w w w . r b h h . o r g
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
Review
article
Mortality
by
sickle
cell
disease
in
Brazil
Giovanna
Abadia
Oliveira
Arduini
1,
Letícia
Pinto
Rodrigues
1,
Alessandra
Bernadete
Trovó
de
Marqui
∗UniversidadeFederaldoTriânguloMineiro(UFTM),Uberaba,MG,Brazil
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t
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Articlehistory: Received15May2016 Accepted9September2016 Availableonline21October2016
Keywords: Sicklecellanemia Mortality
Neonatalscreening Infection
Acutechestsyndrome
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s
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t
Thisworkaimedtocharacterize mortalitybysicklecelldiseaseinBrazil.TheMEDLINE electronicdatabasewassearchedusingtheterms‘mortality’and‘sicklecelldisease’and ‘Brazil’forarticlespublishedinthelastfiveyearsaimingtoprovideacurrentanalysisof thesubjectinquestion.Eightstudiesonmortalitybysicklecelldiseasewerecarriedoutin theBrazilianstatesofMaranhão,Bahia,MinasGerais,RiodeJaneiroandMatoGrossodo Sul.Themajorityofthedeathsoccurredinpatientswithsicklecellanemia,whichisthe mostcommongenotypeandcausesthemostsevereclinicalmanifestationofthedisease. Insummary,therearefewpublishedstudiesonmortalityrelatedtosicklecelldiseasein Brazil,andmostarefromthestateofMinasGerais.Thisstudyemphasizestheimportanceof developingmorestudiesonsicklecelldiseasemortality,sothatitmaybepossibletoprofile genecarriersandgivehealthprofessionalsmoredatatostrategizethedeliveryofmore effectiveassistancetotheseindividuals.Despitetheearlydiagnosisofsicklecelldisease bytheNeonatalScreeningProgramandtheuseofpreventiveandtherapeuticmeasures (penicillin,immunizationandhydroxyurea),mortalitybysicklecelldiseaseontheworld stageisstillsignificant.
©2016PublishedbyElsevierEditoraLtda.onbehalfofAssociac¸ ˜aoBrasileirade Hematologia,HemoterapiaeTerapiaCelular.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Sicklecell disease (SCD)isagenericterm usedtodefine a groupofgeneticchangescharacterizedbythedominanceof hemoglobinS(HbS).Thesechangesincludesicklecellanemia (HbSS)anddoubleheterozygosis,thatis,associationsofHbS withotherhemoglobinvariants,suchasHbDandHbC,and interactionswiththalassemia(Hb S/␣thalassemia,Hb S/+
thalassemia,andHbS/0thalassemia).HbSischaracterized
∗ Correspondingauthorat:UniversidadeFederaldoTriânguloMineiro(UFTM),InstitutodeCiênciasBiológicaseNaturais/ICBN,
Departa-mentodePatologia,GenéticaeEvoluc¸ão,DisciplinadeGenética,CampusI.Prac¸aManoelTerra,330,38015-050Uberaba,MG,Brazil. E-mailaddress:[email protected](A.B.TrovódeMarqui).
1 Theauthorscontributedequallytothiswork.
by a missense mutation in position 6 of the  chain, in which the amino acid glutamic acid is replaced by valine (6GLU→VAL).1ItwasintroducedinBrazilbytheslavetradeof
Negroesduringthecolonialperiod,mainlyforsugarcane plan-tationsintheNortheastand,later,toextractpreciousmetals inthestateofMinasGerais.2,3
SCD predominantly occurs in Afro-descendants; how-ever, it is not exclusive to this population due to evident racial admixture in Brazil. About 34% of the investigated
http://dx.doi.org/10.1016/j.bjhh.2016.09.008
individualswithSCDreportedbeingvictimsofprejudicedue tothediseaseand48.3%reportedaconnectionbetweenthe diseaseandtheirskincolor.4PredominanceofBlackethnicity,
loweducationlevelsandincomewasobservedinstudiesthat characterizedthesociodemographicprofileofpatientswith SCD inBrazil.5,6 InBrazil,the incidence ofSCD is
approx-imately 1–3/1000 live births and in states such as Bahia, whereAfricanancestrypredominates,thisratereaches1/650 newborns.7
SignsandsymptomsofSCDincludehand–footsyndrome, chronichemolyticanemia,vaso-occlusive crises,infections, acute chest syndrome (ACS), acute splenic sequestration (ASS), stroke, priapism and leg ulcers.1,8 It is a chronic
genetic pathology, which negatively affects the quality of lifeofindividualsandtheirfamilies.6,9,10Itexhibits
autoso-malrecessiveinheritanceand,therefore,affectedindividuals are homozygous forHb S (Hb SS). Heterozygous individu-als(Hb AS)havethe sicklecell trait(SCT), thatis,theyare mutant allele carriers, which can be transmitted to their descendants.1 For couples inwhom both individuals have
the SCT, identification of the condition and genetic coun-seling are important before starting a family.11 Difficulty
in distinguishing between the terms carrier and affected individualswas reportedintworecentresearches.12,13 One
showed that only 17 (14.3%) of the 119 mothers whose children presented an abnormal result in the screening test for hemoglobinopathies could acknowledge the dif-ference between the trait and the disease.13 The other,
with 136 educators (94.9% teachers) of public schools in Montes Claros, Minas Gerais, revealed that 64.7% stated therewasnodifferencebetweenSCDandSCT,highlighting that this doubt exists even in people with higher lev-els of education.12 Another unexpected finding was that
39% thought that SCD was a consequence of a lack of nutrients.12
Due to its prevalence and clinical importance, SCD is considered a public health problem in Brazil, and there-forepublicpolicieswereimplemented,including theSickle CellDiseaseProgram14 andNationalPolicyfor
Comprehen-sive Care of Persons with Sickle Cell Disease and Other Hemoglobinopathies,15aimedatprovidingbetterassistance
toaffectedindividuals.Anotheradvancewastheearly diag-nosisofSCD andotherhemoglobinopathies bytheGuthrie test, established byGovernment Decree ofthe Ministry of Health n◦ 822, dated June, 6, 2001, which instituted the
NationalNeonatalScreeningService.16Historicevolutionof
thecreationprocessofneonatalscreeningaroundtheworld, in particular in Brazil, was reviewed by Rodrigues et al.2
InclusionofSCDintheNationalNeonatalScreeningService wasof utmostimportance because affected individuals do not present clinical signs at birth, making early diagnosis essential.
TherapeuticoptionsavailableforSCDincludebonemarrow transplantation,chronictransfusionsandhydroxyurea(HU).
StudieswithpatientsusingHUshowedsignificant reduc-tionsinvaso-occlusivecrises,ACS,infections,hospitalizations andthenumberoftransfusions.17,18
Thiswork aimedtocharacterizemortalitybysickle cell disease inBrazil inrespecttothe frequency,death rateor mortalitycoefficient,ageandcauses.
Methods
The MEDLINE electronic database was searched using the terms‘mortality’and‘sicklecelldisease’and‘Brazil’overthe last five years aimingto provide a current analysis of the subjectinquestion.Fifteenpaperswereidentified,ofwhich only seven were selected based on the title and abstract. Casereportswere excludedand onlythose thatwere pub-lishedasfull-lengtharticlesinEnglishwereconsidered.Other databases,suchasSciELOandBIREME,werealsosearched,but thesamearticleswerefound.Thereferencelistsofthearticles weresystematicallysearchedinordertoidentifyanypotential additionalstudiesthatcouldbeincluded.Eightstudieswere includedinthissystematicreview.
Results
Eight studies on mortality bySCD were carried out in the BrazilianstatesofMaranhão,19Bahia,20MinasGerais,21–23Rio
deJaneiro24,25andMatoGrossodoSul.26
ThestudycarriedoutinMaranhãoassessedtheimpactof theimplementationofneonatalscreeningonhospitalization anddeathratesduetoSCD.Themortalityrateincreasedfrom 0.115to0.216,thatis1.88timeshigher,butthiswasnot statis-ticallysignificant(p-value=0.586)andthemedianageatdeath increasedfrom10yearsto14years(p-value=0.665).19
ArecentresearchcarriedoutinBahia,theBrazilianstate withthelargestblackpopulationandhighestprevalenceof SCD, describedthe epidemiologicalprofileofthe deathsby SCDandreported74deathsin2011correspondingtoa mortal-itycoefficientof0.54per100,000individuals.20Yet,thecauses
ofdeathwerenotspecified.About42%ofthedeathsoccurred inadults(agerange:20–39years).Themajorityofthedeaths (n=64;86.4%)occurredinhospitalwithSalvadorbeingthecity withthehighestnumber(14deaths;18.9%).20
ThemortalityandsurvivalofchildrenwithSCDwere inves-tigated in Minas Gerais.21,22 Between 1998 and 2012, 2591
childrenwerediagnosedwithSCD(1:1.400).Therewere193 deaths(7.4%):153(79.3%)childrenhadHbS/0thalassemia, 34(17.6%)hadHbSCandsix(3.1%)hadHbS/+thalassemia. Ofthedeaths,56.5%occurredinchildrenundertheageoftwo and76.7%inunderfive-yearolds.Themaincausesofdeath were infection (45%), indeterminate(28%) and ASS(14%).21
Theterm ‘sicklecell’wasnotcitedin46% ofdeath certifi-cates.Themortalityratebetween1998and2005was5.43%vs. 5.12%between2005and2012.21Anotherstudyshowedthat
the5-yearestimatedmortalitywaslower,albeitnot signifi-cantly,forchildrenbornbetween2009and2011(n=509)than forthosebornbetween1999and2001(n=624)[mean(standard deviation):5.8%(1.1)vs.6.2%(1.0),respectively].22
Ofthe912newbornswithSCD(639withHbSS,201withHb SC,26withHbSDand46withHbS/+-thal)inRiodeJaneiro referredfortreatmentintheFundac¸ãoHemoriointheperiod from2000to2010,34children(3.7%)diedduetoACS(n=14; 36.8%),sepsis(n=12;31.6%)orASS(n=8;21.1%).24
TwostudiesanalyzedtheeffectofHUtherapyinpatients withSCD.25,26Atotalof267childrenweretreatedwith
ThecausesofdeathwereACS(n=17;45%),infection/sepsis (n=13;34%),stroke(n=4;10%),deathduringpainfulepisodes (n=3;8%)and onedeathwasunrelatedtoSCD (3%).There were36deathsamongnon-hydroxycarbamideusersandonly oneamonghydroxycarbamideusers(2=4.57;p-value=0.03). Survivalamonghydroxycarbamide-treatedchildrenwas sig-nificantlygreaterthanthatamonguntreatedpatients(99.5% vs.94.5%;p-value=0.01).25AstudycarriedoutinMatoGrosso
doSulassessedmortalityandcauseofdeathin63patients withSCD(55hadHbSSand8hadHbSC),taking(n=39)and nottakingHU(n=24).26Ten(15.8%)ofthepatientsdiedwitha
meanageof28.1years,eightwithHbSSandtwowithHbSC; 60%ofthedeathsoccurredinpatientsnottakingHU.Themain causesofdeathwereacuterespiratoryfailure(40%),multiple organfailure(20%),cardiogenicshock(20%),stroke(10%)and septicshock(10%).26
Aprospective cohort of104 pregnant womenwith SCD registered in the Fundac¸ão Hemominas in Belo Horizonte showedthatone-thirdofpregnantwomenhadnearmisses and4.8%died(fivedeaths);thecauses wereACS(n=4)and sepsis(n=1).23
Discussion
Theincreasesintheratesofhospitalizationanddeathafter the implementation of neonatal screening in the state of Maranhãosuggestthat previouslytherewasan underdiag-nosisofSCD and thatscreening, along with other factors, increased ‘visibility’ of the disease in the state. Possible explanations for an increase both in hospitalization and mortality rates after implementing neonatal screening are under-reportingofthediseaseduetodifficultyofdiagnosis, insufficienthospitalcare,incorrectuseoftheinternational diseaseclassification(ICD)codeandlackofhospitalregistry.19
TheauthorsfromBahiaconcludedthatthereisalackof stud-iescorrelatingmortalityinthisgeneticdisorderandthey high-lightedtheneedforfillingoutdeathcertificatescorrectly.20
Itwas evidentthat infection (including pneumoniaand septicemia)andASSwerethemaincausesofinfant mortal-ity.Moreover,theincidenceofdeathwashigherinpatients withsicklecellanemia,themostcommongenotypeandthe mostsevereclinicalpresentationofthedisease.21Theresults
ofMinasGeraisshowedthatneonatalscreeningforSCDwas notsufficienttosignificantlyreducechildmortality.Economic andsocialdevelopmentandincreaseoftheknowledgeabout SCDamonghealthcareprofessionalsandfamilyareneededto overcomethehighmortalityrate.21,22
ThestudiesconductedinthestatesofRiodeJaneiro25and
MatoGrossodoSul26reportedthathydroxycarbamidetherapy
decreasesmortalityamongpatientswithSCD.HUisanagent thatstimulatesfetalhemoglobin(HbF)productionand con-tributesbydiminishingtheinflammatoryandvaso-occlusive phenomena thereby reducing mortality.17,18,26 This drug is
providedfreeofcharge inBraziltopatientswithSCD who meetthecriteriadefinedbytheBrazilianMinistryofHealth HydroxyureaClinicalTreatmentProtocol.Theinclusion crite-riaarethefollowing:(1)documenteddiagnosisofSCD(any genotype),(2)adults≥18years andchildren≥3yearswith
parentalconsent,(3) abilitytofulfillclinical andlaboratory
monitoringand(4)atleastoneofthefollowinginthe preced-ing12months:≥3painfuleventsrequiringmedicaltreatment, ≥oneepisodeofACS,priorstrokeortransientischemicattack,
oneseriousorrecurrentepisodesofpostpubertalpriapism,or aHbconcentration<6g/dLonthreeseparateoccasions.27Data
fromalonger(17yearsoffollow-up)non-randomized prospec-tivestudyofadultswithSCDregistered13(9.9%)deathsinthe HUgroupand49(24.6%)inthegroupnottreatedwithHU.The probabilityof10-yearsurvivalwas86%and65%forHUand non-HU patients, respectively.17 Hydroxycarbamidetherapy
wasalsoassociatedwithdecreasedmortalityamongchildren withSCD.25
PregnantwomenwithSCDhaveahigherriskofmaternal andfetalmortalitywhencomparedtothosewithSCTorthe populationingeneral.23,28,29Aresearchthatassessedthe
evo-lutionofpregnanciesin34womenwithSCDforaperiodof 12yearsreported26.6%ofmiscarriages,sevenfetallosses(3 stillbirthsand 4miscarriages)andonlyonematernaldeath (2.9%) inthepostpartumperiodduetoACS.28 Astudy
car-riedoutinFrance,aimingtodescribematernalmortalityin womenwithSCDfrom1996to2009reported15deaths,with twoofthembysepticshockduringpregnancyand13occurring inthepostpartumperiod,withthesamenumberofdeaths beingattributeddirectlytoSCD.Tenwomenwere homozy-gous(HbSS)forSCD,andfivewerecompositeheterozygotes.29
Arecentreviewoftheliteratureshowedthatmaternaland fetal mortalityratesduringpregnancycanreach11.4% and 20%,respectively.30
Studiescarriedoutinothercountriesalsopresenteddata about mortalitybySCD.Oneofthem,carriedout inAfrica, reported 86 deaths(5.7%;n=20 and 23.3%hospital deaths) among1516patientswithSCD.Twodeathsoccurredin chil-drenundertheageoftwo,22inchildrenunderfive,47deaths inthe5–19agerangeand15inover20-year-oldindividuals.31
AnotherstudycarriedoutinAmsterdam,beforetheNeonatal ScreeningProgramintheNetherlands,identified298children withSCD(189withHbSS,72withHbSC,20withHbS/+and 17 withHb S/0)between1985and 2007.During the obser-vation period,12patients(4%) died,withsepsis/meningitis (n=4;33%)andstroke(n=3;25%)beingthemaincauses.Three deaths occurred bymeningitis (Hb SC,Hb S/ and Hb SS), onebysepsis(HbSS)andthreefatalstrokesoccurredinover 10-year-old patients(twowithHbSS andonewithHb SC). Concerningtheageatdeath,fourchildren(33%)underthe ageof3died,three(25%)werebetween3and18years old andfive(42%)wereovertheageof18.32Thisstudyshowed
that themean age atdeathwas 11.3years and oneoutof 40 children withSCD inthe Netherlands does notsurvive untiladulthood.32InJamaica,of75youngadultpatientswith
SCD, 11 (14.7%)died, with sepsisbeing the maincause of death.33TheNeonatalScreeningPrograminNewYork
iden-tified21(1.1%)deathsafterthediagnosis ofSCDfrom2000 to 2009.Ofthese,14 occurred inunder 2-year-oldchildren andseveninchildrenagedbetween2and9yearsold.Ofthe totaldeaths,16occurredinchildrenwithHbSSorHbS/0
ofchildrenandadultswith SCDshowed adecrease inthe firstgroup(3%)andanincreaseinthesecond(1%)duringthe sameperiodof26years(1979–2005).35Between1990and2010
inIran,theoveralldeathsattributedtohemoglobinopathies decreasedfrom0.51%to0.36%oftotaldeaths.36A
retrospec-tivestudyshowedthatinfectionswerethecommonestcause ofdeathinNigerianSCDpatients.37Themeanageatdeath
was21.3years(range:1–47years)withpeakmortalityinthe 2ndand3rddecadesoflife.Infectionsandthromboembolic phenomenonwerethemaincausesofdeath,in78%and37% ofthecases,respectively.Thiswasfollowedcloselyby ane-miaaloneorincombinationwithacutesequestrationcrises in31%ofpatients.37
Conclusions
Insummary,therearefewpublishedstudiesonmortalityby SCDinBrazil,mostofwhicharefromthestateofMinasGerais. Thisstudyshowstheimportanceofdevelopingmorestudies ondeathrelatedtoSCD,sothatitmaybepossibletoprofile thegenecarrierandgivehealthprofessionalsmoredataso thattheycanstrategizetoprovidemoreeffectiveassistance totheseindividuals.Themaincausesofdeathareinfection, ASSandACS.
InfectionsarethemostcommoncausesofdeathinSCD patientsinBrazilwiththemajorityoccurringinpatientswith sicklecellanemia,themostcommongenotypeandthemost severeclinicalpresentationofthedisease.Studiesshowthat despitetheearlydiagnosisofSCDbytheNeonatalScreening Programandtheuseofpreventiveandtherapeuticmeasures (penicillin,immunizationandhydroxyurea),mortalitybySCD ontheworldstageisstillsignificant.Variablessuchas fre-quency,deathratesormortalitycoefficient,ageandcauses ofdeathwerenottotallyinvestigatedbyallresearchers.This makesitimpossibletoperformamoreaccurateanalysisof mortalitybySCDintheworld.
Conflicts
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Theauthorsdeclarenoconflictsofinterest.
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