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DENGUE: EPIDEMIOLOGY PART 1

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.

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DENGUE: EPIDEMIOLOGY PART 1

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

  2. 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.

  3. 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.

  4. 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

  5. DENGUE FEVER • Incubation period = 5 days • Fever = 5 days • Leukopenia • Moderate thrombocytopenia Simmons et al Phil J Sci 44:1-252, 1931

  6. DENGUE 1 MACULO- PAPULAR RASH. Day 5 after onset of fever.

  7. DISEASE SPECTRUMMILD SEVEREDF DHF+ Thrombocytopenia +++ ThrombocytopeniaHidden Vasc. Perm1? Overt Vasc. Perm.1. Wills BA et al J Infect Dis 190:810-818, 2004

  8. DENGUE HEMORRHAGIC FEVER/DENGUE SHOCK SYNDROME (DHF/DSS)Dengue vasculopathy

  9. DSS GRADE IV

  10. DSS GRADE III

  11. 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 WHY IS DENGUE SUCH A BIG PROBLEM TODAY?

  12. Global Spread of Dengue 50-100 million infections/year Aedes aegypti Countries with active dengue +

  13. WHY TWO SYNDROMES, BENIGN and SEVERE? Observed in two immunological settings. Primary infections in infants. 2. Secondary infections in children and adults.

  14. Two-infectionsThe 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

  15. DHF IN CHILDREN: PROSPECTIVE COHORT STUDIES

  16. DHF IN CHILDREN: PROSPECTIVE POPULATION-BASED STUDIES

  17. DHF IN CHILDREN: PROSPECTIVE POPULATION- BASED STUDIES

  18. SEQUENTIAL DENGUE INFECTIONS Two infections can occur in twelve possible combinations.

  19. 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

  20. No data • 4 – 1 • 4 – 3 KALAYANROOJ S et al AJTMH 2008 in press.

  21. Third infections: resulting in DHF • 1 – 3 – 2 Thailand MAMMAN MP personal communication No DHF • 1 – 2 – 3 Cuba, 2001. GUZMAN MG personal communication

  22. DENGUE VIRUSES, BANGKOK 1973 - 2001

  23. Lags at Which Correlation Between Bangkok and other Provinces Is Maximized p<1e-8 ~148 km/month (months)

  24. DHF AT BANGKOK CHILDRENS HOSPITAL 1O INFECT. 2O INFECTIONS

  25. Fischer and Halstead Yale J Biol Med 42:329-349,1970

  26. Fischer and Halstead Yale J Biol Med 42:329-349,1970

  27. Fischer and Halstead Yale J Biol Med 42:329-349,1970

  28. DHF AT BANGKOK CHILDRENS HOSPITAL

  29. EFFECT OF AVERAGE FORCE OF INFECTION (Ro) ON AGE SPECIFIC SECONDARY INFECTION INCIDENCE Ro = 30% Ro = 20% Ro = 10%

  30. Dengue hemorrhagic fever/dengue shock syndrome has occurred in some (but not all) dengue epidemics since the 1950s,Why?

  31. DHF does not occur if antibodies from first infection neutralize the second infecting virus.

  32. 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.

  33. ADE AND DHF BLOCKED BY NEUTRALIZING ANTIBODIES

  34. 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%

  35. 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

  36. NEUTRALIZATION OF AMERICAN GENOTYPE DEN 2 VIRUSES by 34 DEN 1- IMMUNE HUMAN SERA

  37. ONE-WAY CROSS: 17 DENGUE 2-IMMUNE SERA DO NOT NEUTRALIZE DENGUE-1 VIRUSES

  38. American genotype dengue 2 viruses are neutralized in vitro by human antibodies to dengue 1 BUT … dengue 1 antibodies do not prevent but maydown regulatedengue 2 infections

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