Braz. j. . vol.81 número2

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www.bjorl.org

Brazilian

Journal

of

OTORHINOLARYNGOLOGY

ORIGINAL

ARTICLE

Oral

changes

in

individuals

undergoing

hematopoietic

stem

cell

transplantation

夽

Regina

Haddad

Barrach

a

_,

_Mair

_Pedro

_de

_Souza

b

_,

Daniela

Polo

Camargo

da

Silva

a,∗

,

Priscila

Suman

Lopez

a

,

Jair

Cortez

Montovani

a

a_Universidade_Estadual_Paulista_(UNESP),_São_Paulo,_SP,_Brazil b_Hospital_Amaral_Carvalho,_Jaú,_SP,_Brazil

Received5November2013;accepted27April2014 Availableonline22October2014

KEYWORDS

Mucositis;

Hematopoieticstem celltransplantation; Medicaloncology

Abstract

Introduction:Patientsundergoinghematopoieticstemcelltransplantationreceivehighdoses ofchemotherapyandradiotherapy,whichcausesevereimmunosuppression.

Objective: Toreportanoraldiseasemanagementprotocolbeforeandafterhematopoieticstem celltransplantation.

Methods:Aprospectivestudywascarriedoutwith65patientsaged>18years,with hemato-logicaldiseases,whowereallocatedintotwogroups:A(allogeneictransplant,34patients);B (autologoustransplant,31patients).Atotalofthreedentalstatusassessmentswereperformed: inthepre-transplantationperiod(moment1),oneweekafterstemcellinfusion(moment2), and100daysaftertransplantation(moment3).Ineachmoment,oralchangeswereassigned scoresandclassifiedasmild,moderate,andsevererisks.

Results:Themostfrequentpathologicalconditionsweregingivitis,pericoronitisinthethird molar region,and ulcersatthe thirdmomentassessments. However, atmoments 2and3, themostcommondisease wasmucositisassociatedwithtoxicityfromthedrugsusedinthe immunosuppression.

Conclusion: Mucositis accounted for the increased score and potential risk of clinical complications.Gingivitis,ulcers,andpericoronitiswereotherchangesidentifiedaspotential riskfactorsforclinicalcomplications.

夽

Please citethisarticleas:Barrach RH,de SouzaMP, daSilvaDP, Lopez PS,MontovaniJC. Oralchangesinindividuals undergoing hematopoieticstemcelltransplantation.BrazJOtorhinolaryngol.2015;81:141---7.

∗_{Corresponding}_author.

E-mail:daniela-polo@uol.com.br(D.P.C.daSilva). http://dx.doi.org/10.1016/j.bjorl.2014.04.004

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PALAVRAS-CHAVE

Mucosite; Sistema hematopoético; Oncologia

Alterac¸õesoraisemindivíduossubmetidosàtransplantedecélulashematopoiéticas

Resumo

Introduc¸ão:Pacientes submetidos a transplante de células hematopoiéticas recebem altas doses de quimioterapia eradioterapia que podem causarimunossupressão e doenc¸as orais graves.

Objetivo:Apresentarumprotocolodeavaliac¸ãodedoenc¸asoraisanteseapóstransplantede célulashematopoiéticas.

Método: Estudoclínicoprospectivode65pacientescomidadeacimade18anos,comdoenças hematológicassubmetidas atransplantede células hematopoiéticas,divididos em dois gru-pos:A(transplantealogênico,34pacientes)eB(transplanteautólogo).Foramrealizadastrês avaliaçõesodontológicas:períodoantesdotransplante(momento1),umasemana(momento 2)e100diasapósotransplante(momento3).Em cadamomentoasalteraçõesoraisforam pontuadaseclassificadascomoleve,moderadaegrave.

Resultados: Asalterac¸ões orais mais frequentes foram: gengivite, pericoronite do terceiro molareúlceras.Entretantonosmomentosdoisetrêsaprincipaldoenc¸afoiamucositeassociada atoxicidadesdasdrogasusadasnaimunossupressão.

Conclusão:Mucositefoiprincipalalteração,comapontuaçãomaisaltaecommaiorriscode complicações.Gengivites,úlcerasepericoronitesforamoutrasalteraçõescomriscomenorde complicações.

Introduction

Hematopoietic stem cell transplantation (HSCT) is the replacement of a diseased or deficient bone marrow by normal cells, with the aim of reconstituting the marrow and providing immune system control. It is classified as autologouswhen bone marrow precursor cells come from thepatient,andasallogeneic, when thecells come from anotherperson(donor),whomayormaynotberelatedto therecipient.1,2

Patientswho will undergoHSCT are submitted tohigh dosesofchemotherapyandradiationtherapytoeradicate theunderlyingdisease,whichinducesanintense immuno-suppressionperiod knownasthe conditioning phase. This periodischaracterizedbypossibletissuedamageand infec-tionsduetoimmunosuppressivedrugtoxicity.3---5

Mucositisis oneofthemostcommonoraltissuelesions describedin theseimmunosuppressed patients,caused by thetoxicityofthesedrugs;itresultsinafragilityoftheoral mucosawithdecreasednumbersofbasalcells,andeventhe onsetofulcerations.6---8_It_is_considered_the_most_important oralcavitycomplicationinpatientsundergoingbonemarrow suppression,andisalsothemostcommon,withanincidence of90%.9,10_Kolbinson_et_al.11_described_early_changes_in_the oral mucosa such as erythema, ulceration, and epithelial pseudomembraneformation thatappearbetween fiveand sevendays after theonset of chemotherapy andimprove afterthreeweeks.

Theselesionsrepresentasignificant riskfactorfor sys-temicinfections,particularlyinpatientswithneutropenia, and20---50% ofcasesofsepticemiaoriginatefromtheoral cavity.12---14 _For_Puyal _et _al.,10 _Köstler _et _al.,15 _and Yama-gataetal.,16 _the_rates_of_occurrence_of_oral_lesions_varied,

dependingonthetypeofunderlyingdisease,thetreatment usedandoralstatusbeforeconditioningfortransplantation, andreflectedmainlypre-existingoralconditions.

Lesions such as root fragments, periodontal pockets, periapicallesions,andremovabledenturesareconsidered reservoirsofopportunisticpathogensthatcantrigger infec-tionsduringimmunosuppression.9,17---19

Thesereports indicate that theprevention of oral dis-ease prior to HSCT is extremely important and that oral diseases shouldbetreatedbeforetransplantationto elim-inate potential risk factors for systemic infections.7,20---22 Dreizen et al.22 _reported _that _30---50% _of _patients under-going chemotherapy for oncologictreatment develop oral alterationsorlesions,andthatincidencecanbesignificantly reducedbypriororalintervention.However,wefoundfew studiesintheliterature,exceptthoseformucositis,which attemptedtoquantifyoralalterationsthatoccurinpatients undergoingbonemarrowtransplantation.Whentheauthors, appliedascoretothecondition,theyeliminatedthe subjec-tivenatureofthepotentialofthesealterationsforclinical complications.3,7,8,23---30 _Thus,_the_objective_of_this_research wastodevelopastandardizedmethodforthequantitative evaluationofalterationsorlesionsoftheoralcavity,andto identifythepotentialforclinicalcomplicationsinpatients submittedtoHSCT.

Methods

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bothgenders,withorwithouthematologicalmalignancies, whounderwentHSCTandimmunosuppressioninthe above-mentioned period were included. Patients were grouped according to the type of HSCT: group A (allogeneic), 34 patients; and group B (autologous), 31 patients. Initially, allansweredaquestionnaire,whichcontainedinformation onoral health andoral hygienehabits. Subsequently, the patientswereevaluatedaccordingtothestatusoftheoral cavityat20days,onaverage,beforeconditioningandHSCT (moment1).Thesecond evaluationwascarriedoutinthe first week aftertransplantation (moment 2),and the last evaluation100daysafterHSCT(moment3).

Attheevaluationmoments(1,2,and3)scoresweregiven tothedifferentalterationsfoundintheoralcavity, accord-ingto theproposed dentalstandardization (Table 1).The score giventothe oral alterations wasbased onprevious work,whichgavegreaterorlesserdegreeofimportanceto thehistopathologicalalterationsoftheoralcavity.3,7---10,14,24 Theriskclassificationanddegreesoftoxicitywerebasedon theworkofPorak,14 _Dreizen_et_al.,22_and_Parulekan_et_al.24 Inmoment1,patientswereclassifiedaccordingtotherisk forcomplications:mild(upto15points),moderate(16---30 points),andsevere(31---50points)risk.Inmoments2and3, thedegreesoftoxicitywereclassifiedasfollows:mild (15 points),moderate(16---30points),andsevere(31---50points;

Table1).

Evaluationresultswerecomparedamongthemselvesand between groups. For the variables gender, age, disease, drugsfor conditioning,cell source,andtypeof transplan-tation,thechi-squaredorFisher’sexacttestwereusedfor comparisonofthegroups. Forthevariablesdentalcaries, gingival pockets, tooth mobility, tooth extractions, den-tures, orthodontic devices, oral lesions, bacterial, viral, fungal infections, and mucositis, the Mann---Whitney test was used. Comparison between groups at each evalua-tionwasperformed usingFriedman’s test andcomparison of moments within each group was performed using Fisher’s test. The level of significance was set at 5% (p<0.05).

Results

Aftertheassessmentoforalalterations,theclassificationof risksandtoxicityofpatientswasperformedbysummationof thescores(Tables2---4).Inthefirstassessment,before con-ditioning,most patients receivedamild risk classification inbothgroups.Theonlypatientclassifiedashaving moder-ateriskhadgingivalpockets>6mmandtoothmobility;that patient’sscorewas>16(Table5).

Inthesecondevaluation,ofthe34assessedpatientsin groupA,18hadmildtoxicity,15moderate,andonepatient hadseveretoxicity.IngroupB,ofthe31patientsassessed, 19 had mild toxicity, 11 moderate, and one patient had severe toxicity (Table 6). As it can be observed, the risk and toxicityclassification in both groups were performed according to the presence of mucositis and its degree of severity.

Inthethirdevaluation,asaresultofdeaths,28patients wereassessedingroupAand30patientsingroupB.Allbut onepatient hadmild toxicityin thisassessment, and one patientpersistedwithseveretoxicity(Table7).

Table1 Datastandardizationformwithscoresrelatedto changesintheoralcavity.

Caries:

Nocaries:()

Presenceof1---5decayedteeth:1point() Presenceof5---10decayedteeth:2points() Presenceof10---15decayedteeth:3points() Presenceofmorethan15decayedteeth:4points()

Gingivalpockets:pointspertooth,maximumof15points:

Normal(absenceofbleedingatperiodontalprobing):() Gingivalpocketsof3---5mm:1point()

Gingivalpocketsof5---8mm:2points() Gingivalpockets>8mm:3points()

Toothmobility:Classificationofperiodontaldiseasesand conditions,Armitage,1999:pointspertooth,maximum of15points:

Notoothmobility:()

Mild(1---2mmofclinicalattachmentloss):1point() Moderate(3---4mmofclinicalattachmentloss):2points() Severe(>5mm):3points()

Exodontics:pointspertooth,maximumof10points: Absenceofteethwithextractionindication:() Radicularremains:1point()

Semi-impacted/impactedthirdmolar,withhistoryof pericoronitis:1point()

Prostheses: Noprostheses:() Fulldentures:1point()

Removablepartialdentures:1point() Permanentdentures:1point() Denturesonimplants:1point()

Orthodonticappliances: Noorthodonticappliances:()

Presenceoforthodonticappliances:1point()

Orallesions:pointsperorallesion,maximumof10points. Noorallesions:()

Presenceoforallesions:1point()

Mucositis:WHOclassification: Nomucositis:()

MucositisgradeI:5points() MucositisgradeII:10points() MucositisgradeIII:15points() MucositisgradeIV:20points()

Infections: Noinfections:()

Presenceofbacterialinfection:10points() Presenceofviralinfection:10points() Presenceoffungalinfection:10points()

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Table2 DistributionoforalabnormalitiesobservedinsubjectsfromgroupA. Oralalterations Moment1

n=34

Moment2

n=34

Moment3

n=28 Toothcaries n=19(59.4%) n=19(59.4%) n=18(66.7%) Gingivalpockets n=8(25.0%) n=8(25.8%) n=7(25.9%) Mobility n=5(15.6%) n=6(18.8%) n=5(18.5%) Toothloss n=10(31.2%) n=9(28.1) n=8(29.6%) Prostheses n=14(41.2%) n=14(41.2%) n=10(35.7%)

Orthodontics 0 0 0

Orallesions n=8(23.5%) n=16(47.1%) n=7(53.6%) Infections --- --- n=2(7.2%) Mucositis 0 n=34(100%) 0

Table3 DistributionoforalabnormalitiesobservedinsubjectsfromgroupB. Oralalterations Moment1

n=31

Moment2

n=31

Moment3

n=30 Toothcaries 8(26.7%) 8(26.7%) 7(24.1%) Gingivalpockets 8(26.6%) 8(26.6%) 8(27.6) Mobility 9(30%) 9(30%) 9(31.0%) Toothloss 9(30%) 9(30%) 8(27.6%) Prostheses 18(54.8%) 18(54.8%) 18(54.8%) Orthodontics 2(6.7%) 2(6.7%) 2(6.7%) Orallesions 5(16.1%) 7(22.6%) 5(16.7%)

Infections 0 0 0

Mucositis 0 31(100%) 0

Table 4 Patient distribution by group and grade of mucositis.

Gradeofmucositis Group

A B

n % n %

I 7 20.6 8 25.8 II 9 26.5 10 32.3 III 10 29.4 9 29.0 IV 8 23.5 4 12.9 Total 34 100.0 31 100.0

Table5 Distributionofpatientsbytransplantationgroup andriskatmoment1,p=0.34.

Riskatmoment1

Mild Moderate Total Group n % n % n % A 33 97.1 1 2.9 34 100.0 B 31 100.0 --- 0.0 31 100.0 Total 64 98.5 1 1.5 65 100.0

Table6 Distributionofpatientsbytransplantationgroup andtoxicityatmoment2.

Gradesoftoxicityatmoment2

Group Mild Moderate Severe

n % n % n %

A 18 52.9 15 44.2 1 2.9 B 19 61.3 11 35.5 1 3.2

2=0.50;p=0.78.

Table 7 Distributionofpatients according togroup and toxicityatmoment3.

Gradesoftoxicityatmoment3

Group Mild Moderate Severe

n % n % n %

A 27 96.4 --- 0.0 1 3.6 B 30 100.0 --- 0.0 --- 0.0

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over time within group A (p=0.039). However, a statisti-cally significant difference wasobserved when comparing moment2ofgroupsAversusB,asmucositiswasobserved in 100% of individuals in both groups at these moments (Tables2and3).

Discussion

HSCTisawidelyusedtherapeutictechnique,aimingtocure oncologic patients and to provide disease control.1 How-ever, conditioning with chemotherapy drugs can resultin severaloralandsystemicalterationsinimmunosuppressed patients.3---6_These_{manifestations}_can_increase_the_length_of hospitalstay,increasetreatmentcosts,anddirectlyaffect thequalityandquantityoflifeofthesepatients.25

IntheautologousHSCT,comorbiditiesoccurmostoften due to the underlying disease activity, whereas in allo-geneicHSCT,theyareduetosystemiccomplicationsandthe graftversushostreactionitself.1,2,17,30_The_intense immuno-suppression predisposes transplanted patients to severe infectionsthatcanoccuratanytimeoftransplantation,can becausedbydifferentetiologicalagentssuchasbacteria, fungi,viruses,orparasites.13,21

Establishing risk factors by assessing the status of the oral cavity and systemic complications of HSCT, and by assigningscorestothealterationsatdifferenttimesofthe clinicalfollow-up ofpatientssubmittedto immunoexpres-sion might facilitate the identification of individuals who would potentially have more clinical complications.8,16 _A quantitative analysis using scores eliminates the subjec-tivenatureoftheobservations.24_In_the_present _study,_the developmentand utilization of scores for oral alterations were based on previous studies that sought toassociate, through scores or degrees of intensity, what changes or oraldiseasesassociatedwithtransplantationwould,in the-ory, have greater potential to be associated withclinical complications.14,16,19,22,24

Thecreationoftablesanddentalrecordswasmadebased onthefollowingvariables:dentalcaries, gingivalpockets, toothmobility,rootfragments,toothextractionindication, useofdentures,orthodonticdevices,andorallesions.

Alterations also included the specific complications of HSCT,suchastheoccurrenceofbacterial,fungalandviral infections,aswellasthedegreeofmucositis.8,14,22

Withrespecttodentalcaries,thepresentdataandthose intheliteratureshowednosignificantincreaseinnewdental caries in patients in the post-transplantation period and, astheyarenotrelevanttoHSCTcomplications,theyhave minimalscore.

The gingivalstatus andtoothmobility havea potential riskfactorforcomplications,especiallyperiodontalpockets greater than 6mm.26,27 _Gingival _pockets _of_this _size _favor greater accumulationof bacteriaand necrotictissue,and increase the risks for dental and oral disease; therefore, theyreceivedscoresofupto15,withintermediatevalues betweendentalcariesandmucositis.

Inbothgroupsofthepresentstudy,onlyonepatienthad largergingivalpockets,rangingfrom5mmto8mm,andwas classifiedatmoment1asmoderateriskandatmoments2 and3asseveretoxicity,duetothepresenceofdeepgingival pockets.

Anothercommon observation, in approximately80% of thepatients,wasgingivalhyperemia,probablyduetotoxic reactionstodrugsusedduringconditioning.Anotherlikely causeisoralmucosasensitizationduetoantiseptic mouth-wash(chlorhexidine)usedinoralhygiene. Patientsdonot brushtheirteethforfearthattraumacausedbythebrush cancausebleeding,duetothrombocytopenia.

However,the lackofbrushingcanresultinan increase inbacterialplaque,causinggingivitis, suchasthatseenin individualsatmoment2inbothgroups,withaconsequently greaterrisk ofbleeding. When thereisgingival inflamma-tion,plaquecan form morerapidly in thosesites than in non-inflamedonesandthus,mouthwashwouldbeless effec-tivefororalhygiene.However,inthepresentsample,these alterationswerebarelyobserved,whichwasattributedto moreeffectiveactionsbeforetransplantationbythe treat-inginstitution.1,2,10,16,17

Findings such as tooth extractions and semi-impacted thirdmolarswithahistoryofpericoronitisarementionedin theliteratureashavinglittlepotentialassourceof oppor-tunisticpathogensand,astheywereseldomobserved,they werenotscored.21---23

Semi-impacted third molars were observed in eight patientsfromgroupA andninefromgroupB.At moment 2,togetherwithmucositislesions,therewasformationof plaqueandgingivaoverlyingthetooth.Forthistypeof find-ing,andforprosthesesandorthodonticdevices,1pointwas scored.Shulmanetal.28 _reported_that_orthodontic_devices anddenturesareriskfactorsforstomatitis.

Evenwiththeknowledgeofthisreportofpossiblehealth risks for individuals wearing prostheses, it was not pos-sible to establish statistically significant data correlating them withoral alterations.29 _But _since _we _knew _that _the oralcavity isthe gatewayof infectionsin patients under-goingimmunosuppressionforbonemarrowtransplantation andthatthe useof orthodonticdevices anddenturescan potentiatethem,weaskedourpatientsnottowearthem, ifpossible.21_These_{recommendations}_were_made_before_the first evaluation, and were the reasons for the paucity of alterationsatmoment1.Althoughthatwasnotthepurpose ofthisstudy,wedemonstratedtheimportanceofprevention andtreatmentoforaldiseasestolessentheriskofclinical complicationsinimmunosuppressedindividuals.8,21_This_was alsotheopinionofSonisandKuns,23_who_showed_a_decrease inthesecomplicationswhensuchcarewasperformed.

Some non-infectious oral lesions, such as oral leuko-plakia, gingival hyperplasia, and others that are seldom describedbyotherauthors,alsoinfrequentlywereobserved bythepresentauthors.Orallesionssimilartohemorrhagic lesionsthatweredifficulttocharacterize,butdidnotevoke clinicalcomplaintswereobservedin17patientsfromgroup AandeightpatientsfromgroupBatmoment2,caused per-hapsbythrombocytopenia;thesewereresolvedinmoment 3.

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Inthepresentstudy,theincidenceofmucositiswas100% inthe second evaluation, at moment 2,for both groupA andgroupBpatients.Theriskassociationofmoment2and mucositiswassignificant.Bothgroupsshowedanassociation of the risk classificationand/or toxicity(mild, moderate, severe, andvery severe) with the onsetof mucositis and degreesofintensity.Mostpatientswereclassifiedashaving mildrisk,butthosewhodevelopedmucositiswereclassified ashavingmoderateorsevererisk.

Thesepatientsalsohadoral lesions,moreoftenonthe tongueandlabialmucosa,characterizedaserythemaofthe oral mucosa, lichen planus, generalized erosions, ulcera-tions,andxerostomia.30

Someauthorsreportedthatthisisduetoloworalfood intake,because of pain caused by these lesions.18,21,25 _In the present study, this observation wasmore evident, as 15patientsfromgroupBrequiredtheintroductionof par-enteral nutrition. In this group of patients, the authors observed dysphagia,anorexia, and rapid weightloss soon aftertransplantation,asearlyasmoment2ofthe evalua-tion.

Wedidnotobserveotherinfections,suchasthosecaused byanaerobicorganismsinourstudyprobablydueto preven-tive measures withoral fluconazoleand nystatin, aswell astheuse ofantisepticmouthwash,which areastandard procedureinallpatientsundergoingHSCT.10,14,15

Undoubtedly, the most feared complication of bone marrow transplantation is death, that occurs in 15---20% of allogeneic transplantations and in 5% of autologous transplantations.Is thisrelated tooral alterations? Death occurredinsevenofthepresentpatients,betweenmoments 2and3aftertransplantation. Oneof thedeathsoccurred ingroupB,frommultiple-organfailureandveno-occlusive disease.IngroupA, sixpatientsdied. Ofthese,fourdied duetodiseaserecurrence,one patientdieddue to pneu-moniaandrespiratoryfailure,andonepatientduetoacute host-versus-graftdiseaseandsepsis.Innoneofthemwere thecausesassociatedwithoraldisease.Althoughmucositis isthemain alterationresponsiblefor theincreasein clin-icalcomplications,especiallyinfectiousonesassociatedto conditioning toxicity,such lesions werenot seen in these patients at the time of death, perhaps due to the dra-matic moment experienced by patients and the medical staff.

Conclusion

We affirm that mucositis is the oral cavity alteration of greatest concern as a potential risk for complications in immunosuppressedpatients.Otherlesions,suchasgingivitis andthird-molarpericoronitis,consideredaslow-risk indica-torsin thisstudy were alsoless relevant.This alterations becamemoreevidentwhenthemild,moderateandsevere risk and toxicity scores were used to assess the clinical complicationsinimmunossupressedindividuals.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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