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 MACULOPAPULAR RASH. Day 5 after onset of fever.
DISEASE SPECTRUM MILD DF SEVERE 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 control Deterioration of professionals cities
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 25% of secondary infections
DHF IN CHILDREN: PROSPECTIVE COHORT STUDIES
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 References
o
DHF IN CHILDREN: PROSPECTIVE POPULATIONBASED STUDIES
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 120:653,1984
AJE
References
DHF IN CHILDREN: PROSPECTIVE POPULATIONBASED STUDIES
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 References
o
SEQUENTIAL DENGUE INFECTIONS
Two infections can occur in twelve possible combinations.
Established second infection sequences leading to DHF
• • • • • • • • • • 2–1 3–1 1–2 3–2 4–2 1–3 2–3 1–4 2–4 3–4 Thailand; Indonesia Thailand Cuba, 1981; Cuba 1997; Thailand Thailand Thailand Cuba, 2001; Thailand; Indonesia Thailand, DF in Cuba Thailand Indonesia 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
Cases Cases Cases
200 150 100 50 0 80 60 40 20 0 80 60 40 20 0 80 60 40 20 0 80
Dengue 4
Dengue 3
Dengue 2
Cases
60 40 20 0
Dengue 1
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. 500 400 300 200 100 0 <1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 AGE (YEARS)
2O INFECTIONS
1973-79 1980-89 1990-99
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
700 600 500 400 300 200 100 0 <1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 AGE (YEARS) 1973-79 1980-89 1990-99
0.150
EFFECT OF AVERAGE FORCE OF INFECTION (Ro) ON AGE SPECIFIC SECONDARY INFECTION INCIDENCE
Incidence of DHF relative to age
0.120
0.090
Ro = 30% Ro = 20% Ro = 10%
0.060
0.030
0.000 0 10 20 30 Age (years) 40 50
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 = 88710247. • 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 Genotype Strain GMT SE Asia Venez 16007 20 OBS 9842 27 DEN 2 viruses SE Asia Peru 16681 635 IQT 2913 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