Dengue infection.

Dengue is widespread throughout the tropics and local spatial variation in dengue virus transmission is strongly influenced by rainfall, temperature, urbanization and distribution of the principal mosquito vector Aedes aegypti. Currently, endemic dengue virus transmission is reported in the Eastern Mediterranean, American, South-East Asian, Western Pacific and African regions, whereas sporadic local transmission has been reported in Europe and the United States as the result of virus introduction to areas where Ae. aegypti and Aedes albopictus, a secondary vector, occur. The global burden of the disease is not well known, but its epidemiological patterns are alarming for both human health and the global economy. Dengue has been identified as a disease of the future owing to trends toward increased urbanization, scarce water supplies and, possibly, environmental change. According to the WHO, dengue control is technically feasible with coordinated international technical and financial support for national programmes. This Primer provides a general overview on dengue, covering epidemiology, control, disease mechanisms, diagnosis, treatment and research priorities.

Economic and disease burden of dengue in Mexico.

BACKGROUND: Dengue imposes a substantial economic and disease burden in most tropical and subtropical countries. Dengue incidence and severity have dramatically increased in Mexico during the past decades. Having objective and comparable estimates of the economic burden of dengue is essential to inform health policy, increase disease awareness, and assess the impact of dengue prevention and control technologies. METHODS AND FINDINGS: We estimated the annual economic and disease burden of dengue in Mexico for the years 2010-2011. We merged multiple data sources, including a prospective cohort study; patient interviews and macro-costing from major hospitals; surveillance, budget, and health data from the Ministry of Health; WHO cost estimates; and available literature. We conducted a probabilistic sensitivity analysis using Monte Carlo simulations to derive 95% certainty levels (CL) for our estimates. Results suggest that Mexico had about 139,000 (95%CL: 128,000-253,000) symptomatic and 119 (95%CL: 75-171) fatal dengue episodes annually on average (2010-2011), compared to an average of 30,941 symptomatic and 59 fatal dengue episodes reported. The annual cost, including surveillance and vector control, was US$170 (95%CL: 151-292) million, or $1.56 (95%CL: 1.38-2.68) per capita, comparable to other countries in the region. Of this, $87 (95%CL: 87-209) million or $0.80 per capita (95%CL: 0.62-1.12) corresponds to illness. Annual disease burden averaged 65 (95%CL: 36-99) disability-adjusted life years (DALYs) per million population. Inclusion of long-term sequelae, co-morbidities, impact on tourism, and health system disruption during outbreaks would further increase estimated economic and disease burden. CONCLUSION: With this study, Mexico joins Panama, Puerto Rico, Nicaragua, and Thailand as the only countries or areas worldwide with comprehensive (illness and preventive) empirical estimates of dengue burden. Burden varies annually; during an outbreak, dengue burden may be significantly higher than that of the pre-vaccine level of rotavirus diarrhea. In sum, Mexico's potential economic benefits from dengue control would be substantial.

Secondary infection as a risk factor for dengue hemorrhagic fever/dengue shock syndrome: an historical perspective and role of antibody-dependent enhancement of infection.

Today, dengue viruses are the most prevalent arthropod-borne viruses in the world. Since the 1960s, numerous reports have identified a second heterologous dengue virus (DENV) infection as a principal risk factor for severe dengue disease (dengue hemorrhagic fever/dengue shock syndrome, DHF/DSS). Modifiers of dengue disease response include the specific sequence of two DENV infections, the interval between infections, and contributions from the human host, such as age, ethnicity, chronic illnesses and genetic background. Antibody-dependent enhancement (ADE) of dengue virus infection has been proposed as the early mechanism underlying DHF/DSS. Dengue cross-reactive antibodies raised following a first dengue infection combine with a second infecting virus to form infectious immune complexes that enter Fc-receptor-bearing cells. This results in an increased number of infected cells and increased viral output per cell. At the late illness stage, high levels of cytokines, possibly the result of T cell elimination of infected cells, result in vascular permeability, leading to shock and death. This review is focused on the etiological role of secondary infections (SI) and mechanisms of ADE.

Epidemiological studies on dengue virus type 3 in Playa municipality, Havana, Cuba, 2001-2002.

OBJECTIVES: Recognizing the uniqueness of secondary dengue virus (DENV)-1/3 dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) cases at an interval of 24 years, we sought to estimate DENV infections as well as the ratios between mild disease and DHF/DSS by DENV infection sequence in Playa District (Havana, Cuba) during the 2001-2002 outbreak of dengue virus type 3 (DENV-3). METHODS: A retrospective seroepidemiological study was conducted in 2003 in Playa District. Blood samples were collected from a 1% random sample of residents and were studied for the prevalence of dengue neutralizing antibodies. RESULTS: DENV-3 was found to have infected 7.2% (95% confidence interval (95% CI) 6.0-8.4%) of susceptible individuals (the entire cohort), the majority of whom experienced silent infections. Virtually every individual who had a secondary infection in the sequence DENV-1 then DENV-3 became ill, with a ratio of severe to mild cases of 1:35 (95% CI 1:67-1:23). Secondary infections in the sequence DENV-2/3 were less pathogenic than DENV-1/3. Mild disease accompanying secondary DENV2/3 occurred at a ratio of 1:4.49 infections (95% CI 1:5.77-1:3.42) secondary infections. CONCLUSIONS: The results obtained highlight the role of the infecting serotype and also the sequence of the viral infection in the clinical outcome of a dengue infection.

Virus role during intraepidemic increase in dengue disease severity.

Dengue epidemics in Cuba have repeatedly demonstrated a month-to-month increase in clinical severity during secondary infections. The dengue 2 outbreak that occurred in Santiago de Cuba in 1997 was accompanied by the most severe intraepidemic increase in disease severity reported to date. It was initially proposed that the appearance of neutralization escape mutants during the course of the epidemic might explain this phenomenon. Recent studies have revealed that during the course of this epidemic, nucleotide substitutions appeared only in nonstructural (NS) genes, most of which were silent, except for one change in the NS1 gene. To study whether or not variation in the NS1 gene might be associated with increased disease severity during the epidemic, this gene was partially sequenced from 15 isolates obtained at different times during the 1997 epidemic. Early epidemic isolates differed from those obtained later by replacement only of threonine with serine at position 164 in the NS1 protein, an amino acid rarely found in any genotype of dengue 2 virus. All viruses isolated from patients located in Health Districts, where dengue 2 transmissions occurred late in the epidemic, contained Serine at position 164, indicating that this change was fixed within a few months. Here we argue that this single mutation contributes to viral survival or replication efficiency, resulting in enhanced infection in the presence of enhancing antibodies, a phenomenon that we term increased virus "fitness" in contrast to "virulence," an intrinsic property of the virus.

Dengue: a continuing global threat.

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.

Cost of dengue cases in eight countries in the Americas and Asia: a prospective study.

Despite the growing worldwide burden of dengue fever, the global economic impact of dengue illness is poorly documented. Using a common protocol, we present the first multicountry estimates of the direct and indirect costs of dengue cases in eight American and Asian countries. We conducted prospective studies of the cost of dengue in five countries in the Americas (Brazil, El Salvador, Guatemala, Panama, and Venezuela) and three countries in Asia (Cambodia, Malaysia, and Thailand). All studies followed the same core protocol with interviews and medical record reviews. The study populations were patients treated in ambulatory and hospital settings with a clinical diagnosis of dengue. Most studies were performed in 2005. Costs are in 2005 international dollars (I$). We studied 1,695 patients (48% pediatric and 52% adult); none died. The average illness lasted 11.9 days for ambulatory patients and 11.0 days for hospitalized patients. Among hospitalized patients, students lost 5.6 days of school, whereas those working lost 9.9 work days per average dengue episode. Overall mean costs were I$514 and I$1,394 for an ambulatory and hospitalized case, respectively. With an annual average of 574,000 cases reported, the aggregate annual economic cost of dengue for the eight study countries is at least I$587 million. Preliminary adjustment for under-reporting could raise this total to $1.8 billion, and incorporating costs of dengue surveillance and vector control would raise the amount further. Dengue imposes substantial costs on both the health sector and the overall economy.

Evaluation of commercially available anti-dengue virus immunoglobulin M tests.

Anti-dengue virus immunoglobulin M kits were evaluated. Test sensitivities were 21%-99% and specificities were 77%-98% compared with reference ELISAs. False-positive results were found for patients with malaria or past dengue infections. Three ELISAs showing strong agreement with reference ELISAs will be included in the World Health Organization Bulk Procurement Scheme.

Neutralizing antibodies after infection with dengue 1 virus.

Severity of disease is markedly increased when infection with dengue virus type 2 (DENV-2) follows infection with DENV-1 at an interval of 20 years. Studies have shown that heterologous neutralizing antibody titers are inversely correlated with severity of a second infection. If this mechanism controlled disease severity in Cuba, heterotypic antibody titers should have declined over time. To determine whether phenotypic changes in dengue antibodies occur over time, we analyzed serum samples collected 4-8 and 20-22 years after DENV-1 infection. We found a significant increase in mean titer of homologous DENV-1 neutralizing antibodies and a significant decrease in heterologous antibodies to 1 of 2 genotypes of DENV-2 virus (the American genotype). Asian DENV-2 viruses were not neutralized during either interval; however, the American genotype underwent phenotypic changes in heterotypic viral neutralizing antibodies in the predicted direction. This finding may be related to the time-dependent changes in severity of disease found with secondary dengue infection.

Dengue hemorrhagic Fever caused by sequential dengue 1-3 virus infections over a long time interval: Havana epidemic, 2001-2002.

A dengue epidemic caused by dengue virus 3 (DENV-3) occurred in Cuba in 2001-2002. It included cases of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). We report neutralizing antibody studies on sera from 54 of 78 DHF/DSS patients that provide evidence of infections occurring in the sequence DENV-1 followed by DENV-3. No sera showed infection in the sequence DENV-2 followed by DENV-3. Some sera showed a pattern of infection in the sequence DENV-1 followed by DENV-2 and then DENV-3. However definitive categorization of a tertiary infection was not possible because of broadly reactive antibodies, which could have been raised by infections in the sequence DENV-1 then DENV-3.

Dengue in the Americas and Southeast Asia: do they differ? / El dengue en las Américas y el sudeste asiático: ¿son diferentes?

The populations of Southeast Asia (SE Asia) and tropical America are similar, and all four dengue viruses of Asian origin are endemic in both regions. Yet, during comparable 5-year periods, SE Asia experienced 1.16 million cases of dengue hemorrhagic fever (DHF), principally in children, whereas in the Americas there were 2.8 million dengue fever (DF) cases, principally in adults, and only 65 000 DHF cases. This review aims to explain these regional differences. In SE Asia, World War II amplified Aedes aegypti populations and the spread of dengue viruses. In the Americas, efforts to eradicate A. aegypti in the 1940s and 1950s contained dengue epidemics mainly to the Caribbean Basin. Cuba escaped infections with the American genotype dengue-2 and an Asian dengue-3 endemic in the 1960s and 1970s. Successive infections with dengue-1 and an Asian genotype dengue-2 resulted in the 1981 DHF epidemic. When this dengue-2 virus was introduced in other Caribbean countries, it encountered populations highly immune to the American genotype dengue-2. During the 1980s and 1990s, rapidly expanding populations of A. aegypti in Brazil permitted successive epidemics of dengue-1, -2, and -3. These exposures, however, resulted mainly in DF, with surprisingly few cases of DHF. The absence of high rates of severe dengue disease in Brazil, as elsewhere in the Americas, may be partly explained by the widespread prevalence of human dengue resistance genes. Understanding the nature and distribution of these genes holds promise for containing severe dengue. Future research on dengue infections should emphasize population-based designs.

Las poblaciones de Asia suroriental y de la América tropical son similares y los cuatro tipos de virus del dengue de origen asiático son endémicos en ambas regiones. Aun así, durante períodos quinquenales comparables ocurrieron 1,16 millones de casos de dengue hemorrágico (DH) en Asia suroriental, principalmente en niños, mientras que en las Américas ocurrieron 2,8 millones de casos de dengue, principalmente en adultos, y solo 65 000 casos de DH. El objetivo de esta revisión es explicar estas diferencias regionales. En el sudeste asiático, con la Segunda Guerra Mundial se extendieron las poblaciones del mosquito Aedes aegypti y se diseminó el virus del dengue. En las Américas, los esfuerzos para erradicar el A. aegypti en las décadas de 1940 y 1950 restringieron las epidemias de dengue principalmente a la cuenca del Caribe. Cuba escapó a las infecciones por el genotipo americano del dengue-2 y un endémico asiático del dengue-3 en las décadas de 1960 y 1970. Infecciones sucesivas con el virus del dengue-1 y un genotipo asiático del dengue-2 dio como resultado una epidemia de DH en 1981. Cuando este virus del dengue-2 se introdujo en otros países caribeños encontró poblaciones con un alto grado de inmunidad al genotipo americano del dengue-2. Durante las décadas de 1980 y 1990, la rápida expansión de las poblaciones de A. aegyti en Brasil favorecieron la aparición de epidemias sucesivas de dengue-1, dengue-2 y dengue-3. Estas, no obstante, provocaron principalmente casos de dengue con sorpresivamente pocos casos de DH. La ausencia de altas tasas de formas graves de dengue en Brasil y otros países de la Región puede explicarse en parte por la amplia presencia de genes humanos de resistencia al dengue. La comprensión de la naturaleza y de la distribución de estos genes crea grandes expectativas para frenar las formas graves de dengue. Las investigaciones futuras sobre la infección por los virus del dengue deben poner énfasis en diseños basados en la población

Effect of age on outcome of secondary dengue 2 infections.

OBJECTIVE: Dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) is a growing global health problem. It is not known how age affects the outcome of secondary dengue infections. In an island setting, a large DHF/DSS outbreak in Cuba occurred in 1981. Involved were individuals, 3-40 year old, whose only lifetime dengue exposure was to DEN-1 in 1977 and DEN-2 in 1981. In this report we calculate age-specific DHF/DSS hospitalization and death rates based on secondary DEN 2 infections. METHODS: Published and unpublished hospital and seroepidemiologic data from the 1981 DHF/DSS outbreak were used for the analysis. RESULTS: Children, aged 3 and 4 years, with secondary DEN-2 infections were found to have a high death rate (25.4/10 000 secondary DEN-2 infections). The death rate fell with increasing age, being 15.9-fold lower in the 10-14-year age group. The death rate for children aged 3-14 years was 14.5-fold higher than in young adults aged 15-39 years. The death rate rose somewhat in adults aged 50 years and older. DHF/DSS hospitalization rates showed the same trend as death rates. CONCLUSIONS: Age is an important variable in the outcome of secondary DEN-2 infections. DHF/DSS case fatality and hospitalization rates are highest in young infants and the elderly. The risk that a child will die during a secondary DEN-2 infection is nearly 15-fold higher than the risk in adults.

Effect of dengue-1 antibodies on American dengue-2 viral infection and dengue haemorrhagic fever.

In Iquitos, Peru, no cases of dengue haemorrhagic fever have been recorded in individuals infected with dengue-1 virus followed by American genotype dengue-2 (American dengue-2) virus. We assayed serum samples collected in Iquitos that tested positive for antibodies of monotype dengue-1 and monotype dengue-2 using a plaque reduction neutralisation test to determine their ability to neutralise the infectivity of two dengue-1 viruses, two American dengue-2 viruses, and two Asian dengue-2 viruses. Sera positive for the dengue-1 antibody neutralised dengue-1 viruses and American dengue-2 viruses much more effectively than Asian dengue-2 viruses. Neutralisation of American dengue-2 virus by sera positive for dengue-1 antibodies may account for the absence of dengue haemorrhagic fever in individuals infected with dengue-1 in 1990-91 followed by American dengue-2 virus in 1995 in Iquitos, Peru.

Enhanced severity of secondary dengue-2 infections: death rates in 1981 and 1997 Cuban outbreaks.

OBJECTIVE: To understand the possible effect that length of time has on disease severity with sequential dengue infections. METHODS: Death and hospitalization rates for dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) per 10,000 secondary dengue-2 infections were compared in the same age group for two dengue-2 (DEN-2) epidemics in Cuba. The first DEN-2 epidemic affected all of Cuba in 1981; the second one, in 1997, impacted only the city of Santiago de Cuba. The sensitizing infection for DHF/DSS for each of the DEN-2 epidemics was dengue-1 (DEN-1) serotype virus, which was transmitted in 1977-1979, that is, 4 years and 20 years before the two DEN-2 epidemics. Using published seroepidemiological data from the cities of Havana and Santiago de Cuba, we estimated the rates at which persons aged 15-39 years old and those 40 years and older were hospitalized or died of DHF/DSS in Havana and in all of Cuba in 1981 and in just Santiago de Cuba in 1997. RESULTS: Among adults 15-39 years old the death rate per 10,000 secondary DEN-2 infections was 38.5 times as high in Santiago de Cuba in 1997 as in Havana in 1981. As a further indication of the increased severity coming with a longer period between the initial DEN-1 infection and the secondary DEN-2 infection, the case fatality rate for that same age group was 4.7 times as high in Santiago in 1997 as it was in Havana in 1981. CONCLUSION: We found a marked increase in severity with the longer of the two intervals (20 years) between an initial DEN-1 infection and a secondary DEN-2 infection. Such a difference may be due to subtle shifts in causative dengue strains or to changes with the passage of time in the circulating population of human dengue antibodies. These observations have important implications for dengue control, pathogenic mechanisms, and vaccine development.