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DENGUE: EPIDEMIOLOGY PART 1. SCOTT B HALSTEAD, MD. Director, Research PEDIATRIC DENGUE VACCINE INITIATIVE. TRANSMISSION. Aedes aegypti breeds in clean water in and around houses. Daytime biting.

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Dengue epidemiology part 1
DENGUE:EPIDEMIOLOGYPART 1

SCOTT B HALSTEAD, MD

Director, Research

PEDIATRIC DENGUE VACCINE INITIATIVE


Transmission
TRANSMISSION

  • Aedes aegypti breeds in clean water in and around houses.

  • Daytime biting.

  • Transmission from human to human requires the same female mosquito to bite a viremic human and then bite a susceptible human at an interval of around 10-12 days.


Four viruses
FOUR VIRUSES

  • Life time immunity follows infection to one type.

  • Second, third and possibly four infections are possible.

  • CHILDREN – first infections are mild, largely inapparent.

  • ADULTS - first infections may produce DF, some viruses more overt than others.


Primary infections clinical features
PRIMARY INFECTIONSClinical Features

  • In children –

    DEN 1 & 3 – mild illness

    DEN 2 & 4 – no illness

  • In adults

    DEN 1 & 3 – Disease/Infection ~1; g.i. hemorrhages may accompany peptic ulcer disease.

    DEN 2 & 4 - mild - moderate


DENGUE FEVER

  • Incubation period = 5 days

  • Fever = 5 days

  • Leukopenia

  • Moderate thrombocytopenia

Simmons et al

Phil J Sci 44:1-252, 1931


DENGUE 1

MACULO-

PAPULAR

RASH.

Day 5 after

onset of

fever.


DISEASE SPECTRUMMILD SEVEREDF DHF+ Thrombocytopenia +++ ThrombocytopeniaHidden Vasc. Perm1? Overt Vasc. Perm.1. Wills BA et al J Infect Dis 190:810-818, 2004





Why is dengue such a big problem today

Global population growth

Rural to urban migration

Growth of cities

Deterioration of cities

Jet travel

Health services poorly organized/ underfunded

Lack of vector control professionals

WHY IS DENGUE SUCH A BIG PROBLEM TODAY?


Global spread of dengue
Global Spread of Dengue

50-100 million infections/year

Aedes aegypti

Countries with active dengue +


Why two syndromes benign and severe

WHY TWO SYNDROMES, BENIGN and SEVERE?

Observed in two immunological settings.

Primary infections in infants.

2. Secondary infections in children

and adults.


Two infections the epidemiological data
Two-infectionsThe epidemiological data

  • DHF documented in children (> 1 yr) who circulate infection-acquired dengue antibody. Four prospective cohort and 6 prospective population-based studies.

  • In most studies, DHF comprises 2-5% of secondary infections





Sequential dengue infections
SEQUENTIAL DENGUE INFECTIONS

Two infections can occur in twelve

possible combinations.


Established second infection sequences leading to dhf
Established second infection sequences leading to DHF

  • 2 – 1 Thailand; Indonesia

  • 3 – 1 Thailand

  • 1 – 2 Cuba, 1981; Cuba 1997; Thailand

  • 3 – 2 Thailand

  • 4 – 2 Thailand

  • 1 – 3 Cuba, 2001; Thailand; Indonesia

  • 2 – 3 Thailand, DF in Cuba

  • 1 – 4 Thailand

  • 2 – 4 Indonesia

  • 3 – 4 Thailand


No data
No data

  • 4 – 1

  • 4 – 3

KALAYANROOJ S et al AJTMH 2008 in press.


Third infections resulting in dhf
Third infections: resulting in DHF

  • 1 – 3 – 2 Thailand

MAMMAN MP personal communication

No DHF

  • 1 – 2 – 3 Cuba, 2001.

GUZMAN MG personal communication



Lags at Which Correlation Between Bangkok and other Provinces

Is Maximized

p<1e-8

~148 km/month

(months)


Dhf at bangkok childrens hospital
DHF AT BANGKOK CHILDRENS HOSPITAL Provinces

1O INFECT.

2O INFECTIONS






EFFECT OF AVERAGE FORCE OF INFECTION (R Provinceso) ON

AGE SPECIFIC SECONDARY INFECTION INCIDENCE

Ro = 30%

Ro = 20%

Ro = 10%


Dengue hemorrhagic fever/dengue shock syndrome has occurred in some (but not all) dengue epidemics since the 1950s,Why?


Dhf does not occur if antibodies from first infection neutralize the second infecting virus
DHF does not occur if antibodies from first infection neutralize the second infecting virus.


Bangkok study kliks et al ajtmh 40 444 1989
BANGKOK STUDY neutralize the second infecting virus.Kliks et al AJTMH 40:444, 1989.

  • 40 Bangkok school children had documented secondary DEN 2 infections (pre-infection blood sample contained dengue antibodies).

  • 7 were hospitalized; 33 silent.

  • Undiluted pre-infection sera tested for neutralization or enhancement in human PBL cultures.


Ade and dhf blocked by neutralizing antibodies
ADE AND DHF BLOCKED BY NEUTRALIZING ANTIBODIES neutralize the second infecting virus.


Antigenic structure of virus iquitos study
ANTIGENIC STRUCTURE OF VIRUS: neutralize the second infecting virus.IQUITOS STUDY

  • School children cohorts followed from 1990 until now.

  • DEN 1 transmitted in 1990 - 1994.

  • DEN 2 transmitted from 1995.

  • Prevalence of neutralizing antibodies measured in 1993, 1994 and 1995 cohorts.

  • In 1995, secondary DEN 2 infection rate estimated at 60.5%


No dhf with secondary den 2 american genotype infections
NO DHF with Secondary DEN 2 (American genotype) infections neutralize the second infecting virus.

  • Total population, 5 - 14 yrs-old = 81,479.

  • Total 2ndary DEN 2 infections = 49,266.

  • Estimated hospitalized DHF = 887-10247.

  • Estimated deaths = 18 - 204.

  • DHF cases observed = 0

    Watts DM et al Lancet 354:1431-4, 1999



One way cross 17 dengue 2 immune sera do not neutralize dengue 1 viruses
ONE-WAY CROSS: DEN 1- IMMUNE HUMAN SERA17 DENGUE 2-IMMUNE SERA DO NOT NEUTRALIZE DENGUE-1 VIRUSES


American genotype dengue 2 viruses are neutralized in vitro by human antibodies to dengue 1
American genotype dengue 2 viruses are neutralized in vitro by human antibodies to dengue 1

BUT …

dengue 1 antibodies do not prevent but

maydown regulatedengue 2 infections


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