Post on 11-May-2020
UNIVERSITY OF COLORADO | COLORADO STATE UNIVERSITY | UNIVERSITY OF NORTHERN COLORADO
| Assistant Professor of Pediatrics – Senior Investigator
Director for Latin America
Swahili word “Ka dinga pepo“, then to Spanish word "dengue" meaning fastidious or careful
First record of a case of probable dengue fever is in a Chinese: “water poison” associated with flying insects
First confirmed report in 1789 by Benjamin Rush, “breakbone fever” JF Siler: Mosquito transmission of Dengue fever in the Philippines
Unplanned urban overpopulation of areas leading to inadequate housing and public health systems
Poor vector control, e.g., stagnant pools of water for mosquito breeding
Climate change and floodings Increased international travel (recreational,
business or military) to endemic areas
• Flavivirus of the family Flaviviridae
• 4 serotypes: DEN1, 2, 3, 4 • Transmission cycle between
monkeys/humans and mosquito vectors
• Aedes aegypti and Aedes albopictus are the major vectors
Bosco-Siqueira J. Emerg Infect Dis 2005
Group Mechanism Effects References* Antibody Enhancement of
infection Increased cellular infection and viral load Halstead (1989, 2007)
Immune complex Complement activation Theofilopoulos et al. (1976), Malasit (1987)
T lymphocytes Memory T cell Increased pathology Mongkolsapaya et al. (2006)
Shift from Th1 to Th2 Increased pathology Chaturvedi et al. (2000)
Cytokine Tsunami Increased capillary permeability
Chaturvedi et al. (1999, 2000, 2007)
Macrophage and dendritic cells Cytokine tsunami Increased capillary
permeability Chaturvedi et al. (2006a)
Free radicals: NO, O2–,
etc. Increased capillary permeability
Chaturvedi et al. (2006a)
Metalloprotein Increased capillary permeability Luplertlop et al. (2006)
Vascular endothelial cells (mainly in vitro work)
eNOS, NO, Endothelin Increased capillary permeability
Yuan (2006), Jiang et al. (1999)
Virus virulence American genotype Do not produce DHF/DSS Watts et al. (1999)
Host genetics Polymorphism of genes Increased or decreased predisposition for DHF
Chaturvedi et al. (2006b)
• DENVs are antigenically cross-reactive • Higher viremia relates to disease severity • Antibody-dependent enhancement (ADE) by Fc
gamma receptors of monocytes and macrophages
Peak virus titer (log mosquito infectious doses per milliliter [MID50/ml]) by pleural effusion index on the day
after defervescence
Vaughn D W et al. J Infect Dis. 2000;181:2-9
Halstead SB. Emerg Infect Dis 2002
Age: infants > children > adults Gender: females Ethnicity: African descent protective? Chronic underlying conditions
Frequency distributions of the intrinsic incubation periods of dengue fever cases.
Nishiura H , Halstead S B J Infect Dis. 2007;195:1007-1013
Dr Graham Beards, WHO Guidelines 2009
Dr. Dawson, of this city, describes the onset as sudden…at first there is a slight chill…the temperature in the first 24 hours reaches 105°F, remains for two or three days, and on the third day drops... The pains were very acute and the suffering great…in the head and back and limbs; abdominal pain…sometimes very severe. No position assumed by the patient gives relief. Swelling occurred in and about the joints, especially the ankle.
The eyes were bright and injected. The urine scanty…with the fall of the temperature the rash appears…in about forty to fifty per cent. of the cases.
There was a tendency to hemorrhage from all of the mucous surfaces.
Comparison of the clinical findings of 2 experimental studies on dengue fever.
Nishiura H , Halstead S B J Infect Dis. 2007;195:1007-1013
Blood pressure cuff inflated at MAP for 5 min
Positive = 10 petechiae per square inch
Tourniquet test positive in only 39.1% of all DHF cases in India J Assoc Physicians India. 1999
Feb;47(2):203-4. Vietnam: Sen 41.6% Spe
94.4%, PPV 98.3% NPV 17.3%. Trop Med Int Health. 2002 Feb;7(2):125-32
Type Clinical Case Definition Dengue Fever Probable DF: Fever for 2 to 7 days and one of the
following: cefalea, arthralgia, retrorbital pain, rash, leucopenia or consistent serology Confirmed DF: Virus (+), PCR (+), confirmatory serology, dengue Ag
Dengue Hemorragic Fever (DHF)
All the following criteria: 1. Fever for 2-7 days (sometimes biphasic) 2. Hemorrhagic manifestations 3. Thrombocytopenia (<100,000) 4. Evidence of plasma effusions
Dengue Shock DHF + circulatory collapse: 1. Fast and weak pulse or hypotension 2. Altered conscious status, renal failure
Hemorrhages Thrombocytopenia Plasma effusions
Mean plural effusion index and 95% CI by dengue virus type and antibody response pattern
(○ and dashed lines, primary; and heavy lines, secondary).
Vaughn D W et al. J Infect Dis. 2000;181:2-9
Virus isolation from plasma, blood or tissues
4X increase in antibody titers IgM or IgG
Dengue antigen in serum
PCR from blood, tissue or pathology
Serology Hemmaglutination
Sensitive, easy, specific ideal for sero-epidemiology
MAC-ELISA Day 5: 80% cases + (Puerto Rico) Day 6-10: 93% cases + Day 10-20: 99% + Persistence of IgM for 2-3 months reported
IgG ELISA Non specific, cross reactions
• Rest • Acetaminophen o paracetamol • No aspirin or AINEs • No antibiotics • Oral Rehydration solution (OMS)
• 50 mL/kg for 4-6 hrs • Maintenance 80-100 mL/kg/day
• Alert signs
• No fever for 24 hrs. without antipyresis • Return of appetite • Visible clinical improvement • Good urinary output • Minimum 3 days after shock • No respiratory distress from effusions • Platelet count > 50,000
• Protective clothing during all day during vector season
• Mosquito repellents
• Impregnated bed nets
Lenhart A. Trop Med Int Health. 2008;13(1):56-67.
• Should be safe and immunogenic • Protection before age of exposure (<3
years) • High protection against 4 serotypes • Long term immunity • Current schedule: 0-6-12 months
Live attenuated vaccines Mahidol University (Thailand) and Walter Reed Army
Institute of Research in the USA Tetravalent neutralizing antibody responses achieved in
63% of volunteers after two doses DENV4Δ30 vaccine 30-nucleotide deletion at the 3' site (nucleotides 172–
143) resulted in attenuation Panacea Biotec & Biological E. Ltd. in (India),
Vabiotech (Vietnam) and Butantan (Brazil) Chimeric viruses Sanofi Pasteur and the latter by InViragen
Chimeric Flavivirus Vaccine Technology
5’ 3’ C Non-structural genes
prM E prM E Exchange coat protein genes of dengue 1,2,3,4 (wild-type)
Transfect mRNA
Yellow fever 17D or Dengue genome cloned as cDNA 5’ 3’ C prM E Non-structural genes C prM E Nonstructural genes
Envelope = heterologous virus
RNA replicative ‘engine’ = YF
17D or DENV
5’ 3’ Chimeric cDNA –> transcribe to RNA
Grow virus in cell culture
Seroconversion rates for each DENV serotype after each vaccination.
Morrison D et al. J Infect Dis. 2010;201:370-377 © 2010 by the Infectious Diseases Society of America
Dengue vaccine Control Vaccine Efficacy Heteroge
neity p value
Person-years at
risk
Cases or episodes*
Person-years at
risk
Cases or episodes*
% (95% CI)
Overall Cases 2522 45 1251 32 30·2% (−13·4 to 56·6) 0·0340
Serotype 1 2536 9 1251 10 55·6% (−21·6 to 84·0) ..
Serotype 2 2510 31 1250 17 9·2% (−75·0 to 51·3) 0·0309
Serotype 3 2541 1 1257 2 75·3% (−375·0 to 99·6) ..
Serotype 4 2542 0 1263 4 100·0% (24·8 to 100·0) ..
NS1-antigen positive only 2542 4 1265 0 ND ..
Sabchareon A, Lancet. 2012 Sep 10. pii: S0140-6736(12)61428-7
• Dengue is a common and potentially severe infection with no treatment available (only supportive)
• Suspect in any person with fever from an endemic area
• Early detection and management is key • Prevention is difficult but achievable
and DEN vaccines are promising