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Dengue research needs related to surveillance and emergency response

30 Nov 2007

Source: WHO/TDR

Eng-Eong Ooi ¹ , Duane J Gubler ² , Vu Sinh Nam ³

¹DSO National Laboratories, 27 Medical Drive, #09-01, Singapore 117510
²Asia-Pacific Institute of Tropical Medicine and Infectious Diseases, University of Hawaii, and Department of Tropical Medicine and Medical Microbiology, John A. Burns School of Medicine, 651 Ilalo Street, BSB 320, Honolulu, Hawaii 96813, USA
³Vietnam Administration of Preventive Medicine, Ministry of Health, 138A, Giang Vo, Ba Dinh, Hanoi, Viet Nam

Introduction

Dengue fever/dengue hemorrhagic fever (DF/DHF) is a disease that is endemic in the tropics, has re-emerged to become the most common and most important mosquito-borne viral disease in the world. The current trend is a 4- to 6-yearly cycle of dengue epidemics, with each cycle becoming larger in magnitude.[26] In the absence of an approved vaccine, prevention of viral transmission through public-health measures directed at controlling the density of the vector mosquito population remains the only viable preventive strategy. Effective prevention depends on a well-planned and operated public-health, laboratory-based surveillance programme (Gubler, 1989; Gubler & Casta-Velez, 1991; Rigau-Perez & Gubler, 1997).[21,22,51]

A primary goal of public health surveillance in dengue is to monitor transmission to facilitate prevention of the occurrence and spread of disease. [51] Other goals for surveillance include defining disease severity, determining the cost-effectiveness of public-health prevention programmes, and estimating the burden of disease in the communit.[56] The ideal surveillance programme should thus be able to monitor dengue cases accurately and predict impending epidemics from a background of endemic disease and trigger the necessary preventive measures.

Recent research findings

In recent years, new findings have shed light on factors, other than incomplete immunity, that contribute to epidemic transmission for all four dengue virus serotypes.

Viral factors

Phylogenetic studies have yielded interesting insights into the selection and evolution of the dengue viruses, both temporal and geographical.[37,50,59,67] Such studies may also enable us to gain a better understanding of the viral factors that contribute to dengue virus virulence and epidemic potential.[4,17,19,40] However, although current technology allows us to monitor genetic changes in viruses, the biological effect of these mutations has yet to be elucidated. It is often difficult to attribute genetic variation to specific phenotypic expression, since dengue epidemics are associated with a host of factors that could confound the analysis, and there is no good animal model for dengue. Nonetheless, further investigations in this field may yield fruitful results as genetic changes are likely to contribute to increased or decreased viral fitness and thus epidemic potential and virulence. This includes infectivity and ability to replicate in humans and mosquitoes, thus resulting in increased or decreased transmission. Genetic change in the virus could also influence disease severity, and thus result in more or less clinically overt disease. A critical area of research, therefore, is to determine the influence of viral factors on disease transmission dynamics and disease severity.

Vector control

Various reports have shown that the inclusion of community participation along with the use of old and new vector-control tools [8,36] as well as biological control (Kay & Nam, 2005; Nam et al., 2005) [35,41] have had positive effects on preventing disease transmission. However, sustainability remains a problem, and there is a need to establish proactive, laboratory-based disease- and vector-surveillance programmes that provide a trigger for intensified vector control to prevent epidemic transmission.

Experience gained in Singapore suggests that keeping the density of the vector population below a threshold for epidemic transmission is a moving target. Lowered herd immunity after implementation of effective control measures may paradoxically lead to a rise in the number of cases of dengue, which in turn, requires more intensive vector-control measures to prevent an epidemic.[7,15,44] Identification of predictive entomological thresholds or markers for epidemic dengue, in combination with population susceptibility would thus be a useful area of research. In addition, experience gained recently in Viet Nam [35] reinforces the lessons learned decades ago in Singapore by Chan,[6] that without community involvement, vector control cannot be sustained. Subsequent experience in Singapore shows that sustainability of the vector-control programme is challenging, despite continued public education and law enforcement.

While the role of Aedes aegypti is obvious, the role of Ae. albopictus in maintaining dengue endemicity is less clear. Although Ae. albopictus is an excellent host and experimental vector for dengue viruses,[16,53] it has not been frequently associated with epidemic dengue.[26] The reason for this is thought to be related to this species' ecology and blood-meal seeking behaviour; Ae. albopictus has a broader host range, and usually bites only once in obtaining a blood meal. However, in most countries where dengue is endemic, both species of vectors can be found. Furthermore, in many places such as Singapore, Ae. albopictus outnumber Ae. aegypti and are more widespread geographically. Although Ae. albopictus may not be an efficient vector for epidemic dengue, it may play an important role in endemic transmission, maintaining dengue viruses in the population until the population immunity is sufficiently lowered and the Ae. aegypti population is sufficiently dense to support epidemic transmission.[54,20] Studies on the role that Ae. albopictus plays in dengue transmission may thus be useful in our understanding of the epidemiology of dengue disease.

Population immunity

Several reports of large-scale serological surveys have been published in the last 5 years.[2,10,32,43,57,58,60,66] Although such studies may aid understanding of overall dengue activity in the area, few have attempted to use these data to guide vector-control operations. Serological surveys could be useful in elucidating the roles played by Ae. aegypti and Ae. albopictus during epidemic and inter-epidemic periods. Such a study would be entirely feasible in places like Singapore where the geographical distribution of Ae. aegypti is different from that of Ae. albopictus. With a combination of active virological and entomological surveillance, such a study may improve our understanding on the dynamics of dengue transmission and how these factors in turn contribute to endemic versus epidemic transmission.

Surveillance systems

A common theme that appears in reviews of the areas where research on dengue is needed is that of surveillance. Here, the literature suggests that much could yet be done to improve on the sensitivity and specificity of our surveillance programmes.[22,51,24] Most countries continue to monitor dengue cases by using a passive surveillance approach. An update of the table first published by Gubler in 2002 (table 1) subjectively summarizes the surveillance systems in countries where dengue is endemic. Passive surveillance relies on disease notification by health-care professionals who have a duty to report all suspected cases to public health authorities. However, passive surveillance systems are uniformly insensitive because of the low index of suspicion for dengue during inter-epidemic periods[21,51].

Limitation of passive surveillance

Two main problems are encountered in passive surveillance for dengue. These are:

Dengue infection leads to a wide range of disease manifestations

Dengue infection results in a spectrum of clinical outcomes: completely asymptomatic, undifferentiated viral syndrome, DF, DHF, dengue shock syndrome, and other severe manifestations such as neurotropic disease and hepatic failure[14]. Passive surveillance using case definitions lacks specificity since many other infectious diseases, such as influenza, chikungunya fever, the viral haemorrhagic fevers, enterovirus infections, leptospirosis, malaria, typhoid fever, etc., all present with symptoms and signs that are similar to those seen in patients with dengue in the acute phase of illness[14,28].

The use of passive surveillance alone also ignores patients who present with undifferentiated febrile illness or viral syndrome. This group of patients may represent a large proportion of those with symptomatic dengue infection, depending on the age of the patient and the strain of infecting virus[33]. Any attempt to carry out passive surveillance among this group of cases will not be feasible. However, mild viral syndrome may be of particular use in monitoring dengue transmission during inter-epidemic periods when the incidence of classical DF and DHF is low[21,51]. In countries where dengue circulates hyperendemically, it is likely that emergence of genetic variants with greater epidemic potential may be partially responsible for the cyclical outbreaks [18,20,31] since certain viral clades appear to be more closely associated with increased transmission and severe disease outcomes [4,5,49,61]. Virological surveillance on cases that present with mild viral syndrome may yield such pre-epidemic isolates for comparative analysis. Although more work will need to be done before such data can be used for epidemic prediction, the key to understanding dengue epidemiology lies in better virological surveillance during the inter-epidemic periods[21,22,26].

Variation in the case definitions used

The usefulness of the existing scheme for the classification of dengue and case definitions established according to the WHO guidelines has also come under scrutiny[55,11]. Experiences from various parts of the world suggest that the usefulness of the case definition is not universal[2,12,31,55]. Perhaps more importantly, the WHO case definition underestimates the number of cases of severe dengue among adults[29]. This is a problem that needs to be addressed as dengue infection among travellers [64] and even in endemic countries like Singapore, primarily affects the adult population (Ooi et al., 2001; Ooi et al., 2006) [43,44]. Notwithstanding the current debate over the WHO case definition, there is also no consistency in the way these definitions are applied between countries where dengue is endemic. Different countries classify DF/DHF differently, and there is variation in the types of dengue cases that are included in surveillance reports, countries adopting different criteria for classifying dengue cases[11,24]. Some countries report only DHF while others include DF in their surveillance[24]. The existence of all these different practices contributes to underestimation of the true extent of dengue transmission and limits the ability to compare surveillance data among countries and regions.

WHO and others have advocated active surveillance since the 1980s[21,45,63]. As previously recommended, virological surveillance should be conducted on patients that present with nonspecific viral syndrome, classical DF, with haemorrhagic or neurological manifestation and on all patients with a fatal outcome following viral prodrome[18,21–23,51]. This approach, using sentinel physicians, clinics, and hospitals, would result in a more comprehensive surveillance for the transmission of dengue virus in the population. Yet, in south-east Asia where DF/DHF epidemics are reported every 3 to 6 years, only Malaysia and Singapore have an adequate laboratory capacity (Table 1). Most other countries continue to rely on passive surveillance systems for DHF alone.

The long experience with dengue surveillance and vector control in Singapore has recently been reviewed[44]. One of the lessons learned is the need for surveillance and vector control to be carried out at the regional level[44]. If it is not, countries that attempt to prevent this viral disease are doomed to failure owing to re-importation of both virus and vector because of the rising trend in global trade and travel.

In the Americas, proportionately more countries report both DF and DHF, although good laboratory support is still only available in Cuba, Brazil, Puerto Rico, Nicaragua, and the USA (Table 1). However, few countries carry out active surveillance for dengue disease. This is despite the efforts of PAHO in the 1980s and 1990s to encourage Member States to develop plans for disease prevention and control of DF/DHF[27,46].

The situation in the Pacific has not changed since 2002; only Australia, Tahiti and New Caledonia have good laboratory support for surveillance, although active surveillance with epidemic prediction is carried out only in the state of Queensland, Australia. This north-eastern state remains prone to dengue outbreaks[30], although very active vector surveillance and control is in place to complement the existing epidemiological surveillance[39,52].

To establish an active, laboratory-based surveillance system, coupled with effective community-based, integrated vector control requires both the necessary public funds and political will. Unfortunately, most countries where dengue is endemic have developing economies, and resources that could be channelled to prevention of disease transmission have been directed to other more highly visible public-health programmes. Although, the benefits derived from an effective public-health approach to prevention and control[22] are significant, many countries have preferred to adopt a spend-only-when-needed approach to vector control. This approach is often too little, too late, since most emergency controls are only implemented at the height of the epidemic [21,47,48] and thus represent a waste of public funds.

Solutions and issues to be addressed

Active surveillance

Given the type of information needed for dengue surveillance, it is apparent that passive surveillance alone will not generate sufficient information needed for the prediction of outbreaks. An active, laboratory-based surveillance system and a better understanding of dengue epidemiology are needed for a more cost-effective prevention [21,22,51]. The universal use of the WHO case definitions, in the absence of new developments in this field, is essential to enable the surveillance data to be compared across countries and regions. In addition, the following will also be useful:

• Standardization of the denominator

  While the isolation of dengue virus has been attempted in some parts of the world, the case definition used to select patients for virological surveillance varies from country to country. Furthermore, there is often a lack of denominator, or the extent to which the cases that fit the clinical entities are sampled for dengue virus. This lack of denominator limits the ability to make quantitative assessment of dengue transmission and thus compare the effectiveness of various preventive measures when these are applied in different places. As recommended by Gubler [18,21–23], virological surveillance should include patients that present with nonspecific viral syndrome, in addition to classical DF, with haemorrhagic or neurological manifestation and on all patients with a fatal outcome following viral prodrome. This approach would result in a more comprehensive surveillance on dengue virus transmission in the population.

• Focus on urban centres

  Since all public health authorities operate within certain budget constraints, it would be important to focus the surveillance effort on places where outbreaks are likely to emerge. The work by Cummings et al. [9] has provided good data to support previous epidemiological observations that dengue epidemics emerge from urban environments and then spread to new areas [18,26]. Thus, despite limited resources, focus on tropical urban centres, may enable a surveillance system to be predictive of outbreaks.

Laboratory support for dengue virus surveillance

Laboratory support is a critical component in surveillance [22,51]. In particular, the laboratory should be able to identify not only the presence of dengue virus, but also its serotype, the severity of illness, and whether the patient is experiencing a primary or secondary infection. Furthermore, information on the genetic sequence of the viruses circulating, both during and between epidemics, will be of great value to our eventual ability to predict epidemics.

• Standardization of laboratory methods

  Currently, many countries where dengue is endemic lack laboratory support for dengue surveillance. Among those that do have laboratory support, there exists variation in laboratory methods used for virological surveillance. This is especially true for molecular methods; the literature reports a large number of real-time or end-point reverse-transcriptase polymerase chain reactions (RT-PCRs) for dengue virus. These assays vary in their sensitivity and specificity. Importantly, many of the new serological assays have not been tested for cross-reactivity to other viruses, especially co-circulating flaviviruses like Japanese encephalitis, yellow fever and West Nile viruses. Standardization of the laboratory methods used for virological and serological surveillance, along with the establishment of an international quality assurance programme for such laboratories would yield clear benefits.

  Besides methods for the isolation or detection of dengue viruses, standardization of the genes to be sequenced for phylogenetic analysis should also be determined and agreed upon such that the data can be shared and compared within and between regions. Currently, such studies have ranged from partial to full genome sequences. Obviously full genome sequences will be more informative, although cost prohibits this from being done on a large scale. New developments on mass spectrometry technology-based genomic sequencing [38], chip-based high-throughput resequencing arrays [65] may lower the cost of genetic sequencing when compared with the use of capillary sequencers, and thus allow more viruses to be analysed in this manner. If not, an international agreement and standardization of the region of the genome to be analysed will be useful in making the sequence data more amenable to comparison across countries and regions. Before this can be done, however, studies need to be conducted on the influence of genetic changes on phenotypic expression (see section on viral factors).

• Global laboratory network for dengue surveillance

  It would be beneficial to establish WHO Collaborating Centres for dengue virus surveillance. This would complement and expand the DengueNet system, where morbidity and mortality data are shared among countries. Following the lead of the global influenza and polio surveillance systems, establishing reference laboratories in different regions of the world, which are responsible for more detailed analysis of the dengue virus isolates (such as phylogenetic analysis) may overcome the limitation posed by the lack of public funds for such high-technology laboratory support in countries where dengue is endemic. Countries with the necessary financial and laboratory resources, such as Australia, Japan, Singapore and the USA, could play such an important regional role. This, however, does not negate the fact that every country where dengue is endemic should have at least one laboratory that can support virological surveillance.

Entomological surveillance

The clear need in entomological surveillance is an index or a measure of vector population density that may be predictive of epidemic dengue transmission. Since eradication is not feasible, the goal of public-health preventive measures, in the absence of a vaccine, is to maintain a vector population density that is too low to support sustained viral transmission. It was thought from experience in Singapore in the 1970s that a premises index (the percentage of premises where Ae. aegypti larvae are found) of less than 5% was sufficient to prevent epidemic dengue [7]. However, since the 1990s, it is obvious that in Singapore, dengue incidence has increased dramatically, despite an overall premise index of 2% and below [44]. This, however, may be owing to the insensitive nature of a national premise index; despite the low national index, there are places in Singapore where the density of the Ae. aegypti population is high. Likewise, similar reports of limited ability to predict outbreaks have also been associated with the use of Breteau and container indices. A complicating factor is the role of herd immunity. Clearly, the vector-population densities required for epidemic transmission are lower in regions with low herd immunity [42].

Emergency control

While vector population control in several instances, such as in Singapore and Cuba, has clearly been successful although not completely sustainable, the effectiveness of emergency control, as practiced in most countries, is highly questionable. Most emergency control makes use of a combination of reducing the availability of larval habitats as well as chemical adulticide. Chemical control, other than using those chemicals with residual effect, has only limited usefulness in either preventive or emergency control. Yet, they continue to be used in many places despite the lack of evidence of their effectiveness [21,47,48]. In addition, their indiscriminate toxic activity may also remove the natural predators of the dengue vectors.

In recent years, the development of powerful mathematical and computer tools allows for more sophisticated modelling of outbreaks of infectious disease. Such models also allow for a theoretical assessment of the ecological determinants of epidemic transmission, effectiveness of disease control and preventive measures [1,13,62]. Emergency control measures could perhaps benefit from the use of such a tool to assess their efficacy. They might allow for various control modalities to be assessed for their effectiveness in reducing virus transmission, given a range of likely scenarios. However, for such a tool to be practically useful, validation of the mathematical assumptions need to be carried out with actual epidemiological and entomological data.

A major problem with emergency control operations is that, because of poor surveillance, they are usually implemented near peak epidemic transmission, too late to have any impact on the epidemic [21,23]. The reason for this is that implementing emergency control is a political decision, not a public-health decision. To be fully effective, early warning surveillance systems must have built-in triggers to automatically initiate the emergency control programme.

In conclusion, DF/DHF has emerged as the most important vector-borne viral illness in the tropical world and this is likely to be the case well into the 21st century. In the absence of an approved vaccine, the only means to control this disease is to interrupt the transmission of the virus. This will require a sensitive and cost-effective disease- and vector-surveillance, coupled with a community-based larval-control programme. Few countries where dengue is endemic have such public-health infrastructure in place [24]. The challenge that lies ahead is to put into operation these surveillance and vector-control systems, while exploring how new technologies in genetic sequencing can aid in our understanding of dengue epidemics and capability to predict outbreaks.

Research priorities

• To establish an active laboratory-based multicentre surveillance system for dengue infection in selected countries where dengue is endemic.

• To establish a regional laboratory network to support virological surveillance and information exchange.

• To establish a system, coordinated by reference centres, to share and genetically characterize viruses isolated during epidemics and inter-epidemic periods.

• To initiate research to understand the role of Ae. albopictus in dengue transmission during epidemic and inter-epidemic periods.

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