Sentinel surveillance of influenza and other respiratory viruses, Brazil, 2000-2010

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The

Brazilian

Journal

of

INFECTIOUS

DISEASES

w w w .e l s e v i e r . c o m / l o c a t e / b j i d

Original

article

Sentinel

surveillance

of

inﬂuenza

and

other

respiratory

viruses,

Brazil,

2000–2010

Felipe

Teixeira

de

Mello

Freitas

∗

MinistériodaSaúde,SecretariadeVigilânciaemSaúde,Coordenac¸ãoGeraldeDoenc¸asTransmissíveis,Brasília,DF,Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received29June2012 Accepted3September2012 Availableonline1January2013

Keywords: Inﬂuenza

Respiratorysyncytialvirus Publichealthsurveillance Brazil

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Therearescantydataontheepidemiologyofinfluenzaandotherrespiratoryvirusesin SouthAmericaandBrazil.Theaimofthisstudywastosummarizethedatafromthe Brazil-iansurveillancesystemofinfluenzaandotherrespiratoryvirusesanddiscussthepatternsof viralcirculation.Thesystemisbasedondetectingcasesofinfluenza-likeillnessinsentinel sitesandweeklycollectionoffivenasopharyngealsecretionssamples,whichareprocessed instatepublichealthlaboratoriesforrespiratoryvirusesbyindirectimmunofluorescence assay.Datafrom2000to2010weredescribedovertime,byregion,gender,andagegroup,and ananalysisofSpearmancorrelationwasperformedbetweenmonthlyinfluenzadetection andrainfallandtemperaturedataintwostatecapitalswiththehighestnumberof posi-tivesamples,onefromthenortheastregion(Maceió)andotherfromthesouthernregion (Curitiba).Therewere3,291,946visitsforinfluenza-likeillness;ofthese,37,120had sam-plescollectedand6421testedpositive:1690(26%)influenzaA,567(9%)influenzaB,277 (4%)parainfluenza1,571(9%)parainfluenza2,589(9%)parainfluenza3,742(12%) adeno-virus,and1985(31%)respiratorysyncytialvirus.Overall,increasedactivityofrespiratory syncytialviruswasobservedfromMarchtoJune,precedingthepeakofinfluenzaactivity, fromMaytoAugust,butwithregionaldifferences.InMaceió,therewasaweakcorrelation betweentemperatureandinfluenzadetection(=0.05),butamoderatepositive correla-tionbetweenrainfallandinfluenzadetection(=0.36).InCuritiba,ahighcorrelationwas observedbetweenthedecreaseintemperatureandrainfallandtheincreaseininfluenza detection(=−0.83and−0.78respectively).Thesedataareimportanttoguidepublichealth controlmeasuresasthebesttimeforinfluenzavaccinationanduseofantivirals.

Introduction

Acute respiratory infections of viral origin are among the leadingcausesofmortalityandmorbidityinyoungchildren, elderly,andimmunocompromisedpatientsindevelopedand

∗ _{Correspondence}_address:_Unidade_de_Doenças_{Respiratórias}_e_{Imunopreviníveis,}_{Coordenação}_Geral_de_Doenças_{Transmissíveis,}

Secre-tariadeVigilânciaemSaúde,MinistériodaSaúde,SetorComercialSul,Quadra4,BlocoA,2◦andar,Brasília,DF,Brazil. Tel.:+556132138109.

E-mailaddress:felipetmf@gmail.com

developingcountries.1_The_inﬂuenza_virus_is_the_main

respira-toryvirusthatcanleadtogreaternumberofhospitalizations anddeaths.2–7_In_temperate_countries,_inﬂuenza_activity_has

beenwelldescribed,withmarkedseasonsofinﬂuenzainthe winter,usuallyDecember–AprilintheNorthernHemisphere andJune–SeptemberintheSouthernHemisphere,8_whereas_in

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0 750 1,500 3,000 Km State Region Tropic of capricorn 1 unit 2 units 3 units N North Equator Northeast Southeast Midwest South

Fig.1–MapofBrazildividedbyregionsandstates,showingthelocationofthe60sentinelunitsforrespiratoryvirusesin 2010.

tropicalandsubtropicalregionsoftheworldwithill-defined seasons,thecirculationofinfluenzacanbedescribedasless pronouncedseasonalfluctuationsrelatedtotherainyseason orthatoccurthroughouttheyear.9–11 _In_Brazil,_the

season-alityofinﬂuenzahasbeen describedasawavethatbegins inAprilinnorthernequatorialandtravelstothesouthfora periodofapproximatelythreemonths,reachingthe temper-ateregionsofthecountryinJuly.12_Data_from_the_northeast

regionshowthatinﬂuenzaseasonislinkedtotherainyseason inthisregion.13

Among other respiratory viruses, respiratory syncytial virus (RSV) is the leading cause ofbronchiolitis in infants andisassociatedwithsubstantialmorbidityandmortalityin childrenaged<5yearsold14,15_and_can_also_lead_to

hospitaliza-tionsanddeathinseniorsandadultswithchronicdiseases.2,16

TheRSVseasontypicallyoverlapstheinﬂuenzaseason, begin-ninginthefallandlastingthroughoutthewinterintemperate regions;andintropicalregions,itisassociatedwiththerainy season.17_The_{parainﬂuenza}_virus_(PIV)_is_the_second_leading

causeofbronchiolitisandtheleadingcauseof laryngotracheo-bronchitisorcroupinchildrenaged<5yearsold.18,19_The_PIV-1

andPIV-2circulatemoreoftenduringthefall,causingbiennial epidemicsinchildren,andPIV-1isusuallymoreprevalent.The PIV-3circulatesthroughouttheyearwithlargestcirculationin thesecondhalfoftheyear,duringspring.20

Theinformationonthe epidemiologyand seasonalityof influenzaandotherrespiratoryvirusesiscrucialforthe devel-opmentofeffectivecontrolmeasures, particularlythe best timeforapplicationofinfluenzavaccine.However, informa-tionontheepidemiologyofinfluenzaandotherrespiratory virusesissparseinmiddle-orlow-incomecountries,located intropicalorsubtropicalregionsoftheworld,10,11 _especially

inSouthAmerica.BrazilisthelargestcountryinSouth Amer-ica,extendingover35◦oflatitude,whichincludestheAmazon tropicalareasinthenorthtosubtropicalandtemperateareas inthesouth.TheBrazilianMinistryofHealthbeganinfluenza andotherrespiratoryvirusessurveillancein2000withthe fol-lowingobjectives:(a)monitorthestrainsofinfluenzaviruses that circulate in the five Brazilian regions; (b) respond to unusualsituations;(c)assesstheimpactvaccinationagainst thedisease;(d)followthetrendofmorbidityandmortality associatedwiththedisease;and(e)produceanddisseminate epidemiologicalinformation.21

Theaimofthisstudyistosummarizethedatagenerated bysentinelhealthunitsandstatepublichealthlaboratories from 2000 to 2010 from the national sentinel surveillance systemforinﬂuenzaand otherrespiratoryvirusesand dis-cusstheseasonalityandcirculationofrespiratoryvirusesin Brazil.

Materials

and

methods

Thesentinelsurveillanceofinfluenzaandotherrespiratory virusesbeganwithasentinelunitin2000andexpanded grad-uallytoreach60unitsin2010,reachingatleastoneunitin 26ofthe27states,andallthefiveBrazilianregions(Fig.1). This system is based on a network of sentinel units that includeoutpatientclinics, emergencycare departments,or general hospitals that report weekly via an online system calledSIVEPGripe,theaggregatetotalnumberofvisits,and total visitsfor influenza-likeillness (ILI), definedas acase offeveraccompaniedbycoughorsorethroatwithnoother diagnosis.

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InﬂuenzaA InﬂuenzaB PIV-1 PIV-2 PIV-3 Adenovirus RSV Total n(%) n(%) n(%) n(%) n(%) n(%) n(%) n Year 2000 1(100) 0 0 0 0 0 0 1 2001 11(41) 3(11) 1(4) 0 3(11) 1(4) 8(29) 27 2002 39(21) 33(17) 11(6) 5(3) 19(10) 12(6) 71(37) 190 2003 89(33) 7(3) 8(3) 8(3) 25(9) 46(17) 84(32) 267 2004 158(33) 23(5) 19(4) 5(1) 12(3) 113(24) 141(30) 471 2005 94(30) 10(3) 43(14) 11(3) 36(12) 34(11) 85(27) 313 2006 184(31) 49(9) 36(6) 12(2) 83(14) 61(10) 165(28) 590 2007 229(29) 31(4) 22(3) 9(1) 123(15) 124(15) 257(33) 795 2008 162 (14) 106 (9) 32 (3) 268 (24) 89 (8) 132 (12) 345 (30) 1134 2009 504(36) 107(7) 40(3) 196(14) 84(6) 80(5) 406(29) 1417 2010 219(18) 198(16) 65(5) 57(5) 115(10) 139(11) 423(35) 1216 Region North 185(17) 36(3) 34(3) 60(6) 78(7) 204(18) 510(46) 1107 Northeast 462 (28) 136 (8) 85 (5) 130 (8) 192(11) 260(16) 396(24) 1661 Midwest 202 (30) 75 (11) 37 (6) 51(8) 72(11) 78(12) 148(22) 663 Southeast 334(20) 132(8) 72(4) 170(10) 135(8) 121(7) 681(41) 1645 South 507(38) 188(14) 49(4) 160(12) 112(8) 79(6) 250(19) 1345 Gendera Male 814(26) 272(8) 140(4) 273(9) 282(9) 391(12) 1003(32) 3175 Female 875(27) 293(9) 137(4) 298(9) 306(10) 345(11) 970(30) 3224 Agegroup 0–4 153(10) 45(3) 54(4) 114(7) 178(11) 180(12) 825(53) 1549 5–14 497(22) 118(5) 116(5) 143(7) 243(11) 325(14) 826(36) 2268 15–24 325(46) 103(14) 20(3) 76(11) 35(5) 60(8) 92(13) 711 25–59 647(39) 271(16) 80(5) 211(13) 109(6) 148(9) 199(12) 1665 ≥60 68(30) 30(13) 7(3) 27(12) 24(10) 29(13) 43(19) 228

a _Twenty-two_records_had_unknown_gender.

Inaddition, intheseunits, five samplesof nasopharyn-gealsecretionsshouldbecollectedweeklybyswaboraspirate frompatientswithILI.Samplesaresentandtestedinpublic healthlaboratoriesineachstatebyindirect immunofluores-cenceassay(IFA)fordetectionofinfluenzaAandB,PIV1,2, and3,adenovirus,andRSV.Theresultsarereportedweeklyby thestates’publichealthlaboratoriesthroughtheSIVEP Gripe. Allpositive,inconclusive,and10%ofthenegativesamplesare forwardedtooneofthreenationalreferencelaboratoriesfor respiratoryviruses(InstitutoEvandroChagasinBelém, Insti-tutoAdolfoLutzinSãoPauloandFundaçãoOswaldoCruzin RiodeJaneiro)wheretheyareretestedbypolymerasechain reaction(PCR);positivesamplesforinfluenzaaresubtyped, sequenced,andforwardedtothecollaboratingcenterofWorld Health Organization (WHO) to make part ofthe Southern Hemisphereinfluenzavaccine.

Thedatafromthesentinelunitsandviraldatafromthe states’publichealthlaboratoriesobtainedbySIVEPGripewere analyzeddescriptively,usingPASWStatistics18.0software. Theresultsofviruses’identificationwereanalyzedovertime per month and year and stratified by gender, age group, andregion.Acorrelationanalysiswasperformedusingthe Spearmancorrelationcoefficientbetweenmonthlyinfluenza detectionandaveragemonthlytemperatureandrainfallusing datafrom Maceióand Curitiba, the cities withthe highest numberofpositivesamplesforinfluenzafromthenorthand northeastregionsandfromthemidwest,southeast,andsouth regions,respectively.Maceióislocatedatlatitude9.4◦Sand

hasatropicalclimate.Curitibaislocatedatlatitude25.5◦Sand hasa temperateclimate.Meteorological datawasobtained fromtheNationalInstituteofMeteorologyforthetwocities studiedfromtheperiodofstudy,2000–2010.22

Results

From 2000to2010,atotalof29,318,698patientsvisitswere recordedinthesentinelunitsand3,291,946visitswereforILI (11%).Ofthesepatients,37,120(1%oftotalvisitsforILI)had nasopharyngealsamplescollected;19,369(52%)werefemale withamedianageof12yearsold;20,158(54%)werechildren aged<15yearsold.

Therewere6421(17%)positiveresults;ofthese,1690(26%) werepositiveforinfluenzaA,567(9%)forinfluenzaB,277(4%) forPIV-1,571(9%)forPIV-2,589(9%)forPIV-3,742(12%)for adenovirus,and1985(31%)forRSV.Thenumberofpositive samplesgraduallyincreased,reachingmorethan1000 pos-itive samplesin2008.Thenortheastregionwas theregion withthehighestnumberofpositivesamples,1661(26%),and themidwestregionwiththelowestnumber,663(10%).The RSVviruswasthemainvirusidentifiedamongchildrenaged <15 years old, 1651(43%),and the influenza virus was the mainvirusidentifiedamongpersonsaged≥15yearsold,1040 (40%).Thenumberandproportionrespiratoryviruses identi-fiedbyyear,region,gender,andagegrouparepresentedin Table1.

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Number of viruses identified 450 400 350 300 250 200 150 100 50 0 120 100 80 60 40 20 0 180 160 140 120 100 80 60 40 20 0 90 80 70 60 50 40 30 20 10 0 50 45 40 35 30 25 20 15 10 5 0 200 180 160 140 120 100 80 60 40 20 0

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

Brazil North

Northeast Midwest

Southeast South

Influenza RSV

Fig.2–Numberofinfluenzavirusandrespiratorysyncytialvirus(RSV)identifiedinthesentinelunitspermonthinBrazil andinitsfiveregions,2000–2010.

TheinfluenzavirusandRSVcirculatedthroughouttheyear inBrazilandinallregions.Thecirculationofinfluenzaand RSVoverlappedinthecountryandinallregions,especially inthecoolestmonthsoftheyear,RSVactivitywasgreaterin autumn,fromMarchtoJune,precedingthepeakofinfluenza activity,moreprominentinwinter,fromMaytoAugust(Fig.2). In the northand northeast regions, the influenza virus circulatedthroughouttheyearwithoutperiodsofclear pre-dominance and RSV predominated from April to June. In the midwest, southeast, and south regions, circulation of influenzapredominatedfromMaytoAugust,peakinginJune and July inthe southeastand south regions. There was a greatercirculationofRSVfromMarchtoMayinthemidwest

andsoutheastregions,whileinthesouthregion,apeakofRSV circulationcoincidedwithapeakofinﬂuenzacirculation,in JuneandJuly(Fig.2).

The three types of parainﬂuenza viruses co-circulated everyyearinBrazil,thePIV-3themostfrequent,withthe high-estcirculationinthesecondhalfoftheyear,mostevidentfrom 2007.AmajorpeakofPIV-2wasobservedduring2008and2009 (Fig.3).

From2000to2010,Maceiópresentedlittlevariationin aver-agetemperatureduringtheyearandadefinedperiodofrain and drought. Therewas no significantcorrelation between monthly temperature and influenza detection (=0.05); a moderatepositivecorrelationwasobservedbetweenmonthly

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45 40 35 30 25 20 15 10 5

0 Jan Mar May Jul Sep Nov Jan Mar May Jul Sep Nov Jan Mar May Jul Sep Nov Jan Mar May Jul Sep Nov Jan Mar May Jul Sep Nov Jan Mar May Jul Sep Nov Jan Mar May Jul Sep Nov Jan Mar May Jul Sep Nov Jan Mar May Jul Sep Nov Jan Mar May Jul Sep Nov

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Number of viruses identified

Fig.3–Circulationofparainﬂuenzavirusesdetectedinthesentinelunits,Brazil,2001–2010.

rainfallandinﬂuenzadetection(=0.36).Curitibahadaclear winterseasonwithlowtemperaturesandlowrainfall.There wasahighcorrelationbetweenthedecreaseintemperature andrainfallandtheincreaseininﬂuenzadetection(=−0.83 and−0.78respectively)(Fig.4).

Discussion

DatafromBraziliansentinelsurveillanceofrespiratoryviruses from2000to2010show thattheidentiﬁcation ofinﬂuenza predominatedamongadultsand RSVamongchildrenaged

<15yearsold.BothinﬂuenzaandRSVcirculatedyear-round, andtheRSVseasonpeakedinautumn,betweenMarchand June,precedingthepeakofinﬂuenzaseasonthatoccurredin thewinterbetweenMayandAugust.

Nevertheless,thereareregionaldifferences.Inthenorth andnortheastregionstherewasnoclearperiodof predomi-nanceinthecirculationofinfluenza;averyweakcorrelation was observedbetweenmonthly temperatureand influenza detection, but a moderate correlationbetween rainfall and influenzadetectionwasseeninastatecapitalof northeast-ern Brazil.However, in the midwest,southeast, and south regions,thereisaclearerseasonality,withhigherdetectionof

40 N.º cases ρ = 0.05 35 30 25 20 15 10 5 0 40 35 30 25 20 15 10 5 0 80 70 60 50 40 30 20 10 0 30 25 20 15 10 5 0 30 25 20 15 10 5 0

JanFebMarAprMay

Influenza Temperature

JunJul AugSepOctNovDec

ρ = -0.83 N.º cases N.º cases N.º cases Temp ºC Rainfall mm Temp ºC Rainfall mm 80 70 60 50 40 30 20 10 0 250 200 150 100 50 0 500 450 400 350 300 250 200 150 100 50 0

JanFebMarAprMayJunJul AugSepOctNovDec

ρ = -0.78 ρ = 0.36

Curitiba Maceió

Influenza Temperature

Fig.4–Spearmancorrelationanalysisbetweenmonthlytemperatureandrainfallwithinﬂuenzadetectioninthecitiesof MaceióandCuritiba,2000–2010.

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inﬂuenzaamongthemonthsfromJunetoAugust,correlated withlowtemperaturesandlow-rainfallperiodinasouthern statecapitalofthecountry.ThecirculationofRSVhasa sim-ilar seasonalpattern amongthe north,northeast, midwest andsoutheastregions,predominantlybetweenthemonthsof MarchandMay,andonlyinthesouthernregion,theRSV pre-dominatedduringJuneandJuly,coincidingwiththeinﬂuenza seasoninthisregion.

Our data of viral circulation are in accordance with Brazilianstudiesreportedbyotherauthorswhodiscussthe seasonalityofinfluenzaandRSV.Inastudythatused pneu-moniaandinfluenzamortalitydatafrom1979to2001toassess influenzaseasonalityinBrazil,itwasobservedthatabove lat-itude15◦S(whichincludestheentirenorthernregion,much ofthenortheastregionandpartofthemidwestregion)there isnoclearseasonalityasitoccursbelowthispoint(including thesouth,southeastandmuchofthemidwestregions).The circulationofinfluenzaisdescribedasawavethatstartsinthe equatorialregionsinAprilandreachesthesouthernregions ofthecountryofsubtropicalandtemperateclimateinJuly.12_A

clearpatternofinfluenzaseasonalityinthenorthand north-eastregionswasnotidentified,unlikeother regions,where onecanobservealargernumberofpositivesamples concen-tratedinthemonthsofJuneandJuly.Aprospectivestudyof sevenyearsbasedonviraldatafrom Fortaleza,acapitalof northeasternBrazil,locatedatlatitude4.3◦Sandwithtropical climate,describedtheinfluenzaseasonoccurringinthefirst halfoftheyearinthecity,associatedwiththerainyseason.13

Amoderatecorrelationbetweenmonthlyrainfalland detec-tionofinfluenzacaseswasobservedinMaceió,astatecapital ofnortheasternBrazilwiththesameclimateandlocatednear Fortaleza.Themainfactorsthatdeterminetheseasonalityof influenzaisstillanopenquestion,especiallyintropicalareas oftheworld.Probablythecombinedactionofenvironmental factors(humidity,temperature,and solarradiation),factors relatedtoimmunityinthepopulationanddemographic fac-tors(populationdensity,population flows,school calendar, and travel ormigration) interferes withviral circulation in differentpartsoftheworld.23Humanagglomerationduring therainyseasononthenortherntropicalBraziland during thewinterinsubtropicalandtemperatesouthernBrazilmay drivethedifferencesininfluenzaseasonalityseenindifferent regionsofthecountry.

Unlikeinﬂuenza,surveillancedatashowthatthe circula-tionofRSVisverysimilarinthenorthandnortheastregions tothemidwestandsoutheasternBrazil,occurringmostlyin thefall.Onlyinthesouthernregion,theRSVcirculation pre-vailsin the winteralong withthe circulation ofinﬂuenza. Studies with viral data held in southeastern Brazil in the citiesofRiodeJaneiro,24_Vitória,25_São_Paulo,26,27_Campinas,28

andUberlândia29,30_showed_an_RSV_season_from_February_to

August,peakinginMay.ThestudyofanoutbreakofRSVin Salvador,northeasternBrazil,alsoshowedapatternofviral circulationsimilartothatobservedinthesoutheast, begin-ninginthefallandlastinguntiltheendofwinter.31_Studies

inFortalezaassociatedthecirculationofRSVintheﬁrsthalf oftheyearwiththerainyseason.32,33_Studies_in_the_southern

regioncorroboratesurveillancedataforRSV;theyshoweda predominanceoftheRSVidentiﬁcationinthewinter,between JulyandOctoberinthecitiesofPortoAlegre34_and_Pelotas.35

Amongtheparainﬂuenzaviruses,thetype3wasthemost common,withthehighestcirculationinthesecondhalfofthe yearinearlyspring,apatternsimilartothatobservedin stud-iesconductedinRiodeJaneiro24_and_Fortaleza.20_We_observed

anoutbreakofPIV-2in2008–2009inBrazil;intheUnitedStates thisvirushasbeenassociatedwithepidemicseverytwoyears, co-circulatingwithPIV-1duringthefall.36,37

Thisstudyhaslimitations:itiselevenyearsofa surveil-lance system that hasgradually expanded, the number of positivesamplesisstillsmall,andmorerecentyearsarelikely tobeover-represented.Moreyearswithalargernumberof samplesarestillnecessarytoverifytheobservedpatternsof seasonality.Furthermore,sentineldatacannotbetruly repre-sentativeforthewholepopulationandthesystemofsentinel unitsinvolvesdifferentlevelsofcomplexityofcare;thereis nostandardprotocolforpatientselectionforsample collec-tionwhichcanleadtoaselectionbias.Thelargestnumberof samplesfromchildrensuggestsaselectionbiasforthisgroup, whichprobablyresultedinagreaternumberofpositive sam-plesforRSV.Thetechniqueusedforprocessingthesamples wasIFA,whichhasasensitivityof60–70%whencompared withmolecularbiologytechniquessuchasPCR,38_which_may

haveunderestimatedthenumberofdetectedcasesbecause offalse-negativeresults.

Despite these limitations, the surveillance system for influenza and other respiratory viruses has proved useful to describethe patterns ofviral circulationinthe country. This information is important for deciding the best time for influenza vaccination and treatment decisions for the use ofinfluenza antiviralsaccordingtodiseaseseasonality, besidescontributingwithBraziliansamplesforthe formula-tion ofSouthern Hemisphere’sinfluenzavaccine. Although the implementationanddevelopmentofasentinel surveil-lancesystemforinfluenzaandotherrespiratoryvirusesisthe firststeptounderstandtheepidemiologyofthesevirusesin thecountry,moreinvestmentsininfluenzaandother respira-toryvirusessurveillanceareneededtoobtainepidemiological datathatcanestimateandquantifytheimpactofinfluenza andotherrespiratoryvirusestopublichealth,besides improv-ingthesystem’srepresentativeness,timeliness,andcapacity tointervene.

Conﬂict

of

interest

Allauthorsdeclaretohavenoconﬂictofinterest.

Acknowledgements

Theauthorthankstheinfluenzasurveillanceteamfromthe BrazilianMinistryofHealth:JoséRicardoPioMarins,Marcia LopesdeCarvalho,FabianoMarquesRosa,Walquiria Apare-cidaFerreiradeAlmeida,LibiaRobertadeOliveiraSouza,and DaianaAraujodaSilvafortheirhelpandallprofessionalsfrom Brazilian statesand municipalities involvedwith influenza surveillancewhohaveworkedontheformationand mainte-nanceofinfluenzaandotherrespiratoryvirusessurveillance inBrazil.

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