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

Background: Dengue is a growing problem both in its geographical spread and in its intensity, and yet current global distribution remains highly uncertain. Challenges in diagnosis and diagnostic methods as well as highly variable national health systems mean no single data source can reliably estimate the distribution of this disease. As such, there is a lack of agreement on national dengue status among international health organisations. Here we bring together all available information on dengue occurrence using a novel approach to produce an evidence consensus map of the disease range that highlights nations with an uncertain dengue status. Methods/Principal Findings: A baseline methodology was used to assess a range of evidence for each country. In regions where dengue status was uncertain, additional evidence types were included to either clarify dengue status or confirm that it is unknown at this time. An algorithm was developed that assesses evidence quality and consistency, giving each country an evidence consensus score. Using this approach, we were able to generate a contemporary global map of national-level dengue status that assigns a relative measure of certainty and identifies gaps in the available evidence. Conclusion: The map produced here provides a list of 128 countries for which there is good evidence of dengue occurrence, including 36 countries that have previously been classified as dengue-free by the World Health Organization and/or the US Centers for Disease Control. It also identifies disease surveillance needs, which we list in full. The disease extents and limits determined here using evidence consensus, marks the beginning of a five-year study to advance the mapping of dengue virus transmission and disease risk. Completion of this first step has allowed us to produce a preliminary estimate of population at risk with an upper bound of 3.97 billion people. This figure will be refined in future work.

/pdf/refining-the-global-spatial-limits-of-dengue-virus-f8emry0wk5.pdf

Refining the global spatial limits of dengue virus transmission by evidence-based consensus

Summary: Much remains to be learned about the pathogenesis of the different manifestations of dengue virus (DENV) infections in humans. They may range from subclinical infection to dengue fever, dengue hemorrhagic fever (DHF), and eventually dengue shock syndrome (DSS). As both cell tropism and tissue tropism of DENV are considered major determinants in the pathogenesis of dengue, there is a critical need for adequate tropism assays, animal models, and human autopsy data. More than 50 years of research on dengue has resulted in a host of literature, which strongly suggests that the pathogenesis of DHF and DSS involves viral virulence factors and detrimental host responses, collectively resulting in abnormal hemostasis and increased vascular permeability. Differential targeting of specific vascular beds is likely to trigger the localized vascular hyperpermeability underlying DSS. A personalized approach to the study of pathogenesis will elucidate the basis of individual risk for development of DHF and DSS as well as identify the genetic and environmental bases for differences in risk for development of severe disease.

Dengue Virus Pathogenesis: an Integrated View

Dengue is a spectrum of disease caused by four serotypes of the most prevalent arthropod-borne virus affecting humans today, and its incidence has increased dramatically in the past 50 years. Due in part to population growth and uncontrolled urbanization in tropical and subtropical countries, breeding sites for the mosquitoes that transmit dengue virus have proliferated, and successful vector control has proven problematic. Dengue viruses have evolved rapidly as they have spread worldwide, and genotypes associated with increased virulence have expanded from South and Southeast Asia into the Pacific and the Americas. This review explores the human, mosquito, and viral factors that contribute to the global spread and persistence of dengue, as well as the interaction between the three spheres, in the context of ecological and climate changes. What is known, as well as gaps in knowledge, is emphasized in light of future prospects for control and prevention of this pandemic disease.

/pdf/global-spread-and-persistence-of-dengue-4jert0rib2.pdf

Global spread and persistence of dengue.

Dengue virus presents a growing threat to public health in the developing world. Four major serotypes of dengue virus have been characterized, and epidemiological evidence shows that dengue hemorrhagic fever (DHF), the more serious manifestation of the disease, occurs more frequently upon reinfection with a second serotype. We have studied dengue virus–specific T-cell responses in Thai children. During acute infection, few dengue-responsive CD8+ T cells were recovered; most of those present showed an activated phenotype and were undergoing programmed cell death. Many dengue-specific T cells were of low affinity for the infecting virus and showed higher affinity for other, probably previously encountered strains. Profound T-cell activation and death may contribute to the systemic disturbances leading to DHF, and original antigenic sin in the T-cell responses may suppress or delay viral elimination, leading to higher viral loads and increased immunopathology.

Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever.

The age distribution of cases of dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) in infants under the age of 1 year are reported from Bangkok, Thailand, and for the first time for Ho Chi Minh City, Vietnam; Yangon, Myanmar; and Surabaya, Indonesia. The four dengue viruses were isolated from Thai infants, all of whom were having a primary dengue infection. Progress studying the immunologically distinct infant DHF/DSS has been limited; most contemporary research has centered on DHF/DSS accompanying secondary dengue infections. In designing research results obtained in studies on a congruent animal model, feline infectious peritonitis virus (FIPV) infections of kittens born to FIPV-immune queens should be considered. Research challenges presented by infant DHF/DSS are discussed.

/pdf/dengue-hemorrhagic-fever-in-infants-research-opportunities-3grikvpl2y.pdf

Dengue Hemorrhagic Fever in Infants: Research Opportunities Ignored

Extensive complement activation precedes onset of shock in dengue patients and complement "split products" C3a and C5a could be responsible, directly or indirectly, for the increased vascular permeability and disseminated intravascular coagulation which characterises dengue haemorrhagic fever (DHF) dengue shock syndrome (DSS). As IgG subclasses vary in their capacity to activate the classical complement pathway after combining with antigen, we have used an indirect enzyme linked immunosorbent assay (ELISA) to assess levels of IgG1-4 against each dengue serotype in acute and convalescent sera from patients with disease of varying severity. Acute phase sera from patients with dengue haemorrhagic fever (DHF) or dengue shock syndrome (DSS) contained higher levels of anti-dengue antibodies of the IgG1, complement fixing, subclass than similar sera from dengue fever (DF) patients. Conversely, acute phase sera from DHF and DSS patients contained lower levels of anti-dengue antibodies of the poor complement activating IgG2 subclass than acute phase sera from DF patients. No significant differences were detected between the levels of anti-dengue IgG3 and IgG4 antibody in acute phase sera from DF, DHF, and DSS patients. With the exception of levels of anti-dengue IgG2 antibody from DHF patients which were lower than those from DF and DSS patients, levels of anti-dengue IgG1, IgG2, IgG3, and IgG4 were similar in convalescent sera from all patients. These results provide a possible explanation for the activation of the serum complement system which precedes onset of shock in severe dengue infections.

Changes in levels of anti-dengue virus IgG subclasses in patients with disease of varying severity

Despite a growing body of evidence predominantly, but not exclusively, from Thailand suggesting that the risk of developing dengue shock syndrome (DSS) is greatest following an anamnestic dengue infection, particularly if the most recent infection was with dengue 2 virus, there continues to be debate about the justification for these claims. This report describes a five-year, prospective study in two townships (suburbs) in Yangon (Rangoon) Myanmar (Burma) in which attempts were made to confirm the data from an earlier prospective study in Thailand and to address some of the criticism of earlier studies. This investigation found the incidence of anamnestic dengue infections in DSS patients to be significantly higher than in the community from which they were drawn and a significantly higher risk of developing DSS following an anamnestic infection (particularly with dengue 2 virus) than following a primary infection with any serotype.

Risk Factors in Dengue Shock Syndrome

In 2001, Myanmar (Burma) had its largest outbreak of dengue-15,361 reported cases of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), including 192 deaths. That year, 95% of dengue viruses isolated from patients were serotype 1 viruses belonging to two lineages that had diverged from an earlier, now extinct, lineage sometime before 1998. The ratio of DHF to DSS cases in 2001 was not significantly different from that in 2000, when 1,816 cases of DHF/DSS were reported and dengue 1 also was the most frequently isolated serotype. However, the 2001 ratio was significantly higher than that in 1998 (also an outbreak year) and in 1999, when all four serotypes were detected and serotypes 1, 2, and 3 were recovered in similar numbers. The large number of clinical cases in 2001 may have been due, in part, to a preponderance of infections with dengue 1 viruses.

Myanmar dengue outbreak associated with displacement of serotypes 2, 3, and 4 by dengue 1.

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Dengue Hemorrhagic Fever in Infants: Research Opportunities Ignored

Changes in levels of anti-dengue virus IgG subclasses in patients with disease of varying severity

Risk Factors in Dengue Shock Syndrome

Myanmar dengue outbreak associated with displacement of serotypes 2, 3, and 4 by dengue 1.