Dengue is the most important arboviral disease of humans with over half of the world’s population living in areas of risk. The frequency and magnitude of epidemic dengue have increased dramatically in the past 40 years as the viruses and the mosquito vectors have both expanded geographically in the tropical regions of the world. There are many factors that have contributed to this emergence of epidemic dengue, but only three have been the principal drivers: 1) urbanization, 2) globalization and 3) lack of effective mosquito control. The dengue viruses have fully adapted to a human-Aedes aegypti-human transmission cycle, in the large urban centers of the tropics, where crowded human populations live in intimate association with equally large mosquito populations. This setting provides the ideal home for maintenance of the viruses and the periodic generation of epidemic strains. These cities all have modern airports through which 10s of millions of passengers pass each year, providing the ideal mechanism for transportation of viruses to new cities, regions and continents where there is little or no effective mosquito control. The result is epidemic dengue. This paper discusses this unholy trinity of drivers, along with disease burden, prevention and control and prospects for the future.

https://www.jstage.jst.go.jp/article/tmh/39/4SUPPLEMENT/39_2011-S05/_pdf

Dengue, Urbanization and Globalization: The Unholy Trinity of the 21st Century

Dengue, a major public health problem throughout subtropical and tropical regions, is an acute infectious disease characterized by biphasic fever, headache, pain in various parts of the body, prostration, rash, lymphadenopathy, and leukopenia. In more severe or complicated dengue, patients present with a severe febrile illness characterized by abnormalities of hemostasis and increased vascular permeability, which in some instances results in a hypovolemic shock. Four distinct serotypes of the dengue virus (dengue-1, dengue-2, dengue-3, and dengue-4) exist, with numerous virus strains found worldwide. Molecular cloning methods have led to a greater understanding of the structure of the RNA genome and definition of virus-specific structural and nonstructural proteins. Progress towards producing safe, effective dengue virus vaccines, a goal for over 45 years, has been made. Images

The dengue viruses.

The number of cases of severe dengue disease continues to grow in endemic areas of southeast Asia, Central and South America, and other subtropical regions. Children bear the greatest burden of disease, and the development of an effective vaccine remains a global public health priority. A tetravalent vaccine is urgently needed and must be effective against all four dengue virus serotypes, be cost-effective and provide long-term protection. In this Review we discuss the unique immunological concerns in dengue virus vaccine development and the current prospects for the development of an acceptable vaccine, a goal that is likely to be reached in the near future.

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Prospects for a dengue virus vaccine.

Antibody-dependent enhancement of infection (ADE) is an in vitro serological phenomenon--or a group of phenomena--in which viral infection of susceptible cells is modified by the addition of virus-reactive antibody. Evidence suggests that ADE reflects immunologic processes that occur in vivo. Various severe and even fatal viral conditions of humans and animals, including dengue shock syndrome, the "early-death phenomenon" in experimental infections of immune animals, and other vaccine- and immunoglobulin-modified conditions, have been attributed to ADE by some researchers. ADE has caused great concern in relation to the development of vaccines against dengue virus and human immunodeficiency virus. More data are urgently needed on the mechanisms and determinants of ADE and on its alleged role in disease pathogenesis and in vaccine-associated phenomena.

Antibody-Dependent Enhancement of Infection and the Pathogenesis of Viral Disease

As most of you know, one of the duties of the President of the American Society of Tropical Medicine and Hygiene specified by the by-laws is the presentation of an address at the annual meet ing. I do not know what type of address those responsible for this provision had in mind, but a review of previous presidential addresses reveals a wide variety both of philosophical and scientific topics. Since I do not feel competent to address you on a philosophical subject, I have chosen to review a scientific topic which has been of interest to me during the past few years. In making this choice, I know that the subject matter will be of relatively little interest to those of you in other fields and for this I apologize. I shall illustrate later, however, that the topic I have chosen is especially appropriate for the site of our gathering this year and for the bicentennial which our joint meeting commemorates. Those of you unfamiliar with recent work and discussions on dengue may be puzzled by the first part of the title of this address. I should like to explain that it was chosen to call attention to what I believe is the transparency of arguments used in support of a widely disseminated hypoth esis on the pathogenesis of dengue hemorrhagic feverâ€”but that it was not intended that the analogy be carried so far as to imply that those who have proposed this hypothesis are the counter parts of the two rogues in Hans Christian Ander sen's story.' There has been considerable speculation as to why dengue, long considered an annoying but benign disease, has in the last 20 years become a leading cause of hospitalization and death among children in a number of Southeast Asian countries.2 The life-threatening forms of dengue usually are associated with hemorrhage, hypovolemic shock,

The Emperor's New Clothes revisited, or reflections on the pathogenesis of dengue hemorrhagic fever.

During the course of an outbreak of dengue type 2 on the island of Tahiti, French Polynesia, severe hemorrhagic disease was observed in an unusual number of patients shortly after the onset of a febrile illness. In at least 33 instances, these hemorrhages were severe enough to require hospitalization and 3 patients died. Gastrointestinal bleeding was the most common type of severe hemorrhage observed and gross hematuria was next most common. The available data suggested that most of the hemorrhagic episodes were etiologically related to dengue virus.

Jean-Paul Moreau

Papers

An epidemic of dengue on Tahiti associated with hemorrhagic manifestations.