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DENGUE: EPIDEMIOLOGY PART II. SCOTT B HALSTEAD, MD. Director, Research PEDIATRIC DENGUE VACCINE INITIATIVE. EPIDEMIOLOGY. Risk factors for severe disease. Sequential dengue infection (includes antigenic structure of virus) Race Age Host genetic factors Nutritional status Sex. Race.

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DENGUE:EPIDEMIOLOGYPART II

SCOTT B HALSTEAD, MD

Director, Research

PEDIATRIC DENGUE VACCINE INITIATIVE


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EPIDEMIOLOGY

  • Risk factors for severe disease.

    • Sequential dengue infection (includes antigenic structure of virus)

    • Race

    • Age

    • Host genetic factors

    • Nutritional status

    • Sex


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Race

  • Caucasian & Asian vs African.

    At least 5:11,2

  • Guzman MG et al. AJTMH 42:179-184, 1990.

  • Halstead SB et al AJTMH 65:180, 2001


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BLACKS ARE RELATIVELY RESISTANT TO SEVERE DENGUE ILLNESS

  • A human resistance gene seems to explain the observation that while all dengue virus types circulate in Africa no DHF/DSS cases or outbreaks of DF have been reported.



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DENGUE NEUTRALIZING ANTIBODIES BY AGE IN 210 CHILDREN RESIDENT

IN PORT AU PRINCE, HAITI, 1996.

N =(46) (40) (36) (41) (27) (13) (10) (4)


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AGE RESIDENT


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DHF - EFFECT OF AGE, 1981 Cuba Outbreak RESIDENT

GUZMAN MG et al. Int J Infect Dis 6:18, 2002


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CAPILLARY FRAGILITY RESIDENT

Gamble J et al. Biochem Soc Med Res Soc 98:211-6, 2000.


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GENETIC ASSOCIATIONS RESIDENT Susceptibility Resistance

HLA1: HLA-A*0207 HLA-A*0203

HLA-B*51 HLA-B*52

HLA A24 HLA A33

Vit D2: t allele/352

FcRγII3:

DCSIGN4: CD 209 promoter

TNFα5: TNF 308

1. Loke H et al. JID 184:1369-73, 2001

2. Stephens HA et al. Tissue Antigens 60:309-318, 2002.

3. Loke H et al. AJTMH 67:102-6, 2001

4. Sakuntabthai A et al. Nat Genetics 37:507-13, 2005

5. Fernandez-Mestre MT et al. Tissue Ag 64:468-72, 2004




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Effect of nutritional status on dengue disease severity RESIDENT 1

Well nourished children:

highly susceptible to severe disease

Malnourished: protected against severe disease (protein-calorie malnutrition grade 2 and 3)

1. Thisyakorn U et al. CID 16:295-297, 1993


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SEX RESIDENT


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SEX RATIOS BY DENGUE SYNDROME RESIDENT Bangkok Children’s Hospital, 1962-64



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DHF/DSS in infants, identical to but more severe than DHF/DSS in children

  • Higher case fatality rates, resuscitation requires more fluid per Kg body weight than in older children with 2o infection.

    • Hung NT et al AJTMH 72:370, 2005

  • Circulating cytokines and cytokine levels during acute phase similar to those in older children during 2o infection.

    • Hung NT et al JID 189:221, 2004



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INFANT DHF/DSS DHF/DSS in children


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WHY DO MATERNAL ANTIBODIES ENHANCE DENGUE DISEASE? DHF/DSS in children

CENTRAL ROLE OF MACROPHAGES IN SUPPORTING DENGUE INFECTIONS IN HUMANS


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Dengue viruses are adapted to grow in dendritic cells, DHF/DSS in children

monocytes and macrophages.

Complexed with antibodies dengue viruses enter FcR-bearing cells with great efficiency.


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IMMUNE ENHANCEMENT OF DENGUE INFECTION DHF/DSS in children(Antibody-Dependent Enhancement)

  • In the presence of dengue ADE antibody:

  • increased rate of infection

  • increase in the number of infected cells.

  • increased production of viruses per cell.


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ADE IN HUMAN DENGUE: DHF/DSS in childrenDEN virus load and disease severity


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DEN 3 DHF/DSS in children

VIREMIA

●--● DSS

▲- ▲DHF

□--□ DF

LIBRATY DH et al JID 185:1213, 2002



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Schematic distribution of dengue 2 viruses DHF/DSS in children

in blood and tissues of 31 rhesus monkeys.



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MYANMAR: VARYING CFR severity and size.



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WHY? severity and size.

  • Possible effect of

    • ADE

    • Heterotypic immunity

    • Replacement of serotypes

    • Clade extinctions

  • These possibilities have been explored in mathematical models, most are based upon the hospital epidemiological data from Bangkok or all of Thailand.


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EFFECT OF ADE ON EPIDEMIC CYCLES severity and size.

  • “Enhancement of infection may generate a complex and persistent cyclical or chaotic epidemic behavior ….and coexistence of mutiple strains”

    • Ferguson N et al. The effect of antibody-dependent enhancement on the transmission dynamics and persistence of mutiple-strain pathogens.Proc Natl Acad Sci USA 96:790-4, 1999


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EFFECT OF HETEROTYPIC IMMUNITY ON EPIDEMIC CYCLES severity and size.

  • 8-10 year epidemic cycles are accompanied by clade extinctions.

  • Mathematical model suggests that heterotypic immunity is responsible.

    • Adams B et al PNAS 103: 14234-9, 2006


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SEROTYPE REPLACEMENT severity and size.

  • DENV -1 replaced DENV 2, 3, 4. Related to stochastic event due to low transmission in 1999-2000?

    • Thu HM et al. Myanmar denge outbreak associated with displacement of serotypes 2, 3 and 4 by dengue 1. Emerg Infect Dis 10:693-7, 2004.


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CLADE EXTINCTIONS DUE TO STOCHASTIC EVENTS severity and size.

  • In Myanmar, clades B and C of genotype I DENV -1 circulated with clade A genotype III during the 1990s. After 1998, clade A disappeared leaving only clades B and C.

    • Thu HM et al Lineage extinction and replacement in dengue type 1 virus populations are due to stochastic events rather than to natural selection. Virol 336:163-72, 2005.

  • In Thailand, clades of DENV -3 circulating prior to 1992 disappeared and were replaced by two lineages with common ancestor.Earlier extinctions, 1963, 1973?

    • Wittke V et al. Extinction and rapid replacement of strains of dengue 3 virus during an interepidemic period. Virol 301:148-156, 2002.


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