Introduction HumanT-celllymphotropicvirustype1HTLV-1isaretrovirus thatinfectsmillionsofpeoplethroughouttheworld.1,2 This virusisendemicintheCaribbean,WestandCentralAfrica, SouthAmerica,a
Trang 1w 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
Dislene N dos Santosa,b,c, Kionna O.B Santosb, Alaí B Paixãob,
Q1
Rosana Cristina P de Andradec, Davi T Costac,e, Daniel L S-Martinb,f,
Katia N Sáb,d, Abrahão F Baptistaa,b,d, ∗
a r t i c l e i n f o
Received5May2016
Accepted22November2016
Availableonlinexxx
Keywords:
HumanT-celllymphotropicvirus
typeI(HTLV-1)
Tropicalspasticparaparesis
Chronicpain
a b s t r a c t
predictiveandprotectivefactorsforitsdevelopmentarestillunclear
patientsinfectedwithHTLV-1inSalvador,Bahia,Brazil.Thestudyincludedindividuals infectedwith HTLV-1,over18 years,and excludedthosewithdifficulty torespondthe painprotocol.Dataonsociodemographic,healthbehavior,andclinicalcharacteristicswere collectedinastandardizedway.Theprevalenceratio(PR)ofpainisdescribedandthe fac-torsindependentlyassociatedwiththepresenceofpainwereassessedbymultiplelogistic regression
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
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/)
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Trang 2independentlyassociatedwithneurologicalsymptomsinHTLV-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.3InBrazil,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
neuropathy12,13arealsodescribed.However,themajorityof
infectedpeopleremainasymptomaticanddonotpresentany
clinicalmanifestations
Painfulcomplaintsarepresentin84.3%ofsubjectswith
HTLV-1 regardless of neurological signs and symptoms,14
underscoringtheneedforpreventiveactionsforpain
manage-mentinthesepatients.Painiscorrelatedtoworseningofthe
infectionand isprobablyassociatedwithincreased
expres-sionofpro-inflammatorycytokines.15,16Whenmyelopathyis
present,thepaintendstobechronic,17 reducingfunctional
capacity,18,19 andincreasingthe likelihood ofpsychological
symptoms.20Itisalsoassociatedwithanegativeimpacton
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
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.25TheHospitalAnxietyand Depres-sionScale(HADS)wasusedtosearchforsymptomssuggestive
ofanxietyanddepression.26Painlocation,intensity,andtype (nociceptiveorneuropathic)werealsoregistered,butarenot presentedhere,astheirdiscussionisoutofthescopeofthis study
Variables of interest
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
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Trang 3Data 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
Table 1 – Demographic and health behavior
characteristics of individuals with HTLV-1.
Sex
Age
Marital status
Education
Steady income
Smoking
Alcoholisma
Physical exercise
Religious practicea
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
Pain was more prevalent among women (85.4%) than men (75.5%), although the difference was not statistically
Table 2 – Clinical and lifestyle characteristics of patients with HTLV-1.
Neurological symptoms of HTLV 1
Symptomaticwith/withoutpain 56/09 40.6/07.7 Asymptomaticwith/withoutpain 60/17 37.1/14.6
Comorbidity
Psychoaffective symptoms Anxiety
Depression
Anxiety and depression
Pain treatment Physiotherapy
Medication with pain action
Self-medication habit
HTLV-1:HumanT-celllymphotropicvirustype1
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Trang 4Table 3 – Prevalence of chronic pain according to
socio-demographic variables of individuals with HTLV-1.
Q2
Sex
Age
≥65years 31 81.6 1.00 0.83–1.19 0.90
Marital status
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 0.01
>8studyyears 47 72.3 1.00 –
Steady income
PR,Poissonforprevalenceratio;IC,confidenceintervals;ap<0.05
HTLV-1,HumanT-celllymphotropicvirustype1
(PR=1.26, 95% CI: 1.08–1.48),with less than eight years of education(PR=1.22,95%CI:1.03–1.45)anddoing physiother-apyfortreatingpain(PR=1.20,95%CI:1.05–1.37)weremore likelytopresentchronicpain(Tables3and4 Chronicpain wasalsoassociatedwithlifestyleandclinicalcharacteristics (Table4 Patientsthat reportedpracticeofweeklyphysical activity(PR=0.74,95%CI:0.61–0.89)werelesslikelytopresent chronicpain.Conversely,thosewhoself-medicated(PR=1.29, 95%CI:1.07–1.57),hadsymptomsofanxiety(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)
Table 4 – Prevalence of chronic pain according to lifestyle and clinical conditions of patients with HTLV-1.
Lifestyle
Alcoholism
Smoking
Physicalexercise(≥3days)
Religious practice
Self-medication habit
Clinical features
Neurological symptoms in HTLV-1
Comorbidity
Pain treatment
Physiotherapy
Psychoaffective symptoms
Anxiety
Depression
PR,Poissonforprevalenceratio;IC,confidenceintervals
HTLV-1,HumanT-celllymphotropicvirustype1
a p<0.05
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Trang 5Table 5 – Prevalence ratios (PR) adjusted with their
respective confidence intervals (CI) of 95% among the
factors associated with chronic pain.
Neurological symptoms in HTLV-1
Depression
Self-medication
Physiotherapy
Physical exercise
Religious practice
HTLV-1,HumanT-celllymphotropicvirustype1
Physicalactivity(95%CI:0.67–0.93)andreligiouspractice(95%
CI:0.72–0.95) were factors associatedwith adecrease
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
instability18,21,32that arepotentialsourcesofpainand also
leadtoadjacenttissueinjury,suchasjointcapsulesand
liga-ments,musclesandperipheralnerves.Theinvolvementofthe
posteriorcolumnofthespinalcord33interfereswith
proprio-ceptionandvibratorysensationinthelowerlimbs,7,34which
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 lowerlimbs12maybeconcealedbyself-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.43It
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.45Individualswithhighlevelsofstress
orinfragilesituationssuchaselderly,peoplewithphysical
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Trang 6disabilitiesandsevereclinicaldiseasearethemostbenefited
withreligiosity.46Studiesinchronicpatientsaboutspirituality
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
Theauthorsdeclarenoconflictsofinterest
Acknowledgments
WewishtoacknowledgeEdgardeCarvalho,Coordinatorof
theMultidisciplinary HTLV AmbulatoryofProfessorEdgard
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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