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
 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.
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.
 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
 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?
 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
Dengue since 1955

WHO Data
 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
 Clinical Findings
• Headache, fever, myalgia
• Nausea, vomiting
• Rash (50%)
• Laboratory
– Low WBC
– Low platelets
– Abnormal liver function
 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
Dengue: 2007, CDC
Dengue Fever, 2002
Aedes aegypti
 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
 Aedes Aegypti

• Usually do not disperse beyond 100 m

• Most movement of dengue viruses
occurs via movement of viremic hosts
 Vector Dispersal
Horizontal 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.

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

• Competent vector for 22 arboviruses

– Dengue
– Yellow fever
– Eastern equine encephalitis
– La Crosse virus
– West Nile virus
 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
Aedes albopictus before 1980 & invaded since
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
Brazil: Reported Dengue Cases per Month, 1986-2003

Siqueira et al. EID 2005;11:49.

Reported Cases & Hospitalizations: DF/DHF, Brazil, 1986-2002

Siqueira et al. EID 2005;11:50.

Dengue Hospitalizations/State by Year, 1990-2002

Siqueira et al. EID 2005;11:52.

Cases of Dengue Hemorrhagic Fever

Secretaria de Vigilancia em Saude 2005

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)
Incidence of Dengue by State (low, medium, high)

Ministry of health. 2006.

Dengue Cases Notified by Week by Region, 2006

Secretarias de Estado da Saude

Circulating Dengue Serotypes in Brazil, 2006

Data accumulated until Nov 2006

Dengue Reported Cases and Hospitalizations
due to Dengue/DHF, Brazil, 1986-2008*
900000 Reported Cases Hospitalizations 70000
800000 60000
700000

Hospitalizations
Reported Cases

50000
600000
500000 DEN3 DEN2 40000

400000 30000
DENV3
300000
20000
200000 DENV1 DENV2
100000 10000

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 Endemic / Epidemic Increase in severe

in localized areas virus circulation nationwide cases in children

*Preliminary data; Source:CGPNCD/MOH

 Reported Cases and Hospitalizations due to
DF/DHF by Month, Brasil, 1998 – 2008*
300,000 18000

16000
250,000
14000
Reported Cases

Hospitalizations
200,000 12000

10000
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

 Clinical Outcomes for Dengue with
Complications, Brazil, 2007-2008
Clinical outcomes 2007 2008
Total
(Dengue with complications) N (%) N (%)
Neurological manifestations 401 (11.4) 316 (3.9) 717

Heart Failure / Respiratory Distress 77 (2.2) 61 (0.7) 138

Hepatic Failure 46 (1.3) 21 (0.2) 67

Platelets count <50,000 mm3 1406 (39.9) 4144 (51.4) 5550

GI Bleeding 145 (4.1) 235 (2.9) 380

Fluid Accumulation 276 (7.8) 461 (5.7) 737

Potential DHF (Missing criteria) 1162 (32.9) 2817 (34.3) 3979

Total 3525 8063 11588
Risk Factors for Severe Disease
• Serotype and genotype
• Previous infection
• Age
• Genetics
• Other?
 Global Aviation Network
(civil traffic, 500 largest airports, 100 countries)

PNAS 2004;101:15125.
 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
 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
Chikungunya Virus
 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?
 Clinical Manifestations: Chikungunya

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

Lancet ID May 2007

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.
 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.

 Chikungunya Virus
• High viral concentration >109
• Early appearance IgM and IgG
• Potential risk for nosocomial
transmission

Emerg Infect Dis March 2008

 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.
 Synchronization of Aedes Activity

Lancet ID 2008;8:5.
Aedes Albopictus Female
 Distribution of Dengue, Yellow Fever, & Ae. aegypti

Pink: Ae. aegypti

Blue: Ae. aegypti and dengue epidemic activity
Lined: YF endemic
 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?