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Dengue, also known as dengue fever, is a viral disease transmitted to humans by mosquitoes of the genus Aedes. The incidence of dengue is currently increasing dramatically, and it is now one of the diseases said to be re-emerging. WHO estimates the annual number of cases to be 50 million, including 500,000 cases of dengue hemorrhagic fever, which has a case fatality rate of over 20%. Two and a half billion people live in risk areas. Although initially seen only in the world's tropical and sub-tropical regions, dengue has now reached Europe, where the first two indigenous cases were reported on the French mainland in 2010. As of 2014, the mosquito vector is found in 18 French departments, and there is a real risk that the disease may spread if patients infected with dengue arrive in mainland France.
Causes and origins
Dengue is an arboviral disease (a virus transmitted by insects), belonging to the Flavivirus genus of the Flaviviridae family, like West Nile virus and yellow fever. It is transmitted to humans by mosquitoes of the Aedes genus when the insects feed on human blood. The dengue virus strains are divided into four different serotypes: DEN-1, DEN-2, DEN-3 and DEN-4. Acquired immunity as a result of infection by one of the serotypes provides protection against that particular serotype, but not against the others. Consequently, a person may be infected by all four serotypes during the course of a lifetime. Subsequent infection by another serotype increases the risk of severe dengue, known as dengue hemorrhagic fever. An effective vaccine against dengue should therefore convey protective immunity against all four serotypes.
Classical dengue begins suddenly after an incubation period of two to seven days, with the onset of a high temperature, often with headaches, nausea, vomiting, joint and muscle pain and a skin rash similar to that of measles. After three or four days there is a brief remission before the symptoms worsen, with possible conjunctival hemorrhaging, nose bleeds or ecchymosis. Symptoms then regress rapidly after another week. Recovery follows a convalescence of around two weeks. Although highly debilitating, classical dengue is not considered a serious disease, unlike hemorrhagic dengue.
Complications – dengue hemorrhagic fever
In some patients, for unexplained reasons, the clinical presentation of the disease can develop into two serious forms: hemorrhagic dengue and dengue shock syndrome, which is fatal.
The hemorrhagic form of the disease, which occurs in approximately 1% of dengue cases in the world, is extremely serious: it results in a persistent high temperature, and is often characterized by multiple hemorrhages, in particular in the gastro-intestinal tract, skin and brain. Particularly in children under 15, a state of hypovolemic shock can sometimes ensue (with a decrease in temperature, clamminess and a weak pulse, indicating circulatory collapse), causing abdominal pain and, in the absence of intravenous fluids, death. In all cases it is useful to confirm the etiology with a rapid and precise virological diagnosis, both to establish appropriate patient care and to allow public health surveillance systems to issue an alert and step up vector control measures.
Dengue is currently considered to be a re-emerging disease. With economic globalization and the greater movement of people and goods, it is spreading to new geographical locations, increasingly thriving in urban environments and causing epidemics on a larger scale than ever before. The severe forms of dengue have been more and more widely reported during recent outbreaks.
Originally a tropical disease
Dengue is rife in all intertropical regions. Although until recently restricted to South-East Asia (440,000 cases in China in 1980, 200,000 cases in Thailand in 1987), it is now spreading inexorably to the Indian Ocean, the South Pacific (32,800 cases in Tahiti, Moorea and French Polynesia in 2001), the French West Indies (2003, 2006-2008 and 2009-2010), and Latin America, where the annual number of cases increased 60-fold between 1989 and 1993 in comparison to the previous period (1984-1988).
Since the end of 2009, this disease has soared to epidemic proportions in the West Indies. In 2010, 86,000 cases of dengue were reported in Martinique and Guadeloupe (figures from the InVS). In 2011 and 2012, there was no epidemic outbreak.
The first cases of hemorrhagic dengue appeared in Cuba and the Caribbean in 1981, and the disease reappeared in Cuba in 1996, after a 15-year interval. In 2013, there was an epidemic outbreak in French Guiana, and that year 2.35 million cases were reported in the Americas alone, including 37,687 cases of severe dengue. This worrying resurgence of dengue in Latin America and the Caribbean appears to be linked to the doubtful effectiveness of mosquito vector eradication programs in this region of the world. Other contributory factors appear to be demographic growth, uncontrolled urban development, natural disasters and the impoverishment of populations affected by the disease. Dengue has a major impact on the economies of the countries in which it is rife.
Moving towards colonization of temperate zones
In the last few years the secondary vector of dengue in Asia, Aedes albopictus, has colonized North America and Europe, including France. The mosquito is active in these regions between May 1 and November 30, but its ability to tolerate low temperatures and hibernate has enabled it to subsist during cold spells. The risk of dengue transmission in these regions has now been confirmed, with the detection of the first two indigenous cases in France in 2010, in Nice. In 2012, an epidemic outbreak on the Portuguese archipelago of Madeira resulted in more than 2,000 cases, and imported cases were detected in 10 other European countries outside mainland Portugal.
The latest epidemiological data
According to figures from WHO, cases of dengue were reported in the US state of Florida and in China's Yunnan province in 2013. Dengue has remained widespread in several countries in Latin America, including Honduras, Costa Rica and Mexico. In Asia, Singapore has reported an increase in cases after a hiatus of several years, and outbreaks have also occurred in Laos. In 2014, trends are pointing to an increase in dengue cases in the Cook Islands, Malaysia, Fiji and Vanuatu, and dengue type 3 virus (DEN-3) is affecting the Pacific Island countries again after a 10-year interval.
Fighting the disease
There is currently no specific treatment or vaccine available for fighting this disease, but a number of multi-disciplinary studies are under way. The only existing means of fighting the disease are the control of mosquito vectors in the regions concerned and individual measures to protect against mosquito bites.
At the Institut Pasteur
Dengue is being extensively studied at the Institut Pasteur, with several teams working on complementary and multidisciplinary areas in both fundamental and applied research. The Institut Pasteur's dengue experts have formed a cross-disciplinary working group, jointly directed by Anavaj Sakuntabhai and Frédéric Tangy, to swiftly devise and implement a strategy on the various aspects of the epidemic with the aim of curbing the outbreak. The group is working on the development of innovative therapeutic tools including a new vaccine candidate, prognostic markers and a strategy for controlling viral vectors.
The Flavivirus-Host Molecular Interactions Unit, led by Philippe Desprès, is conducting a number of projects, particularly on the physiology of infection and research into new vaccine and anti-viral therapies. The unit is involved in the KerARBO project, a program financed in 2012 by the French National Research Agency and coordinated by the Institute for Research and Development (IRD) in Montpellier. The KerARBO program aims to provide insight into the replication mechanisms of the virus in the skin, where it is inoculated by mosquito saliva after a mosquito bite. The scientists are also hoping to shed light on the interactions between the mosquito vector Aedes albopictus and dengue virus serotype 4 by developing proteomics techniques to examine infection barriers in mosquitoes. These approaches should open up new avenues for innovative anti-viral strategies. In collaboration with the Laboratory for Urgent Response to Biological Threats at the Institut Pasteur, the Flavivirus-Host Molecular Interactions Unit has also developed an innovative technological platform which conducts a patented process to study the prevalence of dengue in populations within endemic regions.
The Viral Genomics and Vaccination Unit (led by Frédéric Tangy), in collaboration with the Flavivirus-Host Molecular Interactions Unit, has developed a vaccine candidate against the four dengue serotypes. A phase I clinical trial of this vaccine candidate is due to be conducted in the near future by the Austrian biotech company THEMIS Biosciences, based in Vienna. The idea is to combine the dengue vaccine with the vaccine for measles, one of the safest and most effective childhood vaccines.
Anavaj Sakuntabhai, head of the Functional Genetics of Infectious Diseases Unit, has also been coordinator of the DENFREE program since January 2012. This ambitious international project, funded by the European Commission, aims to provide insight into dengue epidemics – now rapidly spreading to regions, including Europe, where the disease was previously not found – with a view to containing them. The scientists particularly hope that the results of the DENFREE program will, in the longer term, provide an evaluation of the potential risks of epidemics occurring, highlight the most effective mosquito control measures and develop a more sensitive and specific diagnostic test than the one currently available.
The Arboviruses and Insect Vectors Laboratory, led by Anna-Bella Failloux, is concentrating on the viral cycle within mosquito vectors and their ability to transmit the virus. This team has demonstrated that the tiger mosquito, Aedes albopictus, which is found in southern regions of France, is as effective as the traditional Aedes aegypti vector in spreading dengue. This raises new questions as to the workings of a "temperate" vector system.
The Genotyping of Pathogens Platform, directed by Valérie Caro, is responsible for sequencing viral strains, and works in collaboration with the other campus-based units.
The Structural Virology Unit, led by Felix Rey, is working on the 3D viral structure, using this approach to try to identify drugs to block the virus.
The team under Hugues Bédouelle, in the Molecular Prevention and Therapy of Human Diseases Unit, has developed recombinant antigens of the dengue virus, enabling serological diagnosis of a recent dengue infection.
Research is also being carried out within the Institut Pasteur International Network, with the implementation of collaborative work on dengue. In this the network can draw upon its solid and recognized structure and close proximity to regions and populations exposed to the virus.
Recently, several Institut Pasteur teams, coordinated by Antoine Gessain, joined forces under the DEVA Transversal Research Program. This program has developed a molecular diagnostic tool for the chikungunya, dengue and West Nile viruses on the Institut Pasteur campus in Paris. It uses a DNA microarray to diagnose acute viral infection from a biological fluid such as blood or serum. This microarray is able to characterize the genome of the virus(es) present in the infected biological sample.
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Caption - Neuronal cells in mice infected with dengue type 1
Statistics from WHO and InVS