Dengue

Edwin J. Asturias | Associate Professor of Pediatrics – Senior Investigator

Director for Latin America

MODULE 5

Symptoms of Dengue Fever

Dengue: Skin rashes

DHF manifestations

• Hemorrhages• Thrombocytopenia• Plasma effusions

Dr Graham Beards, WHO Guidelines 2009

Vector: Aedes aegyptae

Dengue Virus

• 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

Worldwide distribution of Dengue

Number of reported cases and hospitalizations due to dengue and dengue hemorrhagic fever (DHF), Brazil, 1986–2002

Bosco-Siqueira J. Emerg Infect Dis 2005

Factors associated with increase burden of Dengue infections

• 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

DHF pathogenesis (ADE)

• DENVs are antigenically cross-reactive• Higher viremia relates to disease severity• Antibody-dependent enhancement (ADE) by Fc

gamma receptors of monocytes and macrophages

Age distributions of infants hospitalized for DHF/DSS and the protective and infection-enhancing effects of maternal dengue antibodies.

Halstead SB. Emerg Infect Dis 2002

Dengue: a clinical approach

Tourniquet TestRumpel-Leede Capillary-Fragility Test or simply a capillary fragility test

• 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

Confirmatory diagnostic test for Dengue virus infection

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

Immune Response to Dengue

Diagnostic Serology

• 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 ELISANon specific, cross reactions

Approach to the Child with Dengue Fever

• 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

Dengue hospital discharge criteria for children

• 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

Public Preventive measures for Dengue

Individual Dengue preventive strategies

• Protective clothing during all day during vector season

• Mosquito repellents

• Impregnated bed nets

Chimeric Flavivirus Vaccine Technology

5’ 3’C Non-structural genes

prM E prM EExchange coat protein genesof dengue 1,2,3,4 (wild-type)

Transfect mRNA

Yellow fever 17D or Dengue genome cloned as cDNA5’ 3’C prM E Non-structural genesC prM E Nonstructural genes

Envelope = heterologous virus

RNA replicative ‘engine’ = YF17D or DENV

5’ 3’Chimeric cDNA –> transcribe to RNA

Grow virusin cell culture

Dengue vaccine Control Vaccine EfficacyHeteroge

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

Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren 4-11 years of age

Conclusions

• 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