DENGUE:EPIDEMIOLOGY

PART II

SCOTT B HALSTEAD, MD

Director, ResearchPEDIATRIC DENGUE VACCINE INITIATIVE

EPIDEMIOLOGY

• Risk factors for severe disease.– Sequential dengue infection (includes

antigenic structure of virus)– Race– Age– Host genetic factors– Nutritional status– Sex

Race

– Caucasian & Asian vs African.

At least 5:11,2

1. Guzman MG et al. AJTMH 42:179-184, 1990.

2. Halstead SB et al AJTMH 65:180, 2001

BLACKS ARE RELATIVELY RESISTANT TO SEVERE

DENGUE ILLNESS

• A human resistance gene seems to explain the observation that while all dengue virus types circulate in Africa no DHF/DSS cases or outbreaks of DF have been reported.

RACE - SANTIAGO DE CUBA OUTBREAK, 1997

Race DHF % Deaths % Open Pop %

White 130 47.7 3 25.0 30.1

Mixed 60 35.5 6 50.0 42.8

Black 27 16.0 2 16.7 26.8

Asian 3 1.8 1 8.3 0.27

Totals 169 12

0102030405060708090

100

Per

cent

6 7 8 9 10 11 12 13

Age (years)

HETEROTYPIC DENGUE 4 DENGUE 3 DENGUE 2 DEN 1

DENGUE NEUTRALIZING ANTIBODIES BY AGE IN 210 CHILDREN RESIDENT IN PORT AU PRINCE, HAITI, 1996.

N =(46) (40) (36) (41) (27) (13) (10) (4)

AGE

DHF - EFFECT OF AGE, 1981 Cuba Outbreak

GUZMAN MG et al. Int J Infect Dis 6:18, 2002

CAPILLARY FRAGILITY

Gamble J et al. Biochem Soc Med Res Soc 98:211-6, 2000.

GENETIC ASSOCIATIONS

Susceptibility Resistance HLA1: HLA-A*0207 HLA-A*0203 HLA-B*51 HLA-B*52

HLA A24 HLA A33Vit D2: t allele/352FcRγII3:DCSIGN4: CD 209 promoterTNFα5: TNF 308 1. Loke H et al. JID 184:1369-73, 20012. Stephens HA et al. Tissue Antigens 60:309-318, 2002.3. Loke H et al. AJTMH 67:102-6, 20014. Sakuntabthai A et al. Nat Genetics 37:507-13, 20055. Fernandez-Mestre MT et al. Tissue Ag 64:468-72, 2004

NUTRITIONAL STATUS

NUTRITIONAL STATUS OF DHF CASES vs. CONTROLS

Percent distributionControlsMalnutrition

status DHF/DSSN=100

Inf DisN=125

HealthyN=185

Normal 87a 28.8 76.4a

1st degree 9 29.6 31.02nd degree 4 28.8 1.63rd degree 0 12.8 0

a- DHF differs from Healthy controls, p< 0.05

Effect of nutritional status on dengue disease severity1

Well nourished children: highly susceptible to severe disease

Malnourished: protected against severe disease (protein-calorie malnutrition grade 2 and 3)

1. Thisyakorn U et al. CID 16:295-297, 1993

SEX

SEX RATIOS BY DENGUE SYNDROME

Bangkok Children’s Hospital, 1962-64

Syndrome Male Female M/F DF, OPD1 50 44 1.14OPD Control1 106 100 1.06DHF, no shock2 136 115 1.18DSS, all ages2 72 123 0.59DSS, > 4 yrs2 (45) (92) (0.49)Hosp. Control2 42 34 1.24

1. Halstead SB et al, AJTMH 18:972-983, 1969.2. Nimmannitya S etal, AJTMH 18:954-971, 1969

DHF/DSS during primary dengue infections.

DHF/DSS in infants, identical to but more severe than DHF/DSS in children

• Higher case fatality rates, resuscitation requires more fluid per Kg body weight than in older children with 2o infection.– Hung NT et al AJTMH 72:370, 2005

• Circulating cytokines and cytokine levels during acute phase similar to those in older children during 2o infection.– Hung NT et al JID 189:221, 2004

DSS in a 6 month-old infants with hepatomegaly. Vietnam

INFANT DHF/DSSCHILDREN'S HOSPITAL, BANGKOK, THAILAND

0

5

10

15

20

25

30

35

40

0-2 2-4 4-6 6-8 8-10 10-12AGE (months)

1987

1990

1997

1998

WHY DO MATERNAL ANTIBODIES ENHANCE DENGUE DISEASE?

CENTRAL ROLE OF MACROPHAGES IN SUPPORTING

DENGUE INFECTIONS IN HUMANS

Complexed with antibodies dengue viruses enter FcR-bearing cells with great efficiency.

Dengue viruses are adapted to grow in dendritic cells,

monocytes and macrophages.

IMMUNE ENHANCEMENT OF DENGUE INFECTION(Antibody-Dependent

Enhancement)

In the presence of dengue ADE antibody:• increased rate of infection• increase in the number of infected cells.• increased production of viruses per cell.

ADE IN HUMAN DENGUE: DEN virus load and disease

severity

“Peak” viremia in 2o infectionsDF DHF I/II DSS

N 16 26 5Mean, Log 10 5.5 7.6 8.5S.D. 0.8 0.8 1.8

Vaughn D et al, JID 181:2-9, 2000

DEN 3VIREMIA

●--● DSS▲- ▲DHF □--□ DF

LIBRATY DH et al JID 185:1213, 2002

DISEASE SEVERITY CORRELATES WITH

CELLULAR INFECTION

Schematic distribution of dengue 2 viruses in blood and tissues of 31 rhesus monkeys.

In endemic areas, DHF/DSS annual outbreaks differ in

severity and size.

MYANMAR: VARYING CFR

YEAR CASES DEATHS CFR

1986 2,192 111 5.06

1987 7,292 222 3.04

1988 1,181 65 5.5

1989 1,196 52 5.78

1990 6,318 182 2.8

1991 8,055 305 3.7

1992 1,514 40 2.63

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

WHY?

• Possible effect of– ADE– Heterotypic immunity– Replacement of serotypes– Clade extinctions

• These possibilities have been explored in mathematical models, most are based upon the hospital epidemiological data from Bangkok or all of Thailand.

EFFECT OF ADE ON EPIDEMIC CYCLES

• “Enhancement of infection may generate a complex and persistent cyclical or chaotic epidemic behavior ….and coexistence of mutiple strains”– Ferguson N et al. The effect of antibody-dependent

enhancement on the transmission dynamics and persistence of mutiple-strain pathogens.Proc Natl Acad Sci USA 96:790-4, 1999

EFFECT OF HETEROTYPIC IMMUNITY ON EPIDEMIC

CYCLES

• 8-10 year epidemic cycles are accompanied by clade extinctions.

• Mathematical model suggests that heterotypic immunity is responsible. – Adams B et al PNAS 103: 14234-9, 2006

SEROTYPE REPLACEMENT

• DENV -1 replaced DENV 2, 3, 4. Related to stochastic event due to low transmission in 1999-2000?– Thu HM et al. Myanmar denge outbreak

associated with displacement of serotypes 2, 3 and 4 by dengue 1. Emerg Infect Dis 10:693-7, 2004.

CLADE EXTINCTIONS DUE TO STOCHASTIC EVENTS

• In Myanmar, clades B and C of genotype I DENV -1 circulated with clade A genotype III during the 1990s. After 1998, clade A

disappeared leaving only clades B and C. – Thu HM et al Lineage extinction and replacement in dengue

type 1 virus populations are due to stochastic events rather than to natural selection. Virol 336:163-72, 2005.

• In Thailand, clades of DENV -3 circulating prior to 1992 disappeared and were replaced by two lineages with common

ancestor. Earlier extinctions, 1963, 1973?

– Wittke V et al. Extinction and rapid replacement of strains of dengue 3 virus during an interepidemic period. Virol 301:148-156, 2002.