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

During the 1981 dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) Cuban epidemic, bronchial asthma (BA) was frequently found as a personal or family antecedent in dengue hemorrhagic fever patients. Considering that antibody dependent enhancement (ADE) plays an important role in the etiopathogenic mechanism of DHF/DSS, we decide to study the Dengue 2 virus (D2V) capability of replication in peripheral blood leukocytes (PBL) from asthmatic patients and healthy persons. In 90% of asthmatic patients and 53.8% of control group it was obtained PBL with a significant D2V enhancing activity (X2 p < 0.01). Power enhancement was higher in asthmatic group. This is the first in vitro study relating BA and the dengue 2 virus immuno enhancement. The results obtained support the role of BA as a risk factor for DHF/DSS as already described on epidemiological data.

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Dengue 2 virus enhancement in asthmatic and non asthmatic individual

Summary
A study was made of the mechanism of microfocus formation and of the nature of the inclusion bodies that appear in the cytoplasm of RK-13 cells infected by rubella virus.
Direct passage of virus particles from one cell to another, at least in the early stages of the infection, is posed as a possibility, and the lysosomal nature of the cytoplasmic inclusion bodies is demonstrated by histochemical methods. A description is given of conditions required in the monolayer for the formation of a microfocus, which is the characteristic manifestation of the c.p.e. of the rubella virus in this cellular system.

A study of microfoci and inclusion bodies produced by rubella virus in the RK-13 cell line.

It is reported the isolation of 2 dengue strains, 3 in samples from Nicaraguan patients suffering from dengue with hemorrhagic manifestations, which showed the reintroduction of this serotype in the region after being 17 years out of circulation. It is also reported the genetic characterization of the isolated strain, which, according to its classification, belongs to the group of dengue 2 strains isolated in Southeast Asi and which have been associated to hemorrhagic dengue. These results suggest the origin of this strain.

Relaciones genéticas del virus dengue 3 aislado en la epidemia de FHD en Nicaragua, 1994

This paper presents a standardized procedure for the detection of IgM antibodies to dengue virus in blood samples taken from filter paper. The samples were obtained from 118 patients, of whom 91 had been clinically diagnosed with dengue and 27 with a viral infection unrelated to that disease. The first group of patients came from Costa Rica and Nicaragua and the second group from Cuba. All the samples were tested for IgM antibody against dengue virus by means of a capture enzyme immunoassay (EIA). Analysis of the results for patients from all three countries together yielded a sensitivity of 98.1% and a specificity of 98.5% for the test done on whole blood on filter paper stored at 4 degrees C; agreement between the results of that test and those of the EIA using serum samples was 96%. In a comparison of the results obtained with three samples from the same patient--whole blood on filter paper stored at room temperature, the same type of sample stored at 4 degrees C, and serum--the agreement was 86%. This study demonstrates the high diagnostic sensitivity and specificity achieved when whole blood absorbed on filter paper is processed in the manner described in detail in the article. The authors recommend the use of this method in the dengue surveillance programs in the Region.

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[Detection of IgM against the dengue++ virus in whole blood absorbed on filter paper].

The aim of this work was to offer a description of the clinical manifestations developed by patients under 1 year who had dengue virus infection and dengue hemorrhagic fever during the epidemic which broke out in 1981, and to determine if the passive transfer of maternal dengue antibodies to the fetuses influenced the occurrence of a severe development of the disease, through a retrospective study. In 20 cases, type 2 dengue virus infection was confirmed. Eight patients showed the clinical manifestations of dengue hemorrhagic fever of dengue shock syndrome (DHF/DSS), and the other 12 had the typical dengue virus infection. The former were of the white racial phenotype, aged under 6 months. There was a predominance of type 1 dengue antibodies in the mothers of children with DHF/DSS. Fever, rash, vomiting and diarrheas (not frequent) appeared in the two clinical manifestations of the infection; blood leukocytes were predominantly lymphocytic; and erythrocyte sedimentation was always normal. Patients with DHF/DSS presented with some bleeding (87.5%); cyanosis and ascites (37.5%); and shock (25%), as well as hepatomegaly. All these infants with DHF/DSS had thrombocytopenia and most of them showed hemoconcentration. No deaths occurred.

Gustavo Kourí

Papers

Dengue 2 virus enhancement in asthmatic and non asthmatic individual

A study of microfoci and inclusion bodies produced by rubella virus in the RK-13 cell line.

Relaciones genéticas del virus dengue 3 aislado en la epidemia de FHD en Nicaragua, 1994

[Detection of IgM against the dengue++ virus in whole blood absorbed on filter paper].

Dengue fever and hemorrhagic dengue in infants with a primary infection