JTMH Journal

Introduction

Dengue is the most rapidly spreading mosquito-borne arbovirus infection of humans in the world [1,2]. The aetiological agent is the dengue virus (DENV), a member of the Flavivirus genus of positively stranded RNA viruses [2], which is transmitted between persons by the bite of female Aedes spp. mosquitoes [3]. Worldwide, Ae. aegypti and Ae. albopictus are the most competent vectors to transmit DENV [4]. DENV has four formally recognised serotypes, DENV-1 to DENV-4 [1]. In Indonesia, dengue is transmitted mainly by Ae. aegypti [5-7] and all four serotypes are observed, with some case reports of mixed infection [7-11]. Most occurrences of dengue are asymptomatic and self-limiting, possibly three to four times higher than the number of symptomatic infections [12,13]. While a minority of infections cause disease this still represents a huge number of cases, almost 100 million per annum globally [14], that vary from mild to severe and potentially fatal. Severity of infection is directly related to the causal dengue serotype [15]. Although the exact mechanism of pathogenesis of DENV is unclear, if secondary or subsequent infection is with a heterologous serotype to that which caused primary infection the immune pathological phenomenon of antibody-dependent enhancement (ADE) is thought to contribute [16].

As multiple serotypes of DENV circulate in Indonesia, more than half of all clinical cases are due to exposure to more than one serotype [17]. This means that subsequent infection will most likely lead to severe disease manifestations [8]. This may explain the high incidence and mortality rate of dengue in Indonesia and the difficulties in eradicating or controlling outbreaks.

Global Public Health Threat

DENV is endemic in around 125 tropical and subtropical countries, placing at risk of infection more than 2.5 billion people, 40% of the world’s population [15,18,19]. Over the last 60 years the global incidence has escalated by 30-fold to affect many nations [15,18,20,21], including Indonesia [22]. The current global incidence of dengue is conservatively estimated at 400 million reported infections, both asymptomatic and symptomatic, annually [18,20,21]. Table 1 shows officially reported incidence rates of dengue for several countries around the world [23,24]. Cases in Asia account for 75% of the overall dengue disease burden, followed by those recorded in Latin America and Africa. The scale and impact of this major public health concern warrants considerable investment to improve health care systems in tropical developing countries, exemplified by Indonesia, where for many decades’ dengue has been recognised as a so-called emerging infectious disease [24,25]. The World Health Organization (WHO) estimates that over 500,000 people with severe dengue are hospitalized annually and 2.5% of those patients die from severe symptoms and shock [26]. This equates to 1.1 million disability-adjusted life-years (DALYs) globally. The real number of dengue cases in the world is significantly higher than official statistics [3,27]. Worldwide, only 3.2 million symptomatic cases were reported to the WHO in 2015 [28], while the incidence of asymptomatic dengue is considered to be three to four times higher than the number of symptomatic infections [23,29]. This discrepancy is most likely due to a combination of factors: the often self-limiting nature of dengue as a disease [27]; its frequent misdiagnosis [30]; and delayed and inaccurate surveillance data in low-income countries [31].

Disease and Treatment

In 1997 the WHO classified clinical cases of dengue into three different subgroups based on the disease symptoms: dengue fever (DF); dengue haemorrhagic fever (DHF); and dengue shock syndrome (DSS) [20,32]. Since overlap between these manifestations had been observed in 2009 this definition was revised as dengue with or without warning sign and severe dengue [20]. It is acknowledged by clinicians that the illness presents as a spectrum of disease instead of distinct phases. While the revised scheme is more sensitive to the diagnosis of severe dengue, and facilitates triage and case management, issues remain with its applicability, some experts considering that a more specific definition of warning signs is required. This calls for research into the diagnostic value of these warning signs on patient outcomes and the cost-effectiveness of the new classification system to ascertain if the updated classification requires yet further modification, perhaps to include elements of both systems [33]. Currently, there are no antiviral medications to target DENV so treatment of each patient is supportive, i.e. provided to alleviate their disease symptoms only [34]. The main goal of clinical management is to restrict or reverse increased vascular permeability, a hallmark of severe dengue, that leads to leakage of plasma into pleural and peritoneal cavities and shock [34]. In the absence of a cure, therefore, effective prevention, control and early management strategies are important to combat the disease and to reduce both the incidence and mortality rate arising from dengue. Implementation of effective mosquito control and surveillance strategies are critically required for more accurate early prediction and better preparation for outbreaks, as well as to directly reduce local transmission of DENV [2,3,10,32,35-37]. An efficacious vaccine is not currently available, but under development, and would also be beneficial as a prophylactic means to curb dengue incidence and mortality rate [1,21,38,39].

An Emerging Infectious Disease

Just over 4 billion people of the current world population of 7.7 billion live in an urban area. According to a recent WHO prediction, the urban share will grow to 68% (6.4 billion) by 2050 [40]. Rapid urbanization has a profound impact on global health, including being a major predisposing factor for the spread of mosquito-transmitted infectious diseases [25]. The rapid urbanization rate in the capital city of Jakarta, located on the northwest coast of the world's most populous island, Java, contributes to the noted dengue epidemics [10,41-43]. For a little more than 50 years Indonesia has faced the challenge of dengue. In addition to the public health threat, this has caused an enormous national economic burden.

The situation is becoming increasingly problematic as the expanding and more urbanized population, particularly focused on Jakarta, is put in a position of heightened vulnerability due to socioeconomic deprivation and cohabiting with Ae. aegypti mosquitoes. Therefore, vector control strategies, effective infection surveillance and early disease management programmes are key weapons in the armoury to reduce dengue incidence and mortality rates in Jakarta and its environs [24,25].

Incidence in Indonesia

The significant morbidity and mortality that dengue causes contribute a huge economic burden in endemic regions, which is magnified in low-income countries [44-46]. This is a profound problem for Indonesia and poses a serious threat to its 270 million inhabitants [46]. The country is one of the largest dengue hyper-endemic territories in South East Asia and globally [9,47]. The first Indonesian case of dengue was reported in 1968, but by today over 50% of the population is affected by dengue, with over 750,000 new clinical cases confirmed annually [8]. Despite vector control campaigns, the incidence rate of dengue in this, an archipelagic country of 17,000 geographically dispersed islands, remains very high [24]. Thus, it is a matter of some urgency to gain a better appreciation of the considerable public health problem that dengue presents to the people of Indonesia. In part, this may be achieved through detailed clinical profiling of dengue patients, especially those hospitalized in the sprawling megacity of Jakarta. Although the officially recognised incidence of dengue in Indonesia is very high, as for elsewhere there may be significant under-reporting [9,24]. Table 2 shows national dengue incidence and mortality rates from 1968 to 2017. In many years, the only available data were from Jakarta, thus highlighting the overall inaccuracy of reporting of dengue cases nationwide. Some data were reported as incidence rate, others as case numbers [24,48], thereby making epidemiological analysis a difficult task. As a silent infection that does not manifest clinically in the majority of individuals, the country’s rate of infection, if not disease, might be expected to be extremely high [13,49].

Figure 1 shows the dengue risk by region of Indonesia [50]. While the incidence rate varies between provinces [51], the average rate across the country as a whole is 78 per 100,000 population [24]. The Indonesian Government aims to reduce this to < 49 per 100,000 population over the next decade [24]. Clearly, to achieve this ambitious target more effective prevention and control strategies need to be developed [52].

While the dengue incidence rate in Indonesia is increasing [46], the case fatality rate (CFR) has dropped significantly from 41% in 1968 to 0.75% in 2017 [24,53]. However, as the number of reported cases has escalated alarmingly, in fact the absolute number of fatalities from dengue has risen sharply over the same 50-year period, from 23 to 444 cases [54]. According to the WHO, from 2004 to 2010 Indonesia was the country reported to have the highest incidence of dengue in Asia [5,55], and the second highest in the world [47]. As recently as January 2019 there was sudden outbreak of dengue (13,683 confirmed cases and 132 deaths) in Indonesia [56]. An outbreak is declared by the Indonesian authorities when a minimum of 115 dengue-related fatalities is reached [57]. It is probable that this incident exemplified under-reporting, since by this time eight regions had already declared a state of emergency [56]. Between 2008 and 2017, more than 200,000 dengue cases were hospitalized in Jakarta. This represents an incidence rate of 207 per 100,000 population per year [9]. The densely populated capital city of 10.6 million inhabitants, and the surrounding metropolitan area of Jabodetabek with a population that exceeds 30 million people, are collectively a major global hot spot of dengue outbreak. Only very recently have dengue incidence and mortality rates been reported with any regularity from regions outside Jakarta [24]. The Indonesian Government issues alerts to residents of the greater Jakarta agglomeration of the potential threat of dengue infection when an outbreak is predicted, most recently in February and March 2019 [57].

Educational and Economic Burden

Globally, the gender and age distribution of people infected with dengue is heterogeneous [58,59]. In this regard, Indonesia is noteworthy in that dengue occurs mostly in juveniles. By the age of 5-9 years more than 80% of children have experienced infection, as demonstrated by seropositivity for at least one DENV serotype, if not overtly by diagnosed clinical manifestations [55]. At a societal level this scale of childhood illness will reduce attendance at school and thereby have a major negative impact on the education of Indonesia’s young people. While the age of infected individuals ranges from under 12 months to 75-80 years old since 1980 the incidence rate among the urban-dwelling population has been increasing in teenagers aged 15 years and older, at a crucial time in their secondary education [55]. That dengue places a severe economic burden on endemic countries is undoubted, yet the real global cost is uncertain as the expense of vector surveillance and control, and of campaigns to prevent disease spread were often not included in previous cost analyses. Hence, the real economic impact is acknowledged to be grossly underestimated by authorized figures [60]. These show that in Indonesia, US$ 381 million was spent on the combined prevention, control, detection and patient management of dengue in 2015 [47].

For the following year, the latest for which figures are available, in direct response to escalating incidence in immediately previous years the budget ballooned to US$ 2 billion, approximately 22% of the global budget allocated to combat dengue in 2016 [47]. From the perspective of the burden placed on medical laboratory provision, this equates to the screening of over 750,000 cases, mostly in and around Jakarta, followed by the treatment of all those patients diagnosed with clinical symptoms of disease [8].

Classification and Reporting of Dengue Cases

The WHO 1997 dengue classification system requires four essential criteria to be met for consideration as severe disease. Without any one of the four criteria, dengue patients will be classified as DF, although they might have already developed shock. This means that this classification system was not sensitive enough to include some cases of severe dengue [20]. Hence, not only did this result in inaccurate reporting but led to an avoidable potentially life-threatening situation for each misdiagnosed patient. This prompted the WHO within 12 years to revise its dengue classification system [20]. This was an apparent attempt to achieve better case management and to reduce mortality. However, in the decade since its introduction there is no evidence that switching to the 2009 classification system has had an effect in reduce mortality from dengue [20]. In part as a consequence, the mortality rate is unacceptably high in many developing countries, including Indonesia. Ignoring the update of the system, the 1997 classification is still used to report dengue in this country, where only DHF and DSS are diagnosed [9]. Reporting dengue in Indonesia is mandatory within 72 hours after diagnosis [8]. Severe secondary infection could explain the increase in CFR [20]. A possible reason is that nowadays, with different serotypes co-circulating in the population, DENV has become more pathogenic [61]. If the virulence of DENV remains stable, the CFR should be constant over time [61].

Signs and Symptoms of Clinical Infection

Further to a person being bitten by an infectious mosquito the incubation period of dengue prior to onset of illness is around 3-7 days [62]. There are a variety of common symptoms of dengue infection, including fever, headache, rash and myalgia [41,63]. Most clinical symptoms of severe dengue only manifest at late stage infection [35]. Severe plasma leakage is determined by shock (DSS) or fluid accumulation with respiratory distress and ascites. Severe bleeding and significant damage to major organs are often involved [20], affecting the liver (aspartate transaminase (AST) or alanine transaminase (ALT) >1000 U/L detected), heart and central nervous system [64]. In Indonesia, predictors of severity are neither standardized nor used consistently. Clinicians assess for warning signs and symptoms for clinical case management, including spontaneous bleeding, plasma leakage (presence of ascites and pleural effusion), hepatomegaly, abdominal pain, haemoconcentration, thrombocytopenia, and sharp increase of AST or ALT levels [63].

Diagnostic Tests

Diagnosis of dengue infection in the acute phase is important primarily for clinical care, but also facilitates the timely implementation of control measures and outbreak surveillance. Currently, two types of detection method are used to diagnose dengue if infection is suspected, namely direct and indirect tests [65]. Direct testing includes virus isolation [61] and real-time RT-PCR assay [66-68] of different DENV serotypes, and so can provide a differential diagnosis. This type of method is limited in its use due to the short duration and low titre of the viraemia in the peripheral blood of an infected person, up to 7 days after the onset of symptoms [69]. Indirect (serological) testing can be used to attain a rapid diagnosis, as early as the first day of fever, and involves detection in patient serum of developing immunoglobulin (Ig)M and IgG antibodies to DENV non-structural protein-1 (NS-1) [32]. These methods include ELISA, for which there is now a commercially available kit, and immune chromatography [69,70]. Except for a few private institutions public and private hospitals in Indonesia do not yet perform dengue serotype surveillance [8]. Therefore, the great majority of dengue diagnoses are made purely by evaluation of clinical criteria using the outdated WHO 1997 classification system and supported by a basic haematological screen [9], including thrombocyte, leukocyte and haematocrit counts [71]. Not all Indonesian health services can utilize IgM/IgG and NS-1 rapid tests as diagnostic tools due to the relative expense of the immunological reagents and a lack of medical laboratory expertise that is required to run each of these methods [8].

Vector Locations, Behaviours and Breeding

A recent detailed longitudinal study found that the most common mosquito species trapped in Indonesia from which DENV could be isolated was Ae. aegypti (90.9%), while Ae. albopictus contributed only 9.1% of virus-positive samples [7]. Ae. aegypti inhabits urban communities, living in close proximity to humans and resulting in more frequent bites [72] compared to Ae. albopictus which prefers more peri-urban and rural environments, which are thus less populated [73]. Both Ae. aegypti and Ae. albopictus may breed in water-holding vessels, including tyres, pots, tins and glass containers [72,74]. Dengue is particularly common in densely populated urban regions of Indonesia [54], where the co-existence of people and Ae. aegypti provides conditions that are conducive to a high rate of transmission. This is a significant problem in a country where more than half the inhabitants reside in metropolitan areas, notably Jakarta [10]. Rapid urbanization, as has occurred in the capital city in recent years, is associated with poor housing quality, limited safe water supply and restricted access to waste management. These encourage mosquito breeding and are significant contributing factors to the rising dengue incidence rate in Indonesia and other tropical low-income countries that are similarly experiencing accelerated population growth [75]. Moreover, a tropical climate and humid environment are conditions conducive to Aedes mosquito transmission of DENV [24,72].

Mosquito Prevention and Control

Estimates of mosquito abundance, including measurable correlates such as egg production and numbers of adults caught in baited traps, are valuable indicators of the adequacy of disease prevention and control in any given location [1]. There are also several ways to eliminate places where the peri-domestic Ae. aegypti prefers to lay eggs in and surrounding homes [76-78]. In low-income tropical countries where dengue is a public health threat mosquito control is an ongoing necessity, especially in urban areas of high endemicity such as Jakarta [14], in order to reduce the presence of the Aedes vector and thereby to lower the rate of DENV transmission. This can be achieved by effective environmental management, including draining mosquito-breeding containers [76]. Larvicide treatment of pooled water is important to suppress the growth of mosquito populations and thus to reduce the risk of a sudden dengue outbreak [79]. Fogging, the technique of spraying a fine aerosol of fast-acting insecticide, is also used but is only effective for killing adult mosquitoes in enclosed spaces such as household rooms and basements [80]. The limitations to control of Aedes mosquito populations include financial constraints, insecticide resistance and insufficient community involvement [81,82]. The prolonged use of chemicals insecticides has led to widespread development of mosquito resistance [83,84], while its indirect effects on community health and the environment are for debate [80]. Likewise, larvicides, including the commonly used organophosphate temephos (marketed by BASF as Abate^®), are toxic to marine wildlife in which they accumulate, and at high doses can cause nausea and dizziness in people. Moreover, it was reported that temephos did not reduce mosquitoes long-term [80].

In Indonesia, ongoing control efforts are focused on removal of mosquito breeding sites, including the Government-funded Mosquito Nest Eradication Program [24,85]. This involves draining water and recycling waste that are potential sites for mosquito breeding, combined with periodic spraying of chemical larvicides and insecticides to eradicate larvae and winged adults, respectively [9,85]. Chemical fogging of domestic dwellings is widely supported. However, of considerable concern is the recent study reporting that chemical insecticide treatment is no longer an effective way to combat Ae. aegypti in some parts of the country [82]. The Indonesian Government also encourages its citizens to take simple steps towards personal responsibility, such as growing lemon grass in gardens, since the odour of the leave is believed to repel mosquitoes, and stocking ponds with insectivorous fish to consume mosquito larvae [56]. At an individual level there are several ways a person may protect themselves from being fed on by a potentially infectious day-biting Aedes mosquito, including applying repellents [86], wearing trousers and long-sleeved shirts, and sleeping under a mosquito meshed curtain bed net [77]. While these personal measures might appear to be common sense, in dengue endemic areas outreach programmes are sometimes required to increase community awareness. Dengue is particularly prevalent during the Indonesian monsoon season (in Java, from October to March) due to the presence of many puddles of water in which Aedes may breed [87]. However, dengue cases are also reported in the so-called dry season (April to September), when the tropical equatorial climate remains very hot and humid, due to limited implementation of waste management measures [83,88], including routine disposal or emptying of water-holding containers [57]. It is evident that vector control alone cannot effectively reduce dengue incidence and mortality rate in Indonesia and other developing countries. Therefore, for future prevention of dengue there is a compelling need to focus more on the hitherto untapped potential of vaccination [21,38].

Vaccine Progress and Setback

Large-scale vaccination of the public is another common strategy to combat tropical infectious diseases. A prime example of successful immunization against an arbovirus is provided by the closely related flavivirus yellow fever, for which a single vaccine dose is sufficient to induce protection that is potentially life-long [89]. Ideally, a vaccine for dengue should produce a balance of protection against all four serotypes, otherwise the vaccine may prime patients for more severe disease manifestations upon secondary exposure to a serotype different to that which caused primary infection [90]. However, the existence of multiple serotypes, combined with a lack of clear understanding of dengue disease pathogenesis, makes the construction of a vaccine a difficult, slow and very costly process [91,92]. Moreover, cross-reactivity by neutralising antibodies to different DENV serotypes risks activating ADE [93-95]. Therefore, the neutralising ability of antibodies to DENV serotypes is extremely important to vaccine design [96]. For a dengue vaccine ADE poses a significant problem as it may induce or enhance DENV antibodies and thereby increase the risk of severe dengue manifestations in vaccinated persons [95,96].

Despite these development hurdles that are unique to dengue in late 2016 a live recombinant tetravalent vaccine, CYD-TDV (marketed by Sanofi-Pasteur as Dengvaxia) [21,38] received commercial licensing by the WHO for a limited release in some endemic countries, including Indonesia [97,98]. However, following equivocal findings of probable ADE in seropositive individuals, notably in Filipino school children, its roll-out in mass immunization programmes is now blocked [99,100]. A further five vaccine candidates are under evaluation in various stages of clinical trial, including other live-attenuated vaccines, as well as subunit, DNA and purified inactivated candidates. Additional technological approaches, such as virus-vectored and virus-like particle-based preparations, are under evaluation in pre-clinical studies [101,102]. The growing proportion of Indonesian people who live in Jakarta and other urban areas would be set to benefit from receiving an efficacious dengue vaccine [12,24]. However, the vaccination programme using Dengvaxia, currently suspended, has been too limited to date to prove effective [103]. Thus, while an advancement is awaited still the best strategy to both prevent and control the spread of dengue in Indonesia remains the low-technology approach of vector management [57,104].

Conclusion

The global incidence of dengue has increased dramatically since the second half of the twentieth century. This emerging infectious disease has a significant impact on health care systems and is an economy burden to many developing countries in the tropics, including Indonesia. Current reporting systems in Indonesia are inadequate and very probably do not describe with any accuracy the actual situation. The need to ensure proper treatment for dengue, considering the various clinical and immunopathological subtypes of the disease, requires clear profiling or characterization of the individual patient, definition of clinical criteria for diagnosis and/or treatment and collection of real-world data in dengue patient care. Improved clinical profiling of dengue in Jakarta might inform better early case management, implementation of effective prevention and control programmes, and enhanced therapeutic vaccine development.

Acknowledgements

The authors’ preparation of this manuscript and their research discussed herein received no specific financial support.

Conflicts of Interest

The authors declare that they have no competing issues of interest.

Authors’ Contributions

AWTR conceptualized the paper, which was developed further in discussion with TLC and TAP. TLC and AWTR collated articles for review, wrote and critically reviewed various drafts. All authors contributed to preparation of the final version and provided consent for submission.

Figure 1: Dengue risk by geographical region of Indonesia [50].

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