www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
ORIGINAL
ARTICLE
Evaluation
of
the
improvement
of
quality
of
life
with
Azithromycin
in
the
treatment
of
eosinophilic
nasal
polyposis
夽
,
夽夽
Isamara
Simas
de
Oliveira
a,∗,
Paulo
Fernando
Tormin
Borges
Crosara
b,
Geovanni
Dantas
Cassali
c,
Diego
Carlos
dos
Reis
d,
Camilo
Brandão
de
Resende
e,
Flavio
Barbosa
Nunes
b,
Roberto
Eustáquio
Santos
Guimarães
baDepartmentofSurgeryandOphthalmology,UniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil bDepartmentofOphthalmology,OtorhinolaryngologyandPhonoaudiology,UniversidadeFederaldeMinasGerais(UFMG),
BeloHorizonte,MG,Brazil
cDepartmentofGeneralPathology,UniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil dMedicineSchool,UniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil
eInstitutoTecnológicodeAeronáutica,UniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil
Received30January2015;accepted24March2015 Availableonline21September2015
KEYWORDS Eosinophilicnasal polyposis; Azithromycin; SNOT-22
Abstract
Introduction:TheSino-NasalOutcomeTest22(SNOT-22)isanimportanttoolinassessingthe qualityoflife(QoL)ofpatientswithchronicrhinosinusitiswithavalidatedversioninBrazil.The eosinophilicnasalpolyposis(ENP)representsmostofthecasesofnasalpolyposis(85---90%)and belongstothegroupofchronicrhinosinusitis.Itisachronicinflammatorydiseasethatimpacts theQoLofpatients,notonlycausinglocalizedsymptoms,butalsoresultinginageneralmalaise. Thestandardtreatments(corticosteroidsandnasalendoscopicsurgery)leadtopartialcontrol ofsymptoms,butrelapsesarefrequent.Macrolideactingasanimmunomodulatorisapromising toolformoreeffectivecontrolofthisdisease.Studiesarestilllackingtoassesstherealimpact ontheQoLinpatientstreatedwithmacrolides.
Objective:ToevaluatetheimprovementofQL,evaluatedusingSNOT-22,inpatientswithPNSE treatedwithimmunomodulatorydoseazithromycin.
夽 Pleasecitethisarticleas:OliveiraIS,CrosaraPFTB,CassaliGD,ReisDC,ResendeC,NunesFB,etal.Evaluationoftheimprovementof
qualityoflifewithAzithromycininthetreatmentofeosinophilicnasalpolyposis.BrazJOtorhinolaryngol.2016;82:198---202.
夽夽Institution:HospitalSãoGeraldo,HospitaldasClínicasAnnex,UniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil.
∗Correspondingauthor.
E-mail:simasmed@gmail.com(I.S.deOliveira). http://dx.doi.org/10.1016/j.bjorl.2015.03.018
Methods:ThisisapairedexperimentalstudyinpatientswithENP.Comparisonofpre-treatment andpost-treatmentwithazithromycinwasperformed.PatientscompletedtheSNOT-22 ques-tionnaire before the start of treatment and returned for evaluation after eight weeks of treatment.Azithromycinwasprescribedatadoseof500mg,orally,threetimesaweek,for8 weeks.
Results:SNOT-22scoredecreased20.3pointsonaverage.Therewasasignificantdecreasein theSNOT-22(differencegreaterthan14points)in19patients(57.6%).Therewasnosignificant differenceinimprovementinSNOTinsubgroupswithorwithoutasthma/aspirinintolerance. Conclusion: AzithromycinresultedinsignificantimprovementofQoL,assessedbySNOT-22,in thestudiedpopulation.
© 2015 Associac¸ão Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
PALAVRAS-CHAVE Poliposenasal eosinofílica; Azitromicina; SNOT-22
Avaliac¸ãodamelhoradaqualidadedevidacomousodeAzitromicinanotratamento
dapoliposenasossinusaleosinofílica
Resumo
Introduc¸ão: OSino-NasalOutcomeTest22(SNOT-22)estáentreosprincipaisinstrumentosna avaliac¸ãodaqualidadedevidadospacientescomrinossinusitecrônica,comversãovalidadano Brasil.Apoliposenasossinusaleosinofílica(PNSE)representaamaioriadoscasosdepolipose nasossinusal(85%a90%)epertenceaograndegrupodasrinossinusitescrônicas.Éumadoenc¸a inflamatóriacrônicaqueimpactasobremaneiraaqualidadedevida(QV)dospacientes,nãosó pelossintomaslocais,mastambémporresultarememumquadrodemal-estargeral.Os trata-mentospadronizados(corticosteroidesecirurgiaendoscópicanasal)levamaocontroleparcial dossintomaseasrecidivassãofrequentes.Osmacrolídeosusadoscomoimunomoduladoressão umapromissoraferramentaparaumcontrolemaiseficazdessadoenc¸a.Aindafaltamestudos paraavaliarorealimpactonaQVdospacientestratadoscommacrolídeos.
Objetivo: AvaliaramelhoradaQVdopacienteportadordePNSEtratadocomazitromicinaem doseimunomoduladorabaseando-sequestionárioSNOT-22.
Método: Trata-sedeestudoexperimentalautopareadoempacientescomPNSE.Foirealizada acomparac¸ãodospacientespré-tratamentoepós-tratamentocomazitromicina.Ospacientes preencheramoquestionárioSNOT-22antesdoiníciodotratamentoenoretornoapósasoito semanas de tratamento. Foi prescritaazitromicina nadose de500 mg,VO, três vezes por semana,durante8semanas.
Resultados: Ovalor doíndice SNOT-22dospacientesreduziu20,3pontos,em média.Houve diminuic¸ãosignificativadoSNOT-22(diferenc¸amaiorque14pontos)em19pacientes(57,6%). Não houve uma diferenc¸a significativa na melhora do SNOT nos subgrupos com ou sem asma/intolerânciaàaspirina.
Conclusão:AazitromicinaresultouemmelhorasignificativadaQV,avaliadapeloquestionário SNOT-22,napopulac¸ãoestudada.
© 2015 Associac¸ão Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Publicado por Elsevier Editora Ltda. Este é um artigo Open Access sob a licença de CC BY (http://creativecommons.org/licenses/by/4.0/).
Introduction
Quality of life (QoL) is a very important consideration in assessingtheseverityofnasaldisease,clinicaleffectiveness oftreatmentsusedandqualityof careofthesepatients.1
QuestionnairesforQoLhavebeen frequentlyusedin clini-caltrialstodeterminetheimpactcausedbyanintervention in certain diseases, or to evaluate the results of health services.2
TheSino-NasalOutcomeTest22(SNOT-22)isoneofthe maininstrumentsinassessingQoLofpatientswithchronic
rhinosinusitis,withaBrazilian-validatedversion.2Itisa
spe-cificquestionnaireforQoLanalysisinnasosinusaldiseases. Withthistool,evaluationsofnasal,paranasal,psychological andsleep-relatedsymptomsarecarriedout.1
Eosinophilic nasal polyposis (ENP), is found in approx-imately 85---90% all cases of sinonasal polyposis.3---5 This
ENPistheendresultofachronicinflammationofnasal mucosa and paranasal sinuses that greatly impacts QoL of patients,not only by localsymptoms (headache, nasal congestionandchronicsecretion),butalsobyresultingina poorgeneralstatus.7,8
Currently,corticosteroidsareconsideredthemain thera-peuticoptionforENP.9However,thehighratesofrecurrence
ofthe disease, low responsemaintenance, persistenceof symptomsandside effectsof systemiccorticosteroids are themainchallengestoitstreatment.7,10,11Sinusendoscopic
surgeryisreserved forcases ofclinical treatment failure, but even in experienced hands this technique may have recurrenceratesranging from35to50% ofcases.7,12---14 In
clinicalpractice,mostpatientsneedbothtreatments with-out, however, achieving satisfactory results in controlling thesymptoms.15
Thesearchforothertherapeuticoptionsledtothestudy ofdrugsthatcanacttocontroltheinflammatoryprocess, minimizing those so-feared side effects from chronic use of corticosteroids, in additionto maintaininga prolonged therapeutic response. In this context, macrolides stand out.
Azithromycin is a member of the cyclic-structure macrolide class with 15 elements.16 It is the only agent,
amongmacrolides, which does not inhibit the activity of cytochromeP450(involvedinthemetabolismofmanydrugs andincholesterolandsteroidsynthesis).17Azithromycinis
awell-toleratedagentand,accordingtotheEuropean Posi-tion Paper on Rhinosinusitis and Nasal Polyps 2012,18 the
long-term safety of treatment withmacrolides in chronic rhinosinusitisisalreadyestablished.
TheaimofthisstudywastoassessimprovementofQoLin patientswithENPtreatedwithanimmunomodulatorydose ofazithromycinbasedontheapplicationofSNOT-22.
Methods
This study was submitted and approved by the Ethics Committee(opinion approval no. 234,835). Patientswere informed about the study and its objectives and were requested, after assisted reading and orientation,to sign apost-informedconsentform.
The sample consistedof patientswithENP aged18---60 yearsandreferred bythe Brazilian UnifiedHealthSystem (SUS)toperformsurgicaltreatmentintheinstitution.Such patients,withanestablishedclinical,endoscopicand radio-logicaldiagnosisofPNS,hadbeentreatedbyanoptimized standarddrugtherapywithnoappropriateresponse.
The sample size required for the study was estimated using a significance level of 5% (˛=0.05) and statistical powerof 80% (ˇ=0.2). To detect adifferenceof 14 units intheevaluationwithSNOT-22questionnaireandassuming thatthestandarddeviationoftheresultsofthisassessment is <28 (/ε=2), the sample size required is 32, based on the formula n=(2[z (˛/2)+z(ˇ)])*(/ε)2. Similar studies
involved20patients.19,20
Inthescreeningprocedure,thepatientsunderwentafull ENTclinicalexamwithspecialattentiontothenasalarea. Thenasalcavity wasexploredvia anteriorrhinoscopyand nasofibriolaryngoscopy.PNSwasstaged accordingtoSousa etal.21A3.2-mmdiameterflexiblenasofibroscopeMACHIDA
ENTIIIPTMwasused.Allpatientsunderwentbiopsyofnasal
polypstoconfirmadiagnosisofeosinophilia.
Patientswhometthefollowingcriteriawereselected.
Inclusion criteria: Patients witheosinophilic nasal poly-posiswitheosinophilpercentage≥20% andwho,at their clinicalandendoscopicexamination,showednoevidence ofactivenasalinfection(e.g.,purulentdischargeinnasal cavity).
Exclusion criteria: Patients with non-eosinophilic poly-posis such as cystic fibrosis, Kartagener syndrome, antrochoanalpolypsand/oreosinophilicnasalpolyposisin thepresenceofinfection;patientswhousedoralorinhaled corticoidsorantihistaminesorbronchodilatorsinaperiod of30daysprecedingthebeginningofthestudyoratany time during the study period; patients with established cardiovascularand/or liverdisease andpatients withan abnormalelectrocardiogram(e.g.,QTprolongation).
Generaldesignofthestudy
This is a self-paired experimental study in patients with ENP.Aspecific questionnairewasappliedbeforeandafter treatment with azithromycin, with the aim to compare assessmentsofQoL.
Furthertestsfor preparationof the surgicalprocedure wererequested:glutamicoxaloacetictransaminase(GOT), glutamic pyruvic transaminase (SGPT) and alkaline phos-phatase(AP).
Then,AZITM(500-mgcoatedtabletsofazithromycin
dihy-drate,RegMS:No.1.3569.0011,EMSS/A,Hortolandia,SP),1 tablet(500mg)PO3×/week(Mondays,Wednesdaysand Fri-days)foreightweekswasprescribed.Intheninthweek,the patientreturnedtotheclinicforfurtherclinicalevaluation andforcompletinganewSNOT-22questionnaire.
Variableanalyzed
SNOT-22wastranslatedandadaptedtothePortuguese lan-guage in2011.2 It consistsof22 questions/symptomsthat
thepatientcansortfromzero(noproblem)tofive(worst problempossible). Thepatientwasadvisedtoanswer the questions basedonhis/hersymptoms in thetwoprevious weeks. The sum of the values can range from 0 to 110 pointsand,thehigherthisvalue,themoresymptomaticthe patient.
Withthehelpofaresearcher,theparticipantscompleted theSNOT-22questionnairebeforestatingthetreatmentand ontheirreturnaftereightweeksoftherapy.
Statisticalanalysis
Pairedttestwasusedtocomparepre-andpost-treatment means.The confidenceintervalsfor thepercentageswere obtainedbytheClopper---Pearsonmethod.Thefrequencyof binaryvariablesindifferentsubgroupswascomparedusing thechi-squaredtest.
Table1 Post-treatmentresultsofSNOT-22.
Group n MeanreductionofSNOT-22 Significantreduction(>14) CI95%(Clopper---Pearson)
Chosesurgery 11 13.6 4(36.4%) 16.9---69.3%
Didnotchoosesurgery 22 23.7 15(68.2%) 49.8---86.1%
Total 33 20.3 19(57.6%) 42.2---74.5%
Non-significantdifference(p=0.17)betweenpercentagesofgroupsthatchose/didnotchoosesurgery.
significancelevelof5%anda95%confidenceinterval.Data were entered into the database developed on Microsoft ExcelTM.
Results
Thirty-three patients completed the study. The patients’ agesrangedfrom18to69years,withameanof48.84years, with 21 women (63.6%) and 12 men. Seventeen patients (51.5%) had asthma and/or aspirin intolerance. Only one female patient reported side effects (heartburn/burning) duringtheuseofmedication;however,therewasnoneed todiscontinuetreatment.
At the end of the study, 22 patients reported good symptomcontrol,andchosenottoundergosurgical treat-ment.Thesepatientswerekeptinclinicalfollow-up.Eleven patients chose to undergo a surgical procedure, because theydid notfeel fullysatisfied withtheir post-treatment results.
The normalthresholdfortheBrazilianversionof SNOT-22is10points,andavariation>14pointsbetweenSNOT-22 scores of the same patient is considered as significant.2
Thus, in the present study, we had one pre-treatment patientand4post-treatmentpatientswithanormal SNOT-22 score. Only two patients showed a worse result in SNOT-22 (increases of 1 and 4 points, values considered not significant according to the literature). The SNOT-22 scoreof all patientsdecreased by amean of20.3 points. Nineteen patients (57.6%)showeda reduction>14 points, consideredassignificant(p<0.01).Itisestimatedthat,in general,42---74%ofpatientsshowimprovementintheir post-treatment SNOT-22evaluation.Table 1listsan analysisof theresultsofSNOT-22.
Theresponsetothetreatmentwasdifferentinsubgroups with/without asthma or aspirin intolerance. A significant differencein reductionof SNOT-22score between groups withor withoutasthma/aspirinintolerancewasnotfound (Table2).
Table2 Subgroupanalysiswith/withoutasthmaoraspirin intolerance.
Criterion Asthma/aspirinintolerance
Yes(17) No(16) p-Value
SNOT-22reduction>14 8(47.1%) 11(68.8%) 0.364
Discussion
The descriptionof QoL is seen asan unique andpersonal experience,which reflectsnot onlythehealth status,but alsootherfactorsandcircumstancesofthepatient’slife.2
Accordingtothisdefinition,thecomparisonbetweenvalues ofSNOT-22 shouldnot be performed amongpatients, but onecancomparethechange thatoccursbeforeandafter anyinterventioninagivenpatient.
Inpatients analyzed inthe presentstudy,we observed a significant improvement in QoL assessed by SNOT-22 aftertreatmentwithazithromycinfor2months(8weeks). These findings corroborate previous studies,21---24 but for
the first time a study of a specific and well determined group wascarried out. No significant difference between groups with and without asthma/aspirin intolerance was noted.
Interestingly,theimprovementinSNOT-22scoresdidnot affectsignificantlythepatient’sdecision astowhetheror nottoundergosurgery,sincethedecreaseinthe question-nairescorewasnotsignificantlydifferent(p=0.17)forthose groupswhohavechosenordeclinedsurgery.
TheSNOT-22questionnairehastheadvantageof combin-ingspecificissuesofnasosinusaldiseasewithgeneralhealth issues, which can be evaluated separately or together, beforeoraftertreatment.2Inlinewiththeauthorsofthe
translation,culturaladaptationandvalidationofthe SNOT-22questionnaireintoPortuguese,wechoosetostandardize theformofapplication,performingthereadingofthe ques-tionnaireforourpatients,giventhedifficultiesofreading and textcomprehension by the population served by our service.
Clinical interpretability is the main challenge for researchersinterestedinmeasuringQoLquestionnaires,as thesetoolsdonotproduceintuitivelymeaningfuldata,thus makingitdifficulttointerprettheclinicalsignificanceofthe differencesamonggroupsofindividuals.2
InthelasteditionoftheEuropeanPositionPaperon Rhi-nosinusitisandNasalPolyps2012,18 studiesthatevaluated
theeffectofmacrolidesinnasosinusalpolyposisarecited. Amoderateeffectonreducingthe sizeof thepolyps was identified, and this effect has proved more longstanding thanthatachievedwiththeuseofsystemiccorticosteroids. However,thesestudiesalsofailedtoassessQoLandclinical benefitsforpatients.
ENPpatients,particularlythosewithasthmaandaspirin intolerance,presentadifficult-to-controldisease,requiring extensivesurgeryinmostcases.Furthermore,inmanycases thesepatientsaresubjectedtoseveraloperations through-outtheirlife.Intheauthors’opinion,anyadjuvantclinical treatmentthathelpscontrolsymptomsandimprovingQoL ofthesepatients,withoutcausingsignificantadditionalside effects,shouldbeconsidered.
Conclusion
Treatmentwithazithromycin500mg,3×/weekfor8weeks, inthe populationstudied showedsignificant improvement inQoL asassessedby theSNOT-22questionnaire, withno differenceinimprovementbetweengroupswithandwithout asthma/aspirinintolerance.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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