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Dengue Bulletin – Volume 30, 2006 1

Changing Epidemiology of Dengue Haemorrhagic Feverin Indonesia

Tatty E. Setiatia, Jiri F.P. Wagenaarb�, Martijn D. de Kruifb, Albert T.A. Mairuhub,Eric C.M. van Gorpb and Augustinus Soemantria

aPediatric Department, Dr. Kariadi Hospita, JL Dr. Sutomo 16, Semarang, Indonesia

bDepartment of Internal Medicine, Slotervaart Hospital, Department of Internal Medicine (9B),

Louwesweg 6, 1066 EC Amsterdam, The Netherlands

�[email protected]

Abstract

Dengue fever (DF)/dengue haemorrhagic fever (DHF) is a growing public health problem in the subtropics.Dengue was first reported in Indonesia in 1968 and since then the number of reports in the literatureand the number of dengue virus (DENV)-infected cases reported by the Indonesian health authoritieshave increased. This review addresses the changing epidemiology of dengue in Indonesia by means ofa chronological overview. Over time, the morbidity and mortality of dengue disease have increased andDHF epidemics occur throughout all the 29 provinces. The outbreak trend of DHF in the country hasbecome irregular, with a high inter-epidemic background. All dengue serotypes are circulating, althoughsevere disease is predominantly attributed to DENV-3. The case-fatality rate is dropping over time,probably reflecting increased awareness and improved treatment protocols. An increasing percentageof adolescents and adults develop DHF relatively earlier in the course of the disease, compared with thedays when DHF was considered a primarily paediatric illness. Many inter-related factors such asenvironmental, biological and demographic issues influence dengue epidemiology and transmission.

Keywords: Dengue, dengue virus, outbreak, epidemiology, Indonesia.

Introduction

Dengue fever (DF)/dengue haemorrhagic fever(DHF) is a growing public health problem inthe subtropics.[1] In South-East Asia, with a totalpopulation of 1.5 billion, approximately 1.3billion people live at risk of acquiring DF orDHF. Currently, DHF is the leading cause ofhospital admissions and death among childrenin this region.[2]

Major dengue epidemics date back to thelate 17th century. However, the start ofepidemics of severe dengue began in theSouth-East Asia region following World War II,

when conditions for mosquito-borne diseaseswere favourable.[3] DENV infections duringthese latter epidemics were accompanied bysevere haemorrhage, shock and vascularleakage. The first recorded DHF epidemicoccurred in Manila, the Philippines, in 1953.Thereafter the epidemic spread quicklythroughout South-East Asia and further westvia India, Sri Lanka, Maldives and Pakistan, andin the east to China.[3] Many factors are thoughtto be responsible for the global re-emergenceof DF and DHF. These include major globaldemographic changes and worsening of healthcare systems and mosquito controlprogrammes.[1,4]

2 Dengue Bulletin – Volume 30, 2006

Changing Epidemiology of Dengue Haemorrhagic Fever in Indonesia

Indonesia is the largest country in theregion with a population of 245 million. Almostsixty per cent of the people live on the islandof Java, which is most severely afflicted byperiodic outbreaks of dengue disease.[5]

However, the disease is endemic in many largecities and small towns throughout the countryand has also spread to certain smaller villages,where population movement and density arehigh.[6] Epidemic DF has been reported in all27 Indonesian provinces, whereas in 1968 onlytwo provinces had reported dengue cases.[6,7]

This article addresses the epidemiology ofdengue in Indonesia by means of achronological overview.

Methods

Literature search and data sources

A systematic review was performed to identifyeligible articles. The MEDLINE database from1966 through 2005 was searched by tworeviewers (JFPW and MDK). This was done,by combining the Medical Subject Headings(MeSH terms) and text words dengue, denguevirus, outbreak, epidemiology and Indonesia.In addition, the Indonesian Ministry of Health,WHO and experts in the field were contactedfor data on epidemics occurring from 1966through 2005. This exercise was undertakenby two different reviewers (TES and AS).

Study selection and data extraction

All identified epidemiological studies wereselected. The inclusion was restricted to studiesin which primary data describing morbidity ormortality could be extracted. The selection ofstudies and data extraction wereindependently performed by two of the authors(ATAM and JFPW). Any disagreement wasresolved by discussion and if necessary by

adjudication of a third reviewer (ECMG). Aformal meta-analysis was not deemedappropriate, because the selected studies werehighly heterogeneous in terms of selection andnumbers of cases, classification of cases, anddescription of data.

Results

The computer search yielded 116 references.Forty-four articles were excluded after we hadread the title and the abstract that did notaddress the topic under investigation (a list ofthese excluded articles is available with theauthors). For the remaining 72 potentiallyrelevant references, we read the full report todecide whether to select the study for thisreview. Several articles reported on the samestudy and results; therefore, in order to avoidinclusion of duplicate reports, the most detailedversion of each was selected. Some articlesreported on the same study, although differentresults were presented. All these papers weretherefore included. One study investigated thetotal incidence rates in Indonesia from 1968to 1985,[6] and these data were combined withthe data derived from WHO and the Ministryof Health.

The Table summarizes some of thecharacteristics of the selected studies, withclinical outcome and data on virology ifavailable. The majority of the studies describethe results of outbreaks with an in-depth surveyof a selected group of patients. The numberof cases enrolled ranged from 72 to more than2000.

Epidemiological overview

The first cases of DENV infection in Indonesiawere reported in 1968 in the cities of Jakarta(West Java) and Surabaya (East Java).[6,8-10] These



Table: Characteristics of selected studies



reports were followed by reports fromBandung (West Java) and Yogyakarta (CentralJava).[11,12] Since then, suspected dengue caseswere recorded by the Ministry of Health.

Initially, the reported incidence rates wererecorded in Java only and these were relativelylow.[6,8-10] In the early 1980s, these ratesincreased from 10 000 to 30 000 each year,



and since the last 10 years, the reportedincidence rates have further increased toapproximately 30 000 to 60 000 cases eachyear. Significant peaks were reported in 1973and 1988, but during 1998 and 2004, a recordnumber of 72 133 and 78 690 cases weredocumented (Figure 1).[13] Today, dengue hasspread over all 29 Indonesian provinces (Figure2A), with an inter-epidemic backgroundbetween 10 000 and 25 000 cases annually.

The first large recorded outbreak occurredin 1973 (Figure 1). A total of 10 189 caseswas reported, of which 6225 cases werediagnosed in Semarang, the capital of centralJava.[6] No specific data were reported aboutthe severity of the disease. In the next year,another outbreak was reported outside theisland of Java, in Manado, North Sulawesi.[14]

An epidemic of DHF characterized bysevere disease and high viraemia occurred inBantul, a rural area in Central Java, during thelatter part of 1976 and early 1977.[15,16] If allshock cases were considered, no relationshipbetween dengue serotype and disease severitywere found; however, all three fatal cases wereassociated with DENV-3. A year later, a DENV-3 outbreak occurred in Sleman, 40 km northof Bantul, characterized by mild disease.[17]

The age distribution was similar to that of theBantul outbreak; however, less severe caseswere reported in this outbreak (DSS cases:Bantul 37% vs. Sleman 13%).

From 1975 to 1983, a total of 1451serologically-confirmed (haemagglutinationinhibition test) DHF patients from Jakarta werefollowed during their hospital stay.[18] Of these

Figure 1: DHF morbidity and mortality in Indonesia from 1968-2005

The solid line represents the total number of DHF cases officially reported during the years 1968–2005. Thedashed line represents the total number of deaths from DHF per year during the years 1968 till 2005.(Source: WHO, Sumarmo 1987)



Figure 2: The incidence rate and case-fatality rate of DHF in Indonesia in 2005

This figure shows: (A) the number of DHF cases among 100 000 civilians [the incidence rate (IR)] throughout the29 Indonesian provinces in 2005 and (B) the percentage of deaths among reported DHF cases [case-fatality rate(CFR)] throughout the 29 Indonesian provinces in 2005.(Source: Ministry of Health, Indonesia, 2006)

B: DHF case fatality rate

cases, 142 were virologically confirmed. Fataldisease occurred in 34 virologically-confirmedinfections; in 75 cases shock was present (77%of fatal cases). DENV-3 was most frequentlyassociated with severe and fatal infections.

A five-month-long outbreak emerged inSeptember 1993 through February 1994 in thecity of Jayapura, the provincial capital of Papua,easternmost Indonesia. Although the first caseof DHF was reported in 1979, the disease had

A: DHF incidence rate



shown transient disappearance from thisregion.[7] A total of 217 cases were reportedand 72 suspected DHF cases were enrolledduring an outbreak investigation.[7] The majority(68.7%) of the included individuals did not havesignificant levels of specific IgM at the time oftheir admission, 11.4% had a primary infection,17.1% a secondary infection, and theremaining cases had an indeterminate testresult. Nine cultures became positive from 63whole-blood and 68 serum samples inoculatedin mosquitoes.

A prospective study initiated in 1995showed that the incidence for one or moredengue infections among a cohort of 4–9-year-old children in Yogyakarta was 29.2% in thefirst year of the study.[19] An average of 56.2%had antibodies against one or more virus typesat the start of the study; of these, 34.3% hadserological evidence of prior exposure to a singleserotype. Among children without theserological evidence of prior exposure, 26.8%(216 of 805) sero-converted. Six of the 1837included children were hospitalized during thefollow-up; all of them appeared to have asecondary or tertiary dengue infection.

During the period November 1997 till May1998, again, DHF outbreaks were reportedthroughout the Indonesian archipelago.[20]

Eleven provinces were involved, and all theoutbreaks occurred in urban areas. Theoutbreak started during November 1997 inJambi, South Sumatra, and Lampung (westernpart of Indonesia). From here the outbreakspread involving all provinces in Sulawesi andthe provinces of West Nusatenggara and EastTimor, continuing towards Ambon, the capitalof Maluku province, and finally it arrived inJakarta in March 1998. The average attack ratewas 1.2 per 1000 population whereas thehighest attack rate occurred in Palembang, acity in South Sumatra (1.6 per 1000 population).

The trend analysis of the 1998 Palembangoutbreak demonstrated a 3-fold increase of

dengue cases between January and April,compared to historical records.[21] A changingtrend in epidemic transmission was observed,going from a 5-year cyclic occurrence to anannual phenomenon. Concerning agedistribution it has to be noted that a relativelylarge proportion of adolescents and youngadults were infected.

A prospective cohort study was initiatedamong 2536 recruited adult textile factoryworkers in Bandung, West Java, from 2000 till2002.[22] The incidence of symptomatic denguedisease was 18 cases per 1000 persons-yearsand an estimated asymptomatic/mild infectionrate of 56 cases per 1000 persons-years.

In April 2001, a second outbreak occurredin Papua.[23] In Merauke, a town located in thesouth-eastern corner of the province, aretrospective case control study was performed.Fifteen acute cases, 37 convalescing subjectsand 32 comparable controls were enrolled.Dengue virus IgM antibodies were detectedin 27% of the acute clinical cases, 30% in theconvalescing cases and in only 3% of thecontrols. DENV-3 was the only dengue virusserotype detected by RT-PCR, all in the acutesamples. By reviewing hospital records, a totalnumber of 172 suspected cases were identified.The estimated CFR among all suspecteddengue cases was 1.2%.

To study the natural history of DENVinfection in West Jakarta, 785 volunteers wereincluded using a cluster investigation methodin the period from October 2001 to October2003. All subjects were family members orneighbours of 53 index cases, which hadpreviously been hospitalized.[24] At enrolment,11 subjects were viraemic (3 cases DENV-1, 8cases DENV-2). In 5 of these cases the viruscould be isolated. Seventeen new infections(2.2%) were identified post-enrolment. Tenwere positive by the RT-PCR (1 case DENV-1,7 DENV-2, 1 DENV-3 and 1 DENV-4). In 5cases the serotype was confirmed by culture.



Nine post enrolment subjects weresymptomatic, of which one case progressedto DHF. The calculated incidence rate ofdengue infection was 567 cases per 1000persons-years of follow-up, and the calculatedDHF incidence rate was 33 DHF cases per 1000persons-years of follow-up.

In 2004, another outbreak began to spreadthroughout Indonesia, with Jakarta being themost affected area.[25] According to WHO,78 690 cases and over 900 deaths werereported in Indonesia that year. Ten hospitals,all located in Jakarta, included a cohort of 272hospitalized patients to confirm the diseaseetiology.[5] Dengue infection was determinedin 66.2% of all cases, 55.6%, 17.2% and 27.2%had DF, DF with haemorrhagic manifestations,and DHF respectively. Of the confirmed DHFcases, 82.5% had evidence of a secondaryinfection. Viral isolation was attempted on 28acute sera from the serologically positiveindividuals and identified all four serotypes.There was a greater extent of infections amongthose aged 15 years and older.

Virology

In the 1960s, the clinical diagnosis of DHF wasbased on the existence of fever of unknownorigin accompanied by a haemorrhagictendency with or without symptoms of shock.This diagnosis could be supported by a positivehaemagglutination inhibition test. No virusisolations were made at that time. The firstisolations of dengue virus took place during the1970s in Jakarta, Medan (North Sumatra) andSemarang.[11,16,26-28] Limited data suggest thatDENV-2 was the predominant virus in thattime,[29] and indeed DENV-2 was isolated mostfrequently from the Semarang epidemic in1973.[16] The 1974 Manado outbreak showedthat, of the 125 serological identifications ofthe etiological agent, DENV-1 was thepredominant virus in both non-shock and shockcases.[14] Virological surveillance using the

mosquito inoculation technique was performedduring the period 1975–1979 in eightIndonesian cities.[18] A total of 297 cases wereisolated and all four serotypes were found, ofwhich DENV-3 was predominant. In early1976, DENV-3 was increasingly associated withfatal cases of DHF in Jakarta.[30] Epidemics ofDHF associated with DENV-3 continued occurin 1977 in Java and West Kalimantan.[30] It wassuggested that the virulence of DENV-3 hadchanged. During the Bantul epidemic in late-1976, virus isolation was attempted from 69patients who had 4-fold or greater rise in HI-antibody between acute and convalescent sera.Ninety-five isolations succeeded (65%) and 3serotypes were found: DENV-3 (60%), DENV-4 (22.2%) and DENV-1 (17.8%). From allpatients classified as having a primary infection,virus was isolated (100%), in secondaryinfection this number decreased to 57%. Anapproximately 5-fold higher viraemia was foundin secondary infections compared to primaryinfections. Virus titres were comparablebetween the DENV-1, 3 and 4 isolates. Datafrom the Sleman epidemic early-1978 showedthat DENV-3 could be isolated eight times from25 acute samples (32%); no other serotypeswere found. Acute samples were defined asdescribed above. The isolation rate in primaryinfections was 45%, in secondary infections23%. Overall viraemia in Sleman patients waslower, compared to those from Bantul (Bantul67% DENV-3 titres ≥ 10^6 MID

50 per ml,

Sleman 37% DENV-3 titres ≥ 10^6 MID50

perml).

Between 1980 and 1983, a total of 164isolations, using the mosquito inoculationtechnique, were reported from eightIndonesian cities (Medan, Ujung Pandang,Palembang, Jakarta, Yogyakarta, Surabaya,Pontianak, Manado).[6] DENV-2 (n= 57) andDENV-3 (n=73) were predominant. Similarfindings were noticed during the period 1984–1985. Of the 51 virus isolations, DENV-4 wasnot found and DENV-3 (n=24) was



predominant.[6] From 1985 till 1986, 36successful isolates were made out of 377 serumsamples. Serotypes were distributed as follows:DENV-2 (18), DENV-3 (12), DENV-1 (4) andDENV-4 two isolates.

From the 1995-1996 Yogyakartaprospective cohort study, all serotypes wereprevalent at the start of the study.[19] DENV-2slightly predominated and was also mostfrequently transmitted (among all 4 serotypes)during the first year of the study. Of the childrenseen in the hospital because of fever, 11 outof 107 had serological or virological evidenceof a recent dengue infection. DENV-3accounted for most of the cases. Of the 6hospitalized children (DHF=3, DSS=3) theinfection sequence was recognized in 5patients: DENV-2 DENV-1 (n=3), DENV-2DENV-4 (n=1), DENV-1 DENV-3 (n=1). Ofall seroconversions to a second dengueinfection, the sequence DENV-2 DENV-1 andDENV-1 DENV-2 were predominant.

During the prospective Bandung cohortstudy, all four serotypes were detected, withDENV-2 predominating. Three of the four DHFcases were due to DENV-3 virus. The DSS casewas recognized as a secondary infection of thesequence DENV-2 DENV-1.

During the outbreak investigation ofSuwandono et al., from 28 acute sera dengueserotype was confirmed by either RT-PCR orculture.[5] DENV-3 was found in most cases(n=18; 64.3%) followed by DENV-4 (n=4;14.3%), DENV-2 (n=4; 14.3%) and DENV-1(n=2; 7.1%). The DENV-3 isolates showedsimilarities to previous viruses isolated inIndonesia during an outbreak in 1998.

Morbidity and case-fatality rates (CFR)

During the first year of recognition, a total of58 cases (including 24 deaths) wererecorded.[6] In 1970, a total of 34 dengue cases

were identified among 48 suspected paediatricpatients in Yogyakarta.[11] Subsequently, eightwere classified as DHF and two casesprogressed to dengue shock syndrome (DSS).

The Indonesian health care authoritiesreported a dengue morbidity rate of 15.28 per100 000 persons, 30 per 100 000 persons and13.7 per 100 000 persons in the years 1997,2004 and 2005 respectively (unpublished data,Ministry of Health).

In the last decade, dengue disease hascaused more than 400 deaths every year in thecountry, and in 1998, this number went to upto 1414 (Figure 1). When appropriate supportivetherapy is given, the CFR in Asian countriesremains approximately between 0.5% and3.5%.[31] In Indonesia, the CFR has steadilydeclined over time from 41% in 1968[10] to lessthan 2% since 2000, and the lowest rate of1.21% in 2004 (Figure 3).[32] In 2005, the meanCFR was 1.34%, but this number varies betweendifferent provinces (Figure 2B).

Conclusion

Epidemics of DF and DHF have become animportant public health problem throughout theIndonesian archipelago since it was firstrecognized in 1968. The epidemiology of DHFin the country is changing alarmingly given theincreasing number of infections reported fromall provinces. The outbreak trends of dengue,in general characterized as a cyclic pattern,have become somewhat irregular, with a highendemic background. A higher percentage ofadolescents and adults seem to develop DHF.[5]

The median age of DHF patients from Jakartawas 4 years and 11 months during the period1979–1984.[6] Recent data from the Ministryof Health show an increasing number of DHFin children aged 15 years and older(unpublished data, Ministry of Health). Otherreports also show this trend.[5,21] Furthermore,



it may be stated that the reported case-fatalityrate has decreased over time. Increasedawareness and better diagnostics have led toprompt recognition of the infection in healthcare facilities. Improved treatment protocolsand local guidelines have contributed to thisdecline. Hopefully, the case-fatality rates willdecline further in the near future. Concerningclinical outcome in terms of the rating ofdisease severity, it is not clear whether theratios of DF, DHF and DSS have changed. Suchinformation could not be clearly deduced fromthe reports studied. In the field, the diseaseseverity is changing depending on outbreakseverity and not following a regular pattern.

However, there are some drawbacks inthe presented data. Besides more awareness,diagnostic tools and diagnostic facilities haveimproved over time, which undoubtedly haveled to more reporting. Dengue outbreaks arenow recognized earlier, and more sensitive andspecific diagnostic tests help to confirm thedisease. Case definitions of WHO, also used

Figure 3: Case-fatality rate among DHF patients in Indonesia during 1968–2005

The case-fatality rates (%) are denoted on the Y axis in percentages during the years 1968-2005.(Source: WHO, Sumarmo 1987)

by the Indonesian Ministry of Health, are basedon both clinical and diagnostic criteria. It isstated that any suspected or confirmed caseshould be reported. Because it is unlikely thatmany cases will have laboratory confirmation,the reported cases will not always representthe real situation. This accounts even more fora country with many epidemics and a highendemic transmission. Not surprisingly, in thepresented studies, the gap between suspectedand confirmed cases is substantial. Moreover,perhaps some of the referenced older studiesare less convincing. This is because theysometimes lacked a detailed method ofselection and the diagnostic tools used thenwere less accurate. However, it is the only datawe have.

Multiple factors influence the occurrenceof dengue epidemics, of which environmental,biological and demographic factors play acentral role. The dengue incidence isassociated with warmer, more humid climate.[4]

Higher temperatures have been shown to



enhance vector efficiency[33] and mosquito-biting behaviour.[34] Indeed, a marked increasein the rainfall and sustained highertemperatures compared to earlier years werethe key factors during the Palembangoutbreak.[21] Furthermore, the epidemiologicalpattern throughout the year shows a peakincidence of DENV infections during themonths of October through April, usuallycoinciding with the rainy season.[7,10,17,35]

Endemic transmission requires, besides themosquito vector, an immunologically susceptiblepopulation and the circulation of the denguevirus. The presence of multiple circulating strainsand the introduction of new and more virulentviruses increase the incidence of DHFepidemics.[1] Some Indonesian studies clearlyshowed the relevance of secondaryinfections.[5,19] Of all the serotypes identified inIndonesia, DENV-3 was the most frequently

linked to the severe disease.[5,21,36] Importantdemographic factors contributing to thetransmission of dengue viruses also concernunprecedented population growth accompaniedby unplanned and uncontrolled urbanization, aframework in which Indonesia perfectly fits.

Dengue is on the rise in Indonesia. Hence,epidemiological surveillance must beestablished along with education campaignsand sustainable vector control programmes tocontrol its transmission. To obtain good andtrustworthy epidemiological data, surveillancecentres should be well-equipped and shouldfunction in different provinces and report onregular basis to the Ministry of Health. Theincreasing number of severe, potentially fatalcases and the absence of an effective vaccinestress the need to continue all efforts inunderstanding the dengue epidemiology.

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