SARS Update

1
Collaborative Course on Infectious
Diseases January 2008
LECTURE 4 Dengue and Yellow Fever
Mary Elizabeth Wilson mewilson_at_hsph.harvard.edu
Harvard School of Public Health Faculdade de
Ciências Médicas da Santa Casa de São Paulo
Brazil Studies Program, DRCLAS, Harvard
University
2
Objectives

• Describe the epidemiology of dengue and yellow
  fever in Brazil (past and present)
• Understand transmission cycles
• Describe consequences of infection
• Define factors that influence vector populations
• (e.g., location, abundance, extrinsic incubation)
• Describe possible interventions, their strengths
  and weaknesses

3
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?

4
Questions for discussion YF

• Why is yellow fever still present given the
  availability of an effective vaccine?
• Why is YF absent in urban areas although dengue
  and YF can be spread by the same vector
  mosquitoes?
• Should universal YF vaccine be recommended for
  Brazil? Why or why not?
• Can YF be eliminated from Brazil?

5
Dengue

• Mosquito-transmitted flavivirus (RNA)
• Four major serotypes (den-1, den-2, den-3, den-4)
• gt2.5 bil persons live in dengue-endemic areas
• 50-100 mil cases dengue/yr
• Increase in area, cases, severity

6
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

7
Clinical Findings

• Headache, fever, myalgia
• Nausea, vomiting
• Rash (50)
• Laboratory
• Low WBC
• Low platelets
• Abnormal liver function

8
Dengue Hemorrhagic Fever

• Mortality 10-20 (lt1 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

Source Am J Epidemiol 1984120653 and AJTMH
198838172
9
Dengue 2007, CDC
10
Dengue Fever, 2002
11
Aedes aegypti
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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

13
Aedes Aegypti

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

14
Aedes aegypti Distribution in the Americas

15
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

16
Extrinsic Incubation and Dengue

• Temperature inverse relationship with EI period
  (lt20 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

Source Watts et al. Am J Trop Med Hyg
198736143-52.
17
Dengue/Mosquito Interaction

• Aedes aegypti needs a viral titer of 105-107
  particles/ml of blood to become infected
• Vector serves to select viruses that produce high
  viremia

18
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
  gt100 days.

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Aedes Albopictus Female
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Aedes Albopictus

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

21
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

22
Aedes albopictus before 1980 invaded since
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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 deathsgtmalaria
  deaths)

Source Siqueira et al. EID 20051148
24
Brazil Reported Dengue Cases per Month, 1986-2003
Source Siqueira et al. EID 20051149.
25
Reported Cases Hospitalizations DF/DHF,
Brazil, 1986-2002
Source Siqueira et al. EID 20051150.
26
Cases of Dengue Hemorrhagic Fever, 1990 - 2004
Source Secretaria de Vigilancia em Saude 2005
27
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)
28
Incidence of Dengue by State (low, medium, high)
Source Ministry of health, 2006.
29
Dengue Cases Notified by Week by Region, 2006
Source State Secretaries of Health
30
References

• Required
• Material from Secretaria de Vigilancia em Saude
  (portions will be translated into English)
• Massad E, Burattini MN, Coutinho FA, Lopez LF.
  Dengue and the risk of urban yellow fever
  reintroduction in Sao Paulo State, Brazil. Rev
  Saude Publica 200337(4)477-84.
• Siqueira JB Jr, Martelli CM, Coelho GE, et al.
  Dengue and dengue hemorrhagic fever, Brazil,
  1981-2002. Emerg Infect Dis 200511(1)48-53.
• Monath TP. Dengue and yellow fever challenges
  for the development and use of vaccines. N Engl J
  Med 20073572222-5.

31
Circulating Dengue Serotypes in Brazil, 2006
Data accumulated until Nov 2006
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Risk Factors for Severe Disease

• Serotype and genotype
• Previous infection
• Age
• Genetics
• Other?

33
Global Aviation Network (civil traffic, 500
largest airports, 100 countries)
Source PNAS 200410115125.
34
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

35
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

36
Yellow Fever

• Hemorrhagic fever caused by flavivirus
• Transmitted by Aedes mosquito
• 200,000 cases annually
• 90 in Africa
• 7 genotypes but one serotype
• Mortality (CFR up to 50)
• Effective vaccine available

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39
Transmission Cycles

• Sylvatic (forest)
• Primate-mosquito (howler monkeys)
• Aedes or Haemagogus mosquitoes
• Urban
• Human-mosquito-human
• Vertical transmission of virus occurs
  (transovarial in mosquitoes)

40
Yellow Fever

• Incubation 3-6 days
• Extrinsic incubation in Aedes aegypti mosquitoes
  9-12 days
• Last urban YF in Brazil in 1942
• Ratio of inapparentapparent infections 71

41
Yellow Fever Vaccine

• First developed in 1930s
• Live virus vaccine
• All current vaccines derived from 17D strain
• Used in gt400 million persons
• Routine vaccination some endemic countries
• 250,000 vaccinated/yr in US
• Seroconversion 99
• Immunity gt10 years, perhaps lifelong

42
YF Vaccine

• Viremia 3-7 days after vaccination
• Lasts 1-3 days in normal hosts
• Common side effects headache, myalgia, low grade
  fever

43
Severe Adverse Effects

• Hypersensitivity reactions
• Neurotropic disease
• Viscerotropic disease

44
Neurotropic Disease

• Fever, headache, focal neurologic findings
• Onset 4-23 days after vaccination
• CSF pleocytosis
• 4-6 cases/1 million doses of vaccine
  (1/150,000-250,000)
• Most recover without sequelae 6 mortality

45
Viscerotropic Disease

• Multiorgan failure (after 1st dose)
• Onset 2-5 days post vaccine
• High levels viremia multiple organs infected
• High case fatality rate (60)
• Brazil case in 1975 (identified recently)
• Vaccine strain virus (not mutated) virus involved

46
Viscerotropic Disease

• Incidence 1/200,000-400,000
• Risk factors
• First dose of vaccine
• Age
• 1/50,000 in gt60 yr
• Thymic disease
• Immunocompromised
• Genetic factors
• Interferon responses?

47
Use of Vaccine in Brazil

• Routine childhood
• Mass vaccination campaigns
• Concept of blocking belt

48
Basic Reproductive Number (VBD)

• Number of secondary infections spread in a
  community as the result of a single primary case
• Lower for YF than for dengue
• Shorter period of viremia
• Longer extrinsic incubation period

49
Yellow Fever

• Vulnerability
• Exposure
• Susceptibility
• Resilience
• Rapid case detection
• Available/accessible vaccine
• Capacity to organize mass vaccination campaigns

50
Dengue Distribution, São Paulo State
2000
2001

Light shading cities with dengue R0lt1 Dark
shading districts with R0gt1
z
Source Massad et al. Rev Saude Publica
200337481
51
Control Strategy Against YF

• Shaded municipal districts infested with Aedes
  aegypti.
• Dark shaded vaccinated to form blocking belt
• White areas YF vaccine coverage below critical
  proportion Black
• areas have R0gt1 vaccination above critical
  proportion

52
Distribution of Dengue, Yellow Fever, Ae aegypti
Areas infested with Aedes aegypti
Areas with Aedes aegypti and dengue epidemic
activity
Aedes aegypti
Areas with endemic yellow fever
Source Monath T. NEJM 20073572223.
53
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?

54
Questions for discussion YF

• Why is yellow fever still present given the
  availability of an effective vaccine?
• Why is YF absent in urban areas although dengue
  and YF can be spread by the same vector
  mosquitoes?
• Should universal YF vaccine be recommended for
  Brazil? Why or why not?
• Can YF be eliminated from Brazil?

55
References

• Required
• Material from Secretaria de Vigilancia em Saude
  (portions will be translated into English)
• Massad E, Burattini MN, Coutinho FA, Lopez LF.
  Dengue and the risk of urban yellow fever
  reintroduction in Sao Paulo State, Brazil. Rev
  Saude Publica 200337(4)477-84.
• Siqueira JB Jr, Martelli CM, Coelho GE, et al.
  Dengue and dengue hemorrhagic fever, Brazil,
  1981-2002. Emerg Infect Dis 200511(1)48-53.
• Monath TP. Dengue and yellow fever challenges
  for the development and use of vaccines. N Engl J
  Med 20073572222-5.