This article reviews past dengue control efforts and discusses current and future strategies for dengue control. Dengue fever, Dengue epidemiology, Vector control, Dengue vaccine development. In recent years, there have been several "good news stories" in global health, such as a steady decrease in child mortality rates and malaria incidence, as well as the near elimination of polio from the planet.
However, many challenges remain with regard to both emerging infectious disease outbreaks and increasing rates of some neglected tropical diseases [ 1 ]. Dengue fever is an apt example of the latter, having progressively advanced in both the number of endemic countries as well as risk for severe manifestations, such as dengue hemorrhagic fever. In the last half century, the worldwide incidence of dengue has risen fold [ 2 ]. In this paper we explore the environmental and human factors that have given rise to the expansion of this disease, particularly in Asia.
We also highlight the advancements already made throughout the Asia-Pacific region in combating the spread of dengue, and discuss future efforts. Dengue fever DF is among the most common mosquito-borne infections in the world, yet it has long been categorized as a "neglected tropical disease [ 3 ]. Even these numbers are likely an under representation, since many cases are undiagnosed and unreported due to discrepancies in reporting requirements and inadequate surveillance systems.
The actual annual case load may be as high as million Figure 1 [ 6 ]. Recent outbreaks in Malaysia, Taiwan, and India are among the highest those nations have faced in years [ 7 ]. While these numbers have risen steadily in recent decades, they are lower than estimates of actual number of cases and countries affected for various reasons that are discussed in detail later.
From WHO, reprinted with permission [ 5 ]. View Figure 1. Dengue fever is caused by a flavivirus carried by an Aedes mosquito vector Ae. The geographic ranges of these mosquito vectors are expanding steadily Figure 2.
Dengue fever virus does not have a broad range of animal hosts, leaving the human-mosquito cycle as essentially the sole means of transmission [ 9 ]. Now, however, all four serotypes circulate in each of the global endemic regions [ 10 ]. Infection with one dengue virus serotype generally results in long term immunity to the same viral serotype. However, due to complexities of the immune response, subsequent infection with a different serotype can make an individual more susceptible to severe manifestations such as dengue hemorrhagic fever DHF [ 4 ].
In endemic areas with high rates of immunity to the longstanding circulating viral serotype, not only was the population generally non-immune to the newly introduced viral serotypes, but they were also "immunologically primed" to experience more severe symptoms with subsequent infections [ 11 ].
Figure 2: Shaded areas are countries at risk of dengue fever due to presence of Aedes mosquito, as of View Figure 2. The incubation period for dengue virus is five to seven days. Viremia peaks and falls sharply over the following week, thus onward transmission may occur during this time.
Aedes mosquitoes have a very short average flight range, often traveling less than meters' distance in their lifespan, and feed almost exclusively on humans, both indoors and out [ 12 ]. This small range requires them to live in close proximity to humans. Once an infected person becomes viremic, they may remain asymptomatic, develop a mild nondescript febrile illness, or experience a range of symptoms from fever, headache, myalgias, and rash to severe symptoms such as shock, hemorrhage and organ failure.
Severe dengue fever arises primarily due to vascular permeability; the immune response to the virus causes fluid to leak out of the vasculature into tissue spaces, causing shock, organ failure, and hemorrhage [ 4 , 5 ]. Host immune factors are likely primarily responsible for initiating the vascular permeability and plasma loss that characterize dengue infection [ 4 ]. Unfortunately, this classification system had shortcomings. Many of the criteria used as markers of severity required clinical judgment and led to inconsistencies in the epidemiology and classification [ 14 , 15 ].
There were also four different levels of severity for DHF [ 13 ], adding even more complexity to the classification. In the WHO established new diagnosis and management guidelines, altering the case definitions [ 5 ]. As such, these prognostic criteria provided clinicians with a more measurable way of identifying those who are likely to develop SD, and may require more intensive monitoring and support earlier in the disease course [ 5 ].
Even with the WHO diagnostic criteria, shortcomings remain, as altered hemostasis is not factored [ 16 ]. At this time there is no reliable prognostic laboratory test to predict the development of SD. Clinical studies suggest an association between cytokines or mast-cell derived mediators such as chymase, vascular endothelial cell growth factor and IL and severity [ 17 - 19 ]. Importantly, a mechanism was recently shown by which dengue NS1 protein disrupts endothelial cellular integrity [ 20 , 21 ], which could contribute to disease severity.
Prior to WWII, dengue fever occurred in coastal cities throughout the tropics and subtropics, with epidemics occurring periodically. Nevertheless, during the age of exploration and rise of international trade during the 17 th and 18 th centuries, dengue fever spread to tropical cities worldwide, likely due to expansion of Ae aegypti from Africa to Asia and the Americas [ 22 ].
Epidemics of dengue were reported in in the Caribbean and in Central America [ 10 ]. The name "dengue" derives from a word meaning "affected" used in the Caribbean to describe these outbreaks.
The history of dengue fever is complicated by the fact that some outbreaks in the Caribbean during the nineteenth century may have been chikungunya, an alphavirus presenting with clinical manifestations that were called "dengue" at the time [ 23 ].
Once the rise of coastal urban centers and international shipping occurred, dengue became more pervasive and more easily recognized. Since urban centers in the tropics were relatively small, and transportation between them was generally by ocean going ships, epidemics were minimized and each region had only one or two circulating virus strains, so dengue carried little public health importance [ 11 ]. During WWII, due to massive movement of troops, particularly into remote regions of Southeast Asia and the Pacific Islands, dengue spread dramatically.
Dengue had a major impact on troop strength in the Pacific during WWII, and along with malaria, was one of the two major disease threats. Its impact on the region was greater still. By the end of WWII, as a result of the vector and the virus having been spread throughout Asia-Pacific nations, many Asian countries were hyperendemic with all four viruses [ 11 ]. With this spread of globalization and urbanization, particularly in Southeast Asia, the stage was set for dengue hemorrhagic fever epidemics.
The first such epidemic was reported in the Philippines , followed by Thailand , then Malaysia, Singapore, Vietnam, Indonesia, and Myanmar Burma in the s and s. By the s DHF was a leading cause of childhood illness and death in some Southeast Asian nations [ 11 ]. DHF epidemics in the Americas were curtailed though, through a major public health campaign.
While yellow fever elimination was the target of the campaign, dengue rates would decline as well since the viruses share vectors. This effort began with major backing from government officials, significant funding mechanisms, and widespread public health engagement. The mosquito was eliminated from the majority of Brazil, and similar successes were seen in other South American nations. By , with the widespread use of DDT insecticide, hopes were high and a continental Ae.
Despite such broad scale efforts, the early successes were not sustained. Dengue outbreaks occurred during the s and an Asian dengue virus, DEN3, was reintroduced to the Caribbean [ 25 ]. PAHO remained committed to the eradication effort, but political will, funding, coordination, and surveillance decreased, while globalization, international travel, and urbanization were on the rise.
Unfortunately, as the broad coalition of support for this noble effort waned, Ae. Not surprisingly, dengue rates rose steadily throughout the Americas in the s and s, reaching pre-campaign levels by [ 11 ]. The spread of dengue can be closely tied to both the geographic spread, as well as the domestication of its vectors. The primary vector, Ae. Regarding Asian Ae aegypti, historical data suggests African origin as well, whereas genetic data points to subsequent spread from the Americas.
Nevertheless, the present day worldwide domestic Ae. The expansion of dengue fever can be tied to the ecology of Ae. It was first recorded in Europe in , and in the continental US in [ 26 ]. The limited phylogeographic difference in genetics provides evidence for expansion due to human activities [ 26 ]. Cases have continued to increase over the last decade in Cambodia, Laos, Malaysia, Singapore, Philippines and Vietnam.
Dengue's impact on lost productivity is also notable. The DALY burden of dengue is estimated to be , per year worldwide, primarily affecting children [ 10 ]. These studies notably exclude the cost of prevention [ 10 ]. Providing an estimate of dengue's actual impact is difficult as there are extensive variations in national reporting data, and many nations don't have a robust reporting system [ 28 ]. As a result, in there were 2.
In India, where there is no mandatory centralized reporting, there are estimated to be dengue infections for every reported case [ 29 ]. Even if the case load estimate was more accurate, determining the economic burden is even more difficult. Additionally, some economic impact areas, such as impact on tourism, have not been fully explored [ 30 ]. Most commonly, disease burden is calculated using the acute illness of seven days or less standard. However, there are increasing reports of long term post-viral effects, such as chronic fatigue syndrome and depression [ 30 ].
Ideally, the overall impact of the impaired quality of life and poverty rates should somehow be factored into disease burden estimates. Due to domestication and anthropophagy predilection for human feeding vice other vertebrates of the Aedes vectors, dengue is a predominantly urban disease. Currently, all four serotypes circulate throughout the year in Brazil. When the detection of one serotype increases in a certain region, the effect is usually regional and could remain limited to that region, depending on both the geographic location and the population movement in the area for example, if many individuals commute to the city for work.
Furthermore, epidemics sometimes target regions that were unaffected by the last epidemics of a certain serotype, so that the population is susceptible but the municipalities around it are not susceptible. Laboratory monitoring is vital for the assessment of circulating serotypes, which provides Brazilian Government agencies with important data to establish strategies focused on combating dengue through vector control aiming to minimize potential disease outbreaks.
Figure 2 shows that the increase in dengue serotyping is proportional to the number of cases of dengue reported in different regions, although the serotyping percentage is still lower compared with the total cases.
After , some strategies such as laboratory accreditation LACENs and greater funding were adopted to further expand the dengue serotyping coverage. The total percentage of serotyped samples was calculated in relation to the total probable cases observed in each region for every year using data available from the Brazilian Ministry of Health.
The WHO recommends the use of serological methods for the diagnosis of DENVs to provide laboratory confirmation and the use of genomic techniques for the confirmatory test necessary to directly detect the virus. Currently, three basic steps in DENV detection are followed by most diagnostic laboratories: i isolation by animal cell culture; ii viral characterization by the detection of specific antigens NS1 antigen capture enzyme-linked immunosorbent assay, ELISA and the indirect detection of immunoglobulin M IgM , IgG, and virus-specific antibodies in serum; and iii detection of the DENV genomic sequence using a nucleic acid amplification assay based on PCR, with reverse transcription RT-PCR and quantitative PCR qPCR being the appropriate tools for the identification and determination of different serotypes of dengue [ 6 ].
The Brazilian Ministry of Health recommends the use of the following protocol. All patients suspected of DF must be reported and have a blood sample collected for diagnostics. Samples that are negative for dengue will be screened by RT-PCR for chikungunya and Zika virus and other pathogens for differential diagnosis [ 32 ]. In Brazil, the recommendation of the Ministry of Health is that all suspected dengue samples must be serotyped. The PCR protocol of Lanciotti et al.
Several methods based on PCR and qPCR techniques are available in the literature; Table 1 presents the main characteristics of some primers used in these works. Chow et al. This strategy of using consensus primers in PCR depends on DNA sequencing techniques to identify which viral serotype is present in the sample and thus forms a complete molecular diagnostic protocol to characterize the epidemiology of dengue and other flavivirus infections.
This protocol is therefore laborious and costly for the identification of DENV serotypes. Chang et al. These primers were designed in the NS5 gene region encoding the viral RNA polymerase because this region is highly conserved in flaviviruses.
These authors designed consensus primers and specific internal primers for serotyping, but the amplicons had sizes ranging from to bp, making them inappropriate for qPCR assays [ 36 ]. Thus, diagnosis by this protocol still needs improvement. Pierre et al. Again, this method depends on post-amplification sequencing analysis to characterize the type of flavivirus.
Meiyu et al. Five specific internal primers were also developed based on published NS1 gene sequence data: four of them were for the dengue serotypes DENV , and one was for Japanese encephalitis virus JEV.
These primers were combined with DJA - , thus forming five sets of internal primers to produce a hemi-nested assay. The results presented by the authors showed a sensitivity of the PCR assay of Kuno et al. The protocol described by the authors aimed to reduce the discrepancy between molecular and serological classifications. The union of these two methods improves discrimination among the members of the genus Flavivirus when the RT-PCR amplicon is used for genomic sequencing of the flavivirus.
Shu et al. Johnson et al. This method has the advantage of simultaneously identifying all four serotypes, either by using four different probes for each serotype or by using the same probe in separate assays.
However, some disadvantages also exist: the cost of the protocol is high, and three primers are required for each viral serotype, two of which are fluorogenic probes for serotyping by RT-qPCR [ 42 ]. Ayers et al. This protocol requires the sequencing of amplification products for the confirmation and identification of viral species. Protocol validation was performed, but the authors did not determine the sensitivity of the assay; additional research is required to ensure high sensitivity in further experiments.
Lanciotti et al. Based on this observation, Chien et al. The TS3 efficiency was similar to that described by Lanciotti et al.
In the Chien et al. The consensus primers were redesigned, and internal primers were designed to be used in TaqMan RT-qPCR assays in a nested protocol, taking advantage of the Johnson et al.
Salles et al. The modified protocol can use less-expensive and more common polymerase enzymes. With these modifications, this protocol obtained better yields relative to primer efficiency, from This vaccine presents some serious problems that call into question its full effectiveness [ 47 ].
In addition, this vaccine has a high cost, and further studies are needed to prove its efficacy [ 47 ].
This study was based on the possibility that the Dengvaxia vaccine might increase the risk of severe disease in people who had never been exposed to DENV before. Since then, this vaccine has not been considered as a potential prevention tool. The Philippine Health Ministry halted Dengvaxia immunizations due to 14 deaths of children that were associated with vaccination [ 50 ].
In Brazil, the government decided to use Dengvaxia to vaccinate only individuals who are already seropositive [ 49 ]. In Brazil, all three government spheres federal, state and municipality share responsibility for dengue control. The federal level provides guidelines for vector control, allocates resources to the states and purchases insecticides and equipment, such as vehicles mounted with an ultra-low-volume sprayer to support chemical control.
The states assist and supervise municipalities, acquire consumables and small equipment, such as nylon nets and lids for water tanks or mosquito traps, and gather information about the municipalities to notify the Health Ministry.
The municipality is responsible for operations such as management of vector control professionals and actions, following central-level recommendations. In practice, this shared responsibility can reduce the efficiency of vector control; for example, decision-making processes can be bureaucratic and time-consuming [ 51 ].
The prospects of controlling dengue disease are not promising. The number of dengue cases increases in proportion with factors such as deforestation, poor sanitation and climate change [ 51 ]. Three out of four Brazilian municipalities are heavily infested with the mosquito Ae. Reducing the density of Ae. Some vector control initiatives have been conducted. These efforts include re-emphasizing insecticide use, but most mosquito populations are resistant [ 52 , 53 ].
Other initiatives, such as sterilizing mosquitoes by genetic modification or irradiation or even infecting mosquitoes with Wolbachia , have so far shown no success in vector control [ 52 , 53 ]. Another form of prevention consists of an ongoing battle against water accumulation, which is conducive to the reproduction of the mosquitoes that transmit the disease. For this reason, periodic epidemiological surveillance and population awareness are necessary to control the reproduction of the mosquito vector by promoting actions such as the removal of water that accumulates in breeding sites [ 54 ].
This initiative can be efficient in the home, but much water accumulates in peridomicile environments in Brazil due to the precarious system of water supply, sewage and solid waste collection among others. These conditions favor the proliferation of the Ae. Even with the government investing more than half a billion dollars each year in mosquito control, there has been no reduction in vector density that could limit or reduce the spread of dengue in a sustained way [ 56 ].
Without vaccines, effective drugs, or sensitive diagnostic tests, the only available response to reduce disease severity and case fatality is clinical management through enhanced care supported by accessible, sensitive and specific useful diagnostic tests.
These tools will help identify warning signs for severe disease and evidence-based criteria for the standardization of treatment procedures [ 57 ]. Without adequate prevention and treatment, the number of reported cases of dengue has increased in recent years in Brazil and the Americas.
Considering these facts, the population is dependent on methods of prevention and the treatment of symptoms. For this reason, the Secretariat of Health Surveillance SHS must collect information from the data provided by sentinel laboratories, even if not all cases are confirmed due to diagnostic inefficiency and some must be discarded.
Studies are necessary to increase the performance of the available diagnostic methods to guarantee accurate notifications by state health departments and municipalities. Finally, it is important to continue to support the research for more effective diagnosis and treatment of dengue and also for new methodologies of vector control and disease prevention. The origin, emergence and evolution genetics of dengue virus.
Infect Genet Evol. Article PubMed Google Scholar. A structural perspective of the flavivirus life cycle. Nat Rev Microbiol. Fields virology. Google Scholar. Microbiology: An evolving science, 2nd ed.
New York: W. Norton and Company; Prospects for a dengue virus vaccine. World Health Organization. Dengue: guidelines for diagnosis, treatment, prevention and control. New edition. Geneva: World Health Organization; Accessed 8 Dec Gould EA, Soloman T.
Pathogenic flaviviruses. Dengue type 3 infection in Panama. Am J Trop Med Hyg ; Pan American Health Organization ed. Dengue in the Caribbean, Proceedings of a workshop held in Montego Bay, Jamaica, Dengue type 4 infections in U. MMWR ; Dengue fever in Puerto Rico Selected Bibliography CDC. Dengue type 2 virus in East Africa.
MMWR ;,8, Imported dengue type Florida. This conversion may have resulted in character translation or format errors in the HTML version.
An original paper copy of this issue can be obtained from the Superintendent of Documents, U. Contact GPO for current prices. Department of Health and Human Services.
Dengue in the United States, Duane J. Gubler, Ph. Dengue Branch Division of Vector-Borne Viral Diseases Center for Infectious Diseases Introduction Dengue, caused by a virus with four distinct serotypes, is usually a mild illness of short duration; classical symptoms include fever, vomiting, myalgia, headache, severe retro-orbital pain, and lower back pain.
0コメント