LECTURE # 4

Dengue Fever

Mary Elizabeth Wilson, MDmewilson@hsph.harvard.edu

Collaborative Course on Infectious Diseases

January 2009

Harvard School of Public HealthCentro 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;120:653AJTMH 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 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.

Aedes aegypti Distribution in the Americas

19701930's 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 HighNorth 222 AverageNortheast 204 AverageSoutheast 178 AverageSouth 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*

Epidemic waves in localized areas

Endemic / Epidemicvirus circulation nationwide

Increase in severe cases in children

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DEN3DEN3 DEN2DEN2

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, 2007-2008Clinical outcomes

(Dengue with complications)2007N (%)

2008N (%)

Total

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?

PNAS 2004;101:15125.

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

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.

Emerg Infect Dis March 2008

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.

Lancet ID 2008;8:5.

Synchronization of Aedes Activity

Aedes Albopictus Female

Distribution of Dengue, Yellow Fever, & Ae. aegypti

Pink: Ae. aegyptiBlue: Ae. aegypti and dengue epidemic activityLined: YF endemic

Monath T. NEJM 2007;357:2223.

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?