In Taiwan Luke Huang & Jessica Leung

Dengue is a tropical febrile disease Dengue Fever is a tropical febrile disease Febrile = Fever causing Endemic in Latin America, Africa and South and Southeast Asia and the Pacific Classified by WHO as a neglected tropical disease

…and become a MAJOR pandemic in the last 50 years Endemic in more than 100 countries 2.5 billion people at risk ...and has become a MAJOR epidemic Estimated 50 to 100 million cases annually, with several 100,000 cases of the more severe form dengue hemorrhagic fever Endemic in more than 100 countries Leading cause of death in children in some Asian countries Over 2.5 billion people at risk for infection, 2/5 of the world’s population Case-fatality rate for DHF averages 5 percent and 58,000 deaths have been attributed to dengue in the past 40 years www.tatterhood.com/category/gameart/tastyplanet

Dengue fever in Taiwan

How is it spread? Aedes albopictus Aedes aegypti Aedes aegypti A. aegypti can acquire the virus only when the infected person has the virus circulating in their bloodstream Can be transmitted through other members of the subgenus Stegomyia Adapted to urban manmade environments Likes to live in open water containers, tires, etc. Restricted to tropical areas and seasonal Incubation time in mosquito can vary with temperature, strain of virus, species of mosquito and amount of virus ingested Goes over much of mosquito anatomy but transmitted because in salivary glands Once mosquito is infected, can transmit virus for the rest of its life Vertical transmission in mosquitoes can occur but generally not at very high rates Aedes aegypti

How it get into our body? 1.The virus is inoculated into humans with the mosquito saliva. 2.The virus localizes and replicates in various target organs, for example, local lymph nodes and the liver. 3.The virus is then released from these tissues and spreads through the blood to infect white blood cells and other lymphatic tissues. 4.The virus is then released from these tissues and circulates in the blood. 5.The mosquito ingests blood containing the virus. 6.The virus replicates in the mosquito midgut, the ovaries, nerve tissue and fat body. It then escapes into the body cavity, and later infects the salivary glands. 7.The virus replicates in the salivary glands and when the mosquito bites another human, the cycle continues.

Patients may also report other symptoms, such as itching and aberrations in the sense of taste, particularly a metallic taste. In addition, there have been reports of severe depression after the acute phase of the illness .

4 Dengue clinical syndromes Undifferentiated fever; Classic dengue fever; Dengue hemorrhagic fever (DHF) Dengue shock syndrome (DSS) Dengue shock syndrome is actually a severe form of DHF.

Four Stages of DHF Stage 1 Fever and nonspecific constitutional symptoms Positive tourniquet test is only hemorrhagic manifestation Stage 2 Stage 1 manifestations + spontaneous bleeding Stage 3 Signs of circulatory failure (rapid/weak pulse, narrow pulse pressure, hypotension, cold/clammy skin) Stage 4 Profound shock (undetectable pulse and BP)

Dengue Hemorrhagic Fever Danger Signs in Dengue Hemorrhagic Fever Danger Signs in Dengue Hemorrhagic Fever Abdominal pain - intense and sustained Persistent vomiting Abrupt change from fever to hypothermia, with sweating and prostration Restlessness or somnolence *All of these are signs of impending shock and should alert clinicians that the patient needs close observation and fluids.

Spread in Taiwan 2002 2005

How did it become a major public health problem? Ineffective mosquito control Rapid population growth Non-biodegradable packaging Rapid increase in air travel Reasons for DHF and DF as a major public health problem Effective mosquito control is virtually non-existent in most dengue-endemic countries of the world Too much emphasis on ultra-low volume sprays of insecticide for adult mosquito control that is not effective for controlling Ae. Aegypti Demographic changes of uncontrolled population growth and urbanization Increase in non-biodegradable packaging for goods and difficulty of disposing of tires Increased travel of humans by airplane Over 50% of US departures are to tropical areas Public health infrastructure to deal with vector-borne diseases has deteriorated in most countries of the world Crisis mentality- emphasis on emergency control methods rather than developing methods to prevent transmission Because of lack of money and resources http://farm1.static.flickr.com/81/285601911_f859e04e39.jpg

The Dengue Virus Family Flaviviridae Same family as Yellow Fever 4 viral serotypes Family Flaviviridae Same family as Yellow Fever Dengue virus molecular biology 4 viral serotypes Family Flaviviridae (same family as yellow fever) Spherical particles with a lipid envelope enclosing capsid RNA genome made of single strand messenger positive RNA approximately 11 kb in length Genome encodes single open reading frame Long polyprotein is processed by viral and host cell proteases to produce 10 viral proteins

Single strand positive RNA Genome Dengue is an RNA Virus Capsid (core) 2. Membrane 3. Envelope Single strand positive RNA Genome 50 nm

Secondary infections tend to produce DHF…. Antibodies enhance viral replication! Pathology of the dengue virus Binding is mediated by the envelope glycoprotein to the cell surface Original Antigenic sin- antibodies and t cells specific for one strain still recognize different strain because of similarities but aren’t as good at responding This is called antibody-dependent enhancement- increase in infection of monocytic cells by dengue viruses complexes of dengue with bound antibody can interact via the free Fc region of immunoglobulin with fcgamma receptors on the cell surface of monocytic cells Increases the binding of the virus to the cell

There is no specific treatment for DHF ! Treatment of DF Only supportive (treatment of symptoms) Assess for dehydration and ability to drink fluids Therapy for pain (avoid aspirin because of exacerbating hemorrhagic tendencies) Treatment Fluid replacement through IV Medication to reduce fever Blood transfusion if needed Can only treat the symptoms

How can we stop it? Mosquito control: Improved water storage Insecticides Introduction of mosquito-eating fish and copepods

Even Better: A Vaccine Tetravalent live attenuated Intertypic chimaeric vaccine Chimaeric vaccine Effective vaccine still in progress Types of Vaccines Tetravalent live attenuated vaccine Attenuated viruses of all four serotypes were developed at Mahidol university, Thailand Successfully completed phase 2 clinical trials Phase 3 trials underway Contains an antigen from each serotype Intertypic chimaeric vaccine Structural genes from the cDNA copy of an attenuated strain of dengue virus of a given serotype is replaced by the corresponding genes of a different dengue virus serotype Chimaeric vaccines Replaces the E gene of the 17D yellow fever vaccine with the analogous gene of the vaccine targeted flavivirus Pediatric Dengue Vaccine Initiative Established in 2003 at the International Vaccine Institute in Seoul, South Korea Mission: Accelerate evaluation of candidate dengue vaccines Introduction of improved diagnostics To introduce affordable safe vaccines in dengue endemic countries Also serves as a forum for improved advocacy and coordination of global efforts on dengue vaccine development Funded by the Rockefeller foundation, bill and Melinda gates foundation, and the WHO

Reference "Dengue." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 16 Mar. 2010. Web. 30 Mar. 2010. <http://www.cdc.gov/Dengue/>. http://www.libertytimes.com.tw/2012/new/jul/26/today-int11.htm Dengue Haemorrhagic Fever: Diagnosis, Treatment, Prevention, and Control. 2nd ed. Geneva: World Health Organization, 1997. Print. "Dengue." World Health Organization. World Health Organization. Web. 30 Mar. 2010. <http://www.who.int/topics/dengue/en/>. Gubler, D. J., and Goro Kuno, eds. Dengue and Dengue Hemorrhagic Fever. Wallingford, Oxon, UK: CAB International, 1997. Print. Liu, J-W. ,Khor, B-S., Lee, C-H. et al. Dengue Haemorrhagic Fever in Taiwan. 2003. Dengue Bulletin