Dengue epidemiology part 1
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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

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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 epidemiology part 1

DENGUE FEVER

  • Incubation period = 5 days

  • Fever = 5 days

  • Leukopenia

  • Moderate thrombocytopenia

Simmons et al

Phil J Sci 44:1-252, 1931


Dengue epidemiology part 1

DENGUE 1

MACULO-

PAPULAR

RASH.

Day 5 after

onset of

fever.


Dengue epidemiology part 1

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


Dengue hemorrhagic fever dengue shock syndrome dhf dss dengue vasculopathy

DENGUE HEMORRHAGIC FEVER/DENGUE SHOCK SYNDROME (DHF/DSS)Dengue vasculopathy


Dengue epidemiology part 1

DSS GRADE IV


Dengue epidemiology part 1

DSS GRADE III


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


Dhf in children prospective cohort studies

DHF IN CHILDREN: PROSPECTIVE COHORT STUDIES


Dhf in children prospective population based studies

DHF IN CHILDREN: PROSPECTIVE POPULATION-BASED STUDIES


Dhf in children prospective population based studies1

DHF IN CHILDREN: PROSPECTIVE POPULATION- BASED STUDIES


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


Dengue epidemiology part 1

DENGUE VIRUSES, BANGKOK 1973 - 2001


Dengue epidemiology part 1

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

1O INFECT.

2O INFECTIONS


Dengue epidemiology part 1

Fischer and Halstead Yale J Biol Med 42:329-349,1970


Dengue epidemiology part 1

Fischer and Halstead Yale J Biol Med 42:329-349,1970


Dengue epidemiology part 1

Fischer and Halstead Yale J Biol Med 42:329-349,1970


Dhf at bangkok childrens hospital1

DHF AT BANGKOK CHILDRENS HOSPITAL


Dengue epidemiology part 1

EFFECT OF AVERAGE FORCE OF INFECTION (Ro) ON

AGE SPECIFIC SECONDARY INFECTION INCIDENCE

Ro = 30%

Ro = 20%

Ro = 10%


Dengue epidemiology part 1

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 STUDYKliks 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


Antigenic structure of virus iquitos study

ANTIGENIC STRUCTURE OF 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

  • 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


Neutralization of american genotype den 2 viruses by 34 den 1 immune human sera

NEUTRALIZATION OF AMERICAN GENOTYPE DEN 2 VIRUSES by 34 DEN 1- IMMUNE HUMAN SERA


One way cross 17 dengue 2 immune sera do not neutralize dengue 1 viruses

ONE-WAY CROSS: 17 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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