DENGUE:EPIDEMIOLOGY

PART 1

SCOTT B HALSTEAD, MD

Director, ResearchPEDIATRIC 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 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 1MACULO-PAPULARRASH. Day 5 afteronset of fever.

DISEASE SPECTRUM

MILD SEVERE

DF 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

DSS GRADE IV

DSS GRADE III

WHY IS DENGUE SUCH A BIG PROBLEM TODAY?

Global population growth

Rural to urban migration

Growth of citiesDeterioration of

cities

Jet travelHealth services

poorly organized/ underfunded

Lack of vector control professionals

Global Spread of Dengue

Countries with active dengue + Aedes aegypti

50-100 million infections/year

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

STUDIESReferences DHF/2o

Den Inf. DHF/10002o Den Inf.

Russell et al, AJTMH17:600,1968

3/83 36.1

Sangawibha et al, AJE120:653, 1984

4/112 35.7

Burke et al, AJTMH38:172, 1988

7/59 118.6

Graham et al,AJTMH 61:412, 1999

7/120 58.3

DHF IN CHILDREN: PROSPECTIVE POPULATION-

BASED STUDIES

References DHF/2o Den Inf

DHF/10002o Den Inf

Halstead AcadPress 107,1980

2528/125,728

20.1

Russell et al AJTMH18:600,1968

33/2700 12.2

Sangkawibha et alAJE 120:653,1984

18/920 19.6

AJE

DHF IN CHILDREN: PROSPECTIVE POPULATION-

BASED STUDIESReferences DHF/2o

Den Inf DHF/10002o Den Inf

Guzman et alAJTMH 42:179,1990

1213/ 59,875

20.3

Thein et al AJTMH56:566,1997

138/4181 33.0

Guzman et al AJE152:793, 2000

202/4810 42.0

SEQUENTIAL DENGUE INFECTIONS

Two infections can occur in twelvepossible 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 1

Year

Cas

es

0

20

40

60

80

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 /

Dengue 2

Cas

es

0

20

40

60

80

Dengue 3

Cas

es

0

20

40

60

80

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

Cas

es

0

20

40

60

80

Dengue 4

1999 /

Cas

es

0

50

100

150

200

250

300

2000 / 2001 /

DENGUE VIRUSES, BANGKOK 1973 - 2001

p<1e-8~148 km/month

Lags at Which Correlation Between Bangkok and other ProvincesIs Maximized

(mo

nth

s)

DHF AT BANGKOK CHILDRENS HOSPITAL

0

100

200

300

400

500

600

700

<1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16AGE (YEARS)

1973-79

1980-89

1990-992O INFECTIONS

1O INFECT.

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

0

100

200

300

400

500

600

700

<1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16AGE (YEARS)

1973-79

1980-89

1990-99

0.000

0.030

0.060

0.090

0.120

0.150In

cid

en

ce o

f DH

F r

ela

tive

to a

ge

0 10 20 30 40 50Age (years)

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

EFFECT OF AVERAGE FORCE OF INFECTION (Ro) ONAGE SPECIFIC SECONDARY INFECTION INCIDENCE

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 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

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

ASIA SE

ASIA Strain Venez

9842 IQT 2124

Venez 8041

Thai 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- type

SE Asia Venez SE Asia Peru

Strain 16007 OBS 9842

16681 IQT 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