Risk of invasive pneumococcal disease in patients with asplenia/hyposplenism: A nationwide population-based study in Korea, 2009-2018

Risk

of

invasive

pneumococcal

disease

in

patients

with

asplenia/hyposplenism:

A

nationwide

population-based

study

in

Korea,

2009

–2018

Ji-Man

Kang

,

Eun

Hwa

Kim

,

Kyong

Ihn

,

Inkyung

Jung

,

Minkyung

Han

,

Jong

Gyun

Ahn

*

a

DepartmentofPediatrics,SeveranceChildren'sHospital,YonseiUniversityCollegeofMedicine,SouthKorea b

InstituteforImmunologyandImmunologicalDiseases,YonseiUniversityCollegeofMedicine,SouthKorea c

BiostatisticsCollaborationUnit,DepartmentofBiomedicalSystemsInformatics,YonseiUniversityCollegeofMedicine,SouthKorea d

DepartmentofPediatricSurgery,SeveranceChildren'sHospital,YonseiUniversityCollegeofMedicine,SouthKorea e

DivisionofBiostatistics,DepartmentofBiomedicalSystemsInformatics,YonseiUniversityCollegeofMedicine,Seoul,SouthKorea

ARTICLE INFO

Articlehistory: Received27May2020

Receivedinrevisedform7July2020 Accepted9July2020

Keywords: Asplenia

Invasivepneumococcaldisease Relativerisk

Splenectomy Population-basedstudy

ABSTRACT

Objectives:Weaimedtodeterminetheincidenceandrelativerisk(RR)ofinvasivepneumococcaldisease (IPD)inpatientswithasplenia/hyposplenism,usinganationwidepopulation-baseddatabase. Methods:From2009to2018,allclaimedcasesofnewlydiagnosedasplenia/hyposplenismintheNational Health Insurance Servicein SouthKoreawereincluded. Theincidence and RRofIPD inasplenia/ hyposplenismpatientswereinvestigatedusingtheKoreanCenterforDiseaseControlcriteria. Results: Fifty-seven IPD cases wereidentifiedamong 21,376 patients with82,748 person-years of exposure.Thecumulative8-yearIPDincidencewas0.5%;45.6%oftheinfectionsoccurredwithintwo yearsafteranasplenia/hyposplenismdiagnosis.Theage-standardisedincidence ratewas104.5per 100,000person-years(95%confidenceinterval[CI], 103.6–105.4).Patientsaged<5yearshada15.1-times higherriskofIPDthanthoseaged60years(95%CI:5.8–39.5,p<0.0001).TheRRofIPDwas32.0times higherinpatientswithasplenia/hyposplenismthaninthegeneralpopulation(95%CI,21.7–47.0);the standardizedincidenceratiowas17.9(95%CI,11.8–26.0).

Conclusions:Thislargepopulation-basedstudyhighlightsthehighIPDincidencerateandRRinKorean patients with asplenia/hyposplenism. Increased awareness and effective prevention strategies are neededforthesehigh-riskpopulations,especiallychildrenaged<5years.

©2020TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases. ThisisanopenaccessarticleundertheCCBY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background

Asplenia, the absence of the spleen, is typically a result of

splenectomyandisrarelycongenital.Hyposplenismisadisorderin

whichthespleen'sfunctionandsizearereducedduetoseveral

underlyingdiseases(DiSabatinoetal.,2011).Asvariousimmune

cellsandelementsinthespleen,includingheterogeneoussplenic

macrophages,opsonins,IgM,andmemoryBcells,contributetothe

filtering of blood pathogens and induction of an appropriate

immune response, asplenia/hyposplenism can cause serious

bloodstreaminfections,especiallyinfectionscausedby

encapsu-lated pathogens, including Streptococcus pneumoniae, Neisseria

meningitidis, and Haemophilusinfluenzae (Borges daSilva et al.,

2015;RubinandSchaffner,2014).

Numerous studies of such infections, especially invasive

pneumococcaldisease (IPD)after splenectomy, havebeen

pub-lished(Krauthetal.,2008;KingandShumacker,1952;Theilacker

etal.,2016).AsystematicreviewreportedanIPDincidenceof2.9%

inpatientswithseverepost-splenectomyinfections,whileanother

reviewreported890IPDcasesper100,000person-yearsofsevere

post-splenectomyinfectionamong21,404person-yearsof

expo-sure(Cullingfordetal.,1991;Holdsworthetal.,1991).However,

thosestudieswereconductedbeforethe1990sandmaynotreflect

thecurrentsituationaftertheintroductionofthepneumococcal

*Corresponding author at: Department of Pediatrics, Severance Children's Hospital,YonseiUniversityCollegeofMedicine,50-1Yonsei-ro,Seodaemun-gu,PO Box03722,Seoul,SouthKorea.

E-mailaddress:[email protected](J.G.Ahn). 1

Ji-man Kang, Eun Hwa Kim, and Kyong Ihn contributed equally to this manuscript.

https://doi.org/10.1016/j.ijid.2020.07.013

1201-9712/©2020TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

conjugatevaccine(PCV).Also,theeffectofrareconditions,suchas

congenitalaspleniaorhyposplenism,onthedevelopmentofIPD,

comparedwithsplenectomy,isunclear(Williametal.,2007).

Thisstudyaimedtoinvestigate the incidenceof IPDamong

patientswithasplenia/hyposplenismandtodeterminetherelative

risk(RR)ofIPDinthePCVera,usinga nationwide

population-baseddatabase.WealsoevaluatedtheriskfactorsforIPDandthe

occurrenceofinvasiveN.meningitidisandH.influenzaeinfections

inthesehigh-riskpopulations.

Methods

HealthInsuranceReviewandAssessment(HIRA)servicedatabase

South Korea has a universal health coverage system, the

NationalHealthInsuranceService(K-NHIS),whichcovers

approx-imately98%oftheoverallKoreanpopulation(51,420,000citizens

inthe2017census)(Kimetal.,2014).TheHIRAassessestheclaims

fromalmost80,000medicalinstitutionsincludedin theK-NHIS

andhasanextensivedatabasethatcontainsdetailedinformation

aboutthediagnoses,treatment,surgicalhistory,andprescription

drugsofpatientsfromtheentirepopulation.

TheNationalInfectiousDiseaseSurveillanceSysteminKorea

The Korean Center for Disease Control (KCDC)operates the

NationalInfectiousDiseaseSurveillanceSystemandprovides

real-time information on the occurrence of mandatory notifiable

infectiousdiseases throughan InfectiousDisease Portal(http://

www.cdc.go.kr/npt/biz/npp/nppMain.do).TheKCDCpublishesthe

Infectious Disease SurveillanceYearbook annually with various

statisticsoninfectiousdiseases,anddataontheagedistributionof

the general population (KCDC, 2017). S. pneumoniae (since

September 2014), H.influenzae type B (sinceSeptember 2013),

and N. meningitidis (since 2001) infections are mandatorily

notifiablediseases;cliniciansormedicalinstitutionsthatdiagnose

ordetecttheseinfectionsareobligatedbylawtoreportallsuch

cases.Also,theNationalImmunisationProgram(NIP)providesfree

ofcharge vaccination against those pathogensfor thepediatric

population. From 2015 to 2018, the complete vaccination rate

includedintheNIP(exceptN.meningitidis)is94–97%for1-year

oldsand92–95%for2-yearoldsinKorea.

Studypopulation

Allclaimedcasesofasplenia/hyposplenisminSouthKoreafrom

1January2008to31December2018wereincluded.Patientswith

asplenia/hyposplenismwereidentifiedusingtheKoreanClassi

fi-cation of Disease (KCD) codes adapted from the International

Classification of Diseases 10th revision (ICD-10). Patients with

asplenia/hyposplenism were defined as those diagnosed with

congenitalasplenia(Q89.00)/hyposplenism(D73.0)orthosewho

underwent a splenectomy(procedure codes:P2091–P2093). As

previouscasesmayconfoundtheactualincidence,theclaimsdata

for2008wereexcluded,toaccountforawash-outperiod.

Definitions

To analyzetheincidenceandrisk factorsofIPD inasplenia/

hyposplenism patients, all codes defining IPD among the KCD

codeswereincluded[Method1].IPDwasdefinedusingtheKCD

codes,namely,A40.3(pneumococcalsepsis),G00.1(pneumococcal

meningitis),K67.8(pneumococcalperitonitis),J13(pneumococcal

pneumonia),A49.1(pneumococcalinfection),I30.1(pneumococcal

endocarditis), M00.1(pneumococcalarthritis),andB95.3

(pneu-mococcal infections in other sites), with at least one of the

following diagnostic codes: K65.0 (acute peritonitis), M00.8

(arthritisandpolyarthritisduetootherspecifiedbacterialagents),

O85(puerperalsepsis),P23.6(congenitalpneumoniaduetoother

bacterial agents), and/or I33.0 (acute and subacute infective

endocarditis).TocomparetheincidencerateofIPDbetweenthe

patientswithasplenia/hyposplenismandthegeneralpopulation,

weusedtheIPDcriteriaoftheKCDCtounifythecasedefinition

[Method2].TheKCDCcriteriauseonlytheK65andB95.3codesfor

pneumococcalperitonitis(excepttheK67.8code)andexcludethe

A49.1 code for non-specific pneumococcalinfection. In case of

otherinvasiveinfectionsduetoencapsulatedbacteria,invasiveN.

meningitidisinfectionwasdefinedusingtheA39.0–39.9codes,and

invasiveH.influenzaeinfectionwasdefinedusingtheA41.3,A49.2,

G00.0,J14,J20.1,G00.0,andB96.3codes.

Comorbidity was defined as a disease whose code was

registeredorpersistedbetweenoneyearpriortotheindexdate

(datewhenthefirstasplenia-relatedcodewasinserted)and30

daysaftertheindexdate.WeusedtheCharlsonComorbidityIndex

withmodificationstocategorizethecomorbidities(Quan etal.,

2005). We selected Hodgkin’s disease, portal hypertension,

idiopathic thrombocytopenic purpura, thalassemia, hereditary

spherocytosis,autoimmunelymphoproliferativesyndrome,

post-transplantlymphoproliferativedisease,andprimaryimmunode

fi-ciency diseases, includinghemophagocytic lymphohistiocytosis,

astheknownriskfactorsfor severepost-splenectomyinfection

(Bisharatetal.,2001;Sinwar,2014).Antimicrobialprophylaxiswas

defined as administering oral antimicrobials for at least nine

monthswithinoneyearoftheindexdate.IPD-relateddeathswere

definedascasesinwhichthedischargecodefordeathwasused

duringintravenousantimicrobialtreatmentduetoIPD.

Statisticalanalysis

Continuousvariableswereexpressedasthemeanstandard

deviation and were compared using the independent t-test.

Categorical variables were expressed as number (%) and were

compared using the chi-square test or Fisher’s exact test. Cox

proportional hazards regression analysis was performed to

identifythefactorsassociatedwithinfectionriskafterasplenia/

hyposplenism(sex, ageatdiagnosis/surgery,comorbidities, and

causeofasplenia/hyposplenism).TheKaplan-Meiermethodand

log-ranktestwereusedtocomparethecumulativeincidencerates

ofinfectionaccordingtothecauseofasplenia/hyposplenism.

Age-specific rates, age-standardized rates (ASRs), and standardized

incidenceratios(SIR) with95% confidenceintervals (CIs) were

calculated.Rateswereexpressedper100,000 person-years.The

ASRswerecalculatedfordifferentagegroups(0–4,5–19,20–39,

40–59,and 60 years), and the SIR was used tocompare the

incidenceofinfectionbetweenaspleniapatientsandthegeneral

population.Forcomparison,weusedthenumberofreportedcases

ofinfectiousdiseasesinthegeneralpopulation,asrecordedinthe

2017InfectiousDiseaseSurveillanceYearbook(KCDC,2017).The

95%confidenceintervalsofSIRwerecalculatedusinga Poisson

distribution.Allstatisticaltestsweretwo-sided,andPvalues(p)

<0.05wereconsideredstatisticallysignificant.SASEnterprise9.4

software(SASInstitute,Cary,NC)wasusedforstatisticalanalysis.R

software(version 3.0.2,R Foundationfor StatisticalComputing,

Vienna, Austria) was used to draw the cumulative incidence

curves.

Ethicalstatement

Sinceweextractedthepatients’informationafterde-identi

fi-cation, thepatient’sinformed consentwaswaived, and

institu-tionalreviewboardapprovalwasnotrequired.

Results

ThedetailsofpatientselectioninthisstudyareshowninFigure

1.From January2008 to December 2018, 23,542 patientswith

asplenia/hyposplenismwereidentified fromtheHIRAdatabase.

After excluding 2105 patients based on the exclusion criteria,

21,376 (20,524 [96.0%] who underwent splenectomy and 852

[4.0%] diagnosed with congenital asplenia/hyposplenism) were

included.Amongpatientswithcongenitalasplenia,87(10.2%,87/

852)hadthediagnosticcodesforcongenitalheartdiseases,and13

ofthem(14.9%,13/87)hadadiagnosticcodeforrightisomerism.

Themale-to-femaleratiowas52.5:47.5,andtheaverageageatthe

time of asplenia/hyposplenism (at the time of splenectomy or

diagnosis of congenital asplenia/hyposplenism) was 56.0 years

(16.9years).Theannualnumberofclaimedcasesforasplenia/

hyposplenismtendedtoincreaseslightlyover theyears,witha

non-significanttrend(averageannualpercentage change=0.4%;

p=0.08).Themeanfollow-updurationwas3.9years(3.0years).

Table1

Characteristicsofthestudypopulation.

Numberofpatients TotalN,N=21,376 (%) Non-infection, N=21,319

(%) Infection,N=57 (%) P-value Ageatdiagnosisofcongenitalasplenia/splenectomy,

meanyears,SD 56.0216.90 56.0416.88 50.5622.40 0.07 0to4years 123 0.58 118 0.55 5 8.77 <.0001 5to19years 712 3.33 712 3.34 0 0.00 20to39years 2481 11.61 2471 11.59 10 17.54 40to59years 7922 37.06 7905 37.08 17 29.82 Over60years 10,138 47.43 10,113 47.44 25 43.86 Sex Male 11,214 52.46 11,179 52.44 35 61.40 0.17 Female 10,162 47.54 10,140 47.56 22 38.60

Meandurationoffollow-up,years,SD 3.872.97 3.872.97 2.202.12 <.0001

Causesofasplenia Splenectomy 20,524 96.01 20,474 96.04 50 87.72 0.0073 Congenitalasplenia/hyposplenism 852 3.99 845 3.96 7 12.28 Comorbiditiesa Anycomorbidities 20,544 96.11 20,491 96.12 53 92.98 0.28 Cardiovasculardisease 10,889 50.94 10,857 50.93 32 56.14 0.43 Neurologicaldisease 1225 5.73 1219 5.72 6 10.53 0.14 Endocrinedisease 9787 45.78 9757 45.77 30 52.63 0.30 Liverdisease 9111 42.62 9090 42.64 21 36.84 0.38 Respiratorydisease 8773 41.04 8750 41.04 23 40.35 0.92 Renaldisease 656 3.07 655 3.07 1 1.75 1.00 Malignancyorimmunosuppression 14,381 67.28 14,346 67.29 35 61.4 0.34 Gastrointestinaldisease 8925 41.75 8902 41.76 23 40.35 0.83 Rheumaticdisease 1022 4.78 1017 4.77 5 8.77 0.20 Others 9263 43.33 9235 43.32 28 49.12 0.38

Riskfactorsforseverepost-splenectomyinfection 1964 9.19 1959 9.19 5 8.77 0.91

Hodgkindisease 12 0.06 12 0.06 0 0.00 >0.999

Portalhypertension 27 0.13 27 0.13 0 0.00 >0.999

Idiopathicthrombocytopenicpurpura 1581 7.40 1577 7.40 4 7.02 >0.999

Thalassemia 3 0.01 3 0.01 0 0.00 >0.999

Hereditaryspherocytosis 330 1.54 329 1.54 1 1.75 0.5885

Autoimmunelymphoproliferativesyndrome 13 0.06 13 0.06 0 0.00 >0.999

Post-transplantlymphoproliferativedisease 4 0.02 4 0.02 0 0.00 >0.999

Primaryimmunodeficiency 18 0.08 18 0.08 0 0.00 >0.999

Antimicrobialprophylaxisa _{191 0.89 189 0.89 2 3.51 0.09}

SD,standarddeviation. a

Antimicrobialprophylaxiswasdefinedasoralantimicrobialsprescribedforatleastninemonthsduringoneyearaftertheindexdate(datewhenthefirstasplenia-related codewasinserted).

Of21,376patients,themajority(96.1%,n=20,544)hadmorethan

one comorbidity, and the proportion of patients with any risk

factorforseverepost-splenectomyinfectionwas9.2%(n=1964);

only 0.9% (n=191) received oral antimicrobial prophylaxis

(Table 1). The most commonly used oral antimicrobial agents

werecephalosporins(mostlycephalexin, cephradine,cefadroxil,

and cefuroxime),accounting for44.5%, followed byquinolones,

25.2%;penicillin,25.1%;andmacrolides,9.1%.

IncidenceofIPDinasplenia/hyposplenismpatients

Of21,376patientswithasplenia/hyposplenism,57experienced

IPDin82,748person-yearsofexposure.Onlyoneelderlypatient

withIPDhadaconcurrentH.influenzaeinfection.The1-,5-,and

8-year cumulative IPD incidence was 0.1%, 0.3%, and 0.5%,

respectively,afterasplenia/hyposplenism(Figure2A).Almosthalf

oftheinfections(45.6%,26/57)developedwithintwoyearsafter

asplenia/hyposplenism, while 14.0% of the infections (8/57)

developedaftermorethanfiveyears(Figure2B).Byagegroup,

the8-yearcumulativeIPDincidenceinpatientsaged<5yearsof

12.0%wassignificantlyhigherthanthatintheotheragegroups

(0.5%;p<0.0001bylog-ranktest;Figure2C).

ThecrudeincidencerateofIPDwas68.9per100,000

person-yearsinallagegroups(95%CI:52.2–89.3),andtheASRwas104.5

per 100,000 person-years (95% CI: 103.6–105.4). After sex

standardization,the patientswithasplenia aged 0–4 years had

thehighestincidencerateof748.8per100,000person-years(95%

CI:737.3–760.4;Figure2D).

CharacteristicsofIPDinpatientswithasplenia/hyposplenism

Among the 57 IPD cases, IPD developed in the 50 (87.7%)

patients with splenectomy and in seven (12.3%) patients with

congenital asplenia/hyposplenism. There were six (10.5%, 6/57)

IPD-related mortalities. Non-specific pneumococcal infection

(A49.1) was the most common diagnosis (31.6%, 18 patients),

followed bypneumococcalpneumonia(J13),peritonitis(K67.8),

sepsis (A40.3), arthritis (M00.1), and infectious endocarditis

(I30.1), accounting for 31.6% (n=18), 29.8% (n=17), 21.1%

(n=12), 8.8% (n=5), 5.3% (n=3),and 3.5% (n=2) of the cases,

respectively.Amongthe18patientswith‘'non-specific

pneumo-coccal infections’, we additionally searched the other inserted

diagnosticcodestospecifytheinfectionsiteororgan.Therewere

sevencasesofpneumonia(38.9%,7/18),fourcasesofperitonitis

Figure2.Cumulativeincidenceofinvasivepneumococcaldisease(IPD)inpatientswithasplenia/hyposplenism(A).DistributionofIPDafterasplenia/hyposplenism(B). CumulativeincidenceofIPDinpatientswithasplenia/hyposplenismaccordingtoagegroups(C).Sexstandardized,age-specificrateofIPDaccordingtothetwodifferentIPD criteria(D).

(22.2%,4/18),twocasesofskinsofttissueinfection(11.1%,2/18),

twocasesofneutropenicfever(11.1%,2/18),onecaseofbacteremia

(5.6%, 1/18), and one of osteomyelitis (5.6%, 1/18). For the

remaining one patient, it was difficult to estimate the site of

infectionthroughadditionaldiagnosticcodesearching.

TwopatientswithIPDwereobservedinthe0–4yearsgroup.

One was diagnosed with congenital asplenia before his first

birthdayandhadIPDattheageofone.Theotherpatienthada

splenectomyattheageoftwoyearsandhadIPDatfouryears.Both

ofthesepatientssurvived.

RiskfactorsforIPD

Intheunivariateanalysis,youngage(<5years)andcongenital

asplenia/hyposplenismdiagnosisweresignificantriskfactorsfor

IPD(Table2).Afteradjustingforsex,comorbidities,riskfactorsfor

severepost-splenectomyinfections,andantimicrobial

prophylax-is,theIPDratewasstill13.8timeshigherinpatientsaged<5years

than in those aged 60 years (95% CI, 3.7–51.6; p<0.0001);

however,nosignificantdifferenceoccurredforcongenital

asple-nia/hyposplenism (adjusted hazard ratio=1.7; 95% CI, 0.6–4.5;

p=0.33;Table2).

RRofIPDcomparedwiththatinthegeneralpopulation

BasedontheKoreanCDCcasedefinition[Method2],18

non-specific pneumococcal infections, and twelve pneumococcal

peritonitiscaseswereexcludedfromtheanalysis. Detailed

age-specific rates, according to the KCDC criteria, are shown in

SupplementaryTableS1. Accordingtothe agegroupand KCDC

criteria, the crude IPD RR was 32.0 (32.6 vs.1.02 per 100,000

person-years in the asplenia group and general population,

respectively;Table 3).After agestandardization, theRR of IPD

was17.9timeshigherintheasplenia/hyposplenismgroupthanin

thegeneralpopulation(SIR=17.9;95%CI,11.8–26.0;Figure3).In

particular,theSIRintheagegroupsof5–19,20–39,and<5years

were 100-fold higher than the IPD incidence in the general

population(Figure3).

Discussion

This population-based study shows the incidence of IPD in

patientswithasplenia/hyposplenisminthePCVera.Theincidence

rateofIPDinthisstudywas68.9per100,000person-yearsinthe

crude analysis and 104.5 per 100,000 person-years after age

adjustment, which is comparable to that reported in previous

studies(36to3000per100,000person-years,Table3)(Aavitsland

etal.,1994;Arnottetal.,2018;Backhausetal.,2016;Bisharatetal., 2001;Choeetal.,2017;Cullingfordetal.,1991;Eberetal.,1999; Ejstrud et al.,2000; Foss Abrahamsen et al.,1997; Holdsworth etal.,1991;Kyawetal.,2006;Madencietal.,2019;Marrieetal.,

2016).Ourdataalsoshowed thattherisk ofIPDwas17.9

(age-adjusted)to32.0(crude)timeshigherinthestudypopulationthan

inthegeneralpopulation.Previousstudies,sincethe1990s,have

shownthattheRRinaspleniapatientsrangesfrom14.1to36.6

withoutageadjustment(Table3)(Aavitslandetal.,1994;Arnott

etal.,2018;Backhausetal.,2016;Bisharatetal.,2001;Choeetal., 2017;Cullingfordetal.,1991;Eberetal.,1999;Ejstrudetal.,2000; FossAbrahamsenetal.,1997;Holdsworthetal.,1991;Kyawetal., 2006;Madencietal.,2019;Marrieetal.,2016).OurhighRRimplies

thatimprovedawarenessamongpatientsandthedevelopmentof

effectivepreventionstrategiesarestillwarranted,eveninthePCV

era.

This epidemiological study has several strengths. First, our

studyinvestigatedtheIPDincidenceinmorethan21,000patients

with82,000person-yearsofexposure,minimizingthelikelihood

ofoverestimation.Inpreviousstudies,theincidenceofIPDvaried

ineachstudy,from36to3000per100,000persons-years.Several

possible reasonsmay be suggested for this difference, such as

differentcasedefinitions,ethnicity,regionaldiversity,andvarious

nationalvaccinationprograms.Also,thestudypopulation'ssizeis

oneofthemostimportantfactorsinestimatingtheincidenceof

IPD. The number of studies reporting a high incidence of IPD

(>1000per100,000)hasnotbeenlarge;moststudypopulations

havebeenrelativelysmall,withlessthan1000studyparticipants

(Ejstrudet al.,2000; Madenci etal., 2019;Marrieet al., 2016).

Second, our data reflect the status of high pneumococcal

vaccination coverage in the general population. In Korea, the

PCV13/PCV10vaccinationforallyoungchildrenhasbeenincluded

intheNationalImmunisationProgram(NIP)since2014,andthe

pneumococcalpolysaccharide vaccine(PPSV23) forolderadults

aged65yearswasintroducedin2013(Heoetal.,2018).After

implementingtheNIP,thecoveragerateofPCVincreasedfrom65%

in2012to97%in2017,and thatofPPSV23among olderadults

increasedfrom5%in2013to57%in2014(Heoetal.,2018).Thus,it

islikelythatpneumococcalvaccinationsweregivenasscheduled,

Table2

Riskfactorsforinvasivepneumococcalinfectioninpatientswithsplenectomy/asplenia.

Variable CrudeHRa

AdjustedHRa

HR(95%CI) P-value HR(95%CI) P-value Ageatdiagnosis/surgery 0to4years 15.10(5.78 39.46) <.0001 13.79(3.68 51.63) <.0001

　 5to19years 0.73(0.17 3.07) 0.66 0.71(0.16 3.22) 0.66

　 20to39years 1.06(0.48 2.35) 0.89 1.06(0.47 2.44) 0.88

　 40to59years 0.78(0.42 1.45) 0.43 0.79(0.42 1.46) 0.44

　 Over60years 1(reference) 　 1(reference) 　

Sex Male 1(reference) 　 1(reference) 　

　 Female 0.70(0.41 1.19) 0.19 0.73(0.42 1.24) 0.24

Comorbidities No 1(reference) 　 1(reference) 　

　 Yes 0.67(0.24 1.86) 0.45 0.92(0.30 2.75) 0.87

Riskfactorsforseverepost-splenectomyinfection No 1(reference) 　 1(reference) 　

　 Yes 0.80(0.32 2.01) 0.64 0.90(0.35 2.32) 0.82

Antimicrobialprophylaxisb _{No 1(reference) 　 1(reference)}

　 Yes 3.45(0.84 14.13) 0.09 0.51(0.09 2.85) 0.44

Causesofasplenia Splenectomy 1(reference) 　 1(reference) 　

　 Congenitalasplenia/hyposplenism 3.13(1.42 6.90) 0.005 1.66(0.61 4.54) 0.33

CI,confidenceinterval;HR,hazardratio. a

UnivariateandmultivariateCoxregressionanalyseswereperformed.

b _{Antimicrobialprophylaxiswasdefinedasoralantimicrobialsprescribedforatleastninemonthsduringoneyearaftertheindexdate(datewhenthefirstasplenia-related} codewasinserted).

Table 3

Summary of major studies on the incidence of severe infection in patients with asplenia/hyposplenism published since 1990. Country, year

published

Study method Outcome General population Estimated

RR

Ref

Design Population at risk No of

population

Age Study period No of

cases

Definition of cases Case incidence per 100,000 PY (A)

IPD incidence per 100,000 PY (B)

(A)/(B)

UK, 1991 Literature review Post-splenectomy 5902 Any 1952–1987 173 All severe infections

(B, M, PP)

N/Ab

Holdsworth et al. (1991)

Australia, 1991 Literature review Post-splenectomy 21,404 PYs Any 1981–1991 N/A All severe infections

(B, M, PP)

890 Cullingford et al.

(1991)

Israel, 2001 Literature review Post-splenectomy 19,680 Any 1966–1996 236c _{IPDs (B, M) N/A Bisharat et al.}

(2001) Korea, 2019 Population-based cohort Aspleniaa /Hyposplenism 2137/ 82,748 PY

Any 2009–2018 27 IPDs 32.63 1.02 32.0 Our data

Korea, 2017 Single-center, retrospective

Post-splenectomy 213  18 y 1997–2016 6 All severe infections 280d

Choe et al. (2017) Australia, 2018

Population-based cohort

Aspleniaa

/Hyposplenism 3221 Any 2003–2014 28 Encapsulated

bacterial infections 150 (pre-registry) 36 (registry)e Arnott et al. (2018) Australia, 1991 Population-based cohort

Post-splenectomy 1490 Any 1971–1983 22 All bacteremia 280f

Cullingford et al. (1991)

US, 2019

Population-based cohort

Post-splenectomy 195  18 y 2005–2014 13 Sepsis requiring

hospitalization

1800 Madenci et al.

(2019)

Canada, 2016 Case-control Post-splenectomy 825 PYs Any 2000–2014 37 IPDs 3000 82 36.6 Marrie et al. (2016)

Sweden, 2016 Population-based cohort

Post-splenectomy 1500 Any 1996–2008 41 IPDs 210 15.1 14.1 Backhaus et al.

(2016) Scotland, 2006

Population-based cohort

Post-splenectomy 1648 Any 1988–1999 30 All severe infections

(B, M) 890 Kyaw et al. (2006) Denmark, 2000 Population-based cohort

Post-splenectomy 538 Any 1984–1993 38 All bacteremia 2300g

Ejstrud et al. (2000) Switzerland, 1999 Case-series Post-splenectomy (hereditary spherocytosis)

330 Children 1989–1995 4 All severe infections

(B, M) 690 Eber et al. (1999) Norway, 1997 Single-center, retrospective Post-splenectomy (Hodgkin’s disease)

325 15 68 1969–1980 10 IPDs (B, M) 226 11 20.5 Foss Abrahamsen

et al. (1997)

Norway, 1994 Case-control Post-splenectomy 3000 PYs N/A 1992–1993 8 IPDs

(culture-confirmed)

267 11 25.0 Aavitsland et al.

(1994) B, bacteremia; IPD, invasive pneumococcal disease; M, meningitis; N/A not applicable; PP, pneumococcal pneumonia; PY, patient-years; RR, relative risk.

a_{Asplenia includes post-splenectomy.}

b_{S. pneumoniae accounts for 56.7%, and H. influenzae accounts for 6.3% of cases.} c_{S. pneumoniae accounts for 66% of cases among 358 etiology-proven, invasive infections.} d

3 Pneumococcal bacteremia infections.

e

27 Invasive pneumococcal infections and one Neisseria meningitidis infection.

f

S. pneumoniae infection accounts for 31.6% of cases (six cases).

g

Enterobacteria infections were the most prevalent (45%), and only one S. pneumoniae infection was report.

J.-M. K ang et al. / International Journal of Infectious Diseases 98 (2020) 486 – 493 49

regardlessoftheaspleniastatusinyoungchildrenorolderadult

patients.PCVvaccination inyoung childrencanalsochangethe

carriagestrain ofolder populationsfrom PCVserotypes toless

virulent, non-PCV serotypes, which may indirectly affect the

unvaccinated adult patients with asplenia/hyposplenism (Kim

etal.,2016;RubinandSchaffner,2014).However,wecouldnotfind

significantdifferencesintheincidenceofIPDamongpatientswith

asplenia/hyposplenismbeforeandafter2014,whenPCV/PPSV23

wasintroducedintheNIP(89.5and77.0per100,000person-years

beforeandafter2014,respectively,p=0.59).Apossible

explana-tionmaybethepresenceofreportingbias.InKorea,sincePCVwas

includedintheNIPin2014,reportingofIPDbecamemandatory.

Therefore,therewasapossibilityofunderreportingbefore2014.To

clarify PCV's effects on this population, a long-term study,

includingpneumococcalserotypeanalysis,iswarranted.

The extremely low coverage rate (0.9%) of antimicrobial

prophylaxisinSouthKoreaisoneofourmostunexpectedfindings.

We defined antimicrobial prophylaxis as the use of oral

anti-microbialsforatleastninemonthswithinoneyearoftheindex

date; only 0.9% of the study population fit this criterion. For

reference,only2.3%ofpatientsareprescribedfor3–6months,and

only1.2%areprescribedfor6–9months;therefore,itseemsthat

theoralantimicrobialprescriptionforprophylaxisitselfhasbeen

notwellpracticedinSouthKorea,regardlessoftheprescription

periodaftersplenectomyordiagnosisofasplenia/hyposplenism.

Wedo notknowtheexactcauseofthisfinding,butthelackof

awarenessoftheimportanceofantimicrobialprophylaxisandthe

traditionalmedical habitsof prescribingnon-antimicrobial

pro-phylaxis among clinicians, including surgeons in South Korea

mightbethepossiblecauses.Thisfindingremindsusthatactual

clinicalpracticemaybeinconsistentwiththeguidelines.Inthis

case, establishing and managing a patient registry can have

practicaladvantages.Arnottetal.recentlyreportedadecreasein

IPDincidencefrom150to36 per100,000 person-years among

3221patientswithasplenia/hyposplenismafterenrolmentinthe

SpleenRegistryinAustralia.Theyemphasizedtheimportanceofa

long-term,multi-disciplinaryapproachincludingeducation,

clini-calguidance,includingadviceonantimicrobialprophylaxisand

emergency medicine, and a personalized vaccine report for

registrantsandclinicians(Arnottetal.,2018).However,concerning

cost-effectiveness, the emergence of antimicrobial-resistant

pathogens and poorcompliance, high-level evidence for these

recommendationsarestilllacking;therefore,furtherstudiesare

neededontheexacteffectof eachpreventionstrategy,suchas

vaccination schedule or antimicrobial prophylaxis (Khasawneh

etal.,2019;Spijkermanetal.,2018).

Holdsworthetal.reportedthattherateofpost-splenectomy

infectioninchildrenaged<5yearswas10.4%,whichwashigher

than0.9%ofadults(Holdsworthetal.,1991).Weconfirmedthata

patientage<5yearsisasignificantriskfactorforIPDinpatients

with asplenia/hyposplenism. There was no difference in the

incidence rate between splenectomy-related and congenital

asplenia/hyposplenismafter ageadjustmentinthemultivariate

analysis. This finding, regardless of the cause of asplenia/

hyposplenism,emphasizesthatthespleen'simmunologicalrole

is particularly important in younger children who still lack

immunological experience - both in terms of immunological

maturityandexposuretopathogens.Aranburuetal.reportedthat

memoryBcellsininfantswerelessmutated,resultinginreduced

affinitymaturation,butbecamehighlymutatedat6–7yearsofage

inthepresenceofagerminalcenterandspleen(Aranburuetal.,

2017).Theyalsoreportedthatchildrenwithcongenitalasplenia

couldnotproducehighlymutatedIgMmemoryBcells,evenlater

inlife.Thesefindingsimplythatvaccinationmaybesub-optimally

effective for infants and young children with splenectomy or

congenitalasplenia/hyposplenismcomparedtothatfor

splenec-tomizedadultpatients.Whenclinicallydeterminingthetimingof

splenectomy,itiscriticaltoconsiderdelayingthesurgeryafterfive

yearsofage,anditisalsonecessarytoinduceasufficientmemory

immuneresponsebycompletingPCVvaccinationbeforesurgery.

Thisstudyhad somelimitations. First,it was a retrospective

study;underreportingwaspossible.However,despitethepossibility

ofunderestimation,theunderreportingbiascouldbeoffsetbecause

thesameKCDCcriteria[Method2]wereusedwhendeterminingthe

RR ofIPDinthepatientpopulationcomparedwiththatinthegeneral

population. Secondly, sincethedata onvaccination recordsand

pneumococcal serotypes were notavailable in the HIRA database, the

direct effects of IPD following pneumococcal vaccination and

serotype differences could not be assessed. Thirdly, the rate of

antimicrobialprophylaxisinpatientswithasplenia/hyposplenism

was extremely low in Korea (0.9%); thus, the sample size was

insufficientforassessingitseffectiveness.Finally,theprevalenceof

some high-risk factors, such as thalassemia and hereditary

spherocytosis,isverylowamongKoreanpeople,makingitdif_ficult

toassesstheadditionalIPDriskassociatedwiththesediseases.

Nevertheless, this is the largest population-based study to

provideinformationonthehighIPDincidenceinpatientswith

asplenia/hyposplenisminthePCVera.Itisalsothefirststudyto

presenttheage-specificRRforIPDinhigh-riskpatientscompared

withthatinthegeneralpopulation.Ourdatasupportedthenotion

thatyoungchildrenhadahigherincidenceofIPDthanotherage

groups.Moreover,congenitalasplenia/hyposplenismdidnothave

an additional risk of IPD compared to splenectomy, in the

multivariateanalysis.

In conclusion, the incidence of IPD was high at 104.5 per

100,000person-yearsinKoreanpatientswith

asplenia/hyposplen-ism.Thisrisk was more than 18 timeshigher than that in the

generalpopulation.Increasedawarenessregardingthesehigh-risk

populations,especially childrenaged<5 years,is required,and

furtherstudiesareneededtoassesstheeffectivenessofpreventive

methods,includingpneumococcalvaccination.

Contributions

Ji-ManKang,KyongIhn,andJongGyunAhndesignedthestudy,

analyzedandinterpretedthedata,andwrotethemanuscript.Eun

HwaKimandMinkyungHancollected,assembled,andanalyzed

the data. Inkyung Jung analyzed and interpreted the data. All

authorscriticallyreviewedandapprovedthemanuscript.

Conflictofinterest

None.

Acknowledgments None.

Funding

ThisworkwassupportedbytheBasicScienceResearchProgram

throughtheNationalResearchFoundationofKorea(NRF)fundedby

theMinistryofEducation[grant number:2019032869] andThe

MinistryofEducationcommissionedtotheNRF.

AppendixA.Supplementarydata

Supplementarymaterialrelatedtothisarticlecanbefound,in

theonlineversion,atdoi:https://doi.org/10.1016/j.ijid.2020.07.013.

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