DENGUE: EPIDEMIOLOGY PART 1

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DENGUEEPIDEMIOLOGYPART 1
SCOTT B HALSTEAD, MD
Director, Research PEDIATRIC DENGUE VACCINE
INITIATIVE
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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.

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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.

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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

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DENGUE FEVER

• Incubation period 5 days
• Fever 5 days
• Leukopenia
• Moderate thrombocytopenia

Simmons et al Phil J Sci 441-252, 1931
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DENGUE 1 MACULO- PAPULAR RASH. Day 5 after onset
of fever.
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DISEASE SPECTRUMMILD SEVEREDF
DHF Thrombocytopenia
ThrombocytopeniaHidden Vasc. Perm1?
Overt Vasc. Perm.1. Wills BA et al J Infect
Dis 190810-818, 2004
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DENGUE HEMORRHAGIC FEVER/DENGUE SHOCK SYNDROME
(DHF/DSS)Dengue vasculopathy
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DSS GRADE IV
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DSS GRADE III
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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

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Global Spread of Dengue
50-100 million infections/year
Aedes aegypti
Countries with active dengue
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WHY TWO SYNDROMES, BENIGN and SEVERE?

• Observed in two immunological settings.
• Primary infections in infants.
• 2. Secondary infections in children
• and adults.

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Two-infections The epidemiological data

• DHF documented in children (gt 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

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DHF IN CHILDREN PROSPECTIVE COHORT STUDIES
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DHF IN CHILDREN PROSPECTIVE POPULATION-BASED
STUDIES
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DHF IN CHILDREN PROSPECTIVE POPULATION- BASED
STUDIES
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SEQUENTIAL DENGUE INFECTIONS
Two infections can occur in twelve possible
combinations.
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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

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No data

• 4 1
• 4 3

KALAYANROOJ S et al AJTMH 2008 in press.
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Third infections resulting in DHF

• 1 3 2 Thailand

MAMMAN MP personal communication
No DHF

• 1 2 3 Cuba, 2001.

GUZMAN MG personal communication
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DENGUE VIRUSES, BANGKOK 1973 - 2001
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Lags at Which Correlation Between Bangkok and
other Provinces Is Maximized
plt1e-8 148 km/month
(months)
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DHF AT BANGKOK CHILDRENS HOSPITAL
1O INFECT.
2O INFECTIONS
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Fischer and Halstead Yale J Biol Med
42329-349,1970
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Fischer and Halstead Yale J Biol Med
42329-349,1970
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Fischer and Halstead Yale J Biol Med
42329-349,1970
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DHF AT BANGKOK CHILDRENS HOSPITAL
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EFFECT OF AVERAGE FORCE OF INFECTION (Ro) ON AGE
SPECIFIC SECONDARY INFECTION INCIDENCE
Ro 30 Ro 20 Ro 10
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Dengue hemorrhagic fever/dengue shock syndrome
has occurred in some (but not all) dengue
epidemics since the 1950s,Why?
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DHF does not occur if antibodies from first
infection neutralize the second infecting virus.
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BANGKOK STUDYKliks et al AJTMH 40444, 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.

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ADE AND DHF BLOCKED BY NEUTRALIZING ANTIBODIES
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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

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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 3541431-4, 1999

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NEUTRALIZATION OF AMERICAN GENOTYPE DEN 2
VIRUSES by 34 DEN 1- IMMUNE HUMAN SERA
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ONE-WAY CROSS 17 DENGUE 2-IMMUNE SERA DO NOT
NEUTRALIZE DENGUE-1 VIRUSES
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American genotype dengue 2 viruses are
neutralized in vitro by human antibodies to
dengue 1
BUT dengue 1 antibodies do not prevent but may
down regulate dengue 2 infections