1. In Taiwan
Luke Huang & Jessica Leung

2. 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

3. …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

4. Dengue fever in Taiwan

5. 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

6. 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.

7. 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 .

8. 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.

9. 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)

10. 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.

11. Spread in Taiwan
2002
2005

12. 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

13. 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

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

15. 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

16. 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

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

18. 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

19. Reference
"Dengue." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 16 Mar Web. 30 Mar <
Dengue Haemorrhagic Fever: Diagnosis, Treatment, Prevention, and Control. 2nd ed. Geneva: World Health Organization, Print.
"Dengue." World Health Organization. World Health Organization. Web. 30 Mar <
Gubler, D. J., and Goro Kuno, eds. Dengue and Dengue Hemorrhagic Fever. Wallingford, Oxon, UK: CAB International, Print.
Liu, J-W. ,Khor, B-S., Lee, C-H. et al. Dengue Haemorrhagic Fever in Taiwan Dengue Bulletin