Higher incidence of Zika in adult women than adult men in Rio de Janeiro suggests a significant contribution of sexual transmission from men to women

Higher

incidence

of

Zika

in

adult

women

than

adult

men

in

Rio

de

Janeiro

suggests

a

significant

contribution

of

sexual

transmission

from

men

to

women

Flavio

Codec¸o

Coelho

*,

Betina

Durovni

,

Valeria

Saraceni

,

Cristina

Lemos

,

Claudia

Torres

Codeco

,

Sabrina

Camargo

,

Luiz

Max

de

Carvalho

,

Leonardo

Bastos

,

Denise

Arduini

,

Daniel

A.M.

Villela

,

Margaret

Armstrong

a

Fundac¸a˜oGetulioVargas,PraiadeBotafogo,190,RiodeJaneiro,Brazil

b

SecretariaMunicipaldeSaude,RiodeJaneiro,Brazil

c

ProgramadeComputac¸a˜oCientı´fica,Fundac¸a˜oOswaldoCruz,RiodeJaneiro,Brazil

d

InstituteofEvolutionaryBiology,UniversityofEdinburgh,Edinburgh,UK

e_{MINESParistech,PSLResearchUniversity,CERNACentreforIndustrialEconomy,i3,CNRSUMR9217,Paris,France}

1. Introduction

ViraldiseasestransmittedbyAedesaegyptimosquitoes,suchas dengue,yellow fever,chikungunya,and Zika,have traditionally beenrestricted tothe tropical regions of theworld, given the intoleranceof the vectors tocolder climates.1 In theseregions

transmission tends to be modulated by temperature, slowing down significantly when temperatures drop below 208C. The trendinglobalwarminghaslongbeenarguedtobeathreatto publichealth,asthiswillextendthereachoftropicaldiseases.1–3

Preparedness for thesediseases is theorder of thedayfor the healthagenciesofcountrieswithatemperateclimate.

TheemergenceZikaasaglobalpandemicthreatischangingthe traditionalriskscenarios.TheZikavirushastheabilitytoinfect otherspeciesofmosquitoes,4,5_{therebypotentially extendingits}

reach. Aedes albopictus, for instance, is well established in

ARTICLE INFO

Articlehistory: Received24June2016

Receivedinrevisedform16August2016 Accepted27August2016

CorrespondingEditor:EskildPetersen, Aarhus,Denmark Keywords: Zika Sexualtransmission Dengue Age-adjustedincidence SUMMARY

Objectives:TherecentemergenceofZikainBrazilanditsassociationwithanincreasedrateofcongenital malformationshasraisedconcernsoveritsimpactonthebirthrateinthecountry.Usingdataonthe incidenceofZikain2015–2016and denguein2013and 2015–2016forthecity ofRiodeJaneiro (population6.4million),amassiveincreaseofZikainwomencomparedtomenwasdocumented. Methods:Theage-adjustedincidencewascomparedbetweenmenandwomen.Anegativebinomial PoissongeneralizedlinearmodelwasfittedtotheZikaincidencedatatodeterminethesignificanceof sexualtransmissionstatistically.

Results:EvenaftercorrectingforthebiasduetothesystematictestingofpregnantwomenforZika,there werefoundtobe90%moreregisteredcasesper100000womenthanmeninthesexuallyactiveage group(15–65years);thiswasnotthecaseforagegroups<15yearsand>65years.Assumingthat infectedmentransmitthediseasetowomenintheirsemen,butthattheconverseisnottrue,someextra incidenceinwomenistobeexpected.Analternatehypothesiswouldbethatwomenvisitdoctorsmore oftenthanmen.Totestthis,theincidenceofdenguefeverwascomparedinmenandwomenin2015and in2013(beforeZikareachedRiodeJaneiro):inbothyears,womenwere30%morelikelytobereported withdengue.

Conclusion:WomeninthesexuallyactiveagegrouparefarmorelikelytogetZikathanmen(+90% increase);sexualtransmissionisthemostprobablecause.Womeninthe15–65yearsagegrouparealso 30%morelikelytobereportedwithdenguethanmen,whichisprobablyduetowomenbeingmore carefulwiththeirhealth.

ß2016TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases. ThisisanopenaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).

* Correspondingauthor.

E-mailaddress:fccoelho@fgv.br(F.C.Coelho).

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

j o urn a l hom e pa ge : ww w. e l s e v i e r. c om/ l o ca t e / i j i d

http://dx.doi.org/10.1016/j.ijid.2016.08.023

1201-9712/ß2016TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

temperate climates. Moreover, the Zika virus can also be transmitteddirectly from human tohuman.6 The sexual route seemstobethemostcommonalternateformoftransmission,but thevirusisalsopresentinotherbodilyfluidssuchassalivaand urine.7–9

TherecentarrivalofZikainBrazilin2014,andthespeedwith which it spread throughout the country and into neighboring countriesinjustafewmonths,seemstoindicatealternateformsof transmission.

Inthisstudy,theage-adjustedincidenceofZikacomparedto dengueinthecityofRiodeJaneirowasanalyzedandtherelative importance of the sexual route of transmission to the overall incidenceofZikawasestimated.Byconsideringthisadditionaland asymmetricrouteoftransmission,itwasexpectedthatahigher incidenceofZikawouldbeseeninwomeninthesexuallyactive agegroup.

2. Methods

ThedatausedinthisanalysiswereobtainedfromtheRiode Janeirohealthsecretariat,andconsistofeverynotifiedcaseofZika and dengue for theyears 2013 (dengue only), 2015 (Zika and dengue), and 2016(Zika and dengue,up toApril).Each record includes the date of notification, International Classification of Diseases tenth revision (ICD-10) code, age in years, sex, and gestationalstatus.

TheofficiallyestimatedpopulationofRiodeJaneirofor2015, based on the 2010 census, was also used (6.4 million people: 3 million men, 3.4 million women;Figure 1). All age-adjusted incidencesusedinthisstudywerecalculatedusingthispopulation asstandard.

Thecaseswereaggregatedtothesameageclasses,asshownin thecity’sagepyramid(Figure1).Theclassesare5yearswideand incidence values are presented as the number of cases per 100000inhabitants.

The incidence of Zika in women was calculated with and withoutpregnantwomen,toavoidbiases.Thecityhealthservices havesystematicallytestedpregnantwomendisplayingaskinrash, duetothehighriskofbabiesdevelopingneurological complica-tionscausedbyintrauterineZikavirusinfection.

Tocheckthestatisticalsignificanceoftheincreaseinincidence observedinwomen,aPoissongeneralizedlinearmodel(GLM)was first fitted to the number of cases of Zika and dengue (2013) aggregated by age class. Since these initial models displayed significantover-dispersion,anegativebinomialGLMwasfittedto thesamedata.LetYbethenumberofcases;thefinalmodelisthen:

YiNegBinðpi;rÞ

pi¼r=ðrþ

m

logð

m

b

b

b

b

þ

b

(1)

The‘Active’dummyvariabletakesthevalue1forageclasses above15yearsandlessthan65yearsofage,and0otherwise.

3. Results

DuringtherecentZikaepidemicinRiodeJaneiro,whichstarted inlate2015,atotalof29301cases,20315womenand8986men, werenotifiedassuspectedZikacasesbasedonclinicalassessment. During the same period, 102754 total cases of dengue were notified, with46305beingmenand56449beingwomen.The incidencebyagegroupforZikaintheperiodJanuary2015toApril 2016isshowninFigure2.Afterremovingthepregnantwomen fromthedataset,theincidencesshowninFigure3wereobtained. Theagedistributionofpregnantwomenremovedfromthesample isshownintheSupplementaryMaterial(FigureS1).

Forcomparison,Figure4showstheagedistributedincidenceof dengueinthe2015–2016period.Notethattheextraincidencein womenisfarlesspronounced.Thedengueincidencein2013was

Figure1.AgepyramidforthecityofRiodeJaneiro.Thesenumbersareofficialprojectionsbasedonthecensusof2010.Themalepopulationisrepresentedinblue,andthe femalepopulationinred.

alsoinvestigated(Figure5),tomakesurethatthepatternwasnot specifictothe2015dengueepidemic.

Thecombinedincidenceinthesexuallyactiveagegroup,from 15yearsto65yearsofage,isshowninTable1,alongwiththeratio oftheincidenceinwomentotheincidenceinmeninthesameage group.

The regression results indicated a significantly higher Zika incidence for sexually active women (1.7767, 95% confidence interval (CI) 0.500 to 3.053, p=0.006). Sex alone was not a significantpredictorofZikaincidence(0.2120,95%CI1.207to 0.783,p=0.676).Fordengue,beinginthesexuallyactiveagegroup andbeingawomanwasnotasignificantriskfactor(0.7196,95%CI 0.321to1.761,p=0.138).Again,sexalonedidnotprovetobea significantriskfactorfordengue.

4. Discussion

If Zika virus is being transmitted both through vectors and sexually in Brazil and other American countries in this recent epidemic,itisimportanttoestimatetherelative importanceof eachroute.Accordingtotheavailableevidence,theprincipalway totransmit Zika virussexually is throughexposure toinfected seminalfluid.FemaletomalesexualtransmissionofZikavirushas beenreported,10_{butnoinformationisavailableabouthowlikely}

suchatransmissionis.Assumingheterosexualintercoursetobefar moreprevalentthanhomosexualsexbetweenmen,asurplusof Zikacasesinwomenduetosexualtransmissioncanbeexpected. Moreoveractiveviruseshavebeenisolatedfromsemenmorethan 3weeksaftertheonsetofsymptoms,9_{whichgreatlyincreasesthe}

Figure2.IncidenceofZikainmenandwomenbyagegroup.Theincidenceisinunitsofcasesperhundredthousand.

Figure3.IncidenceofZikainmenandwomenbyagegroup,excludingpregnantwomen.Pregnantwomenareexcludedbecauseextraeffortsweremadebythehealth servicestoidentifyallpossibleZikacasesinthisgroupduetotheirbabiesbeingathighriskofdevelopingneurologicalcomplications.

transmissionperiodforsusceptiblefemales. Ontheotherhand, withoutsignificantsexualtransmissionandintheabsenceofan observationalbiasfavoringwomen,anequalincidenceacrossage groupswouldbeexpected.

Whatwasobserved,however,wasamarkedlyhigherincidence inwomen,asshown inFigure2.AsmentionedintheMethods section,thereisatleastoneobservationalbiastowardsreporting womencases,duetoconcernsaboutmicrocephalyandtherisksto babies.Inordertominimizethis,pregnantwomenwereremoved fromthesample(Figure3).Whatisseenisthattheextraincidence remains,butisrelativelysmaller.However,thisextraincidenceis morepronouncedinthereproductiveagegroup;thesewomenare morelikely tovisit a physicianregularlyand thus Zikawill be detectediftheyareinfected.

Toconfirmthehypothesisthatwomenaremorelikelytobe diagnosed with exanthematic fever syndromes during their reproductiveyears,dengueincidencewasassessedbyagegroup (Figures4and5).Duringthe2015–2016period,itispossiblethat some Zikacases mayhave been misdiagnosedas dengue, thus ‘contaminating’ thedengueincidencewithsexualtransmission. Thustheincidenceofdenguein2013wasalsoassessed,whenZika wasunlikelytobecirculatinginRiodeJaneiro.Itcanalsonotbe discountedthatthereisevidencethatpregnantwomenaremore likelytodevelopseveredengue.11_{Otherfactorsthatcouldexplain}

thehigherincidenceinwomenare(1)womenaremorelikelyto stayathomeandbemoreexposedtothevector,and(2)womenof afertileagearemorepredisposedtoseeadoctorassoonasthey develop symptoms for fear of complications in an as yet

Figure4.Age-adjustedincidenceofdengueinmenandwomenforthe2015–2016period.

undetectedpregnancy.Theauthorsbelievethatthe2013dengue dataserveasagoodcontrolforthedifferentialexposureofwomen tothevector.Asforthebehavioralchangesassociatedwiththefear of having a baby with microcephaly, the 2015–2016 data on denguealsorepresentagoodcontrolforthis,duetothesimilarity ofthesymptomsofdengueandZika.

AscanbeseeninTable1,theextradetectioninwomendueto thebehaviorofseeingadoctorregularlycouldaccountforatmost a30%higherincidencethaninmen,ifalltheextraincidenceof dengueinwomenisattributedtothis factor.However,forZika, evendiscountingpregnantwomen,anincidencethatisalmost90% higher than for men is observed. This extra incidence can be attributedtotheextracasescausedbysexualtransmission.

Throughsexualtransmission,Zikaisnolongerconstrainedto tropicalandsubtropicalregionsandwillbeabletoreachnorthern Europe,thenorthernUSAandCanada,andnorthernAustralia,as wellas Japan and Korea. Although it would be harder for the diseasetoinvadethesehigherlatitudes,theincidencesarelikelyto behigherasmenwhocatchZikaabroadcantransmitlocallyfor weeksorevenmonths.

TheimmediateconsequenceofthishigherincidenceofZikain womeninthereproductiveagegroupisamuchhigherexpected numberofneurologicallycompromisedbabiesthanifthedisease wasonlytransmittedthroughvectors.Goingfurther,womenliving inZika-infestedareaswillthinktwice aboutfallingpregnant,at leastthosewithaccesstobirthcontrol.Thiscouldwellleadtoa dropinthebirthrate,particularlyinthemiddleclasses.

AstheAedesmosquitoisknowntobepresentinthesouthern statesoftheUSAaroundtheGulfofMexico,3_{insouthernEurope,}2

andin northernAustralia,anoutbreak couldstartbecauseof a returningtraveler,especiallyifsexualtransmissionpropagatesit as well. Health authorities in developed countries are already warningtravelersvisitingZika-infectedareastoconsiderdelaying

pregnancies.12,13_{Whatwouldhappentothebirth ratein these}

countriesifZikabecameendemic?AdropinbirthsinEuropecould haveseriouseconomicconsequences.14

Funding:None.

Conflictofinterest:None.

AppendixA.Supplementarydata

Supplementarydataassociatedwiththisarticlecanbefound,in theonlineversion,athttp://dx.doi.org/10.1016/j.ijid.2016.08.023.

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Aggregatedincidenceinmenandwomeninthesexuallyactiveagegroupof15–65 years.Thelastcolumnshowstheratiooftheincidenceinwomentotheincidencein men. Disease Incidencein women Incidencein men Ratio, women/men Zika 5382.58 2854.85 1.88 Dengue2015–16 16628.04 13941.05 1.19 Dengue2013 32201.37 25410.52 1.27