Dengue is a systemic viral infection transmitted between humans by Aedes mosquitoes. For some patients, dengue is a life-threatening illness. There are currently no licensed vaccines or specific therapeutics, and substantial vector control efforts have not stopped its rapid emergence and global spread. The contemporary worldwide distribution of the risk of dengue virus infection and its public health burden are poorly known. Here we undertake an exhaustive assembly of known records of dengue occurrence worldwide, and use a formal modelling framework to map the global distribution of dengue risk. We then pair the resulting risk map with detailed longitudinal information from dengue cohort studies and population surfaces to infer the public health burden of dengue in 2010. We predict dengue to be ubiquitous throughout the tropics, with local spatial variations in risk influenced strongly by rainfall, temperature and the degree of urbanization. Using cartographic approaches, we estimate there to be 390 million (95% credible interval 284-528) dengue infections per year, of which 96 million (67-136) manifest apparently (any level of disease severity). This infection total is more than three times the dengue burden estimate of the World Health Organization. Stratification of our estimates by country allows comparison with national dengue reporting, after taking into account the probability of an apparent infection being formally reported. The most notable differences are discussed. These new risk maps and infection estimates provide novel insights into the global, regional and national public health burden imposed by dengue. We anticipate that they will provide a starting point for a wider discussion about the global impact of this disease and will help to guide improvements in disease control strategies using vaccine, drug and vector control methods, and in their economic evaluation.

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The global distribution and burden of dengue

Dengue fever, a very old disease, has reemerged in the past 20 years with an expanded geographic distribution of both the viruses and the mosquito vectors, increased epidemic activity, the development of hyperendemicity (the cocirculation of multiple serotypes), and the emergence of dengue hemorrhagic fever in new geographic regions. In 1998 this mosquito-borne disease is the most important tropical infectious disease after malaria, with an estimated 100 million cases of dengue fever, 500,000 cases of dengue hemorrhagic fever, and 25,000 deaths annually. The reasons for this resurgence and emergence of dengue hemorrhagic fever in the waning years of the 20th century are complex and not fully understood, but demographic, societal, and public health infrastructure changes in the past 30 years have contributed greatly. This paper reviews the changing epidemiology of dengue and dengue hemorrhagic fever by geographic region, the natural history and transmission cycles, clinical diagnosis of both dengue fever and dengue hemorrhagic fever, serologic and virologic laboratory diagnoses, pathogenesis, surveillance, prevention, and control. A major challenge for public health officials in all tropical areas of the world is to devleop and implement sustainable prevention and control programs that will reverse the trend of emergent dengue hemorrhagic fever.

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Dengue and Dengue Hemorrhagic Fever

Dengue and dengue hemorrhagic fever.

Dengue fever and dengue haemorrhagic fever are important arthropod-borne viral diseases. Each year, there are ∼50 million dengue infections and ∼500,000 individuals are hospitalized with dengue haemorrhagic fever, mainly in Southeast Asia, the Pacific and the Americas. Illness is produced by any of the four dengue virus serotypes. A global strategy aimed at increasing the capacity for surveillance and outbreak response, changing behaviours and reducing the disease burden using integrated vector management in conjunction with early and accurate diagnosis has been advocated. Antiviral drugs and vaccines that are currently under development could also make an important contribution to dengue control in the future.

Dengue: a continuing global threat

Dengue viruses occur as four antigenically related but distinct serotypes transmitted to humans by Aedes aegypti mosquitoes. These viruses generally cause a benign syndrome, dengue fever, in the American and African tropics, and a severe syndrome, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), in Southeast Asian children. This severe syndrome, which recently has also been identified in children infected with the virus in Puerto Rico, is characterized by increased vascular permeability and abnormal hemostasis. It occurs in infants less than 1 year of age born to dengue-immune mothers and in children 1 year and older who are immune to one serotype of dengue virus and are experiencing infection with a second serotype. Dengue viruses replicate in cells of mononuclear phagocyte lineage, and subneutralizing concentrations of dengue antibody enhance dengue virus infection in these cells. This antibody-dependent enhancement of infection regulates dengue disease in human beings, although disease severity may also be controlled genetically, possibly by permitting and restricting the growth of virus in monocytes. Monoclonal antibodies show heterogeneous distribution of antigenic epitopes on dengue viruses. These epitopes serve to regulate disease: when antibodies to shared antigens partially neutralize heterotypic virus, infection and disease are dampened; enhancing antibodies alone result in heightened disease response. Further knowledge of the structure of dengue genomes should permit rapid advances in understanding the pathogenetic mechanisms of dengue.

https://science.sciencemag.org/content/sci/239/4839/476.full.pdf

Pathogenesis of dengue: challenges to molecular biology

Do escape mutants explain rapid increases in dengue casefatality rates within epidemics

In 1987, Kouri et al. published in Transactions their integral hypothesis to explain the development of dengue haemorrhagic fever (DHF) epidemics (Kouri, G.P., Guzman, M.G., Bravo, J.R., 1987. Why dengue haemorrhagic fever in Cuba? 2. An integral analysis. Trans. R. Soc. Trop. Med. Hyg. 81, 821-823). Based on observations carried out during the 1981 Cuban DHF epidemic, the authors integrated in one model the most advanced knowledge at that time. Observations in the last 20 years confirm the importance of this multifactorial and unifying view of the problem, where the interaction between the host, the virus and the vector in an epidemiological and ecosystem setting might determine DHF as a final outcome. Investigations on the interaction among host, virus and mosquito with an ecosystemic view are needed.

Dengue haemorrhagic fever integral hypothesis: confirming observations, 1987–2007

Summary background The 55th World Health Assembly declared dengue prevention and control a priority and urged Member States to develop sustainable intersectoral strategies to this end. To provide evidence for the reorientation of the dengue prevention policy in Cuba, we launched an intervention study to document the effectiveness of a local-level intersectoral approach. methods We used a quasi-experimental design. Social scientists introduced participatory methods to facilitate dialogue in the biweekly meetings of the intersectoral Health Council of the intervention area. This council subsequently developed an intersectoral plan for dengue prevention, of which the core objective was to design and implement activities for communication and social mobilization. In the control area, routine dengue control activities continued without additional input. Knowledge, attitudes and perceptions of dengue, and entomological indices were compared inside and between the areas before and after the 1-year intervention period. results In the intervention area the Health Council elaborated an intersectoral plan for dengue prevention focused on source reduction. The Aedes aegypti control methods consisted in eliminating useless containers in the houses and surroundings, covering tanks, and cleaning public and inhabited areas. It was implemented through communication and social mobilization. The Health Council in the control area occasionally discussed dengue issues but did not develop a coordinated action plan. Good knowledge about breeding sites and disease symptoms increased significantly (by 49.7% and 17.1% respectively) in the intervention area as well as the proportion of respondents eliminating containers in and around their houses (by 44%). No changes were observed in the control area. The House Index in the intervention area was 3.72% at baseline and decreased to 0.61% after 1 year. In the control area it remained stable throughout the study period (1.31% and 1.65% respectively). conclusion The introduction of a participatory approach by social scientists promotes changes in intersectoral management. This facilitates social mobilization which, in its turn, leads to significant changes in knowledge, attitudes and dengue-related practices in the population and eventually to more effective control of Ae. aegypti.

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Intersectoral coordination in Aedes aegypti control. A pilot project in Havana City, Cuba.

An association between viral diseases and increased oxidative stress has been suggested. The time course of serum levels of total antioxidant status (TAS), peroxidation potential (PP), glutathione (GSH), lipid peroxidation measured as hydroperoxides, and malondyaldehyde and 4-hydroxyalkenals (MDA + 4-HDA), as well as antioxidant enzymatic activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx), were measured in 22 serologically confirmed dengue patients. Most of the patients had dengue fever and three of them had dengue hemorrhagic fever. The redox parameters were compared with those of age- and sex- matched controls. No significant difference was observed for levels of GSH and TAS between patients and controls. Levels of PP, MDA + 4-HDA, and SOD were significantly higher. Levels of GPx and total hydroperoxides were significantly lower in patients in comparison with controls. These findings suggest that the alteration in redox status could result of increased oxidative stress and it may play a role in the pathogenesis of the disease.

Oxidative stress in adult dengue patients.

Dengue is one of the most important infectious diseases in tropical and subtropical countries. At present, the only strategy available to reduce the incidence of dengue is vector control. The World Health Organization and the Pan American Health Organization have called on all nations to take the needed steps to help diminish the burden of this disease and its medical and socioeconomic impact. It is hoped that it will be possible to reverse the increase in dengue and help control its spread through a coordinated, effective international response, along with epidemiological, clinical, and virological research that brings together the most advanced methods and techniques. This piece summarizes the most up-to-date information on dengue, analyzes current epidemiologic trends in the Region of the Americas, discusses the main global and Western Hemisphere initiatives to control the disease, and presents the main areas of research that should be developed in the immediate future.

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Gustavo Kourí

Papers

Do escape mutants explain rapid increases in dengue casefatality rates within epidemics

Dengue haemorrhagic fever integral hypothesis: confirming observations, 1987–2007

Intersectoral coordination in Aedes aegypti control. A pilot project in Havana City, Cuba.

Oxidative stress in adult dengue patients.

El dengue y el dengue hemorrágico: prioridades de investigación