The burden and costs of sepsis and reimbursement of its treatment in a developing country: An observational study on focal infections in Indonesia

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University of Groningen

The burden and costs of sepsis and reimbursement of its treatment in a developing country

Purba, Abdul Khairul Rizki; Mariana, Nina; Aliska, Gestina; Wijaya, Sonny Hadi; Wulandari,

Riyanti Retno; Hadi, Usman; Hamzah; Nugroho, Cahyo Wibisono; van der Schans, Jurjen;

Postma, Maarten J

Published in:

International Journal of Infectious Diseases

DOI:

10.1016/j.ijid.2020.04.075

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Purba, A. K. R., Mariana, N., Aliska, G., Wijaya, S. H., Wulandari, R. R., Hadi, U., Hamzah, Nugroho, C.

W., van der Schans, J., & Postma, M. J. (2020). The burden and costs of sepsis and reimbursement of its

treatment in a developing country: An observational study on focal infections in Indonesia. International

Journal of Infectious Diseases, 96, 211-218. https://doi.org/10.1016/j.ijid.2020.04.075

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The

burden

and

costs

of

sepsis

and

reimbursement

of

its

treatment

in

a

developing

country:

An

observational

study

on

focal

infections

in

Indonesia

Abdul

Khairul

Rizki

Purba

a,b,c,l,

*

,

Nina

Mariana

d

,

Gestina

Aliska

e

,

Sonny

Hadi

Wijaya

f,g

,

Riyanti

Retno

Wulandari

h

,

Usman

Hadi

i

,

Hamzah

j

,

Cahyo

Wibisono

Nugroho

k

,

Jurjen

van

der

Schans

a,m

,

Maarten

J. Postma

a,b,l,m

a

DepartmentofHealthSciences,UniversityofGroningen,UniversityMedicalCenterGroningen,Groningen,TheNetherlands

b

DepartmentofPharmacologyandTherapy,FacultyofMedicine,UniversitasAirlangga,Surabaya,Indonesia

c_Department_of_Medical_{Microbiology,}_University_Medical_Center_Groningen,_University_of_Groningen,_Groningen,_The_Netherlands d

DirectorateofResearchonInfectiousandCommunicableDiseases,Prof.Dr.SuliantiSarosoInfectiousDiseaseHospital,Jakarta,Indonesia

e

DepartmentofPharmacologyandTherapeutics,FacultyofMedicine,M.DjamilHospital,Padang,Indonesia

f

HospitalQualityAssessment,UniversitasAirlanggaGeneralAcademicHospital,Surabaya,Indonesia

g

DepartmentofInternalMedicine,FacultyofMedicine,UniversitasDiponegoro,Semarang,Indonesia

h

DepartmentofPharmacy,DinasKesehatanKotaSurabaya,Surabaya,Indonesia

i_Department_of_Internal_Medicine,_Faculty_of_Medicine,_Universitas_Airlangga,_Dr._Soetomo_General_Academic_Hospital,_Surabaya,_Indonesia j_Department_of_{Anesthesiology}_and_Reanimation,_Universitas_Airlangga,_Dr._Soetomo_General_Academic_Hospital,_Surabaya,_Indonesia k

DepartmentofInternalMedicine,UniversitasAirlanggaAcademicHospital,Surabaya,Indonesia

l

UnitofPharmacoTherapy,-Epidemiologyand-Economics(PTE2),DepartmentofPharmacy,FacultyofScienceandEngineering,UniversityofGroningen,The Netherlands

m

DepartmentofEconomics,EconometricsandFinance,FacultyofEconomics&Business,UniversityofGroningen,Groningen,TheNetherlands

ARTICLE INFO

Articlehistory:

Received31January2020

Receivedinrevisedform27April2020 Accepted28April2020 Keywords: Sepsis Focalinfection Survivors Developingcountries Universalhealthinsurance Hospitalcosts

ABSTRACT

Objectives:Thisstudyaimedtodeterminetheburdenofsepsiswithfocalinfectionsinthe resource-limitedcontextofIndonesiaandtoproposenationalpricesforsepsisreimbursement.

Methods:Aretrospectiveobservationalstudywasconductedfrom2013–2016oncostofsurvivingand non-survivingsepsispatientsfromapayerperspectiveusinginpatientbillingrecordsinfourhospitals. Thenationalburdenofsepsiswascalculatedandproposednationalpricesforreimbursementwere developed.

Results:Ofthe14,076sepsispatients,5,876(41.7%)survivedand8,200(58.3%)died.Themeanhospital costsincurredpersurvivinganddeceasedsepsispatientwereUS$1,011(SE23.4)andUS$1,406(SE 27.8),respectively.Thenationalburdenofsepsisin100,000patientswasestimatedtobeUS$130million. Sepsispatientswithmultifocalinfectionsandasinglefocallower-respiratorytractinfection(LRTI)were estimated asbeingthetwowiththehighesteconomicburden (US$48millionandUS$33million, respectively,within100,000sepsispatients).Sepsiswithcardiovascular infectionwasestimatedto warrantthehighestproposednationalpriceforreimbursement(US$4,256).

Conclusions:MultifocalinfectionsandLRTIsarethemajorfocalinfectionswiththehighestburdenof sepsis.Thisstudyshowedvaryingcostestimatesforsepsis,necessitatinganewreimbursementsystem withadjustmentofthenationalpricestakingtheparticularfociintoaccount.

Introduction

Sepsis is estimated to involve 31.5 million cases each year worldwide(Fleischmannetal.2016).Ofthesecases, 19.4millionare characterizedbyseveresepsis,accountingfor5.3milliondeaths annually(Fleischmannetal.2016).Theseestimatesarederivedfrom data compiled forhigh-income countries.However, thehighest

* Correspondingauthorat:UniversitairMedischCentrumGroningen,Hanzeplein 1,Groningen9700RB,TheNetherlands.

E-mailaddress:khairul_purba@fk.unair.ac.id(A.K.R.Purba).

https://doi.org/10.1016/j.ijid.2020.04.075

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

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

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mortalitiesoccurinlow-incomecountries,followedbylow-middle incomecountries(LMICs)(Chengetal.2008).Thereisasurprising lackofdataonmortalityandcostsamongsepsispatientsinLMICs such as most African and Asian countries, including Indonesia (Fleischmannetal.2016;Ruddetal.2018).Indonesia,whichisthe mostpopulated country in SoutheastAsia and thefourth most populatedcountryglobally,hasahighincidenceofcommunicable diseases(GuptaandGuin2010;Theworldbank2018).Ascertaining the granularity of the sepsis burden in Indonesia has become essentialinlightofthegovernment’sintroductionofanewnational health insurance system (Jaminan Kesehatan Nasional) (Health MinistryoftheRepublicofIndonesia2014).In2018,universalhealth coverage (UHC), provided by a single national payer, became availablefor203millionpeople(Agustinaetal.2019).Duringthe period 2019–2020, coverage will be extended to the entire Indonesianpopulation(approximately 264 millionpeople) (The worldbank2018; Agustina et al.2019).Accordingly,a national reimbursementpriceforeachdiseasewillneedtobeaccountedfor withinthereimbursementsystem (Pisaniet al.2017;Mboi etal.2018; Agustinaetal.2019).

The economic burden of sepsis, which includes providing medicationandﬂuidresuscitationduringhospitalization,hasbeen reported tobe veryhigh (McLaughlinet al. 2009). In the United States, hospitalizationcostsforsepsispatientswereapproximatelyUS$20 billionin2011(Pfuntneretal.2006).Aprevioussystematicreview, which mostly included studiesperformed in the United States, revealedthatanessentialanalysisoftheeconomicburdenofsepsis concerned an evaluation between survivors and non-survivors becauseofamajordifferenceinthemeantotalhospitalcostsperday (US$351vs. US$948, respectively) (Areﬁanetal.2017). The difference inburdenbetweensurvivorsandnon-survivorsisunknowninLMICs. Internationalbudgetaryguidelinesforsepsismanagementmostly apply to developed countries and therefore may require cost adjustmentsofservicebundlesrelatingtosepsismanagementin resource-limitedsettings(Beckeretal.2009;Tufanetal.2015).

Afocalinfectionterminologywasfirstlyintroducedin1910by WilliamHunter, who elaborated therelationship between focal infections and systemic diseases(Reimann andHavens 1940).Afocal infection is a potential source of microorganisms that may disseminate intodeep tissue and spread tothe bloodstream. A furtherimpactofthedisseminationofthemicroorganismsandtheir toxininthebloodstreamisactivationoftheinflammatorymediators andworseningorgandysfunctionduetosepsis(BabuandGomes 2011).Accordingtothethirdconsensusdefinitionsforsepsisand septic shock (Singer et al. 2016), sepsis has at least an underlying focal infection as an entry ofthepathogen to the systemic circulation. Each focalinfectioncausingsepsiscomeswithdifferentcomplications, withawiderangeofcosts.Therefore,thereimbursementofsepsis needs cost adjustments accordingtotheunderlying focal infection.In Indonesia,sepsisandtheassociatedfocalinfectionsarenotcoded togetherwhencalculatingthenationalpriceofdiseases,resultingin possible under-budgeting for sepsis-relatedexpenditure (Health MinistryoftheRepublicofIndonesia,2016).Therefore,a reevalua-tionofthecostsforsepsishasbecomeurgentforcountrieslike Indonesia,includingdealingwithunderlyingfocalinfections.This studyanalyzedcostsfor survivinganddeceasedsepsispatients, explicitly consideringunderlyingfocalinfections.Inaddition,itthen estimatednationalpricesforreimbursementunderUHCbasedon theanalyzedburdenandcostsofsepsis.

Methods Studydesign

Aretrospectiveobservationalstudywasconductedonpatients withsepsisinfourIndonesianmedicalcenters:(1)Dr.Soetomo

General Academic Hospital in Surabaya, a national healthcare referral center, with 1,514 beds,serving eastern Indonesia; (2) Universitas Airlangga Hospital in Surabaya, a teaching medical centerwith180bedsinSurabaya;(3)TheProf.Dr.SuliantiSaroso NationalCenterforInfectiousDiseasesHospital,with180bedsin Jakarta;and(4)Dr.M.DjamilHospitalinPadang,anationalreferral center with 800 beds, serving western Indonesia. Inpatient registries and hospital discharge data were obtained from the DepartmentofMedicalRecordsfortheperiod01January2013to 31December2016.Thedatasetcoveredpatients’demographics, diagnoses, hospital-discharge mortalities, laboratory tests, and medications.

Criteriaforselectingpatients

Allpatientswithsepsisandaged18yearswereincluded.The diagnosisofsepsiswasclarifiedbythephysicians.Thecriteriafor sepsis diagnosis followed the Indonesian Ministry of Health adopted Third International Consensus Definitions for Sepsis and Shock, Sepsis-3(Singer et al.2016) and diagnostic criteria for sepsis entailedin the Sequential Organ FailureAssessment (SOFA)scorethatincludesatleasttwoofthefollowingthree‘quick’ SOFA (qSOFA) criteria: systolic blood pressure 100 mmHg, respiratoryrate22breathsperminute,andincorporatingaltered mentation(GlasgowComaScalescore<15)(HealthMinistryofthe Republic of Indonesia2017).The studycategorized singlefocal infections per site of theinfection as cardiovascularinfections (CVIs), gastrointestinal tract infections (GTIs), lower-respiratory tractinfections(LRTIs),neuromuscularinfections(NMIs),urinary tractinfections(UTIs),andwoundinfections(WIs).WIsrecognized atthesitesofsurgeryweresubclassifiedassurgicalsiteinfections (SSIs).Thephysiciansconfirmed SSIdiagnosesaccordingtothe CentersforDiseasesControlandPrevention(Horanetal.1992). Focal mouth and dental infections were included in the NMI categorysincethoseinfectionsanatomicallyinvolvedsofttissues suchasnervesandmuscles.Sepsispatientswithtwoormorefocal infections weregrouped into sepsis with multifocal infections. Moreover, an unspecified focal infection was labeled as an unidentifiedfocalinfection(UFI).TheInternationalClassification ofDiseasesversion10wasappliedtodetermineandrecordfocal infections(seeSupplement1).

Costcalculation

Cost was analyzed from a payer perspective using billing records that included the costs of beds, drugs, laboratory and radiologyprocedures,othermedicalfacilities,andtotalcosts.Bed costs encompassed hospital administration fees, daily room services,nursingandmedicalstaffcare,andtechnicians’services. Drug costs were extracted from the pharmacy department’s budget that covered expenses relating to drugs, _fluids, blood productsfortransfusion,disposabledevices,mechanical ventila-tors,oxygentherapy,andpharmacyservices.Physiotherapists’–as rehabilitationspecialists_–consultancycostswererecordedand considered under patients’ bed service costs. Costs for admin-istrations, patient transfer and ambulance, and otherexpenses were included in the costs for other medical facilities. The hospitalization costs per admission were analyzed, considering thedaysspentinanintensivecareunit(ICU), presenceofSSIs, typesoffocalinfections,andwhetherthepatientsurvivedornot. The2016currencyexchangerate(US$1=13,308.33IDR)wasused, as applied by the Organization for Economic Cooperation and Development(OECD)toconvertIndonesianRupiahs(IDR)intoUS Dollars (US$) (Organization for Economic Cooperation and Development2016),withinflationratesof6.40%for2013,6.42% for2014,6.38%for2015,and3.53%for2016(WorldwideInflation

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Data2020).Theeconomicburdenofsepsiswasassessedaccording tothedistributionofdiseaseincidenceoverfocalinfectionsand the mean cost of each focal infection using a denominator of 100,000patientswithsepsis(TheWorldBank2016a).

Extrapolationofthecosttothenationallevel

Thenationalcostsforsepsiswereanalyzedbasedontherates deﬁnedbytheIndonesianHealthMinistryforIndonesiaCaseBase Groups (INA-CBGs). The INA-CBGs’ rateswere used asnational projections for extrapolating the sepsis costs – obtained from patient’sbillingrecords–intoProposedNationalPrices(PNPs)for sepsisreimbursementsbyconsideringthefollowingfouraspects (HealthMinistryoftheRepublicofIndonesia,2016).

Thefirst aspectconcerned theroomclasses in thehospital, whichweredividedintothreeclasses:ClassI,patientshadmore privacywithinoneroom,accommodatinguptotwopatients;Class IIaccommodatingthree orfourpeople;ClassIIIservice accom-modating fiveor six people in a room (Health Ministry of the Republic ofIndonesia, 2016;Presidentof Republic of Indonesia 2016).ThisstudyprovidedthePNPinClassIIIasthereference.It calculatedtheactualcostsfromClassesI,IIandIII_ðCP)_–obtained frompatient’sbillingrecords–anddividedthembythespecific factor(α)accordingtotheINA-CBGsat1.4,1.2,and1.0,respectively (HealthMinistryoftheRepublicofIndonesia,2016).

Thesecondaspectconcernedprivateorpublicsector owner-ship of the hospital. In the INA-CBG system, reimbursement providedbythegovernmentthroughsubsidieswas1.03(β)times higherforprivatehealthcareservicescomparedwiththepublic healthcareservices(HealthMinistryoftheRepublicofIndonesia, 2016).

Thethirdandfourthaspectsconcernedthetypeofhospitaland theregionwherethehospitalislocated,tocorrespond withthe specific INA-CBG prices (ICPj) that were published by the Indonesian Ministry of Health in 2016 (Health Ministryof the RepublicofIndonesia,2016).Theclassificationofhospitaltypein IndonesiawascategorizedintotypesA,B,CandDonthebasisof the medical specialist services (see Supplement 2) (Health MinistryoftheRepublicofIndonesia,2016;PresidentofRepublic ofIndonesia2016;HealthMinistryoftheRepublicofIndonesia, 2019).TherewerefiveINA-CBGregionscovering34provincesin total(Supplement3)(HealthMinistryoftheRepublicofIndonesia, 2016).TheICP for hospitaltype A in RegionI was usedas the denominatorreferenceforICPinthecalculationofaPNP,sincethe actualcostswereobtainedfromthehospitalswithtypeAlocated intheINA-CBGRegionI.Eventually,foraparticularfocalinfection inpatient,ina class ofroom,ina specifictype ofhospital,in a certainregionundertheprivateorthepublicsectors,aPNPfor sepsiswithanxfocalinfectionwasdefinedasinthefollowing formula: PNPx¼ CP

a

Þ ICPj ICP_{Hospital Type A in Region I} #

b

"

Inbrief,thefouraspectsfordevelopingaPNPwerethemean actualcostsreflectingthesinglemeanclasspriceðCP),thespecific factor(α)ofeachClassroom,thespecificINA-CBGprices(ICPj),and thegovernmentsubsidyfactor(β).Thisstudydeveloped280PNPs (sevenfocalinfections,fourtypesofhospitals,twosectors,andfive regions) for reimbursement of sepsis with particular focal infections in the five INA-CBG regions. To compare with the referenceICPs,thePNPswerecategorizedintothreegroups:those with a small difference with the ICP of < US$500, a medium differenceofUS$500–1,000,andamajordifference>US$1,000.

Statisticalanalyses

Data wereanalyzed using IBM SPSS statistics 25, providing descriptive dataonbaseline characteristicsin percentages. Chi-squaretestswereperformedtodeterminethedifferencesbetween surviving and deceased sepsis patients. 1,000 samples were bootstrapped, andin caseswhere thedatawereoverlyskewed the standard error (SE) was adjusted for the mean cost. An IndependentSamplet-testwasappliedtoevaluatethestatistical cost difference between the surviving and deceased patient groups. Subgroup analyses of hospitalization costs relating to ICU treatment, having SSIs, and types of focal infections were performed.Statisticalsigniﬁcancewasdeﬁnedwhenthep-value was<0.05.

Results

Ofthe14,076patientswithsepsis,5,876(41.7%)survivedand 8,200(58.3%)died.Thepatientswerepredominantlymale(53%). The average age among all patients was 49.4 ( 18.9) years. Surviving and deceased sepsis patients evidenced statistical differences for thefollowing single focal infections:LRTIs (38% vs.62%,respectively,p<0.001),UTIs(56%vs.44%,respectively,p< 0.001),andWIs(18%vs.82%,respectively,p<0.001).Thirty-one percent of the sepsis patients were diagnosed with multifocal infections with a signiﬁcant difference between surviving and deceased patients(40%vs.60%, respectively,p<0.001). Ofthe 2,138 sepsis patientswith SSIs, 74.2% died. Also, patientswith sepsiswhowerehospitalizedinanICUdemonstratedahighcase fatality rate (69%). Table 1 presents a summary of the clinical characteristicsofsurvivinganddeceasedsepsispatients. Hospitalizationcosts

The costs per admission for surviving and deceased sepsis patientswere, respectively:US$1,011 (23.4) and US$1,406( 27.8)(i.e.,adifferenceofUS$396,p<0.001).Themeancostforall sepsis cases was US$1,253 ( 19.4). Among non-ICU sepsis patients, the averagecost was lowerfor surviving patients(US $96024.3)comparedwiththatofdeceasedpatients(US$1,189 23.6)peradmission(p<0.001).ForICUsepsispatients,thecostper admissionwasUS$1,618(47.9),withrespectivemeancostsofUS $1,187(61.7)andUS$1,785.5(56.3)forsurvivinganddeceased patients(p<0.001),respectively.Thecostincurredforpatients withsepsiswhohadSSIswashighercomparedwiththatincurred forpatientswhodidnothaveSSIs(US$2,938vs.US$926).Table2 showsthesecostsdividedintounitcostsforbeds,laboratoryand radiology,pharmacy,andothermedicalfacilities.

Thenationalburdenofsepsis

Theanalyses ofthetreatmentcostsperadmissionforsepsis patientswithfocalinfections(seeTable2)indicatedthatthecost washighestforsepsispatientswithCVIs(US$1,731),followedby thosewithWIs(US$1,703),multifocalinfections(US$1,584),LRTIs (US$1,122),NMIs(US$986),UTIs(US$748),andGTIs(US$720).The nationalburdenofsepsisrevealedatotalbudgetofUS$130million (US$5,7million)per 100,000patients. Sepsis withmultifocal infections had the highest national burden of disease within 100,000sepsispatients(US$48million),followedbysepsiswith LRTIs(US$33million),UFIs(US$15million),UTIs(US$11million), GTIs (US$10.7 million), WIs (US$8.6 million), NMIs (US$2.7 million),andCVIs(US$0.9million).Figure1depictstheeconomic burdenofsepsiswithfocalinfections.

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Theprospectivenationalpriceforsepsispatients

ThelowestpricewithintheINA-CBGsystem(ICP)wasforUFI sepsis,withtheICPatUS$298inatypeDpublichospitalinRegion 1,forwhichaPNPofUS$803wasestimated(difference:US$505). ThehighestPNPwasforsepsiswithCVIsintypeAprivatehospitals in Region 5 (US$4,256) compared with the ICP of US$2,270 (difference:US$1,986).AremarkabledifferencebetweenthePNP andICPwasevidentforhealthcareservicesrelatingtosepsiswith WIsintypeAprivatehospitalsinRegion5(US$3,995vs.US$1,421; difference:US$2,574).ReimbursementlevelsundertheoverallPNP forsepsiswerehigherforalltypesofprivatehospitalscompared withthoseforpublichospitals(alltypes)inallINA-CBGregions. Out of 280 PNPs, 87 (31.1%) had major differences from the referenceICPs(>US$1,000).PNPswithamajordifference were predominantlyfor reimbursementof sepsis withWIs (Table3). Supplement4presentsthedetailsbetweenthePNPsandtherates speciﬁedfor theICPsfor sepsis withfocalinfections in allﬁve regionsofIndonesia.

Discussion

In this study, the economic burden for focal infections associated withsepsis was comprehensively determinedin the resource-limitedsettinginIndonesia.Sepsiswasmostlyinduced byLRTIs,accountingforthehighassociatedtotalcostperpatient. BesidesLRTIs,theﬁndingsindicatedastrongcorrelationbetween high costs and having SSIs. The costs especially increased for patients with multifocal infections. In the broader scale, the economic burdenof sepsis withfocalinfections was higherfor deceased patients than for surviving patients. In the new Indonesian UHC system, the reimbursement for sepsis entails fouraspects:classofpatient’sroom,governmentsubsidies,typeof hospital,andINA-CBGregion.Moreover,thecurrentﬁndingsshow thegreatdifferenceincostsbetweenPNPandICP,especiallyfor sepsis-relatedcostswiththefocalinfectionsofWIsandCVIs.

Thereisconvincingevidenceofapositivecorrelationbetween LRTIsandsepsiswithregardtomortalityoutcome(Jajaetal.2019). Over the last decade, LRTIs have been the most prevalent

Table1

Baselinecharacteristicsofsurvivinganddeceasedsepsispatients.

Characteristics Allcases(n=14,067) % Survivors(n=5,876) % Deceased(n=8,200) % p-value Sex

Male 7,467 53.0 3,115 41.7 4,352 58.3 0.943

Female 6,609 47.0 2,761 41.8 3,848 58.2

Aged60years 1,638 11.6 626 38.2 1,012 61.8 0.002

Singlefocalinfections

CVI 110 0.8 39 35.5 71 64.5 0.179 GTI 1,328 9.4 565 42.5 763 57.5 0.534 LRTI 3,932 27.9 1,486 37.8 2,446 62.2 <0.001* NMI 368 2.6 153 41.6 215 58.4 0.947 UTI 1,348 9.6 755 56.0 593 44.0 <0.001* WI 1,049 7.5 191 18.2 858 81.8 <0.001* Multifocalinfections 4,304 30.6 1,700 39.5 2,604 60.5 <0.001* UFIsepsis 1,637 11.6 987 60.3 650 39.7 <0.001* HavingSSIs 2,138 15.2 551 25.8 1,587 74.2 <0.001* ICU 4,297 30.8 1,328 30.9 2,969 69.1 <0.001*

Abbreviations:CVI,cardiovascularinfections;GTI,gastrointestinaltractinfection;ICU,intensivecareunit;LRTI,lower-respiratorytractinfection;NMI,neuromuscular infection;SSI,surgicalsiteinfection;UFI,unidentiﬁedfocalinfection;UTI,urinarytractinfection;WI,woundinfection.

*

Statisticallysigniﬁcant,p<0.05.

Table2

Hospitalizationcostsforsepsispatientsperadmission(in2016US$). Hospitalizationcost Allcases

mean(SE)

Survivedmean(SE) Deceasedmean(SE) Costdifference p-value Non-ICUstay

Bedcosts 222.12(3.72) 196.31(5.17) 242.16(4.95) 45.85(7.49) <0.001 Laboratoryandradiologycosts 327.29(6.24) 276.49(8.65) 366.49(8.28) 90.01(12.55) <0.001 Pharmacycosts 404.61(7.15) 369.76(10.37) 431.74(9.53) 61.98(14.40) <0.001 Othermedicalfacilitiescosts 142.14(2.30) 126.49(3.24) 154.29(3.07) 27.80(4.64) <0.001 ICUstay

Bedcosts 330.29(9.81) 243.08(13.05) 364.27(11.52) 121.19(21.76) <0.001 Laboratoryandradiologycosts 416.60(14.29) 297.47(18.40) 462.711(16.77) 165.25(31.74) <0.001 Pharmacycosts 662.612(20.59) 491.54(26.36) 729.47(24.19) 237.93(45.64) <0.001 Othermedicalfacilitiescosts 207.33(6.07) 151.53(7.56) 229.08(7.12) 77.56(13.45) <0.001 HavingSSIs

No 925.92(13.13) 838.59(19.75) 988.55(17.18) 149.96(26.58) <0.001* Yes 2,937.89(88.80) 2,595.84(133.88) 3,042.17(101.32) 446.33(209.61) 0.033* Typesoffocalinfections

CVI 1,731.09(90.18) 1,634.30(168.91) 1,750.87(98.95) 116.57(240.24) 0.628 GTI 719.76(25.12) 618.06(33.50) 792.711(32.77) 174.65(50.70) 0.001* LRTI 1,122.47(29.76) 818.83(30.51) 1,306.77(37.42) 487.94(60.88) <0.001* NMI 985.62(73.65) 855.84(101.65) 1,076.29(95.69) 220.45(149.21) 0.140 UTI 747.83(29.81) 733.51(41.95) 765.31(44.42) 31.81(59.91) 0.595 WI 1,702.58(221.88) 1,579.36(264.01) 1,765(272.84) 186.60(468.17) 0.690 Multifocalinfections 1,583.51(19.36) 1,363.16(51.83) 1,723.78(56.05) 395.64(39.58) <0.001* UFI 1,268.26(65.14) 1,315.27(84.09) 1,197.25(102.94) 118.02(133.11) 0.375 Abbreviations:CVI,cardiovascularinfections;GTI,gastrointestinaltractinfection;ICU,intensivecareunit;LRTI,lower-respiratorytractinfection;NMI,neuromuscular infection;SSI,surgicalsiteinfection;SE,standarderror;UFI,unidentiﬁedfocalinfection;UTI,urinarytractinfection;WI,woundinfection.

*

Statisticallysigniﬁcant,p<0.05.

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communicablediseaseinIndonesia(2018).Theeconomicburden ofsepsiswithLRTIsinICUsinadevelopingcountrysuchasTurkey was estimatedat US$2,722 per patient(Gumuset al. 2019).In addition,LRTIssuchascommunity-acquiredpneumonia contrib-ute high morbidity in terms of more hospitalizations for ICU admissions,requiringmechanicalventilators, andfurthersepsis complications(SliglandMarrie2013;RemingtonandSligl2014; Montulletal.2016).Inaddition,elevatedhospitalizationcostsfor ICUpatientswithLRTIswerestronglyassociatedwiththeuseofa mechanicalventilator,presenceofseveresepsisandsepticshock (Gumusetal.2019).Conﬁrmingtheseresults,somestudieshave reportedthat inadditiontobeinginducedbyLRTIs,sepsis also originatesfromWIs,GTIsandUTIs(approximately16.5%, 16.7%and 28.3%,respectively)(Mayretal.2014;Jajaetal.2019;Shankar-Hari etal.2019).SepsisarisingfromGTIsandWIsismostlyassociated with surgical wounds (Muresan et al. 2018; Jaja et al. 2019). Infectionsonthesite of surgeriesafterelective andemergency proceduresthatcontributetosepsisaccountfor5.8%and24.8%, respectively(Shankar-Harietal.2019).Apreviousstudycovering 6.5 million elective surgeries performed in the United States reportedanincidenceof1.2%ofpost-surgicalsepsiscases,witha highmortalityrate of26% (Vogel etal.2010).Thecurrentdata revealedahighcasefatalityrateofsepsiswithSSI.SSI-relatedcosts thatincludemedicines,prolongedlengthofstayandreadmission couldrisetoUS$22,130perpatient(Purbaetal.2018).

Inthecurrentstudy,sepsiswithCVIspresented thehighest cost per inpatient but accounted for the lowest national economic burden for sepsis, with focal infections giving relatively low numbers. In a previous systematic review, endocarditis was reported to be a rare disease with costly consequences(Abegazetal.2017).SepsiswithUTIs,orurosepsis, commonlycauseskidneydysfunction,leadingtohighmortality rates. In the current study, the urinary tract ranked third in incidence as an infection site associated with sepsis. The incidenceof urosepsisin theUnitedStatesis about30%andis higher amongwomen compared withmen (Esper et al.2006; Kumar et al. 2019). The study was in line with the current ﬁndings,whereamongUTIsthefemaleandmaleratiowasat2:1. The incidence of sepsis associated with multifocal infections remains unknown, particularly in developing countries, but it was found that theyare the costliest. Identifying multisource infections with sepsis prior to the occurrence of organ dysfunctionisthus anurgenttask(Zhouetal.2019).

Thefurtherimpactsofsepsis-relatedcostsshouldbe consid-eredwhenformulatinganationalbudgettosupportprivateand publichealthcareservices.In2016,Indonesia’shealthexpenditure wasapproximatelyUS$111.6billionor3.1%ofitsGDP(TheWorld Bank2016b).Thus,establishingsufficienthealthcarefacilitiesto supportthecareofsepsispatientsisachallenge.Accordingtothe National Health Account data published by the OECD in 2016, Indonesia’s inpatient expenditure amounted to IDR158,499.2 billion(orUS$11.9billion)(OrganizationforEconomicCooperation andDevelopment2016;TheWorldBank2016b).Thisexpenditure accountsfor40.9%ofthecountry’snationaltotalhealth expendi-tureofIDR387,648.5billionorUS$29.1billion(TheWorldBank 2016b).Forthesepsisinpatientexpenditure,thecurrentfindings suggestthatthepricesinthecurrentINA-CBGsshouldbeupwardly adjustedaswellasmadespeci_ficforinfectionsites.Asaspeci_fic item in the INA-CBGs, each individual pays health coverage according to the class of service selected. The service class categoriesmerelyrelatetotheprovisionofroomswithspecific numbersofbeds.Therefore,thiscategorizationisineffective,asall patientsreceivethesamemedicalservicesorevenwhentheyare placed in ICUs or isolated rooms. Additionally, community healthcare centers, which play an essential role in resource-limited settings in preventing infection complications such as sepsis,couldpotentiallyserveasabudgetcontrolmechanismby averting hospital infections and then reducing inpatient costs (Kumaretal.2019).

Itisbelievedthatthisistheﬁrststudytoassesstheburdenof disease,incorporatingthecostsandmortalityoutcomesofsepsis with focal infections, in a resource-limited setting. Notably, it offersarobustmethodologyforcalculatingthenationalpricefor sepsis based on a consideration of particular focal infections. However,thestudyhadseverallimitations.First,itdidnotassess thecostsassociatedwithlossesinproductivityduring hospitali-zation,andindirectcostswerenotrecorded.Moreover, infrastruc-turecosts–suchassecuritysystems,parkingandtransportation– were not included. Second, post-sepsis impact on individual patients’ occupational or educational trajectories, and those of theirrelatives,wasnotassessedbecausethedataobtainedfrom the hospitalswerenot linkedtothesocioeconomic statuses of individualpatients. Third,thenationalpricewas modeledwith reference to four referral centers. Nevertheless, the resulting nationalmodelseemedreasonable.Forth,itwas aretrospective studyandpotentialbiascouldhaveexistedsuchasmisdiagnosis

Figure1.Theeconomicburdenofsepsiswithparticularfocalinfectionsfor100,000patientswithsurvived(ingreen)anddeceased(inblue)(Forinterpretationofthe referencestocolourinthisﬁgurelegend,thereaderisreferredtothewebversionofthisarticle).

Note:CVI=cardiovascularinfections,GTI=gastrointestinaltractinfection,LRTI=lower-respiratorytractinfection,NMI=neuromuscularinfection,UFI=unidentiﬁedfocal infection,UTI=urinarytractinfection,andWI=woundinfection.

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and under-reported focal infections. However, the study was conductedwithabigsamplesizetoprovideepidemiologicaland health economic ﬁndings that are needed by the Indonesian governmentforimprovingthenewhealthinsurancesystemwitha resource-limited setting. Last, it did not consider following hospital discharge, particularly for ICU patients. Evidently, the highermortalityrateamongsepsispatientsafterbeingdischarged wasalate-onsetoutcomeoftheirICUstays(Aguiar-Ricardoetal. 2019;Biasonetal.2019;Freitasetal.2019).

Conclusions

It isessentialtoconsidermortalityandfocalinfectionsinan assessmentoftheburdenofsepsis.Eachunderlyingfocalinfection determinestheparticularcourseofsepsis.Inaresource-limited

contextsuchasthatofIndonesia,whereanewUHCsystemhas been introduced,the adequate provision of healthcare services requiresareevaluationand recalculationofthepriceforsepsis. Furthermore,in context,sepsis caseswithmultifocal infections and LRTIs should be categorized as high-burden sepsis cases, reﬂectingthemostobviousexamplesrequiringadjustmentstothe national price for private and publichealthcare services reim-bursement.

Contributions

AKRP,NM,GA,RRWandMJPinitiallycontributedtodeveloping theconceptandthedesignofthework.AKRP,NM,GA,SHW,UH, HH, and CWN provided patients, collected and conﬁrmed the clinicaldata.AKRP,NM,GA,RRW,JvdS,andMJPconducteddata

Table3

TheproposednationalpriceperpatientforsepsiswithfocalinfectionsinallﬁveregionsofIndonesia(in2016US$).

*Includingsurgicalsiteinfections.

Note:ThecolorsindicatethedifferencebetweenthePNPforsepsiswithfocalinfectionswiththeratesspeciﬁedfortheINA-CBGs(thegreenindicatesagroupoflowPNPswith asmalldifference(<US$500),theblueindicatesagroupofmiddlePNPswithamediumdifference(US$500–1,000),andtheredindicatesagroupofhighPNPswithamajor difference(>US$1,000)).ThecomparisonbetweenPNPandINA-CBGratesisprovidedinSupplement3.

Abbreviations:CVI,cardiovascularinfections;GTI,gastrointestinaltractinfection;ICU,intensivecareunit;INA-CBGs,IndonesiaCaseBaseGroups;LRTI,lower-respiratory tractinfection;NMI,neuromuscularinfection;PNP,proposednationalprice;UFI,unidentiﬁedfocalinfection;UTI,urinarytractinfection;WI,woundinfection. 216 A.K.R.Purbaetal./InternationalJournalofInfectiousDiseases96(2020)211–218

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analysesandsynthesis.Allauthorswroteandrevisedtheworkand approvedtheﬁnaldraftbeforesubmission.

Ethicalapproval

The study was approved by the ethical committee of Dr. Soetomo General Academic Hospital, Surabaya (No. 418/Panke. KKE/VII/2017),AirlanggaUniversityHospital(No.114/KEH/2017), andtheNationalCenterofInfectiousDiseasesatProf.Dr.Sulanti SarosoHospital,Jakarta(No.02/xxxviii.10/5/2018).Thestudymet the Indonesian governmental requirements on conducting re-searchandtheethicalprinciplesformedical researchinvolving humansubjectsunderthe HelsinkiDeclaration(WorldMedical Association2013).Alldatawasdeidentiﬁedtoguaranteepatient anonymity.

Con_ﬂictofinterest

MJPreceivedgrantsandhonorariafromvariouspharmaceutical companies,none of which are related tothis study. The other authorsdeclarenoconﬂictofinterest.

Acknowledgments

WewouldliketothankDr.Zarfan,Dr.MaulanaA.Empitu,M.Sc (from Department of Pharmacology and Therapy, Universitas Airlangga, Surabaya, Indonesia), Hendro Suprayogi (from Dr. SoetomoGeneralHospital,Surabaya,Indonesia),andMrs.Rosita Prananingtias (from Universitas Airlangga Academic Hospital, Surabaya,Indonesia) for collectingdata for this study. We also thankJosueAlmansaOrtiz(fromDepartmentofHealthSciences, UMCG,the Netherlands) for checking thestatistic results. This studysupportedby theGroningen UniversityInstituteforDrug Exploration(GUIDE)oftheGraduateSchoolofMedicalSciencesat the University Medical Center Groningen (UMCG), in the Netherlands. The study was also supported by the Directorate GeneralofHigherEducation(DIKTI),oftheMinistryofEducation andCulture,intheRepublicofIndonesia[No.224/D3.2/PG/2016] and theFaculty of Medicine at Universitas Airlangga [No.305/ UN3.5/SDM/2016].Moreover,wethankthefollowingindividuals fortheircontributiontothisstudy:Dr.Aﬁf,Sp.KKandBuDiana,Ak from Universitas Airlangga Academic Hospital in Surabaya, Indonesia.

AppendixA.Supplementarydata

Supplementarymaterialrelatedto thisarticle can befound, inthe onlineversion,atdoi:https://doi.org/10.1016/j.ijid.2020.04.075. References

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