Factors associated with pain in individuals infected by human T-cell lymphotropic virus type 1 (HTLV-1)

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Factors

associated

with

pain

in

individuals

infected

by

human

T-cell

lymphotropic

virus

type

1

(HTLV-1)

Dislene

N.

dos

Santos

_,

_Kionna

_O.B.

_Santos

_,

_Alaí

_B.

_Paixão

_,

Rosana

Cristina

P.

de

Andrade

_,

_Davi

_T.

_Costa

_,

_Daniel

_L.

_S-Martin

_,

Katia

N.

Sá

_,

_Abrahão

_F.

_Baptista

a_{UniversidadeFederaldaBahia,ProgramadePós-graduac¸ãoemMedicinaeSaúde,Salvador,BA,Brazil} b_{UniversidadeFederaldaBahia,LaboratóriodeEletroestimulac¸ãoFuncional,Salvador,BA,Brazil}

c_{UniversidadeFederaldaBahia,HospitalProfessorEdgardSantos,Servic¸odeImunologia,Salvador,BA,Brazil} d_{UniversidadeEstadualdoSudoestedaBahia,VitoriadaConquista,BA,Brazil}

e_{UniversidadeFederaldaBahia,FaculdadedeMedicinadaBahia,Salvador,BA,Brazil} f_{EscolaBahianadeMedicinaeSaúdePública,Pósgraduac¸ãoepesquisa,Salvador,BA,Brazil}

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Articlehistory:

Received5May2016 Accepted22November2016 Availableonline21December2016

Keywords:

HumanT-celllymphotropicvirus typeI(HTLV-1)

Tropicalspasticparaparesis

Retroviridaeinfections Chronicpain

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Introduction:DespitethehighprevalenceofchronicpaininindividualsinfectedwithHTLV-1, predictiveandprotectivefactorsforitsdevelopmentarestillunclear.

Objective:ToidentifyfactorsassociatedwithchronicpaininindividualswithHTLV-1.

Methods:Thiscross-sectionalstudywasconductedinareferencecenterfortreatmentof patientsinfectedwithHTLV-1inSalvador,Bahia,Brazil.Thestudyincludedindividuals infectedwithHTLV-1,over18years,andexcludedthosewithdifficultytorespondthepain protocol.Dataonsociodemographic,healthbehavior,andclinicalcharacteristicswere col-lectedinastandardizedway.Theprevalenceratio(PR)ofpainisdescribed,aswellasthe factorsindependentlyassociatedwiththepresenceofpain,whichwereassessedbymultiple logisticregression.

Results:Atotalof142individualswereincludedinthestudy,mostlyfemale(62.7%),aged 20–64years(73.2%),married(61.3%),withlessthaneightyearsofeducation(54.2%),andwith asteadyincome(79.6%).MultivariateanalysisshowedthatbeingsymptomaticforHTLV-1– sensorymanifestations,erectiledysfunction,overactivebladder,and/orHAM/TSP(PR=1.21, 95%CI:1.05to1.38),self-medication(PR=1.29,95%CI:1.08–1.53),physiotherapy(PR=1.15, 95%CI:1.02–1.28),anddepression(PR=1.14,95%CI:1.01–1.29)wereassociatedwithan increased likelihoodofpresentingpain.Onthe other hand,physicalactivity(PR=0.79, 95%CI:0.67–0.93)andreligiouspractice(PR=0.83,95%CI:0.72–0.95)wereassociatedwitha decreasedlikelihoodofhavingpain.

∗ _{Correspondingauthor.}

E-mailaddress:afbaptista@ufba.br(A.F.Baptista).

http://dx.doi.org/10.1016/j.bjid.2016.11.008

1413-8670/©2016SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Conclusion: Theuseofself-medication,physiotherapyandthepresenceofdepressionare independentlyassociatedwithneurologicalsymptomsinHTLV-1infectedpatients. Reli-giouspracticeandphysicalactivityarebothprotectiveforthedevelopmentofpain.

©2016SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.Thisis anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Introduction

HumanT-celllymphotropicvirustype1(HTLV-1)isaretrovirus thatinfectsmillionsofpeoplethroughouttheworld.1,2 _This

virusisendemicintheCaribbean,WestandCentralAfrica, SouthAmerica,andJapan.3_{InBrazil,thenationalprevalence}

isunknown, but thereare differences among geographical regions.4,5 _{Salvador, the major city in the Northeastern of}

Brazil,hasaround1.76%ofits populationinfectedwiththe virusandisconsideredtohavethesecondhighestnumberof casesinthecountry.5,6

Clinical and neurological manifestations of the disease caused by HTLV-1 are multiple. The HTLV-1 associated myelopathy/tropicalspasticparaparesis(HAM/TSP)andAdult T-cell leukemia/lymphoma (ATL) are the worst clinical manifestations of this disease, affecting around 5.0% of infected patients.3,7 _Uveitis,8 _{poliomyositis, arthropathy,}9,10

sicca syndrome, urologic disturbances,10,11 _{and peripheral}

neuropathy12,13_{arealsodescribed.However,themajorityof}

infectedpeopleremainsasymptomaticanddonotpresentany clinicalmanifestations.

Painfulcomplaintsarepresentin84.3%ofsubjectswith HTLV-1 regardless of neurological signs and symptoms,14

underscoringtheneedforpreventiveactionsforpain manage-mentinthesepatients.Painiscorrelatedtoworseningofthe infectionand isprobablyassociatedwithincreased expres-sionofpro-inflammatorycytokines.15,16_{Whenmyelopathyis}

present,thepaintendstobechronic,17 _{reducingfunctional}

capacity,18,19 _{andincreasingthe likelihood ofpsychological}

symptoms.20_{Itisalsoassociatedwithanegativeimpacton}

qualityoflifeandindividualautonomy.19,21

Few studies to date have investigated pain symptoms ininfectedindividuals withoutmyelopathy.Therefore, it is importanttodeterminewhetherpaincouldbeconsidereda characteristicofHTLV-1infection.22 _{Abetterunderstanding}

ofthepainphenomenainpatientswithoutmyelopathycould informhealthpoliciesaimingtopreventthenegativeimpact ofpaininpatientswithHTLV-1.Thus,thisstudyaimedto iden-tifyfactorsassociatedtonociceptiveandneuropathicchronic paininpatientswithsymptomaticandasymptomaticHTLV-1.

Material

and

methods

Thiscrosssectionalstudywasconductedatareferencecenter forthetreatmentofpatientsinfectedwithHTLV-1,the Mag-alhãesNetoAmbulatorycareunit attheHospitalProfessor Edgard Santos in Salvador-BA, Northeast of Brazil. HTLV-1 seropositive patients are commonly referred from blood banks,clinicsandhospitalsintheregiontothiscenter.

Sampleselectionconsistedofinvitingdailythefirstthree individualsscheduledfortheneurologistappointment,which categorized the patientsaccordingto thecriteria described bellow.DatacollectionoccurredbetweenJuly2012andJanuary 2014.

Individuals diagnosedwith HTLV-1 byantibodies detec-tion using ELISA method (Cambridge Biotech, Worcester, MA)andconfirmedbytheWesternblottest(HTLVBlot2.4, Genelabs, Science Park Drive, Singapore) were included in the study. Individuals over 18 years old, with or without pain, were assessed by a neurologist using the neurologi-calscalesExtendedDisabilityStatusScale(EDSS)andOsame Motor Dysfunction Scale (OMDS).23,24 _{Patients were}

strati-fiedaccordingtocriteriaestablishedbyCastroCosta(2006)22

as“asymptomatic”(EDSS=0/Osame=0);“possibleor proba-ble HAM/TSP”(EDSS<2/Osame=0);and “definedHAM/TSP” (EDSS≥2/Osame>1).Individualswithdifficultiesto answer thepainevaluationprotocolwereexcluded.Thenumberof participantswasdefinedbyasamplesizecalculationpowered todetectadifferenceinpainprevalenceof80%between sub-jectswithandwithoutmyelopathy,withaconfidenceinterval of95%.14

Sociodemographicandclinicaldatawerecollectedthrough astandardizedformadministeredbyasingletrained exam-iner.Chronicpainwasdefinedascontinuousorrecurrentpain forsixmonthsormore.25_{TheHospitalAnxietyand}

Depres-sionScale(HADS)wasusedtosearchforsymptomssuggestive ofanxietyanddepression.26_{Painlocation,intensity,andtype}

(nociceptiveorneuropathic)werealsoregistered,butarenot presentedhere,astheirdiscussionisoutofthescopeofthis study.

Variablesofinterest

The dependent variable was chronic pain (dichotomous 0/1), while the independentvariables included sociodemo-graphic, clinical, and behavior characteristics, as well as comorbidities(rheumatologicdisease,hypertension,diabetes, sicklecellanemia,systemiclupuserythematosus,myasthenia gravis, polymyositis, osteoporosis, osteopenia, osteoarthri-tis, esophageal reflux, gastric ulcer, umbilical hernia, disc herniation,hemorrhoids,psoriasis,heartdisease,and occupa-tionaldiseases).Useofmedicationsforpainwasself-reported (taking medicines without prescription orreusing previous prescription)andalsoverifiedatthepatient’smedicalchart (listofmedicationsprescribedbyaphysician).Patientswere classified regardingthe neurologicalmanifestationsrelated toHTLV-1insymptomatic(sensory manifestations,erectile dysfunction,overactivebladder,and/orHAM/TSP)and asymp-tomaticpatients.

Data analysis was done in three steps. In the first descriptivestep,itwascalculatedthe absoluteand relative frequencies,centraltendencyanddispersionmeasuresofthe variables of interest. In the second step it was performed univariateanalysisusingtheprevalenceratioasameasure ofassociation and the respective95% confidence intervals (95% CI), considering p<0.05 as a parameter forstatistical significance.Toassess thesimultaneouseffectofvariables, it was conducted amultiple logistic regression analysis of exploratory nature (MLRA), seekingto assess the indepen-dentassociationofthedependentvariablewiththecovariates understudy.

ThebackwardMLRAwasconductedaccordingtothe pro-ceduresrecommendedbyHosmerandLemeshow,withthe pre-selectionofvariablesforinclusionintheanalysismade bythe likelihood ratio test, adopting ap-value ≤0.25.A

p-value<0.05wasadoptedtoobtain thefinalmodel.Inorder to adjustthe association measure, it was usedthe robust methodofPoissonforprevalenceratio(PR)estimates,to cor-rect the overestimation of OR and appropriate confidence intervals.27

TheEthicsCommitteefromHospitalUniversitário Profes-sorEdgardSantos,FederalUniversityofBahia/UFBA(Protocol 21/2011), approved this study. All participants signed an InformedConsentForm.

Table1–Demographicandhealthbehavior characteristicsofindividualswithHTLV-1.

Variable(N=142) Frequency n (%) Sex Female 89 62.7 Male 53 37.3 Age ≥65 38 26.8 <65 104 73.2 Maritalstatus Withoutapartner 55 38.7 Withapartner 87 61.3 Education ≤8yearsofschooling 77 54.2 >8yearsofschooling 65 45.8 Steadyincome No 29 20.4 Yes 113 79.6 Smoking Yes 13 09.2 No 129 90.8 Alcoholisma Yes 61 43.3 No 80 56.7 Physicalexercise Yes 59 41.5 No 83 58.5 Religiouspracticea Yes 84 60.0 No 56 40.0

HTLV-1,HumanT-celllymphotropicvirustype1. a _Missingdata.

Results

Ofthe160individuals withHTLV-1screenedforthisstudy, 18(11.25%)wereexcludedbecausetheyreportedpresenceof painforlessthan sixmonths,didnotfillalltheevaluation protocol,orrefusedtoparticipate.Oftheremaining142 par-ticipants,themajoritywasfemale(62.7%),aged20–64years (73.2%),andlivedwithapartner(61.3%).Regardingeducation andearnings,54.2%ofsubjectshadlessthaneightyearsof educationand79.6%hadsteadysalary,9.2%reporteduseof tobacco,43.3%hadregularalcoholconsumption,41.5% per-formedphysicalexerciseforthreeormoredaysaweek,and 59.2%admittedsomereligiouspractice(Table1).

The overall prevalence of chronic pain was 81.7%. Regardingtheclinicalcharacteristicsandlifestylebehaviors among participants, 54.2% were defined as asymptomatic HTLV-1 and 52.8% had at least one comorbidity. The majority had no anxiety or depression (75.4%) and had self-medication habit (61.5%) (Table 2). The comorbidi-ties potentially related to pain (listed in methods section) werepresentin51.7%.SymptomaticEDSS<2/Osame=0was observedin28.4%,EDSS≥2/Osame>1in23.3%,and asymp-tomatic EDSS=0/Osame=0 in 48.3%. Of the patients who complainedfrompain,only26.7%reportedphysiotherapy.

Painwasmoreprevalentamongwomen(85.4%)thanmen (75.5%),althoughthe differencewasnotstatistically signif-icant (p=0.10). Subjects symptomaticfor HTLV-1 (PR=1.26,

Table2–Clinicalandlifestylecharacteristicsofpatients withHTLV-1.

Variable(N=142) Frequency

n %

NeurologicalsymptomsofHTLV1

Symptomaticwith/withoutpain 56/09 40.6/07.7 Asymptomaticwith/withoutpain 60/17 37.1/14.6

Comorbidity Yes 75 52.8 No 67 47.2 Psychoaffectivesymptoms Anxiety Yes 49 34.5 No 93 65.5 Depression Yes 45 31.7 No 97 68.3

Anxietyanddepression

Yes 35 24.6 No 107 75.4 Paintreatment Physiotherapy Yes 33 23.2 No 109 76.8

Medicationwithpainaction

Yes 49 33.1

No 95 66.9

Self-medicationhabit

No 55 38.7

Yes 87 61.3

Table3–Prevalenceofchronicpainaccordingto socio-demographicvariablesofindividualswithHTLV-1.

Variable(N=116) n % PR 95%CI p Sex Female 76 85.4 1.13 0.94–1.34 0.10 Male 40 75.5 1.00 – Age ≥65years 31 81.6 1.00 0.83–1.19 0.90 <65years 85 81.7 1.00 – Maritalstatus Withoutapartner 47 79.3 1.07 0.92–1.25 0.30 Withapartner 69 85.5 1.00 Education ≤8studyyears 69 89.6 1.22 1.03–1.45 0.01a >8studyyears 47 72.3 1.00 – Steadyincome No 92 81.4 1.01 0.84–1.22 0.80 Yes 24 82.8 1.00 –

PR,Poissonforprevalenceratio;IC,confidenceintervals. HTLV-1,HumanT-celllymphotropicvirustype1. a _p<0.05.

95% CI: 1.08–1.48),with less than eightyears of education (PR=1.22,95%CI:1.03–1.45)anddoingphysiotherapyfor treat-ing pain (PR=1.20, 95% CI: 1.05–1.37) were more likely to presentchronicpain(Tables3and4).Chronicpainwasalso associatedwithlifestyleandclinicalcharacteristics(Table4). Patients that reported practice of weekly physical activity (PR=0.74,95%CI:0.61–0.89)werelesslikelytopresentchronic pain. Conversely, those who self-medicated (PR=1.29, 95% CI: 1.07–1.57), had symptoms of anxiety (PR=1.24, 95% CI 0.08–1.43),anddepression(PR=1.27,95%CI:1.11–1.44)were morelikelytopresentchronicpain.

In the MLRA analysis, the presence of neurological symptoms associated with HTLV-1 (being symptomatic), depression, self-medication, and physiotherapy remained independently associated withincreasedlikelihood of pre-sentingchronicpain. Individualsclassifiedas symptomatic were1.21timesmorelikelytopresentpainfulsymptomsthan asymptomaticHTLV-1patients(95%CI:1.05–1.38).Thosewho self-medicatedwere1.29timesmorelikelytoreportchronic painthanthosewhodidnothavethishabit(95%CI:1.08–1.53). Physicalactivity(95%CI:0.67–0.93)andreligiouspractice(95%

Table4–PrevalenceofchronicpainaccordingtolifestyleandclinicalconditionsofpatientswithHTLV-1.

Variable n % PR 95%CI p-Value Lifestyle Alcoholism Yes 49 80.3 0.95 0.81–1.12 0.599 No 67 83.8 – – Smoking Yes 10 76.9 0.92 0.68–1.26 0.597 No 106 82.8 – –

Physicalexercise(≥3days)

Yes 40 67.8 0.74 0.61–0.89 <0.001a No 76 91.6 – – Religiouspractice Yes 65 77.4 0.86 0.74–1.00 0.072 No 50 89.3 – – Self-medicationhabit Yes 78 89.7 1.29 1.07–1.57 0.002a No 38 69.1 – – Clinicalfeatures NeurologicalsymptomsinHTLV-1 Symptomatic 60 92.3 1.26 1.08–1.48 0.002a Asymptomatic 56 72.7 – – Comorbidity Yes 60 80.0 0.95 0.81–1.11 0.583 No 56 83.6 – – Paintreatment Physiotherapy Yes 31 93.9 1.20 1.05–1.37 0.038a No 85 78.0 – – Psychoaffectivesymptoms Anxiety Yes 46 93.9 1.24 1.08–1.43 0.006a No 70 75.3 – – Depression Yes 43 95.6 1.27 1.11–1.44 0.003a No 73 75.3 – –

PR,Poissonforprevalenceratio;IC,confidenceintervals. HTLV-1,HumanT-celllymphotropicvirustype1. a _p<0.05.

Table5–Prevalenceratios(PR)adjustedwiththeir respectiveconfidenceintervals(CI)of95%amongthe factorsassociatedwithchronicpain.

Variables PR CI(95%) NeurologicalsymptomsinHTLV-1 Symptomatic 1.21 1.05–1.38 Asymptomatic 1.00 – Depression Yes 1.14 1.01–1.29 No 1.00 – Self-medication Yes 1.29 1.08–1.53 No 1.00 – Physiotherapy Yes 1.15 1.02–1.28 No 1.00 – Physicalexercise Yes 0.79 0.67–0.93 No 1.00 – Religiouspractice Yes 0.83 0.72–0.95 No 1.00 –

HTLV-1,HumanT-celllymphotropicvirustype1.

CI:0.72–0.95) were factors associatedwith adecrease like-lihood of chronic pain. The physical activity reduced the likelihoodofchronicpainby21%,whilereportofareligious practicereduceditby17%(Table5).

Discussion

This study aimed to investigate factors associated with chronic pain in patients with HTLV-1, identifying their strengthofassociation.Themagnitudeoftheseassociations wasnotreportedinpreviousstudies,especiallyinpatients withHAM/TSP.14,21,28

Individualswithneurologicalsymptomsassociatedwith thevirus(symptomaticindividuals)weremorelikelytoreport pain. This group usually has a higher pro-viral load and increased cytokines expression that indicates an inflam-matory process.29,30 _{The inflammation mainly affects the}

thoracic spinal cord segment31 _{and leads to weakness in}

thelowerlimbs(paraparesis)accompaniedbyhyperreflexia and Babinski signal.7,10,12 _{The worsening of neurological}

symptoms cause muscle impairment, postural and joint instability18,21,32_{that arepotentialsourcesofpainand also}

leadtoadjacenttissueinjury,suchasjointcapsulesand liga-ments,musclesandperipheralnerves.Theinvolvementofthe posteriorcolumnofthespinalcord33_{interfereswith}

proprio-ceptionandvibratorysensationinthelowerlimbs,7,34_which

alsocontributestothisinjurycycle.

Depression increased the likelihood of chronic pain in patients withHTLV-1 in this study. Theoverall prevalence ofdepressive symptomswere 31.7%,and were foundtobe independentlyassociatedwithchronicpain.Apreviousstudy reported a frequency of moderate to severe depression in 59%HAM/TSPandin22%asymptomaticpatients.20

Psycho-affectiveproblemsareoftenassociatedwithotherdiseases. Moreover,inmostcases,itleadstoworseningoftheevolution

ofboththepsychiatricdisorderandthe diseaseitself,with highermorbidityandmortality.Thissymptomisoften under-diagnosedandhasirregular therapeuticassistance,notably thelackofdifferentialdiagnosisforchronicallyillpatients.35

Therelationshipbetweenself-medicationandchronicpain pointstoatypicalbehaviorofsubjectsaffectedbyprolonged exposure topain. The practiceis common among individ-ualswithchronicdiseases,elderlyandfemale,36,37 _common

characteristicsinthepopulationwithHTLV-1.Symptoms sug-gestiveofinfectionsuchasweakness,tiredness,andpainin lowerlimbs12_{maybeconcealedbyself-medication,delaying}

diagnosis ofthe diseaseand consultationwithaspecialist. Amongthe medications with indiscriminateuse, the most frequentwasanti-inflammatorydrugs,whichcanirritatethe gastricmucosaandleadtorenalinjury,38,39 _{conditionsthat}

should be better monitored in individuals infected by the virus.

Inthisstudy,individualswhoweremorelikelytohavepain were inphysiotherapy,whichhasasoneofitsmain objec-tivestheinhibitorymodulationofpainbyreducingperipheral and centralstimulithatsensitizethe nervoussystem.40 _As

cross-sectionalstudiesdonotestablishcausalrelationship,it isdifficulttoestablishwhetherthisassociationisduetothe demandfortreatmentofpainorphysiotherapyitselfcauses morepaininpatients.Thefewclinicaltrialsthattestedthe efficacyofphysiotherapyinpatientswithHTLV-1showedthat therapeuticexercisecanbeusefulinreducingpainintensity, andimprovingqualityoflife.41,42Forthisreason,our hypoth-esisisthatthestrengthofassociationfoundinthisstudyis relatedtoworsepainconditions.Theprofessionalsassisting patientswithpainusuallytrytocontrolitwithmedicationand rest,postponingindicationofphysiotherapyforlater,limiting theresourcesavailableforthetreatmentofpainfulsymptoms. Multidisciplinarycentersofassistanceforindividualsinfected withHTLV-1shouldreferpatientstophysiotherapyearlyon, evenbeforethecomplaintofpain.

Thepositiveimpactonpainofregularphysicalactivityin patients withHTLV-1 reinforcestheidea thatregular exer-cisehasnumerousbenefitsforpeople withchronicpain,43

althoughitsanalgesiceffectivenessisquestioned.43,44

Exer-cisinghasregulatoryactionintheendogenousmechanisms ofpaincontrolandmaybeusefulinreducinganxiety, depres-sion, and mentaldisabilities. It alsoimproves self-esteem, socialparticipation,intellectualandphysicalproductivity.43_It

islikelythatregularexerciseisoneofthebestwaystocontrol paininthiscondition.Cohortstudiescomparingthe evolu-tionofpainfulsymptomsinHTLV-1infectedactiveindividuals withthosewhoareinactivecanhelptestingthishypothesis.

Inthisstudy,admittingtohavefaithwasassociatedwith a lowerlikelihood ofchronicpain complaints.This finding indicates the important role of belief and attitude among chronicallyillpatients.Apositiveimpactofreligiosityinthe relearning process todeal witha new uncomfortable con-ditionoflifehasbeenreported.45 _{Thecreedhasapositive}

influenceonhealth, particularlyformentalhealththrough changesinlifestyleandsocialsupport.46 _{Religiouspractices}

ispositivelyassociatedwithpsychologicalwell-beingandlife satisfactionindicators.45_{Individualswithhighlevelsofstress}

orinfragilesituationssuchaselderly,peoplewithphysical disabilitiesandsevereclinicaldiseasearethemostbenefited

withreligiosity.46_{Studiesinchronicpatientsaboutspirituality}

andfaithshowtherelevanceofthisissueinthedoctor–patient relationshipandinchangingthelookonlifeandfightingthe disease.45,46

Themajorlimitationofthisstudyisthelackof compari-sonbetweenHTLV-1participantswithanuninfectedcontrol group. Longitudinal studies are recommended to establish causalrelationshipwithgreateraccuracy,incontrastto cross-sectional studies. The findings presented here add to the understanding of chronic pain in patients with HTLV-1 by describingthestrengthoftheassociationbetweenpain symp-tomsandclinical/demographicalfactors,whichmayhelpin futureresearchesandinclinicaldecisions.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgments

WewishtoacknowledgeDrEdgardeCarvalho,Coordinator oftheMultidisciplinaryHTLVAmbulatoryofProfessorEdgard SantosHospitalforallowingthisworktobeheldatthis facil-ity.ThisstudywasfundedbyNationalCouncilforScientific andTechnologicDevelopment(CNPq),andtheCoordination ofImprovementofHigherLevelPersonnel(CAPES).Wealso acknowledgeFernandaCostaQueirós,JanineRibeiroCamatti andIasmynAdéliaVictorFernandesdeOliveirafortheir valu-able contributionin assessingthe participants and forthe criticalreviewofthemanuscript.

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