Epidemiology of Japanese encephalitis in the Philippines prior to routine immunization
Anna Lena Lopez
a, Peter Francis Raguindin
a,b,*, Josephine G. Aldaba
a, Ferchito Avelino
c, Ava Kristy Sy
d, James D. Heffel fi nger
e, Maria Wilda T. Silva
caInstituteofChildHealthandHumanDevelopment,NationalInstitutesofHealth,UniversityofthePhilippinesManila,Manila,Philippines
bInstituteofSocialandPreventiveMedicine,UniversityofBern,Bern,Switzerland
cDepartmentofHealth,Manila,Philippines
dResearchInstituteforTropicalMedicine,Manila,Philippines
eWorldHealthOrganizationRegionalOfficefortheWesternPacific,Manila,Philippines
ARTICLE INFO
Articlehistory:
Received13August2020
Receivedinrevisedform15October2020 Accepted21October2020
Keywords:
Japaneseencephalitis Japaneseencephalitisvaccines Philippines
Childhoodimmunization
ABSTRACT
Background:Findingswerepublishedin2015thathighlightedtheendemicityofJapaneseEncephalitis (JE)inthePhilippines.Thepolicymakersrespondedbyconductinganimmunizationcampaignand strengthening the surveillance system. Using data on the revitalized surveillance system, the epidemiologyofJEinthecountrywasupdated.
Methods:Electronicdatabasesweresearched,andconferenceproceedingsrelatedtoJEinthePhilippines wereidentifieduntil31December2018.Surveillancedatafrom01January2014to31December2017 wereused.The2015populationcensuswasusedtoestimatethenationalandregionalincidencefor childrenaged<15years.
Results:FourstudiesreportedtheseroprevalenceofJEinthePhilippines,whichshowedincreasing seroprevalencewithincreasingage.Seroprevalencerateswerefrom0%forinfants(aged<1year)to 65.7%inadolescents(12–18years)beforetheimmunizationcampaign.Amongfivestudiesontheclinical profileofJE,casefatalityrangedfrom0to21.1%andneurologicsequelaerangedfrom5.2to81.8%of diagnosedcases.Inthesurveillancedata,JEcasespeakedannuallyfromJulytoOctober,coincidingwith thewetseason.Thenationalincidencewasestimatedataminimumof0.7JEcases/100,000among childrenaged<15years,buthigherrateswereseeninthenorthernregionsofthecountry.
Conclusion: Improved surveillance affirmed the burden of JE in the Philippines. A subnational immunizationcampaign inApril2019was conductedinthenorthernregionsof thecountry.This paperhighlightstheimportanceofincludingtheJEvaccineintheimmunizationprogramandsustained high-qualitysurveillancetomonitoritsimpactonJEcontrol.
©2020TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.
ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc- nd/4.0/).
Introduction
The Philippines is endemic for Japanese encephalitis (JE) (Heffelfinger et al., 2017;Lopez et al., 2015). Caused bythe JE virus, JE is primarily transmitted by Culex tritaeniorhynchus mosquitoes, which are found in rice paddies (Erlanger et al., 2009;MisraandKalita,2010;Keiseretal.,2005).Thecohabitation of animals withhumansettlements and increasedirrigation of land,featuresthatarecommonlyseeninanagriculturalcountry, are considered factors associated with high viral transmission
(Erlangeretal.,2009;Keiseretal.,2005).Asystematicreviewwas conductedin2014andavailablesurveillancedatawereanalyzedto assesstheepidemiologyofJEinthePhilippines(Lopezetal.,2015).
Since then, the country has expanded the existing acute encephalitissyndrome(AES)surveillanceas aproxy forJE,and laterintegratedthiswiththesurveillanceforothercentralnervous system infections known as the acute meningitis-encephalitis syndrome(AMES)surveillance.
The World Health Organization (WHO) recommends the inclusion of JE vaccines in routine immunization programs in countrieswherethediseaseisconsideredapublichealthpriority (World Health Organization, 2015; World Health Organization RegionalOfficefortheWesternPacific,2018).Immunizationisthe cornerstone of JE control (Erlanger et al., 2009; World Health Organization, 2015; Technical Working Group on Japanese
*Corresponding author at: Institute for Social and Preventive Medicine, UniversityofBern,Mittelstrasse43,3012Bern,Switzerland.
E-mailaddress:peter.raguindin@ispm.unibe.ch(P.F.Raguindin).
https://doi.org/10.1016/j.ijid.2020.10.061
1201-9712/©2020TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).
ContentslistsavailableatScienceDirect
International Journal of Infectious Diseases
j o u r n a l h o m ep a g e : w w w . e l s e v i e r . c o m / l o c a te / i j i d
Encephalitis,2014),andthePhilippines’DepartmentofHealthis considering theinclusion ofJE vaccineinthe country’sroutine nationalimmunizationprogram.Tosupportthecountry’sdecision, thisanalysisofavailablesurveillancedatawasconductedandthe systematicreviewonJEthatwasconductedin2014wasupdated.
Methods Systematicreview
PubMed and local databases (Philippine Index Medicus, PIMEDICUS, andHealth ResearchandDevelopmentInformation Network, HERDIN) were searched for articles using the terms
“Japaneseencephalitis”and“Philippines”.Presentationsfromlocal medical conventionswerealsocheckedforconferenceproceed- ings and abstracts. Technical reports, theses and epidemiologic reportswerealsoincluded.Thesearchwasmadetoincludestudies that were not included in the past review, and in addition to articlesfrom01January2014to31December2018.Abstractsand summarieswerereviewedforrelevancebythreeauthors(ALL,PFR andJGA).Fullarticleswereextractedandexaminedtoensurethat therewasnodoublereporting.Datawereextractedandcollated
for analysis. A detailed description of the methods has been previouslypublished(Lopezetal.,2015).
Studies on seroprevalence were collated to identify JE seroprevalence rates by age group. Seroprevalence rate was definedastheproportionofsubjectswiththeminimumprotective levelofJEvirus-neutralizingantibodies(1:10)asdetectedbythe plaque-reduction neutralization test (PNRT) (Hombach et al., 2005).Studiesonclinicalprofileandoutcomeswerecollated.Since approximately 30% of surviving patients have serious residual neurological,psychosocial,intellectualand/orphysicaldisabilities (World Health Organization, 2015), information on neurologic deficits,whenavailable,wasincluded.
Surveillancesystem
ThePhilippine IntegratedDisease Surveillanceand Response (PIDSR) system is an integrated surveillance system for all identifiedprioritydiseasesandeventsinthecountry.Allprivate and public health facilities submit reports for this case-based surveillancewithoutmandatorylaboratoryconfirmation.Within thissystemareseveralsurveillancesystems,someofwhichneed laboratory confirmation. Thesurveillance for acuteencephalitis
Figure1.MapofthePhilippinesshowinglocationsofsentinelhospitalsandaverageannualJapaneseencephalitisminimumincidenceofchildrenaged<15years(case/
100,000)byprovince2015–2017.
syndrome (AES) and bacterial meningitis surveillance was establishedin2008aspartofthePIDSR.In2013,AESandbacterial meningitissurveillancewerecombinedintotheacutemeningitis- encephalitis syndrome(AMES)surveillancein sentinelhospitals throughoutthecountry.AMESiscase-basedsurveillanceinselect hospitalsthatincludeslaboratorytesting.By2016,therewerenine sentinelsitesforAMESsurveillance.Thehospitalswereselected basedontheirlaboratorycapacity,humanresourcesandlogistical resourcesforspecimenprocessingandtransport(Figure1).Case definitionsusedinthesurveillanceareinBox1.Sentinelhospitals were distributed across the different regions of the country.
Specimens(serumandcerebrospinalfluid,CSF)collectedforthe surveillancewerestoredlocallyat2–8 Cforupto3daysuntil transporttotheResearchInstituteforTropicalMedicine(RITM)- NationalJELaboratory,wheretestswereperformed.Thepresence ofJEvirus-specificIgMantibodyinasinglesampleofCSForserum, as detected by an IgM-capture enzyme-linked immunosorbent assay(ELISA),isconfirmatoryforJE.
Dataanalysis
Todescribetheepidemiologiccharacteristicsofthediseasein thecountry,allAMES,AESandJE-confirmedcasesidentifiedfrom thesurveillancesystemweretabulated.Reportsfrom01January 2014to31December2017wereincludedinthedescriptionofthe epidemiologic characteristics.The datawerealsodisaggregated intodifferentmonthstodeterminetheseasonalityofthedisease, andintodifferentadministrativeregionstolookintodisparitiesof incidenceestimatesindifferentareas.
ToestimatetheincidenceofJE,thisanalysiswaslimitedtodata fromlaboratory-confirmedJEcasescollectedfrom01January2015 to31December2017.The2015NationalCensusofthePhilippines was used for children aged <15 years as the denominator (Philippine Statistical Authority, 2018). The AMES surveillance
wasstartedin2013,andphasedintroductioninthedifferentsites wasperformedfrom2013to2014;assuch,2014datawerenot includedintheestimateforincidence.Analysiswaslimitedtothe agegroupwiththehighestburden–childrenaged<15years–tobe comparablewithpastestimatesbyCampbelletal.(2011)andin linewiththeWHO recommendationsonJEvaccination (World HealthOrganization,2015;WorldHealthOrganization,2006).This incidence estimate was based on data from nine sentinel surveillance hospitals.The three-year average onthe reporting ofJE caseswas computedusing theaddressesof childrenwith confirmedJEinfectionatprovincialandregionallevels.Thedisease estimatedincidencewasmappedtostratifyareasthathadhighor lowdiseasetransmission.
Ethicalconsideration
Thestudyuseddatafromclinicalstudiesandpublichealth surveillance data, which comprised aggregated information withnopatientidentifiers.Surveillancedatawereprovidedby the Philippine Department of Health (DOH) Epidemiology Bureau, in compliance with the Data Privacy Act of the Philippines.Noethicalclearancewassought,sinceallsurveil- lance data provided by the Epidemiology Bureau were de- identified, and aggregated data and additional data were obtainedfrompublishedarticles.
Results
Literaturereview
Figure2showstheresultsoftheliteraturesearch.Fourstudies on seroprevalence and five studies on the clinical profile and outcomesofJEwereidentified.Nostudieslookingatanimalhosts andmosquitovectorsonJEwereidentified.
Box1.CasedefinitionsusedinJapaneseencephalitissurveillancea.
Acutemeningitisencephalitissyndrome(AMES)
Acaseofsuspectedacutemeningitis-encephalitisisapersonofanyagewithsudden-onsetfever,plusoneof:
Changeinmentalstatus(includingalteredconsciousness,confusion,disorientation,coma,orinabilitytotalk)align="none"
New-onsetseizures(excludingsimplefebrileseizures)align="none"
Neckstiffnessorothermeningealsigns.align="none"
Casesarethenclassifiedfollowingthecaseclassificationforacuteencephalitissyndrome(AES)orbacterialmeningitis.
Acuteencephalitissyndrome(AES)
AcaseofAESisdefinedasapersonofanyagewithacute-onsetfeverandatleastoneofthefollowing:
Changeinmentalstatus(e.g.confusion,disorientation,coma,orinabilitytotalk)align="none"
New-onsetseizures(excludingsimplefebrileseizures).align="none"
CaseclassificationforAES
Laboratory-confirmedJapaneseencephalitis(JE)
*AnAEScasethathasbeenlaboratory-confirmedasJE.
ProbableJE
*AnAEScasethatoccursinclosegeographicalandtemporalrelationshiptoalaboratory-confirmedcaseofJE,inthecontext ofanoutbreak.
AES–otheragent:
*AnAEScaseinwhichdiagnostictestingisperformedandanetiologicagentotherthanJEvirusisidentified.
AES–unknown:
*AnAEScaseinwhichdiagnostictestingisnotperformedortestingwasperformedbutnoetiologicagentwasidentifiedorin whichthetestresultswereindeterminate
Seroprevalencestudies
FourstudiesreportedontheseroprevalenceofJEinthecountry (Feroldietal.,2012; Gatchalianet al.,2008;Victoret al.,2014;
Dubischaretal.,2017;Nealonetal.,2018).Thesestudiesincluded baselineserologicassessmentsonvaccinesforflavivirus(i.e.JEand Dengue) performed in clinical trials. There were different age group classifications among the four studies, which hindered pooled analysis. Three studies were conducted in Manila and Muntinlupa, which are both highly urbanized cities with populations >500,000 and population densities of 12,000– 71,000/km2 (Philippine Statistical Authority, 2018). One study wasconductedinSanPabloCity,whichwasless-urbanized,witha population of 266,000 and a populationdensity of 1347/km2 (PhilippineStatisticalAuthority,2018).
AntibodiestoJEinthehighlyurbanizedcitiesofManila and Muntinlupa were lower (Feroldi et al., 2012; Gatchalian et al., 2008;Victoretal.,2014;Dubischaretal.,2017)comparedwiththe less-urbanizedSanPablo(Nealonetal.,2018)intheyoungerage groups.Forstudiesreportingseroprevalenceacrossdifferentage groups, increasing age appeared to correlate with increasing antibodyseropositivityinbothhighlyurbanizedandlessurban- izedareas.Bothareashadcomparableseroprevalenceratesinthe olderagegroups, with65.7%seroprevalence amongthose aged
>12–18 years inManila and Muntinlupaand 63% among those aged10–14yearsinSanPablo(Table1).
Clinicalprofile
FivestudiescharacterizedtheclinicalprofileandoutcomesofJE casesinthePhilippines(Alcarazetal.,2016;Mangalinoetal.,2018;
BalderasandTrajano,2018;Agoretal.,2018;Torioetal.,2018).
Three were retrospective record reviews that utilized clinical samplesconfirmedusingJEIgMELISAperformedattheRITM;two were prospective cross-sectional studies. All studies used the AMES case definitions (Mangalino et al., 2018; Balderas and Trajano,2018;Agoretal.,2018;Torioetal.,2018),exceptforone thatusedtheAEScasedefinitions(Alcarazetal.,2016).Thestudies were conducted in tertiary referral hospitals: the Philippine GeneralHospitalinManila,whichservespeoplelivinginManila and other provinces (mostly from Region 4A); Baguio General HospitalinBaguioCity,whichservespeopleresidinginprovinces and surrounding theCordilleraRegion; Cagayan Valley Medical CenterinTuguegaraoCity,whichservespeoplelivinginRegion2 andsomefromtheCordilleraRegion;JBLingadMedicalCenterin SanFernando City, Pampanga, which servespeople from Pam- pangaandBataaninRegion3;andDr.PaulinoJ.GarciaMedical Center in Cabanatuan City, Nueva Ecija, which mainly serves people from Nueva Ecija, in Region 3 (Table2). A slight male predominancewasseenamongcases(from55.2to63.3%).Four studies had proportions of JE-confirmedcases among suspects disaggregatedintotwoagegroups:theproportionofJE-confirmed casesinthegroupaged<5yearsrangedfrom26.7to50%,whilefor the5–14years agegroup,therangewas 48.1–63.2%.Discharge outcomeswereassessedinallstudies.Casefatalityratesranged from0to21.1%(Alcarazetal.,2016;Mangalinoetal.,2017).The lengthofhospitalstaywasrecordedintwostudies,whichwas2–3 weeksuntildischarge.Twostudies(Alcarazetal.,2016;Balderas andTrajano,2018)gradedtheseverityoftheneurologicdeficits among those who survived, and 37.9–45.4% had moderate-to- severeneurologicdeficitsondischarge.Allstudieswerefoundin thenorthernregionsandnoneinotherpartsofthecountry.
Figure2. FlowchartofJapaneseencephalitisstudiesidentifiedfromliteraturereviewthatwereincludedinthisanalysis.
*Includingstudiesthatweremissedinthesearchfromapastpublication.
Table1
SummaryofserologicstudiesonJapaneseencephalitisinthePhilippinesincludedinthisanalysis.
Author Studyyear Location Subjectstested Agegroup Seroprevalence
Gatchalianetal.(2008)andVictoretal.(2014) 2005 Muntinlupaa 490 8months 5.3%
Feroldietal.(2012)andCapedingetal.(2018) 2008 Muntinlupaa 709 12–18months 3.2%
Dubischaretal.(2017) 2010 MuntinlupaandManilaa 20 6–11months 0%
100 1–2years 3.2%
201 3–12years 14.4%
140 13–18years 65.7%
Nealonetal.(2018) 2011 SanPablob 149 2–4years 21%
202 5–9years 42%
249 10–14years 63%
aHighly-urbanizedcities.MuntinlupaCityandManilaCityarebothpartoftheMetroManila.
bLess-urbanizedcity.SanPabloispartofLaguna,aprovinceoutsideofMetroManila.
Surveillancedata
From01January2014to31December2017, therewere790 laboratory-confirmedcasesfrombothAESandAMESsurveillance systems,whichcomprised13.8%ofallreportedsuspectedcases.
Therewasasubstantialincreaseinthenumberofreportedcases from2014to2017(Figure3).Therewere1432suspectedcases/
yearand196confirmedcases/yearfrom2014to2017.Therewasa two-foldincreaseinsuspectedand confirmedJEcasesreported from2014(448suspectedcasesand49confirmedcases)to2015 Table2
ClinicalprofileofJapaneseencephalitis(JE)casesinthePhilippines,2014–2018.
Author,hospitallocation,years covered
Studydesign JE-
confirmed/
suspected cases, n/N(%)
AgeofJE- confirmedcases
<5years,n(%)
5–14 years,n(%)
Sex,males, n(%)
OutcomeofdiagnosedJE cases;
lengthofhospitalstay
Alcarazetal.(2016),Philippine GeneralHospital,Manila
RetrospectivechartreviewofAEScasesadmittedin Jan2011toDec2014,aged0–18yearsold
11/64 (17.2)
Noage breakdownfor JEcases
Nosex breakdownfor JEcases
Died:0(0) Moderate-to-severe deficitsa:5(45.4) Slightdisability:2(18.2) Alivewithnosignificant disability:4(36.4) Noinformationonlength ofstayofJEcases BalderasandTrajano(2018)Baguio
GeneralHospital,BaguioCity
RetrospectivechartreviewofAMESandJEconfirmed casesadmittedfromApril2015toApril2017, aged1–18yearsold
36/198 (18.2)
<5years:8
(26.7)b 5–14years:14 (60.0)
19(63.3)b Died:1(3.4)c Moderatetosevere deficits:11(37.9) Mildneurologicdeficits9 [31.0)
Completelyrecovered:8 (27.6);
Averagelengthofhospital stay:22days
Agoretal.(2018)CagayanValley MedicalCenter,TuguegaraoCity
RetrospectivechartreviewofAMESandJEconfirmed casesadmittedfrom
Jan2014toDec2016, aged1–18yearsold
52/453 (11.5)
<5years:26
(50.0) 5–14yea rs:25(48.1)
30(57.7) Died:1(2) Alivewithdeficits:
29(55.8) Alive:22(42.3)d Noinformationonlength ofstayofJEcases Mangalinoetal.(2018)
JBLingadMedicalCenter,San FernandoCity
Prospective,Cross-sectionalstudyofAMESandJE confirmedcasesadmittedinJan2015toJun2016 aged1–18yearsold
38/272 (14.0)
<5years:13/38
(34.2) 5–14yea rs:24/38(63.1)
21(55.2) Died:8(21.1)
Alivewithdeficits:2(5.3) Alive:28(73.7) Medianlengthofstay:16 days(range1–50days) Torioetal.(2018)
Dr.PaulinoJ.GarciaMedical Center,CabanatuanCity
Prospective,Cross-sectionalstudyofAMESandJE confirmedcasesadmittedinApr2015toMar2016 aged1–18yearsold
68/115 (59.1)
<5years:25
(36.8) 5–14yea rs:43(63.2)
40(58.8) Died:5(7.4)
Alivewithdeficits:5(7.4) Alive:58(85)
Noinformationonlength ofstayofJEcases
aBasedonthemodifiedRankinscalethatiscommonlyusedtomeasurethedegreeofdisabilityordependenceontheactivitiesofdailylivingofpeoplewhosuffereda strokeorothercausesofneurologicaldisability.
bOf30includedintheanalysis.
cOf30,onewenthomeagainstmedicaladviceprecludingoutcomeassessment;therefore,29includedintheanalysis.
d Includesoneeachwhowenthomeagainstmedicaladviceduetofinancialreasons.
Figure 3.Monthly distribution ofsuspected andconfirmed Japanese encephalitis (JE) cases, Philippines, January 2014 to December2017. Data are from acute meningoencephalitissyndrome(AMES)andacuteencephalitissyndrome(AES)surveillanceunderthePhilippineIntegratedDiseaseSurveillanceandResponse(PIDSR).
(1149suspectedcasesand127confirmedcases)andthree-foldand six-foldincreasesfrom2014to2016(1964suspectedcasesand313 confirmed cases) and 2017 (2159 suspected cases and 301 confirmedcases).Figure2alsoshowstheseasonalityofconfirmed andsuspectedJEcasesfrom2014to2017.AlthoughJEcaseswere reportedin almostevery month,thehighest number was seen duringthemonthsofJulytoOctober,whenanaverageof18–32 confirmedcasesofJEwereseenpermonth.November,December andJanuaryhadthefewestcasesreported(5–8casesreportedper month). The highest number of suspected cases was among childrenaged2monthsto2years(n=1,967,33.2%),whilethe highestnumberofconfirmedcaseswasamongchildrenaged2–4 years (n = 194, 23.0%).The highest proportion of JE-confirmed casesoutofallsuspectedcaseswasseenamongchildrenaged5–10 years,at32.0%(293/915)(Figure4).
From 2015to 2017, there were697 laboratory-confirmedJE casesamongchildrenaged<15years,withanaverageof232cases/
year.SuspectedcasesofJEwerereportedinallregionsandin91.5%
(75/82)provincesinthecountry.Usingthe2015censusasthebase population, theestimated national annualized incidence was a minimumof0.7cases/100,000childrenaged<15years.Annually, theestimatedincidenceincreasedfrom0.3in2015to0.9cases/
100,000childrenaged<15yearsin2016and2017.However,there were wide differences among the regions. The regions in the northern part of the country had higher annual estimated incidence rates. The Cagayan Valley (Region 2), Ilocos (Region 1), Cordillera Administrative Region (CAR), and Central Luzon (Region3)hadthehighestincidenceratesat3.1(95%CI2.2–4.4), 2.6(95%CI1.8–3.5),2.6(95%CI1.4–4.3),and2.1(95%CI1.6–2.6) cases/100,000 children aged <15 years (Figure 1). By further disaggregating the data into provinces, the highest annual incidence rates (per 100,000 children aged <15 years) were recordedinthenorthernprovincesofLaUnion(5.9,95%CI3.1–10), Cagayan(5.7,95%CI3.5–8.8)andPampanga(4.5,95%CI3.1–6.2).
Ratesashighas8.6/100,000childrenaged<15years(95%CI5.2– 13.3) were reported in La Union in 2017. The three highest reporting provinces each have a sentinel hospital for AMES surveillance.
Discussion
ThepreviousreportconfirmedtheendemictransmissionofJE in thePhilippines and documenteditswide distribution inthe country,mainlythroughthesentinelsurveillancesystem(Lopez
et al., 2015). It detected 1432 suspected cases/year and 196 confirmed cases/year (2014–2017), which is notably higher compared with the previous publication (287 suspected cases/
year and 19 confirmed cases/year in 2011–2013) (Lopez et al., 2015).Therehaspresumablybeenanincreaseintheawarenessof JE among clinicians, which resulted in increased reporting of suspectedcasesinthesurveillancesystem.
Thisupdateisimportantasabaselineminimumcaseincidence foruseinestimatingtheimpactofJEvaccinationinthecountry.
TheresultsarealsoessentialforsomeAsiancountriesthatareyet to decide on routine vaccination. This update supports earlier findings and provides a more accurate estimate of JE burden, includinganestimateofthediseaseincidenceinthePhilippines.
Althoughthe annual estimatedincidence of JEamong children aged<15yearswaslowerthantheestimatesofCampbelletal.
(2011)of10.6/100,000,therewereprovincesinthecountrythat hadestimatesofupto8.6/100,000.Thepeakofcasesoccuredin JulytoOctober,coincidingwiththewetseason,whichemphasized theseasonalityofthedisease.Therewasawidedisparityinthe clinicaloutcomesofJEcasesreportedinthedifferenthospitals.
Thismayhavebeenduetoinherentdifferencesintheseverityof thecasesseenorthehospitals’capacitiestomanagesuchcases.
Inthisreview,theseroprevalencedatamirroredtheproportion of infected population, as seen from the surveillance data.
Cumulativecasesrevealedthat78%oftheconfirmedcasesbelong tochildrenaged<15years.ApaststudybyNealonetal.showed 63% seropositivityfor childrenaged 10–14years(Nealon et al., 2018), while Dubischar et al. showed 65.7% seropositivity for childrenaged12–18years(Dubischaretal.,2017).Serologicresults fromboth studies weretakenfrom avaccine clinicaltrial,and subject to selection bias. However, previous seroprevalence studies, which focused on determining JE transmission in the community,had the same conclusion. Theyalsoshowed lower proportionsofchildrenthatwereseropositiveforJEvirusinthe urbansetting,andolderchildrenwerelikelyinfectedbythevirus thanyoungerchildren(Hammonet al.,1958;Crossetal.,1977;
Arambulo, 1974). Overall, these findings highlight that the pediatric age group is the primary target population in an immunizationstrategyagainstJE.
Thisstudywasnotwithoutlimitations.First,thecalculatedJE incidence was only based on JE-confirmed cases, which were dependent on the performance of the surveillance and varied throughtheyearsandindifferentregions,sincethesurveillance systemwasslowlyintroduced.Thedifferencesinthenumberof Figure4.AgedistributionofconfirmedandsuspectedJapaneseencephalitis(JE)cases,andthecumulativepercentageofconfirmedJEcases,January2014toDecember2017.
Datafromacutemeningoencephalitissyndrome(AMES)andacuteencephalitissyndrome(AES)surveillanceunderthePhilippineIntegratedDiseaseSurveillanceand Response(PIDSR).
casesreportedwerelikelyduetotheaccessibilityofsentinelsites, theyearbywhichsurveillancewasstartedandtheperfromance qualityofthesurveillancesystem.In2014,sentinelhospitalswere justbeingestablishedandsurveillancepersonnelwereonlybeing trained.Sincenotallregionshavesentinelsurveillancehospitals and the populationmay access other hospitalsapart from the sentinelsites,itislikelythatmorecaseswerenotreported.Hence, the national or regional incidence that was reported probably underestimatedthetrueincidence.Itisinterestingtonotethatthe three provinces with the highest incidence of JE had sentinel surveillancehospitals,whichmayreflectthetrueincidenceinthe Philippines.Thecaseincidenceratesthatwereestimatedfromthe surveillancesystemweresimilartootherAsiancountries(Garjito et al., 2018; Kumar et al., 2018; Kari et al., 2006).Second, the information on clinical profile and outcomes was mostly retrospective with short observation periods. Table 2 shows a widedisparityintheoutcomesamongdifferentfacilities,limiting thegeneralizabilityoftheresultsandleavingthetrueimpactofthe diseaseonlong-termmorbidityandmortalityunknown.Deaths that were identified were mostly during hospitalization. The neurologicdisabilitieswerenotfollowedwithalongertimeframe.
Long-termcomplicationsofthecasesseenonextendedfollow-up areusefulinfurtherascertainingthesocialandeconomicburden of thedisease.Third,allseroprevalencedatacame fromclinical trials;hence,therewasinherentbiasinsubjectrecruitment.Two studiesincludedthewholepediatricagegroup,whiletheother studies focusedontheseroprevalence of infantswhowerethe intendedtargetsofthevaccines.Dataonseroprevalenceamong adultswereunavailable.Age-stratificationalsovariedamongthe studies,whichlimitedthecomparisonsacrossstudies.
JE controlis consideredas a priorityinthe WHO’sWestern PacificandSouth-EastAsiaRegions.ThecornerstoneofJEdisease controlcontinuestobevaccination(Heffelfingeretal.,2017;World Health Organization,2015; WorldHealthOrganization Regional OfficefortheWesternPacific,2018).InApril2019,thePhilippines’ DOH provided Japanese Encephalitis Vaccine Live (SA14-14-2) (Chengdu Institute of Biological Products Co. Ltd China) as a campaignvaccinationinfourregionswiththehighestburdenof thedisease.TheuseoftheSA14-14-2vaccineinthePhilippines was deemed cost-effective compared with no vaccination, regardless of the vaccination strategy that was implemented (Vodickaetal.,2020).Thelive-attenuatedJEvaccinewaspilotedin a campaigntargettingchildrenaged <5 years,and is currently being considered for routine immunization for infants aged 9 months(togetherwiththefirstdoseofmeasles-mumps-rubella).
Thispaperpresentsadditionalinformationsupportingearlier findingsthatJEisendemicinthePhilippines.Itisbelievedthatthis is the first study to present a case-based minimum incidence estimateofJEinthePhilippinesandprovidebaselineestimates priortotheJEvaccinationcampaign.Continuedstrengtheningof thesurveillancesystemwillbeimportanttomonitorthevaccine’s impact and tosupport JE disease control efforts. More refined surveillancedatawillbeusefultoidentifyotheragegroupsand areasofhighestrisk,whichwillbetargeted.
Conflictsofinterest None.
Funding
Thestudyreceivednofundingfromanyorganizationoragency.
Ethicsregistration
Thestudyusedpubliclyavailabledatafortheanalysis.
Authorcontributions
Conceived and designed the experiments: ALL PFR JGA.
Performedtheexperiments:ALLPFRFAAKS.Analyzedthedata:
ALLPFRJDH.Contributedreagents/materials/analysistools:ALLPFR JGAFAAKSMWS.Wrotethepaper:ALLPFRJGAFAAKSJDHMWS.
Acknowledgments
We thank LuzvimindaGarcia of theDisease Prevention and ControlBureau-DepartmentofHealthforherassistanceandVon LuigiValeriooftheNationalInstitutesofHealth-Universityofthe PhilippinesManilafordraftingthefiguresandmaps.
AppendixA.Supplementarydata
Supplementarydataassociatedwiththisarticlecanbefound,in theonlineversion,athttps://doi.org/10.1016/j.ijid.2020.10.061.
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