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LECTURE # 4 Dengue Fever Mary Elizabeth Wilson, MD mewilson@hsph.harvard

Collaborative Course on Infectious Diseases January 2009. LECTURE # 4 Dengue Fever Mary Elizabeth Wilson, MD mewilson@hsph.harvard.edu. Harvard School of Public Health Centro de Pesquisa Gonçalo Moniz, Fundação Oswaldo Cruz (Fiocruz) Brazil Studies Program, DRCLAS, Harvard University.

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LECTURE # 4 Dengue Fever Mary Elizabeth Wilson, MD mewilson@hsph.harvard

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  1. Collaborative Course on Infectious Diseases January 2009 • LECTURE # 4 • Dengue Fever • Mary Elizabeth Wilson, MD • mewilson@hsph.harvard.edu Harvard School of Public Health Centro de Pesquisa Gonçalo Moniz, Fundação Oswaldo Cruz (Fiocruz) Brazil Studies Program, DRCLAS, Harvard University

  2. References • Required: • Siqueira JB Jr, Martelli CM, Coelho GE, et al. Dengue and dengue hemorrhagic fever, Brazil, 1981-2002. Emerg Infect Dis 2005;11(1):48-53. • Teixeira Mda G, Costa Mda C, Barreto ML, Mota E. Dengue and dengue hemorrhagic fever epidemics in Brazil: what research is needed based on trends, surveillance, and control experiences? Cad Saude Publica 2005;21(5):1307-15.

  3. Reference: General Overview • Optional: • Wilder-Smith A, Gubler DJ. Geographic expansion of dengue: the impact of international travel. Med Clin N Am 2008;92:1377-1390.

  4. Objectives • Describe the epidemiology of dengue fever in Brazil • Understand transmission cycles • Describe consequences of infection • Define factors that influence vector populations • (e.g., location, abundance, extrinsic incubation) • Understand receptivity of region to other vector-borne viruses

  5. Questions for discussion: dengue • Why is dengue causing increasingly severe epidemics? • How is the virus maintained? • Where do new serotypes come from? • Explain the seasonality and year-to-year changes in epidemiology. • A dengue vaccine is under development. Discuss factors critical in its evaluation. • Why does mortality vary by region?

  6. Dengue • Mosquito-transmitted flavivirus • Four major serotypes (den-1, den-2, den-3, den-4) • >2.5 bil persons live in dengue-endemic areas • 50-100 mil cases dengue/yr • Increase in area, cases, severity

  7. Dengue since 1955 WHO Data

  8. Dengue Infections • Incubation 4-7 days (3-14) • Infection • Asymptomatic or mild • Acute febrile illness (dengue fever) • Dengue hemorrhagic fever (DHF) • Dengue shock syndrome (DSS) • No chronic carrier state

  9. Clinical Findings • Headache, fever, myalgia • Nausea, vomiting • Rash (50%) • Laboratory • Low WBC • Low platelets • Abnormal liver function

  10. Dengue Hemorrhagic Fever • Mortality > 20% (<1% with good care) • Risk for DHF increased ~100x with 2nd infection (different serotype) • Thailand, 2 cohort studies • DHF rate 0 in primary infection • 1.8% and 12.5% with 2nd • Virulence may also vary by genotype Am J Epidemiol 1984;120:653 AJTMH 1988;38:172

  11. Dengue: 2007, CDC

  12. Dengue Fever, 2002

  13. Aedes aegypti

  14. Aedes Aegypti • Wide distribution in urban areas • Well adapted to contemporary urban life • Breeding sites • Discarded plastic containers, cans • Used tires, flowerpots, tree holes • Enters homes; prefers human blood • Nervous feeder; multiple hosts

  15. Aedes Aegypti • Usually do not disperse beyond 100 m • Most movement of dengue viruses occurs via movement of viremic hosts

  16. Vector DispersalHorizontal and Vertical • Study site: Singapore • Ae aegypti & Ae albopictus fed rubidium-laced blood; female offspring released • Female movement traced (oviposition sites) • Findings: • Horizontal: radius of 320 m • Vertical: release on level 12 of 21-story apt; dispersed to top and bottom Liew C, Curtis CF. Med Vet Entomol 2004;18:351-60.

  17. 1930's 2002 1970 Aedes aegypti Distribution in the Americas

  18. Environmental Influences on Vector • Presence or absence • Abundance; longevity of adult • Time for development • Frequency of biting • Blood feeding frequency increases with higher temperatures • Extrinsic incubation period (time for virus to disseminate in mosquito) • Seasonality of pathogen transmission

  19. Extrinsic Incubation Period • Time between entry of organism into vector and time when vector can transmit pathogen • Sensitive to environmental conditions • If extrinsic incubation period exceeds lifespan of vector, it cannot transmit infection

  20. Extrinsic Incubation and Dengue • Temperature: inverse relationship with EI period (<20 C Ae aegypti eggs do not hatch) • 12 days for mosquitoes at 30 C • 7 days at 32 and 35 C • Temperature required for effective transmission depends on virus & vector Watts et al. Am J Trop Med Hyg 1987;36:143-52.

  21. Vertical Transmission of Dengue Virus • Transovarial transmission of virus can occur • Ae aegypti eggs subjected to adverse hatching conditions can remain viable in the environment >100 days.

  22. Dengue/Mosquito Interaction • Aedes aegypti needs viral titer 105-107 particles/ml of blood to become infected • Vector serves to select viruses that produce high viremia in humans

  23. Aedes Albopictus Female

  24. Aedes Albopictus • Competent vector for 22 arboviruses • Dengue • Yellow fever • Eastern equine encephalitis • La Crosse virus • West Nile virus

  25. Aedes Albopictus • Main vector in Hawaii dengue outbreak, 2001-2002 • Introduced into North America in 1985 via used tires from Asia • Within 12 yr, spread to 25 states (dispersal followed interstate highways) • Recent introductions into many parts of Latin America

  26. Aedes albopictus before 1980 & invaded since

  27. Chronology of Dengue in Brazil • 1981-1993: localized epidemics • 1981 outbreak den1 & den4 in NW • 1986 den1 in Rio de Janeiro State • 1990 intro den2 Rio State; first confirmed DHF • 1994-2002: epidemic/endemic countrywide • 1994-1999 Ae aegypti dispersed countrywide • 1999 widespread outbreaks • 2000 intro den3 in Rio State • 2002 large outbreaks (dengue deaths>malaria deaths) Siqueira et al. EID 2005;11:48

  28. Brazil: Reported Dengue Cases per Month, 1986-2003 Siqueira et al. EID 2005;11:49.

  29. Reported Cases & Hospitalizations: DF/DHF, Brazil, 1986-2002 Siqueira et al. EID 2005;11:50.

  30. Dengue Hospitalizations/State by Year, 1990-2002 Siqueira et al. EID 2005;11:52.

  31. Cases of Dengue Hemorrhagic Fever Secretaria de Vigilancia em Saude 2005

  32. Regional Incidence rate of Dengue per 100,000 persons, 2006 Midwest 453 High North 222 Average Northeast 204 Average Southeast 178 Average South 20 Low Brazil 185 Average Source: SVS/SES (data until week 52, subject to modifications)

  33. Incidence of Dengue by State (low, medium, high) Ministry of health. 2006.

  34. Dengue Cases Notified by Week by Region, 2006 Secretarias de Estado da Saude

  35. Circulating Dengue Serotypes in Brazil, 2006 Data accumulated until Nov 2006

  36. 900000 70000 Reported Cases Hospitalizations 800000 60000 700000 50000 600000 40000 500000 Hospitalizations Reported Cases 400000 30000 DENV3 300000 20000 200000 DENV1 DENV2 10000 100000 0 0 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 Epidemic waves in localized areas Increase in severe cases in children Endemic / Epidemic virus circulation nationwide Dengue Reported Cases and Hospitalizations due to Dengue/DHF, Brazil, 1986-2008* DEN2 DEN3 *Preliminary data; Source:CGPNCD/MOH

  37. Reported Cases and Hospitalizations due to DF/DHF by Month, Brasil, 1998 – 2008* 300,000 18000 16000 250,000 14000 200,000 12000 10000 ReportedCases Hospitalizations 150,000 8000 100,000 6000 4000 50,000 2000 0 0 98 99 00 01 02 03 04 05 06 07 08 Reported cases Hospitalizations * Dark bars represent January

  38. Clinical Outcomes for Dengue with Complications, Brazil, 2007-2008

  39. Risk Factors for Severe Disease • Serotype and genotype • Previous infection • Age • Genetics • Other?

  40. Global Aviation Network (civil traffic, 500 largest airports, 100 countries) PNAS 2004;101:15125.

  41. Receptivity to Introductions • Physicochemical environment • Intermediate and reservoir hosts; vectors • Housing, sanitation, living conditions • Nutrition, immunity, genetics • Human behavior and activities • Surveillance, access to care

  42. Increase in Dengue Fever • Urbanization, especially in tropics • Growing population • More urban areas large enough to sustain ongoing viral circulation • Poor housing, inadequate water supply • Poor vector control and resistance • Travel and migration

  43. Chikungunya Virus

  44. Chikungunya Virus • Alphavirus, family Togaviridae (first identified in Tanzania, 1953) • Emerged in Indian Ocean islands 2005 • Has moved to India, other countries in region; explosive outbreaks; high attack rates • Spread by Aedes aegypti and Ae albopictus • Will it spread to the Americas?

  45. Clinical Manifestations: Chikungunya • Rash 39-50% • Myalgia 50-60% • Headache 50-70% • Arthralgia 78-100% • Severe, incapacitating, persistent • Fever 100% Lancet ID May 2007

  46. Monthly chikungunya cases, expected deaths, and reported deaths, Ahmedabad, India, 2006. Error bars show 99% confidence intervals. July through December showed a statistically significant difference between mortality rates. Emerg Infect Dis March 2008

  47. Outbreak in Italy, 2007 • 4 July – 27 Sept: 205 human cases in two villages northeastern Italy (175 lab-confirmed) • Clinical attack rate increased with age • CHIKV found in Ae albopictus • Index case visitor from India Rezza et al. Lancet 2007;370:1840-6.

  48. Chikungunya Virus • High viral concentration >109 • Early appearance IgM and IgG • Potential risk for nosocomial transmission Emerg Infect Dis March 2008

  49. Chikungunya Virus • Point mutation of virus associated with enhanced replication of virus in mosquito midgut (Ae. albopictus) • More rapid dissemination into mosquito salivary glands • 100-fold higher virus concentration in mosquito saliva • Mutation absent initially (Reunion outbreak); later found in >90% isolates Tsetsarkin KA, et al. A single mutation in chikungunya virus affects vector specificity and epidemic potential. PLoS Path Dec 2007.

  50. Synchronization of Aedes Activity Lancet ID 2008;8:5.

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