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
Review
article
Prevalence
of
Guillain-Barré
syndrome
among
Zika
virus
infected
cases:
a
systematic
review
and
meta-analysis
Ludovica
Barbi
a,
Antonio
Victor
Campos
Coelho
b,
Luiz
Cláudio
Arraes
de
Alencar
c,d,
Sergio
Crovella
e,f,∗aKing’sCollegeLondon,DepartmentofGlobalHealthandSocialMedicine,London,UnitedKingdom bUniversidadeFederaldePernambuco,DepartamentodeGenética,Recife,PE,Brazil
cUniversidadeFederaldePernambuco,DepartamentodeMedicinaTropical,Recife,PE,Brazil dInstitutodeMedicinaIntegralProfessorFernandoFigueira,Recife,PE,Brazil
eScientificInstituteforResearch,HospitalizationandCare(IRCCS),InstituteforMaternalandChildHealth,Trieste,Italy fUniversityofTrieste,DepartmentofDevelopmentalandReproductiveSciences,GeneticUnit,Trieste,Italy
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Articlehistory:
Received6November2017 Accepted9February2018 Availableonline12March2018
Keywords: Arboviruses Zikavirus Guillain-Barrésyndrome Epidemiology Emergentdiseases
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Zika virus (ZIKV) is an emergent flavivirus transmitted mainly through Aedes spp. mosquitoesthatisposingchallengetohealthcareservicesincountriesexperiencingan outbreak.UsuallyZIKVinfectionismild,butinsomecasesithasbeenreportedtoprogress intoneurologicaldiseasessuchasmicrocephalyininfantsandGuillain-Barrésyndrome (GBS)inadults.GBSisadebilitatingautoimmunedisorderthataffectsperipheralnerves. SinceZIKVcausedmassiveoutbreaksinSouthAmericainthepastfewyears,weaimedto systematicallyreviewtheliteratureandperformameta-analysistoestimatetheprevalence ofGBSamongZIKV-infectedindividuals.WesearchedPubMedandCochranedatabasesand selectedthreestudiesforameta-analysis.WeestimatedtheprevalenceofZIKV-associated GBStobe1.23%(95%CI=1.17–1.29%).Limitationsincludepaucityofdataregarding previ-ousflavivirusinfectionsandZIKV-infectionconfirmationissues.Ourestimateseemstobe low,butcannotbeignored,sinceZIKVoutbreaksaffectsanoverwhelmingnumberof indi-vidualsandGBSisalife-threateningdebilitatingcondition,especiallyinpregnantwomen. ZIKVinfectioncasesmustbecloselyfollowedtoassurepromptcaretoreducetheimpact ofGBSassociated-sequelaeonthequalityoflifeofthoseaffected.
©2018SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/ by-nc-nd/4.0/).
∗ Correspondingauthor.
E-mailaddress:crovella@burlo.trieste.it(S.Crovella). https://doi.org/10.1016/j.bjid.2018.02.005
Introduction
Zikavirus(ZIKV)isanarbovirusthatbelongstothe Flaviviri-daefamily,thesameofDengue(DENV)virus.1ZIKVismainly transmittedthroughAedesspp.mosquitoes’bites,but trans-missionbybloodtransfusionandsexualintercoursecanalso occur.2Non-humanprimatesseemtobethereservoirhosts forZIKV,buttheprimaryspecieshavenotyetbeenidentified.3 Until2007,ZIKVwaslimitedtoAfricaandAsia,andonly mild cases were reported.4 After 2007, ZIKV cases started to increase remarkably, causing outbreaks in many differ-entcountries.ThefirstmajoroutbreakofZIKVinfectionwas recorded in French Polynesia in October 2013.2 The virus subsequently spread through the Pacific reaching Brazil in mid-2015;thelargestoutbreakwasreportedinthiscountry, anduptodatetheWorldHealthOrganization(WHO)has esti-matedapproximately3–4millioncasesofZIKV.3
ZIKVinfectionisthoughttobesymptomaticonlybetween 18% and 35% ofthe cases,resulting ina mildillness with symptomssuchasfever,myalgia,maculopapularrash,and arthralgia.3,5,6However,thereisnowgrowingevidencethat ZIKVinfection isrelatedtoarangeofneurologicdisorders, suchasGuillain-Barrésyndrome(GBS)inadults7and micro-cephalyin infants.2 This linkhas been hypothesized after the parallel upsurge ofZika cases along cases ofGBS and microcephaly,particularlyduringtheBrazilianoutbreak. Con-sequently,theincreaseinthenumberofcasesledtheWHO todeclarea publichealth emergency ofinternational con-cern.However,itisrelevanttomentionthatsomecasesof ZIKVhavebeenprobablymisclassifiedbecauseofthe molec-ularsimilarityoftheviruswithDENV1leadingtoserological crossreactivityinserologictestsemployingantibodiesfor lab-oratorydiagnosis;the RT-PCRbased moleculartestismore effectivebutonlyusefulduringthefirstweekofinfection.
GBS is a rare but serious autoimmune syndrome that attackstheperipheralnerves,causingaprogressiveparalysis. Typically,aninfectioneventuallytriggersautoantibodies tar-getinggangliosidesinthemembraneofnervouscells,causing respiratoryor gastrointestinalsymptomsbeforemore obvi-ousneurologic/motorimpairment.8Ithasamortalityrateof approximately5%,and20%ofthepatientsaffectedusually areleftwithsignificantdisability.3Thissyndromewasalready associatedwithZIKVinfectionduringtheoutbreakinFrench Polynesia.Indeed,theriseandfallofZikacaseswasfollowed byasimilartrendintheonsetofGBS.4However,the mecha-nismsbywhichZIKVinfectioncausesGBShavenotyetbeen established;ithasbeensuggestedthattheviruscould exacer-batetheimmuneresponsetriggeringanimmunopathogenic process that determines, inturn, the onset ofGBS.3 Some patients“developedneurologicalsymptomsduringor imme-diatelyafterthe[ZIKV]infection,suggestingaparainfectious rather than postinfectious pattern that istypically seen in GBS”,asnotedinarecentreview.9Thesesymptomsinclude muscleweakness,inabilitytowalk,facialpalsy,and respira-torydistress.In2015,1708casesofGBSwerereportedinBrazil representinga 19%increase incomparisontotheprevious year.2
Therefore,weaimedtosystematicallyreviewtheliterature andperformameta-analysistoestimatetheprevalenceofGBS
amongZIKV-infectedindividualsanddiscussthemostrecent findingsregardingtherelationbetweenZIKVandGBS.
Methods
Literaturesearchandsystematicreview
Following the recommendations of the PRISMA statement forconductingsystematicreviews,10wesearchedforstudies publishedoninternationaljournalsregardingZIKVinfection and its relationship with GBS. Our inclusion criteria were epidemiological/observational studies, such as case series, epidemiological surveys, cross-sectional or cohort studies, whichshouldhaveinvolvedadultindividuals.Exclusion crite-riawere reviewstudies,studies writteninlanguages other than English, Portuguese or Spanish and papers without explicitnumericaldataneededforthecalculationofthe meta-analysis.
Theusedkeywordswere“Zika”and“neurologicaldefects”. Wesearchedforpaperspublishedanytimeuntilearly Novem-ber 2017 in two databases: PubMed and Cochrane Library. On the PubMed database, 53 abstractswere found. On the CochraneLibrarydatabase,thekeywordusedwasonly“Zika”, retrieving23papers,sincethecombinationwith“neurological defects”didnotresultinanypaper.
Thus, the initial systematic review strategy found 76 abstracts. Among these, 56 abstracts were not relevant to ourobjective.Theremaining20studiesfull-textwerefurther reviewed.Amongthose,sevenwerereviewstudies,twodid notreportnumberofindividualsaffectedbyGBS,andwecould notextractthenecessarydatafromeightstudies.Therefore, threestudies(totalingninesamples)wereselectedforfurther meta-analysis.11–13
Two of the authors performed data collection indepen-dentlyandregisteredstudies’datainelectronicspreadsheets. Additionally,eachauthorcriticallyreviewedthequalityofthe studiesbyansweringaCASPchecklist14andthestudieswere deemedtohavesatisfactoryquality.
Theauthorsunified thedata,resolvingany inconsisten-ciesoromissionsbeforefurtheranalysis.Thedatacollected fromthestudiesincludedyearofsampling/publication, coun-trywherethestudywasperformed,andsamplesizes(number ofZIKVinfectioncasesandnumberofGBScases).Thesedata wereusedtocalculatetheoutcomeofinterest,whichwasthe observedGBSprevalenceamongZIKV-infectedindividuals(in otherwords,thenumberofGBScasesdividedbythenumber ofZIKVinfectedcases).TheindividualobservedGBS preva-lencewerethenincludedinameta-analysisforthecalculation ofapooledZIKVinfection-associatedGBSprevalence.
Meta-analysis
Search records (n=76)
Irrelevant records to the proposed objective (n=56
Full-text review (n=20)
Reviews (n=7)
Number of individuals affected by GBS not reported (n=2)
We could not extract data (n=8)
Meta-analysis (n=3; 9 samples)
Fig.1–Flowchartofstudiesselectedforfull-textreview andinclusiononthemeta-analysis.
The heterogeneity between studies’ sample sizes was expressedthroughI2measureand2statistic.ACochran’sQ testwithn−1degreesoffreedom(in whichnisthe num-berofstudies included, and withsignificancelevel ˛=0.10 forthistest)was conductedtoassessif heterogeneitywas significantly different from zero. If so, the heterogeneity wasclassifiedaccording tothe observedI2 measure:≤25%, between25 and50%,between50and 75%,andbetween75 and100%,respectivelyconsideredaslow,moderate,high,and veryhighheterogeneity.
The meta-analysis was performed through the “meta” package16forRsoftware,version3.4.1(RCoreTeam,Vienna, Austria)(June2017).17
Results
Summaryoftheselectedstudies
Asmentionedbefore,threestudieswereselectedforinclusion inameta-analysis.11–13Fig.1isaflowchartshowingstudies selection.Atthetimeofreportingofthefirst study (Febru-ary2014),which wasconductedinFrench Polynesia,DENV seropositivitywasaround23.2%,withanestimatednumberof 12,400–25,700peopleinfectedbyDENVduringthe2013–2014 FrenchPolynesianoutbreak.TheestimatednumberofZIKV infectedindividualsduringthisoutbreakwas29,000 individ-uals.However,just 8262suspected casesofZIKV infection werereported,sincemostinfectedindividualsdidnotsearch healthcareandthediagnosiswasnotlaboratoryconfirmed; amongthese,396caseswereconfirmedbyRT-PCR.Outofthe 38FrenchPolynesianGBS-affectedpatients,16needed inten-sivecareunithospitalization.Atthetimeofreporting,five werestillhospitalized.NoGBS-associateddeathsoccurred.11 ThesecondstudywasconductedintheNetherlandsand wasanobservationalstudythatconductedafollow-upof18 ZIKVinfected adultDutch individuals (mean age 49 years,
range8to61years;12females)whohadtraveledtoSuriname andDominicanRepublic.AsinglecaseofGBSwasobserved, ina60-year-oldwoman.Theauthorsreportedthatshehadan “underlyingillness”,butitwasnotclearwhatthiscondition was,andtheydidnotelaboratefurtherifitwaspreexistent orcouldhavepredisposedtoGBSoccurrence.Dengue virus-specificimmunoglobulinG(IgG)positiveserologywaspresent infourpatientsandweakIgMpositiveserologywaspresent inthreeindividualsoutof13withavailabledataamongthe 18Dutchindividuals;eightofthemhadpreviouslyreceived yellowfevervaccination.12
ThethirdstudysummarizedcaseseriesfromsevenSouth American, CentralAmerican and Caribbeancountries. The authorsanalyzedhealthreportsandobservedanaggregated numberof164,237casesofZIKVinfectionreportedbetween January2015andMarch2016inBrazil(stateofBahia), Colom-bia, DominicanRepublic, ElSalvador,Honduras, Suriname, andVenezuela.Amongthesecases,1474casesofGBSwere reported.13
Meta-analysisresults
Thetotal samplenumber polled bythe meta-analysis was 164,651ZIKV-infectedindividuals.Amongthem,1513 devel-opedGBS.Accordingtoafixedeffectmeta-analysismodel,an estimated1.23%ofZIKVinfectioncasescouldprogresstoGBS (95%CI=1.17–1.29%).Averyhighsamplesizeheterogeneity wasobserved,I2=99.1%and2=0.86(Cochran’sQ=932.3with eightdegreesoffreedom,p<0.001).
TheseresultsaresummarizedinFig.2,whichisaForest plotdisplayingthestudies,theirsamplesizesandconfidence intervals,andinTable1,whichliststhecharacteristicsofthe studiesincludedinthemeta-analysis.
Discussion
ZIKVinfectionusuallyhasamildpresentation,butrecently it hasbeendemonstrated its relationshipwithcentral ner-vous system sequelae,such as microcephalyin newborns, encephalitis,andGBS,whicharebeingregardedasthe “neu-rologicalsyndromeofZIKVinfection”.18Therefore,anyZIKV suspectedinfectionmustbecloselyfollowed,19especiallyin pregnant women, since several studies indicate that ZIKV impairs central nervous system development of fetuses.20 Moreover,whereasGBSmortalityoccursinaround5%ofthe cases,thisnumberrisesto10–35%iftheGBS-affectedperson isapregnantwoman.8
Despitethegrowingevidence,currentlytherearenoresults fromprospectivecohortstudiesaboutZIKVneurological con-sequences.Therefore,weperformedasystematicreviewof studies andconductedmeta-analysismodeling toestimate theprevalenceofGBSassociatedwithZIKVinfection.
num-Author, year GBS cases Zika virus-infected Proportion 95%-CI Weight French polynesia 2014 Duijster 2016 Dos santos 2016 Dos santos 2016 Dos santos 2016 Dos santos 2016 Dos santos 2016 Dos santos 2016 Dos santos 2016 Fixed effect model
Heterogeneity: l 2 = 99%, τ2 = 0.86, p < 0.01 38 1 155 320 45 184 71 15 684 396 18 30266 68118 1416 11054 17485 3097 32801 164651 0 0.02 0.04 0.06 0.08 0.1 0.01 [0.01; 0.01] 0.02 [0.02; 0.02] 0.00 [0.00; 0.01] 0.02 [0.01; 0.02] 0.03 [0.02; 0.04] 0.00 [0.00; 0.01] 0.01 [0.00; 0.01] 0.06 [0.00; 0.27] 0.10 [0.07; 0.13] 0.00 [0.00; 0.01] 2.3% 0.1% 10.4% 21.4% 2.9% 12.2% 4.8% 1.0% 45.0% 100.0%
Fig.2–ForestplotoftheprevalenceofGBSassociatedwithZIKVinfection.Theplotdisplayspooledsamplesize(164,651 ZIKV-infectedindividuals),individualprevalenceestimatesbyeachstudy,pooledprevalenceestimate(fixedeffectsmodel), thecorresponding95%confidenceintervals,studyweighting(fixedeffectsmodel)andsamplesizeheterogeneitymeasures andCochran’sQtestforheterogeneityp-value.
Table1–Summaryofstudies’characteristics.
Country Reference Year ZIKVinfectioncases GBScases
FrenchPolynesia 11 2014 396 38
Netherlands 12 2016 18 1
Brazil(Bahiastate)
13 2016 30,266 155 Colombia 68,118 320 DominicanRepublic 1416 45 ElSalvador 11,054 184 Honduras 17,485 71 Suriname 3097 15 Venezuela 32,801 684
ZIKV,Zikavirus.
GBS,Guillain-Barrésyndrome.
bers. Toillustrate this,we highlight the findings ofa case series(includedinourmeta-analysis)withdatafromseven countriesofSouthandCentralAmericain2015andearly2016. InElSalvador,thenumber ofGBSdiagnosiswas100%(two times)higherthanpre-ZIKVinfectionoutbreak.InVenezuela, thisincreasewasanimpressive877%(almost10timeshigher). InthestateofBahia,Brazil,oneofthemostaffectedcountries bytheepidemics,thenumberofGBSdiagnosisalmosttripled during the same period (increase of171%).13 Therefore, if newoutbreaksofZIKVareexpected,thentheoccurrenceof GBScaseswilllikewiseaccompanythem,bringingnew bur-den to individuals and healthcare services in the affected countries.
Ourmeta-analysishassomelimitations.First, wecould notassessiftheindividualshadpreviousflavivirusinfections (suchasDENVoryellowfevervirus),becausesuitableclinical and/orlaboratorydatawerelacking.GBSinassociationwith DENVandotherflavivirushasalsobeenreported,9butitis cur-rentlyunknownifpreviousinfectionscouldincreasetherisk forZIKV-associated GBS occurrencedue tocross-reactivity. Moreresearchisneededtoaddressthisissue.Second,someof thereportedZIKVinfectionarejustsuspected(notconfirmed byRT-PCRorothermethods).13Besidesthesetwolimitations, it isimportanttoremarkthat symptomaticZIKVinfection are the minority amongthe cases.3,5,6 Therefore, our ZIKV
infection-associatedGBSprevalenceestimatemaybe under-estimated,intheory.
Conclusion
Weperformed ameta-analysistoobtain aprevalence esti-mateofGBScausedbyZIKVinfection.Thisestimateseems tobelow,butcannotbeignored,sinceZIKVoutbreaksaffects an overwhelming number of individuals, mostly in South and CentralAmerica,posinga challengetohealthcare ser-vices.ZIKVinfectioncasesmustbecloselyfollowedtoassure promptcaretoreducetheimpactofGBSassociated-sequelae onthequalityoflifeofthoseaffected.
Funding
byFundac¸ãodeAmparoàCiênciaeTecnologiadePernambuco (FACEPE–BFP-0018-2.02/17).
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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1. deOliveiraWK,CarmoEH,HenriquesCM,etal.Zikavirus infectionandassociatedneurologicdisordersinBrazil.NEngl JMed.2017;376:1591–3.
2. AraujoAQ,SilvaMT,AraujoAP.Zikavirus-associated neurologicaldisorders:areview.Brain.2016;139Pt8:2122–30. 3. BlazquezAB,SaizJC.NeurologicalmanifestationsofZika
virusinfection.WorldJVirol.2016;5:135–43.
4. BroutetN,KrauerF,RiesenM,etal.Zikavirusasacauseof neurologicdisorders.NEnglJMed.2016;374:
1506–9.
5. FlamandC,FritzellC,MatheusS,etal.Theproportionof asymptomaticinfectionsandspectrumofdiseaseamong pregnantwomeninfectedbyZikavirus:systematic monitoringinFrenchGuiana,2016.EuroSurveill.2017;22. 6. LozierMJ,BurkeRM,LopezJ,etal.Differencesinprevalence
ofsymptomaticZikavirusinfectionbyageandsex-Puerto Rico.JInfectDis.2016:2017.
7. Cao-LormeauV-M,BlakeA,MonsS,etal.Guillain-Barré SyndromeoutbreakassociatedwithZikavirusinfectionin FrenchPolynesia:acase–controlstudy.Lancet.
2016;387:1531–9.
8. PachecoLD,SaadAF,HankinsGD,ChiosiG,SaadeG. Guillain-Barresyndromeinpregnancy.ObstetGynecol. 2016;128:1105–10.
9. UnciniA,ShahrizailaN,KuwabaraS.Zikavirusinfectionand Guillain-Barresyndrome:areviewfocusedonclinicaland electrophysiologicalsubtypes.JNeurolNeurosurgPsychiatry. 2017;88:266–71.
10.LiberatiA,AltmanDG,TetzlaffJ,etal.ThePRISMAstatement forreportingsystematicreviewsandmeta-analysesof studiesthatevaluatehealthcareinterventions:explanation andelaboration.PLoSMed.2009;6:e1000100.
11.FrenchPolynesia.DirectiondelaSanté.BureaudeVeille sanitaire.Pointdesituationau7février2014surles épidémiesdedengueetzikaencours;2014.Availablefrom: http://www.hygiene-publique.gov.pf/IMG/pdf/bulletindengue
07-02-14.pdf
12.DuijsterJW,GoorhuisA,vanGenderenPJ,etal.Zikavirus infectionin18travellersreturningfromSurinamandthe DominicanRepublic,TheNetherlands,November 2015–March2016.Infection.2016;44:797–802.
13.dosSantosT,RodriguezA,AlmironM,etal.ZikaVirusand theGuillain–BarréSyndrome–caseseriesfromSeven Countries.NEnglJMed.2016;375:1598–601.
14.CriticalAppraisalSkillsProgramme.CASPCohortStudy Checklist;2017.Availablefrom:
http://www.casp-uk.net/checklists
15.DerSimonianR,KackerR.Random-effectsmodelfor meta-analysisofclinicaltrials:anupdate.ContempClin Trials.2007;28:105–14.
16.SchwarzerG.meta:Meta-AnalysiswithR.Rpackageversion 3.7-1;2014.
17.RCoreTeam.R:ALanguageandEnvironmentforStatistical Computing.Vienna,Austria:RFoundationforStatistical Computing;2017https://www.R-project.org/Vienna
18.daSilvaIRF,FronteraJA,BispodeFilippisAM,NascimentoO, GroupR-G-ZR.Neurologiccomplicationsassociatedwiththe ZikavirusinBrazilianadults.JAMANeurol.2017;74:1190–8. 19.SebastianUU,RicardoAVA,AlvarezBC,etal.Zika
virus-inducedneurologicalcriticalillnessinLatinAmerica: SevereGuillain-BarreSyndromeandencephalitis.JCritCare. 2017;42:275–81.
20.GarcezPP,LoiolaEC,MadeirodaCostaR,etal.Zikavirus impairsgrowthinhumanneurospheresandbrainorganoids. Science.2016;352:816–8.
