SARS Update

1
Collaborative Course on Infectious
Diseases January 2009
LECTURE 4 Dengue Fever Mary Elizabeth
Wilson, MD mewilson_at_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 200511(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 200521(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 2008921377-1390.

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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

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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?

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Dengue

• Mosquito-transmitted flavivirus
• 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

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Dengue since 1955
WHO Data
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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

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Clinical Findings

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

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Dengue Hemorrhagic Fever

• Mortality gt 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

Am J Epidemiol 1984120653 AJTMH 198838172
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Dengue 2007, CDC
12
Dengue Fever, 2002
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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

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Aedes Aegypti

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

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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 200418351-60.
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Aedes aegypti Distribution in the Americas

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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

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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

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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

Watts et al. Am J Trop Med Hyg 198736143-52.
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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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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

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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

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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

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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)

Siqueira et al. EID 20051148
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Brazil Reported Dengue Cases per Month, 1986-2003
Siqueira et al. EID 20051149.
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Reported Cases Hospitalizations DF/DHF,
Brazil, 1986-2002
Siqueira et al. EID 20051150.
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Dengue Hospitalizations/State by Year, 1990-2002
Siqueira et al. EID 20051152.
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Cases of Dengue Hemorrhagic Fever
Secretaria de Vigilancia em Saude 2005
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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)
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Incidence of Dengue by State (low, medium, high)
Ministry of health. 2006.
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Dengue Cases Notified by Week by Region, 2006
Secretarias de Estado da Saude
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Circulating Dengue Serotypes in Brazil, 2006
Data accumulated until Nov 2006
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Dengue Reported Cases and Hospitalizations due to
Dengue/DHF, Brazil, 1986-2008
DEN2
DEN3
Preliminary data SourceCGPNCD/MOH
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Reported Cases and Hospitalizations due to DF/DHF
by Month, Brasil, 1998 2008
Dark bars represent January
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Clinical Outcomes for Dengue with Complications,
Brazil, 2007-2008
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Risk Factors for Severe Disease

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

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

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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

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Chikungunya Virus
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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?

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Clinical Manifestations Chikungunya

• Rash 39-50
• Myalgia 50-60
• Headache 50-70
• Arthralgia 78-100
• Severe, incapacitating, persistent
• Fever 100

Lancet ID May 2007
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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
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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 20073701840-6.
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Chikungunya Virus

• High viral concentration gt109
• Early appearance IgM and IgG
• Potential risk for nosocomial transmission

Emerg Infect Dis March 2008
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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 gt90 isolates

Tsetsarkin KA, et al. A single mutation in
chikungunya virus affects vector specificity and
epidemic potential. PLoS Path Dec 2007.
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Synchronization of Aedes Activity
Lancet ID 200885.
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(No Transcript)
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Aedes Albopictus Female
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Distribution of Dengue, Yellow Fever, Ae.
aegypti
Pink Ae. aegypti Blue Ae. aegypti and dengue
epidemic activity Lined YF endemic
Monath T. NEJM 20073572223.
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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?