Global Burden of Dengue

About Dengue:

A Most Virulent Disease

Dengue, a viral disease carried by mosquitoes, and its more serious variant, dengue hemorrhagic fever (DHF), are probably the most widespread reemerging diseases. In 1998 there were 1.2 million cases of dengue and DHF reported. Over 15,000 of these cases led to deaths.

Dengue is a mosquito-born viral disease that burdens tropical regions around the world. Yearly, in addition to tens of millions of cases of severe dengue fever, an average of 500,000 persons, mostly children, are hospitalized with dengue hemorrhagic fever with high case fatality rates. No specific treatment is available. The 20-21st century dengue pandemic is the direct result of contemporary demographic and life-style trends - the population explosion, urbanization and rapid transportation of large numbers of people. Vector-control strategies have been insufficient to counter this pandemic.

Dengue:
The next vaccine preventable disease ?
A video from sanofi pasteur ( 7 minute video)

The Burden of Dengue:

Disease Burden and Cost Effectiveness of a Pediatric Dengue Vaccine

The baseline disease burden of dengue in SE Asia for the cohort is 0.42 DALYs per 1000 population, of which 52% is due to premature mortality and 48% to acute morbidity. The baseline cost of treatment is US$ 99 per 1000 population per year. Although DHF constitutes only 6% of clinical cases, it represents 68% of the disease burden and 67% of the treatment costs. The economic feasibility of a pediatric tetravalent dengue vaccine was estimated to be highly cost-effective.

PDVI has undertaken a review of the oft-cited estimates of the burden of dengue. Table 1 summarizes and compares the new estimates with the old.

Table 1. New Estimates of the Burden of Dengue

	New Estimates	Earlier Estimates
Population at risk	3.6 billion(55% of world population)	2.5 - 3 billion (40% of world population)
Endemic countries	124	>100
Dengue Infections*/year	70-500 million	50 - 100 million
Cases of Dengue Fever/year	36 million
Cases of Dengue Haemorrhagic Fever and Dengue Shock Syndrome/ year	2.1 million	250,000 - 500,000
Deaths/ year	21,000	20,000

*Includes asymptomatic infection which increases risk of more severe disease with subsequent infection

Disease Burden Estimates

The earlier estimates were made over a decade ago and the exact methods of calculation were not published. Since dengue virus has continued to expand globally and the total cases reported has increased in established areas, reexamination of the global burden of dengue is needed. PDVI staff has carried out such a reexamination.

To determine countries with populations at risk for dengue in the last 25 years, we used three types of data.

1)	PubMed and country Ministry of Health and World Health Organization websites for reports of dengue incidence data, outbreaks, or serosurveys for individual counties to identify laboratory confirmed dengue infection;

2)	Published literature on travelers where the locale of travel of a laboratory confirmed dengue case was identified;

3)	Maps to identify additional countries at risk that have no published data but are contiguous to countries reporting dengue disease.

We then estimated the total population at risk by summing the 2007 estimated census population of those countries identified. For countries where dengue was limited to certain regions (e.g. China or Argentina), we reduced the population at risk to include only the regions at risk. The best data on the true incidence of dengue virus infection were available from dengue field sites of the PDVI field site consortium (see section XX below). In addition, we surveyed the published literature, ministries of health and World Health Organization reports and websites, to determine the best estimates of each of the level of disease severity in the spectrum of disease that can occur following dengue infection.

Using published reports we identified 110 countries with populations at risk for dengue. Published reports identified an additional three countries. Since countries not conducting dengue surveillance but surrounded by countries reporting dengue fever are also likely to have similar rates of dengue infections to their neighbors (contiguous-country method), we added an additional 11 countries, 9 of which were in Africa. Applying these findings to the 2007 estimated census data, we estimate that 3.6 billion people (or 55% of the world's population) currently live in areas at risk for dengue.

Next we examined data provided by PDVI field sites in Asia and Latin America. Interestingly, the one-year rate of dengue fever based on data from field sites in Puerto Rico, Nicaragua, Thailand, Cambodia, and India, indicate the annual incidence of dengue fever is approximately 1%. When compared to the national surveillance data of these countries, field site data indicate on the order of 10 to 100 times greater incidence than currently reported national data. PDVI has supported a capture-recapture study to document the rate of underreporting of the national system in Cambodia. This study was limited to only the most severe forms of dengue which were hospitalized and therefore were more likely to be reported to the national system. This capture-recapture study revealed that more severe dengue cases were underreported by a factor of seven. The underreporting of milder cases is likely to be much greater.

To determine the annual infection rate we used published literature based on cohort studies that reported the ratio of symptomatic to asymptomatic patients. Because these ratios varied by year and geographic location, we multiplied this range by the average incidence of symptomatic dengue infection from the PDVI consortium field sites, 1%. This gave us an estimated true annual rate of dengue infection is 70?500 million. Knowing the rate of asymptomatic infection is important because the most severe forms of dengue fever?dengue hemorrhagic fever and dengue shock syndrome?are 100 times more common in patients who were previously infected, even if that infection was asymptomatic. To estimate the rate true rate of symptomatic disease, we multiplied the same average dengue incidence rate by the total world population living in areas where dengue infection can be locally acquired; 36 million cases of symptomatic dengue per year.

In contrast to the rates of dengue fever, the rates of dengue haemorrhagic fever (DHF) vary by region for reasons that include differences in the proportion of the population who have already had a dengue infection, the number of dengue serotypes circulating in a given geographic region, the sequence of the infecting serotypes, and virulence of the infecting strain. The highest rates occur in the Southeast Asian and Western Pacific WHO Regions where all four serotypes are constantly circulating, followed by the Americas Regions. In Africa, the situation with DHF is not known. While there are published reports showing dengue infections are occurring in Africa, dengue surveillance is not conducted there and no DHF has been reported. To account for these variations we calculated the an average ratio of dengue fever to DHF by region using published literature and national surveillance data available on country and WHO regional office websites. For the Southeast Asian and Western Pacific regions we calculated average ratio of dengue fever to DHF to be 1:0.9. For the Americas it was calculated to be 1:0.04 and for Africa, since we did not have data, we assumed no additional cases occurred there. Totaling the region specific DHF rates, we estimate that 2.1 million cases of dengue hemorrhagic fever and dengue shock syndrome occur annually worldwide. Finally, since most deaths from death occur among patients with DHF, we estimated the total number of dengue deaths by applying an average case fatality rate of 1% to total number of DHF cases world-wide; this gave us a total of 21,000 deaths due to dengue annually.

In addition to cases occurring in endemic countries, travelers are also at risk for dengue. According to the World Tourism Organization, 125.4 million international tourists visited countries in 2004 where they were at risk of dengue infection. In a prospective study of Dutch travelers to Thailand, 2.9% developed symptomatic dengue infection. Applying this rate to the total number of travelers who went to areas where risk of dengue infection was possible, an additional 3.6 million dengue cases are estimated. The addition of travelers'data increased the total yearly number of dengue fever worldwide to approximately 40 million.

Previous calculations of the total and percent of the world population living in countries may have been underestimates. We used PDVI field site data, published literature, and data from ministries of health and WHO to reevaluate the current global burden of dengue virus infections. We found the burden of symptomatic dengue infection to be even greater than previously estimated. Table 2 provides a comparison of symptomatic dengue infection compared to other tropical diseases. At 36 million symptomatic cases a year (40 million if tourists are included in the estimate), dengue is the most important mosquito borne virus infection world wide, and the second of all mosquito borne infections (second to only to malaria, a parasitic infection). While these estimates place dengue virus as third in causes of death, it is an urban disease that is expanding and currently effecting at least 124 countries world-wide. PDVI plans to continue to refine these disease estimates in the coming year and publish the results in a peer reviewed journal.