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.
• 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
• 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

! 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 SPECTRUM

MILD SEVERE

DF DHF
+ Thrombocytopenia +++ Thrombocytopenia
Hidden 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
DSS GRADE IV
DSS GRADE III
WHY IS DENGUE SUCH A BIG
PROBLEM TODAY?

Global population Jet travel

growth Health services
Rural to urban poorly organized/
migration underfunded
Growth of cities Lack of vector
Deterioration of control
cities professionals
 Global Spread of Dengue

50-100 million infections/year

Countries with active dengue + Aedes aegypti

 WHY TWO SYNDROMES,
BENIGN and SEVERE?

Observed in two immunological

settings.
1. Primary infections in infants.
2. Secondary infections in children
and adults.
 Two-infections
The 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
o
References DHF/2 DHF/1000
o
Den Inf. 2 Den Inf.
Russell et al, AJTMH 3/83 36.1
17:600,1968
Sangawibha et al, AJE 4/112 35.7
120:653, 1984
Burke et al, AJTMH 7/59 118.6
38:172, 1988
Graham et al, 7/120 58.3
AJTMH 61:412, 1999
 DHF IN CHILDREN:
PROSPECTIVE POPULATION-
BASED STUDIES
References DHF/ DHF/1000
2o Den Inf 2o Den Inf
Halstead Acad 2528/ 20.1
Press 107,1980 125,728
Russell et al AJTMH 33/2700 12.2
18:600,1968
Sangkawibha et al 18/920 19.6
AJE
AJE 120:653,1984
 DHF IN CHILDREN:
PROSPECTIVE POPULATION-
BASED STUDIES
o
References DHF/2 DHF/1000
o
Den Inf 2 Den Inf
Guzman et al 1213/ 20.3
AJTMH 42:179,1990 59,875
Thein et al AJTMH 138/4181 33.0
56:566,1997
Guzman et al AJE 202/4810 42.0
152:793, 2000
 SEQUENTIAL DENGUE
INFECTIONS

Two infections can occur in twelve

possible combinations.
 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
• 4–1
• 4–3

KALAYANROOJ S et al AJTMH 2008 in press.

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 VIRUSES, BANGKOK 1973 - 2001
Seasonal Occurrence of Serologically Confirmed Dengue Virus Infection and Dengue Serotypes
at the Queen Sirikit National Institute for Child Health from 1973-2001.

300

250
Cases

200

150

100

50

0
80
60 Dengue 4
Cases

40
20
0
80
60 Dengue 3
Cases

40
20
0
80
60 Dengue 2
Cases

40
20
0
80
60 Dengue 1
Cases

40
20
0
1973 / 1974 / 1975 / 1976 / 1977 / 1978 / 1979 / 1980 /1981/ 1982/1983 / 1984 / 1985 / 1986 / 1987 /1988 /1989 /1990 / 1991 / 1992 / 1993 / 1994 / 1995 / 1996 / 1997 / 1998 / 1999 / 2000 / 2001 /

Year
Lags at Which Correlation Between Bangkok and other Provinces
Is Maximized

(months)

p<1e-8
~148 km/month
 DHF AT BANGKOK CHILDRENS
HOSPITAL

700
600 1O INFECT.
500
400 1973-79
1980-89
300 2O INFECTIONS 1990-99
200
100
0
<1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
AGE (YEARS)
Fischer and Halstead Yale J Biol Med 42:329-349,1970
Fischer and Halstead Yale J Biol Med 42:329-349,1970
Fischer and Halstead Yale J Biol Med 42:329-349,1970
 DHF AT BANGKOK CHILDRENS
HOSPITAL

700
600
500
400 1973-79
1980-89
300 1990-99
200
100
0
<1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
AGE (YEARS)
 0.150
EFFECT OF AVERAGE FORCE OF INFECTION (Ro) ON
AGE SPECIFIC SECONDARY INFECTION INCIDENCE
0.120
Incidence of DHF relative to age

Ro = 30%
Ro = 20%
0.090 Ro = 10%

0.060

0.030

0.000
0 10 20 30 40 50
Age (years)
 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.
 BANGKOK STUDY
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

40 school children with secondary dengue

infections, Bangkok, 1980
Undiluted sera Hospitalized Silent
DEN 2 PRNT + 1 29
DEN 2 PRNT - 6* 4*
7 33
* Undiluted sera enhanced growth of DEN 2 in human
monocyte cultures.
Kliks et al AJTMH 40:444-451, 1989
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
• 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

DEN-2 genotypes
Virus DEN-1 AMER SE SE
ASIA ASIA
Strain Venez IQT Venez Thai
9842 2124 8041 16681
GMT 875 262 32 29
Kochel T, et al Lancet 360:310, 2002
 ONE-WAY CROSS:
17 DENGUE 2-IMMUNE SERA
DO NOT NEUTRALIZE DENGUE-1
VIRUSES
DEN 1 viruses DEN 2 viruses

Geno- SE Asia Venez SE Asia Peru

type
Strain 16007 OBS 16681 IQT
9842 2913
GMT 20 27 635 417
 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