JPediatr(RioJ).2016;92(2):103---105
www.jped.com.br
EDITORIAL
Microcephaly
and
Zika
virus
夽
Microcefalia
e
vírus
Zika
Consuelo
Silva
de
Oliveira
a,b,∗,
Pedro
Fernando
da
Costa
Vasconcelos
a,b,caSectionofArbovirologyandHemorrhagicFevers,InstitutoEvandroChagas(IEC),SecretariadeVigilânciaemSaúde(SVS),
MinistériodaSaúde(MS),Ananindeua,PA,Brazil
bUniversidadedoEstadodoPará,Belém,PA,Brazil
cResearchandReferenceinArbovirus,WorldHealthOrganization(WHO)CollaboratingCenter,Organizac¸ãoPan-Americanada
Saúde(OPAS),Brasília,DF,Brazil
The originalisolation oftheZikavirus (ZIKV),aFlavivirus
member of the Flaviviridae family, wasobtained in 1947 fromthebloodof afebrilerhesusmonkey exposedat the ZikaforestnearLakeVictoria,intheoutskirtsofEntebbe, the capital of Uganda.1 ZIKV was also isolated fromwild mosquitoes in the same area and later periodic human febrilecaseswereattributedtoZIKVin Ugandaandother countriesinWestandEastAfrica.Later,inthe1960s,ZIKV wasdetectedinAsiaandtheviruswasisolatedfromAedes aegyptimosquitoes,initiallyinMalaysiaand,subsequently, inseveralcountriesinAsia,showingthatthisarbovirusalso occurredoutsidetheAfricancontinent.2Thisnewfacetof ZIKV,i.e.,abilitytocauseepidemicdiseasetransmittedby
Aedesaegypti,discloseda newmilestonein the epidemi-ologyofthisarbovirusinfection.ItwasclearthatZIKVhad managedtoadapttoanoldacquaintanceofhumans,Aedes aegyptimosquitoes,transmittersofurbanyellowfever,four serotypes of dengue fever, chikungunya virus, and other arbovirusesinAsiaandAfrica.
Since the 1960s,sporadic cases of ZIKV infectionhave been reportedinhumans3; duetoitssporadic occurrence
夽
Pleasecitethisarticleas:deOliveiraCS,daCostaVasconcelos PF.MicrocephalyandZikavirus.JPediatr(RioJ).2016;92:103---5.
∗Correspondingauthor.
E-mail:consuelooliveira@iec.pa.gov.br(C.S.deOliveira).
andlowseveritypattern,littleimportancewasgiventothis arbovirusuntilaZikafeverepidemicoccurredonYapIsland intheRepublicofMicronesiain2007,withthedescription ofarashfebrilesyndromeofmildintensityandahigh per-centageofasymptomaticcases.4ThisepisodeonYapIsland wasfollowedbyothers,inthePacificOceanregionof Poly-nesiaandinsomeSoutheastAsiancountries,withoutbreaks confirmedby serologyor polymerasechain reaction(PCR) forthe ZIKVonEasterIsland, andinthe SolomonIslands, theCookIslands,Indonesia,Malaysia,Thailand,andFrench Polynesia.5---7 In the latter, retrospective epidemiological studiessuggestedthe occurrenceofapproximately30,000 infections and, for the first time, cases of Guillain-Barre syndrome(GBS)wereobservedassociatedwithZIKV infec-tion,aswellasthenotificationofthefirstcasesofperinatal transmission,8 warning of the potential complications of congenitalarbovirusinfections,basedonpreviousreportsof encephalopathy,hemorrhagicfever,andfetaldeath,among others,associatedwithchikungunyaanddengueviruses.In aretrospectiveanalysis oflivebirthsduringthisoutbreak in Polynesia, 17 cases of central nervous system malfor-mations,includingmicrocephalyin fetusesand newborns, wereidentifiedfromMarch2014toMay2015.Noneofthe pregnantwomenreportedsignsofZIKVinfection,but anti-bodies(IgG)toFlaviviruswerefoundinfourwomentested byserology, suggesting asymptomatic infection.9 Similarly asinBrazil,FrenchPolynesiahealthauthoritiesalsobelieve
http://dx.doi.org/10.1016/j.jped.2016.02.003
104 deOliveiraCS,daCostaVasconcelosPF.
thatZIKVmaybeassociatedwithbirthdefectsifpregnant womenareinfectedduringthefirstorsecondtrimesterof pregnancy.
AftertheconfirmationofthefirstcasesofZikafeverin Brazilin May 2015, initiallyin the Northeast,10 therewas a rapid spread of the virus to other parts of the coun-try,followed bythe significantincrease innotifications of newbornswithmicrocephalyintheBrazilianLiveBirth Infor-mation System (Sistema de Informac¸ão de Nascidos Vivos [SINASC]), with the recording of 141 suspected cases of microcephalyinNovember2015inthestateofPernambuco, afterwhichanexcessivenumberofcasesinother northeast-ernstates(ParaíbaandRioGrandedoNorte)weredetected, in addition tothe recordsof miscarriages and stillbirths. Faced with this new scenario, the Ministry of Health of Brazildeclaredtheeventasapublichealthemergencyof nationalconcern.11Itwasalsoverifiedthatthefirstmonths ofpregnancyofchildren bornwithmicrocephalymatched thelargestperiodof circulation ofthe ZIKVinthe North-east, andthere wasno correlation with familyhistory of geneticdisease,or testsdemonstratingapattern ofother knowninfectiousprocesses.
The causal association was carried out by Instituto Evandro Chagas (IEC) of the Ministry of Health through the isolation the ZIKV frombrain tissue and detection of the virus in cerebral spinal fluid (CSF), brain tissue, and fragments of several viscera (heart, lungs, liver, spleen and kidney) of a newborn that died shortly after birth.11 Subsequently, these results were reinforced with the detectionofIgMantibodiestoZIKVintheCSFof12children born with microcephaly. All tests for other infectious agentsassociatedwithwhatis medicallyknownasTORCH syndrome(toxoplasmagondii, other agents, rubella virus, cytomegalovirus,andherpessimplexvirus,types1and2), aswellasdengueandchikungunya,werenegative(Azevedo etal.;personalcommunication).
Anotherimportantcontribution toelucidatethe causal associationwastheidentificationofZIKVtheamnioticfluid of two pregnant women from the state of Paraiba with a history of rash illness and fetuses with microcephaly detectedatthefetalultrasonography.12 Afterthisfinding, further studies were conducted, which allowed the com-plete sequencing of the virus isolated from the amniotic fluid,withthephylogeneticanalysisdisclosingthatthevirus shares97-100%ofitsgenomicidentitywiththeAsianstrain isolatedduringthe outbreakin FrenchPolynesia andthat thepresenceoftheviralgenomeinthepatientsforafew weeksaftertheacutephasesuggeststhattheintrauterine viralloadresultsfrompersistentreplication.13Asadditional evidence,theidentificationoftheZIKVgenomein placen-talcellsinan8-weekmiscarriageusingRT-PCRtechniques reinforcedthepotentialofplacentaltransmission.14
Recently,theCentersforDiseaseControlandPrevention (CDC)confirmedthepresenceofthevirus,usingRT-PCRand immunohistochemistry,inthebraintissueoffournewborns withmicrocephalyand/orseverebrainmalformationsthat diedafterbirth,andintheplacentasofmiscarriedfetusesat 12weeksofgestation.15Similarfindingswereidentifiedby Mlakaretal.,16whoidentifiedtheviralgenomeinthebrain andplacentaofafetusmiscarriedinthe32ndweekof gesta-tionthathadmultiplebrainlesionsandintrauterinegrowth retardation detected after the 29th week of gestation,
whichconfirmsthevirusneurotropism,withapossibleviral persistenceinbraintissueandsevereplacentalimpairment. Furthermore,therehasbeenincreasingevidencethatin addition tothe brain, the eyeswould be the next target organofZIKV,asthepresenceofoculardisorders(macular atrophy)hasbeenobservedinchildrenwithmicrocephaly17 and,more recently,macular and perimacularlesionswith optic nerve atrophy,18 as described in ten children with microcephaly duringthe Zika outbreakin the capital city ofSalvador,stateofBahia.
Consideringtheseverityofthesituation,therapidspread of ZIKVin the Americancontinent, andthe difficulties of diagnosisforanemergingarbovirusinfectioninthe Ameri-cas,aswellasthehighriskofthevirusspreadingtoother continents,theWHOdeclaredtheZIKVepidemican impor-tant international public health event, according to the International Health Regulations, and convened an emer-gency committee. The disclosure of the WHO note was followedbyadescriptionoftheevent.19
Oneofthemajorlimitationstobeovercomeisthelackof commercialserologicalandmoleculartestsforthediagnosis ofZIKV,astheexistingin-housetestsarecurrentlylimited to reference laboratories, which are unable to meet the demandsof publichealth laboratories.Infact,thereisan urgentnecessitytodeveloprapidtests (immunochromato-graphic), serological (IgM- and IgG-ELISA) and molecular testsfortheearlydiagnosisofZIKVinfection,especiallyfor themostvulnerablegroups,i.e.,pregnantwomenand indi-vidualswithautoimmuneconditionsandchronicdiseases.20 Therehavebeenrecentrecordsofdeathsinpatientswith chronicdiseases,lupus,hemolyticanemia,sickle-cell ane-mia, and others, which means these groups should have prioritizedaccesstothediagnosisofZIKVinfection.
Thereisaclearneedtoreinforceantivectorialmeasures, which isthe onlycurrently availableconcrete measureto reduce casesofZIKVinfections.It isurgent thatconcrete actionsbetakenatallpubliclevelstogetherwiththe par-ticipationofsocietytoreducevectorinfestationindices;by reducingthe numberofvectors,wewillreduce incidence ratesand,obviously,thenumberofcasesofmicrocephaly andothercongenitalmalformations.
TheBrazilianMinistryofHealthmadethepolitical deci-sion to develop a vaccine against ZIKV. Regarding this subject,thereareseveralpossibleapproachestothe devel-opment of a vaccine to prevent ZIKV infection, which include:inactivatedvirusvaccine,attenuatedlivevirus vac-cine,chimericlivevirusvaccine,DNAvaccine,andsubunit vaccine. Undoubtedly, the subunit and DNA vaccines are thosethatdonotposeriskstopregnantwomenandspecial groups,andcanbeobtainedquickly,thesameoccurringwith theinactivatedvirusvaccine.Itisimportanttonote, how-ever,thatwhatevertheadoptedformulationis,pre-clinical andclinical trialsphasesI,II, andIIIwilltake someyears untilalicensedproductforuseinhumansisobtained.
MicrocephalyandZikavirus 105
together with the assistance and financial support of all memberstatesandcivilsocietyworldwide.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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