19:55---9.

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10.FokkensJ,LundV,MullolJ,BachertC,AlobidI,BaroodyF,etal. TheEuropeanPositionPaperonrhinosinusitisandnasalpolyps 2012.Rhinology.2012;23Suppl.:1---299.

11.Ortiz E, Nakamura E, Magalhães R, Souza CA, Chone CT, Vigorito AC, et al. Prognostic value of sinus CT scans in hematopoieticstemcelltransplantation.BrazJ Otorhinolaryn-gol.2010;76:618---22.

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W,etal.Clinicalutilityofcomputedtomographyscreeningof chest,abdomen, andsinusesbeforehematopoietic stemcell transplantation:the St.Jude experience. BiolBlood Marrow Transplant.2009;15:490---5.

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