DeclineinrespiratorydeathsnotassociatedwithinfluenzainRussia:

effectoftheintroductionofthepneumococcalconjugatevaccine

(PCV13),orimprovementincare?

EdwardGoldstein1,*

1. CenterforCommunicableDiseaseDynamics,DepartmentofEpidemiology,

HarvardTHChanSchoolofPublicHealth,Boston,MA02115USA

*.egoldste@hsph.harvard.edu

Abstract

Background.Pneumococcalvaccination(PCV13)forchildren(aswellasolder

adults)inRussiawasintroducedin2014,withnopriorPCV7use.Whilepneumonia

hospitalizationrates,bothinchildrenandadultsdidn’tdecreaseinthefollowing

years,respiratorymortalityratesdeclinedwithtime.Moreover,thereisastrong

associationbetweenantibiotic,includingmultidrugresistanceandPCV13vaccine

serotypesforS.pneumoniaeinchildreninRussia,andpresenceofS.pneumoniae

amongsepsiscasesinRussiaduringtherecentyearshasbeenverylow.Annual

variabilityininfluenzacirculationmayaffectsomeofthechangesinrespiratory

mortalityrates,obscuringthetrendsinrespiratorymortalityrelatedto

pneumococcalvaccination.

Methods.Weappliedtheinferencemethodfromourrecentstudyofinfluenza-

associatedmortalityinRussiatorelatemonthlyrespiratorymortalityratesbetween

09/2010and08/2019tomonthlyindicesofinfluenzacirculationandbaselinerates

ofmortalitynotassociatedwithinfluenza,allowingforapotentialtrendinthe

baselineratesstarting2015.

Results.Baselineratesofrespiratorymortalitynotassociatedwithinfluenza

decreasedwithtimestartingfromthe2014/15season(witheachseasonrunning

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fromSeptembertoAugust),withthe2018/19baselineratesofrespiratory

mortalityper100,000individualsbeinglowerby12.41(95%CI(10.6,14.2))

comparedtothe2010-2014period.

Conclusions.Whileimprovementincaremighthavecontributedtothereductionin

theratesofrespiratorymortalitynotassociatedwithinfluenzainRussia,theabove

temporallyconsistentreductioniscompatiblewiththegradualreplacementof

vaccineserotypesinthetransmissionandcarriageofS.pneumoniaefollowingthe

introductionofPCV13.Furtherworkisneededtobetterunderstandtheimpactof

PCV13ontheepidemiologyofrespiratoryinfectionsandrelatedmortalityinRussia.

Introduction

Pneumococcalconjugatevaccine(PCV13)wasintroducedinRussiain2014,with

highuptakeinyoungchildrenreportedby2016[1].Serotypereplacement

comparedtocarriagedatafromthepre-PCV13yearswasfound[2-4],withserotype

replacementfollowingpneumococcalvaccinationalsohavingtakenplaceinother

countries[5,6].WhileratesofpneumoniafollowingtheintroductionofPCV13in

Russiahavenotdecreased,neitherinchildren[1],noroverall[7],onecanseea

notabledeclineintheratesofmortalityforrespiratorycausesintheyearsfollowing

therolloutofPCV13[8].Someofthatdeclinemaypotentiallybeexplainedbya

strongassociationbetweenantibiotic,includingmultidrugresistanceandPCV13

vaccineserotypes[3,4],withresistantinfectionswithvaccineserotypes(compared

tonon-vaccineserotypes)beingmorelikelytodevolveintothemostsevere

outcomes,includingsepsisanddeath.Indeed,amajorstudyofsepticinfectionsin

St.Petersburg,Russiafoundthatrespiratorytractwasthemostcommonsourceof

thoseinfections,andS.pneumoniaewasfoundveryrarelyforthosecases[9].

InthisstudyweaimtoevaluatethetrendsinrespiratorymortalityratesinRussia

followingtheintroductionofPCV13vaccination.Annualvariabilityininfluenza

circulationmayaffectsomeofthechangesinrespiratorymortalityrates,obscuring

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theabovetrends.Forexample,therateofrespiratorymortalityinRussiaduringthe

2014/15season(SeptemberthroughAugust)washigherthanduringeachofthe

fourpreviousseasons(2010/11through2013/14),withthatdifferencebeing

relatedtothemortalityassociatedwiththemajor2014/15influenzaseason[10].

Thus,inordertostudytrendsinrespiratory(orpneumonia)mortalityrates,one

oughttoadjusttheobservedratesfortheeffectofinfluenzacirculation.Here,we

applytheinferencemethodologyfromourrecentstudyofinfluenza-associated

mortalityinRussia[10]torelatethemonthlyratesofrespiratorymortality,

providedbytheRussianFederalStateStatisticsService(Rosstat)[8]totheindices

ofmonthlyincidenceofinfluenzaA/H3N2,A/H1N1,andBinRussia(derivedfrom

thesurveillancedatafromtheSmorodintsevResearchInstituteofInfluenza(RII)

[11]),adjustingforbaselineratesofrespiratorymortalitynotassociatedwith

influenza.Moreover,weincludetermsforthetrendinbaselineratesofnon-

influenzaassociatedrespiratorymortalitytoexaminethechangeinthoserates

followingtheintroductionofPCV13.Wealsodiscussthepotentialcausesforthe

changesinrespiratorymortalityrates,includingtheeffectofpneumococcal

vaccination.

Methods

Data

MonthlydataonmortalityforrespiratorycausesinRussiawereobtainedfrom[8].

Monthlymortalitycountsforrespiratorydeathswerethenconvertedtomonthly

ratesofmortalityper100,000individualsusingpopulationdatafromRosstat(with

annualpopulationestimatesinterpolatedlinearlytoestimatethepopulationby

month).

Weeklydataontheratesofinfluenza/AcuteRespiratoryIllness(ARI),

(грипп/ОРВИ)consultationper10,000individualsinRussiaareavailablefrom

[11].Dataontheweeklypercentofrespiratoryspecimensfromsymptomatic

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individualsthatwereRT-PCRpositiveforinfluenzaA/H1N1,A/H3N2andinfluenza

Barealsoavailablefrom[11](undertheLaboratoryDiagnosticslink).

Incidenceproxies

Onlyafractionofindividualspresentingwithinfluenza/ARIsymptomsareinfected

withinfluenza.Wemultipliedtheweeklyratesofinfluenza/ARIconsultationper

10,000individuals[11]bytheweeklypercentagesofrespiratoryspecimensfrom

symptomaticindividualsthatwereRT-PCRpositiveforeachofinfluenzaA/H1N1,

A/H3N2andB[11]toestimatetheweeklyincidenceproxiesforeachofthe

correspondinginfluenza(sub)types:

Weeklyinfluenza(sub)typeincidenceproxy=(1)

Rateofconsultationsforinfluenza/ARI*%AllrespiratoryspecimensthatwereRT-

PCRpositiveforthatinfluenza(sub)type

Asnotedin[12],thoseproxiesareexpectedtobeproportionaltotheweekly

populationincidencefortheeachofthemajorinfluenza(sub)types(hencethename

“proxy”)–infact,thoseproxiesestimatetheweeklyratesofconsultationforARI

associatedwiththecorrespondinginfluenza(sub)types,dividedbythesensitivityof

theRT-PCRtest.MonthlyincidenceproxiesforinfluenzaA/H1N1,A/H3N2andB

wereobtainedastheweightedaverageoftheweeklyincidenceproxiesforthose

weeksthatoverlappedwithagivenmonth;specifically,foreachinfluenza(sub)type

andmonth,theincidenceproxyforeachweekwasmultipliedbythenumberofdays

inthatweekthatwerepartofthecorrespondingmonth(e.g.7iftheweekwas

entirelywithinthatmonth),thentheresultsweresummedoverthedifferentweeks

anddividedbythenumberofdaysinthecorrespondingmonth.Torelatethe

incidenceproxiesforthemajorinfluenza(sub)typestomonthlymortalityrates,we

firstshifttheweeklyincidenceproxiesbyoneweekforwardtoaccommodatefor

thedelaybetweeninfectionanddeath[12],thenusetheshiftedweeklyincidence

proxiestoobtainthecorrespondingmonthlyincidenceproxiesasabove.

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Therelationbetweenanincidenceproxyandtheassociatedmortalitymaychange

overtime.Inparticular,influenzaBischaracterizedbythecirculationof

B/YamagataandB/Victoriaviruses.Itisknownthattheagedistributionforthe

B/YamagatainfectionsisnotablyolderthanfortheB/Victoriainfections[13,14].

Correspondingly,therelationbetweentheincidenceproxy(whichreflectsinfluenza

incidenceinthegeneralpopulation)andinfluenza-relatedmortality(whichfor

influenzaBlargelyreflectsmortalityinolderindividuals)maybequitedifferentfor

influenzaB/YamagatacomparedtoinfluenzaB/Victoria.Whiletherearenodataon

theweeklypercentagesofB/YamagataandB/Victoriaamongthetestedrespiratory

specimensin[11],suchwhole-seasondataareavailablein[11].Foreachinfluenza

season(runningfromSeptembertoJune),weobtaintheproportionsofinfluenzaB

specimensfromthatseasonthatwereforB/YamagataandB/Victoria(usingdata

fromthelastreportedweekduringthatseason[11]),andmultiplytheweekly

incidenceproxyforinfluenzaBduringthatseasonbythecorresponding

proportionstoestimatetheweeklyincidenceproxyforeachofinfluenza

B/YamagataandB/Victoria.Finally,the2014/15seasonwascharacterizedbythe

globalcirculationofanovelA/H3N2variant.Mortalityforthatvariantispotentially

differentfromthemortalityforthepreviouslycirculatingA/H3N2strains.

Correspondingly,torelateA/H3N2torespiratorymortality,wesplittheA/H3N2

incidenceproxyintotwo:one(called𝐴/𝐻3𝑁2!) equalingtheA/H3N2proxy

between09/2010through08/2014,zeroforsubsequentmonths;theother(called

𝐴/𝐻3𝑁2!) equalingtheA/H3N2proxybetween09/2014through08/2019,zerofor

previousmonths.Figure1plotsthemonthlyincidenceproxiesforinfluenza

A/H3N2(twoproxies),A/H1N1,B/YamagataandB/Victoriabetween09/2010and

08/2019(108months).

InferenceModel

Let𝑀(𝑡)betheaveragedailyrespiratorymortalityrateper100,000duringmonth

𝑡 (with𝑡 = 1for09/2010,𝑡 = 108for08/2019),and𝐴/𝐻3𝑁2!(𝑡),𝐴/𝐻3𝑁2!(𝑡),𝐴/

𝐻1𝑁1(𝑡),𝐵/𝑉𝑖𝑐𝑡𝑜𝑟𝑖𝑎(𝑡),𝐵/𝑌𝑎𝑚𝑎𝑔𝑎𝑡𝑎(𝑡)betheincidenceproxiesforthedifferent

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influenza(sub)typesonmonth𝑡asdescribedintheprevioussubsection.The

inferencemodelin[10,12]suggeststhat

𝑀 𝑡 = 𝛽! + 𝛽! ∙ 𝐴/𝐻3𝑁2!(𝑡)+ 𝛽! ∙ 𝐴/𝐻3𝑁2!(𝑡)+ 𝛽! ∙ 𝐴/𝐻1𝑁1(𝑡)+ 𝛽! ∙ 𝐵/

𝑉𝑖𝑐𝑡𝑜𝑟𝑖𝑎(𝑡)+ 𝛽! ∙ 𝐵/𝑌𝑎𝑚𝑎𝑔𝑎𝑡𝑎(𝑡)+ 𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 + 𝑁𝑜𝑖𝑠𝑒(2)

Herethenoiseiswhitenoise(linearregression),and𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒isthebaseline

averagedailyrateofrespiratorymortalityper100,000notassociatedwith

influenzacirculation.Weassumethatthisrateisperiodicwithyearlyperiodicity,

excpetforthepotentialtrendstarting2015.Wewillmodelitas

𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑡 = 𝛽! ∙ cos!!"!"

+ 𝛽! ∙ sin!!"!"

+ 𝛽! ∙ Jan t + SE t + Trend(3)

Here𝐽𝑎𝑛isavariableequaling1forthemonthofJanuary,0otherwise.Thereason

forincludingthisvariableisthatthemonthly(ratherthanannual)mortalitydatain

[8]isoperational,withsomeofthemortalitynotregisteredduringagivencalendar

yearbeingaddedtoJanuaryofthenextyear[15].The(temporal)trendismodeled

asaquadraticpolynomialinthemonthstarting01/2015(thusthemonthforthe

trendequals0priorto01/2015,itequals1for01/2015,itequals13for01/2016

etc.,andthetrendisaquadraticfunctionofthatmonth).Finally,thesummereffect

SE t equals1forthemonthofJuly,2forthemonthofAugust,and0forother

months.Thereasonforincludingthisvariableisthatthereisaconsistentdipin

respiratorymortality(Figure2)duringthemonthsofJulyandAugust(particularly

August),presumablyhavingtodowiththedeclineinthetransmissionofrespiratory

viruseswhenschoolsareclosed/weatherishot,andthisdipcannotbe

accommodatedbythetrigonometricmodelineq.3.Whilethisvariablewasn’t

includedinthemodelin[10],itsinclusionresultsinasignificantimprovementin

themodelfit,andexcludingthisvariablehasaveryminoreffectontheestimationof

thetrendinrespiratorymortalityfollowingtheintroductionofPCV13.

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Results

Figure1plotsthemonthlyproxiesfortheincidenceofinfluenzaA/H3N2(splitinto

twoasdescribedinMethods),A/H1N1,B/Yamagata,andB/Victoriaduringour

studyperiod(09/2010through08/2019).

Figure1:MonthlyproxiesfortheincidenceofinfluenzaA/H3N2(splitintothe

09/2010thoughthe08/2104periodandthe09/2014throughthe08/2019

period),A/H1N1,B/Yamagata,andB/Victoriabetween09/2010through08/2019.

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Figure2presentsthefitsforthemodelineq.2fortheaveragedailyratesof

respiratorymortalityper100,000individualsbymonth(blackcurve)forthe

monthsof09/2010through08/2019.Thosemodelfitswerelargelytemporally

consistentsavefortheearlypartofthestudyperiod,whichmaypartlyhavetodo

withdataqualityforthatperiod---seeDiscussion.Figure2alsoexhibitsthe

averagedailybaselinerates(bymonth)ofrespiratorymortalityper100,000people

notassociatedwithinfluenzabetween09/2010though08/2019.Thoserates

declinedduringtheperiodfollowingtheintroductionofPCV13vaccination.

Figure2:Averagedailyratesofrespiratorymortalityper100,000peoplebymonth

(blackcurve);fitsforthemodelineq.2(redcurve);averagedailybaselinerates(by

month)ofrespiratorymortalityper100,000peoplenotassociatedwithinfluenza

(greencurve)between09/2010though08/2019.

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Table1presentstheestimatesoftheratesofinfluenza-associatedrespiratory

mortalityduringeachofthe2010/11throughthe2018/19seasons(September

throughAugustforeachseason),aswellastheexpectedseasonalbaselineratesof

respiratorymortalitynotassociatedwithinfluenza.Thoseexpectedseasonalrates

weremodeledasconstantforthe2010/11throughthe2013/14seasons(savefora

tinychangeduringthe2011/12seasonduetothefactthat2012wasaleapyear).

Subsequently,thosebaselineratesdeclined,withadeclineof12.41(10.6,14.2)

respiratorydeathsnotrelatedtoinfluenzaper100,000individualsduringthe

2018/19seasoncomparedtothe2010/11throughthe2013/14seasons.

Season Rateofinfluenza-

associatedrespiratory

mortality

Expectedrateofnon-

influenzarelated

respiratorymortality

Reductioninrespiratory

mortalityratefollowing

PCV-13introduction

2010/11 2.52(1.5,3.6) 49.01(47.9,50.1)

2011/12 0.08(-0.8,0.9) 49.15(48,50.2)

2012/13 2.76(1.7,3.8) 49.01(47.9,50.1)

2013/14 0.66(-0.1,1.4) 49.01(47.9,50.1)

2014/15 4.43(3.5,5.4) 47.87(46.9,48.9) 1.14(0.8,1.5)

2015/16 2.65(1.9,3.3) 44.05(42.8,45.3) 5.1(3.9,6.3)

2016/17 3.02(1.6,4.4) 40.63(39.3,42) 8.38(6.8,9.9)

2018/18 3.21(2.6,3.8) 38.19(37,39.4) 10.82(9.3,12.3)

2018/19 2.58(2,3.1) 36.6(35,38.2) 12.41(10.6,14.2)

Table1:Seasonalratesofinfluenza-associatedmortalityinRussiaforthe2010/11

throughthe2018/19seasons(SeptemberthroughAugust),expectedseasonalrates

ofnon-influenzaassociatedrespiratorymortality,andreductioninnon-influenza

associatedmortalityfollowingtheintroductionofPCV13startingthe2014/15

season.

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Discussion

ThepneumococcalconjugatevaccinePCV13wasintroducedinRussiain2014,with

uptakeincreasingsignificantlyduring2015[1].Thiswasfollowedbyapronounced

declineinrespiratorymortality,includingpediatricmortality[1],thoughnotthe

ratesofpneumoniahospitalizationinRussia[1,7].Someofthereasonsfortheabove

discrepancymayhavetodowiththefactthatvaccinestrainsforPCV13aremuch

moredrug-resistant,aswellasmultidrug-resistantcomparedtonon-vaccinestrains

inRussia[3,4].Influenzacirculationaffectstheratesofrespiratorymortality,as

wellaschangesinthoserateswithtime.Tobetterunderstandthetrendsin

respiratorymortalitynotassociatedwithinfluenzacirculationinRussia,weapplied

theinferencemodelin[10,12]toestimatethe(baseline)ratesofnon-influenza

respiratorymortality,aswellastrendsinthosebaselinerates.Wefounda

consistentdeclineintheratesofnon-influenzarespiratorymortalitystarting2015.

Moreover,thisfindingwasrobustwithregardtoseveralassumptionsmadeinour

inferencemodel.

Akeyquestionisrelatedtothecausesbehindtheaforementioneddeclineinthe

ratesofnon-influenzarespiratorymortality.Improvementincarecouldpotentially

contributetodeclineinrespiratorymortalityrates.Atthesametime,changesinthe

epidemiologyofpneumococcus,particularlyreductioninthecarriageofvaccine-

typestrainsinchildrentookplaceinRussia[2-4].IntheUS,virtualdisappearanceof

thewinterholidayseasonbumpinpneumoniamortalitytookplacefollowingthe

introductionofthePCV7vaccine(Figure2in[12]),withthatbumppriortothe

introductionofPCV7ascribedtothetransmissionofpneumococcalstrainsfrom

youngchildrentotheirgrandparentsduringtheholidayseason.InRussia,

transmissionofS.pneumoniaefromyoungchildrentoolderindividualsmightbe

evengreaterthanintheUSduetodifferencesincontactsbetweenthoseagegroups

forthetwocountries.Additionally,non-vaccinestrainsofS.pneumoniainchildren

inRussiaaremuchlessantibiotic-resistantcomparedtovaccinestrainsforPCV13

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[3,4].Allofthissuggeststhatthedeclineinnon-influenzarespiratorymortality

ratesestimatedinthisstudyisalsoconsistentwiththereplacementofvaccine

serotypesinthetransmissionandcarriageofS.pneumonia,withthatreplacement

beingmorepronouncedyear-to-yearasmoreasmoreandmoreyoungchildrenare

protectedbythevaccine[5].Furtherworkisneededtobetterunderstandthe

impactofPCV13ontheepidemiologyofS.pneumonia(includingserotype

replacementintheelderlypopulation)andrelatedmortalityinRussia.

Ourpaperhassomelimitations.Weonlyhadaccesstomonthlymortalitydata;

moreover,thosedataareoperational,withsomedelaysinreporting,andsome

unreporteddeathsduringagivencalendaryearbeingreportedforJanuaryofthe

nextyear[15].Moreoverthosedataweremadeavailableafterthestartofthestudy

period[15],withtheearlierdataextractedretrospectively.Influenzasurveillance

datacanalsobesubjecttonoisesuchasthediscrepancybetweenthetimingof

specimencollectionandtesting/reporting.Forthe2013/14season,influenza

circulationwasstillsignificantbyweek20of2014,with18%ofrespiratory

specimenstestingpositiveforinfluenzaduringthatweek[11];however,no

surveillancedataforthesubsequentweeksduringthatseasonareavailablein[11].

Allofthismightexplainsomelackoftemporalconsistencyinthemodelfit(Figure

2),particularlyduringtheearlypartofthestudyperiodwhenthequalityofthedata

maybemorequestionable.Finermortalitydatastratifiedbyweek/agegroupare

neededtogetamorecomprehensiveunderstandingofdeclineintheratesof

respiratorymortalitynoassociatedwithinfluenzaintheperiodfollowingthe

introductionofPCV13inRussia.

Webelievethatdespitetheabovelimitations,ourresultssuggestarobustdecline

theratesofrespiratorymortalitynotassociatedwithinfluenzafollowingthe

introductionofPCV13inRussia.Thatdeclineisconsistentwithreplacementof

vaccineserotypesofS.pneumoniaethataremoredrug-resistantcomparedtonon-

vaccineserotypesinRussia.Furtherworkisneededtobetterunderstandtheimpact

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ofPCV13ontheepidemiologyofS.pneumoniaandrelatedsevereoutcomes,

includingmortalityinRussia.

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