MODULE 5. Dengue. Edwin J. Asturias Associate Professor of Pediatrics Senior Investigator Director for Latin America

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1 MODULE 5 Dengue Edwin J. Asturias Associate Professor of Pediatrics Senior Investigator Director for Latin America

2 Symptoms of Dengue Fever

3 Dengue: Skin rashes

4 DHF manifestations Hemorrhages Thrombocytopenia Plasma effusions

5 Dr Graham Beards, WHO Guidelines 2009

6 Vector: Aedes aegyptae

7 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

8 Worldwide distribution of Dengue

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10 Number of reported cases and hospitalizations due to dengue and dengue hemorrhagic fever (DHF), Brazil, Bosco-Siqueira J. Emerg Infect Dis 2005

11 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

12 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

13 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

14 Dengue: a clinical approach

15 Tourniquet Test Rumpel-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 Feb;47(2): Vietnam: Sen 41.6% Spe 94.4%, PPV 98.3% NPV 17.3%. Trop Med Int Health Feb;7(2):125-32

16 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

17 Immune Response to Dengue

18 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 ELISA Non specific, cross reactions

19 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 ml/kg/day Alert signs

20 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

21 Public Preventive measures for Dengue

22 Individual Dengue preventive strategies Protective clothing during all day during vector season Mosquito repellents Impregnated bed nets

23 Chimeric Flavivirus Vaccine Technology Yellow fever 17D or Dengue genome cloned as cdna 5 C prm E E Non-structural Nonstructural genes genes 3 prm E prm E Exchange coat protein genes of dengue 1,2,3,4 (wild-type) 5 C Non-structural genes 3 Chimeric cdna > transcribe to RNA 5 3 Transfect mrna Grow virus in cell culture Envelope = heterologous virus RNA replicative engine = YF 17D or DENV

24 Protective efficacy of the recombinant, liveattenuated, CYD tetravalent dengue vaccine in Thai schoolchildren 4-11 years of age Dengue vaccine Personyears at risk Cases or episodes * Personyears at risk Control Cases or episodes * Vaccine Efficacy % (95% CI) Heteroge neity p value Overall Cases % ( 13 4 to 56 6) Serotype % ( 21 6 to 84 0).. Serotype % ( 75 0 to 51 3) Serotype % ( to 99 6).. Serotype % (24 8 to 100 0).. NS1-antigen positive only ND.. Sabchareon A, Lancet Sep 10. pii: S (12)

25 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