Dengue and Yellow Fever: the Anatomy of Decline and ... · • Typhoid fever • Leptospirosis •...

Dengue and Yellow Fever: the Anatomy of Decline and Emergence

Duane J Gubler

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Dengue and Yellow Fever: The Anatomy of Decline and Emergence

1

Duane J. Gubler, Professor and DirectorSignature Research Program in Emerging Infectious Diseases

Duke-NUS Graduate Medical School, Singapore and

Asia-Pacific Institute of Tropical Medicine and Infectious Diseases, John A Burns School of Medicine,

University of Hawaii, Honolulu

Dengue and yellow fever: decline and emergence

Background on epidemiology and clinical

Yellow fever decline

Re-emergence of dengue

2

Re emergence of dengue

Reasons for re-emergence of dengue

Re-emergence of yellow fever?

Possible explanations for the lack of yellow fever re-emergence

Yellow fever and dengue viruses

Family: Flaviviridae

Genus: Flavivirus

Yellow fever virus; Prototype flavivirus

Dengue viruses

3

Dengue viruses

Serotypes: Denv-1Denv-2Denv-3Denv-4


Duane J Gubler


Nonstructural geneFlavivirus phylogeny

Mosquito-borne

JEMVE

WNSLE

ROCILH

BAGBSQIGUKOK

KEDZIKA

DEN1

4

Tick-borne

No vector

Insect0.1

DEN3DEN2

DEN4YF

SEPENT

LITBE

LGTALK

DTPOW

RBMML

MODAPOI

KRVCFA

TB

Yellow fever and dengue virus genome

5Kuhn, et al., 2006

AfricaTransmission cycles of yellow fever

Monkey

Ae. africanus

Enzootic zone

HumanHuman

Ae. furcifer

Zone of emergence

Ae. aegypti

Epidemic zone

etc.

?Trans-ovarial

Trans-ovarialMonkey

6

Monkey

Ae. africanus

Monkey Human

Ae. furcifertayloriluteocephalusopokafricanussimps. nietc.

Other vertebrate?monkey

Tick(Amblyomma)

TickAe. aegypti

Known part of cycleSpeculative part of cycle

trans-mission

trans-mission

Monkey


Duane J Gubler


Yellow fever transmission cycle in the Americas

Monkey

Haemagogus

T i l Monkey TransovarialHuman Human

Ae. aegypti

7

Monkey Marmoset

Haemagogus

Transovarial yMarmosetTransovarialHuman Human

Ae. aegypti

Urban cycleJungle cycle

Transmission and maintenance cycles of dengue viruses

Aedes Mosquitos

Aedes Mosquitos

Primates Primates Humans Humans HumansHumansVertical

transmissionVertical

transmissionVertical

transmission

Aedes Mosquitos

8

Aedes aegyptiAedes MosquitosAedes

Mosquitos

Aedes aegypti

9


Duane J Gubler


Principal urban vector of DEN and YF

Vector: Aedes aegypti

Biology:

Urban

10

Day biting

Breeds in domestic water

Preferentially bites man

Highly efficient epidemic vector

Aedes aegypti

11

12


Duane J Gubler


Disease: the original viral hemorrhagic fever, a systemic illness with

High viremia

Yellow fever

13

Hepatic, renal, myocardial injury

Hemorrhage

Shock syndrome

Case fatality, 20%

Dengue hemorrhagic fever

Fever, or recent history of acute fever

Hemorrhagic manifestations

Low platelet count (100,000/mm3 or less)

14

p ( )

Objective evidence of vascular leakage

Case fatality rate: average 5%

Pan American Organization: Dengue and Dengue Hemorrhagic Fever: Guidelines for Preventionand Control; PAHO: Washington, DC, 1994: 13

Differential diagnosis of dengue and yellow fever

Influenza

Measles

Rubella

M l i

15

Malaria

Typhoid fever

Leptospirosis

Rickettsial infections

Bacterial sepsis

Other viral hemorrhagic fevers


Duane J Gubler


16

Yellow fever history 1600s - Virus, vector introduced from Africa

1648 - Yucatan epidemic, Mayan records

1750 - Term yellow fever first used in Barbados

18th-19th Centuries - major epidemics, Americas, Europe, West Africa

1900 - Reed demonstrates filterable virus transmitted by Ae. aegypti; vector control begins

17

ecto co t o beg s

1904-1912 - Yellow fever controlled in Cuba and Panama

1905 - Last outbreak in U.S. (New Orleans)

1927 - Virus isolated in Africa

1932 - YF jungle transmission cycle (Brazil, then Africa) sylvatic mosquitoes and non-human primates

1936 - Yellow fever vaccine developed

1946 - Aedes aegypti eradication program in Americas

Importance of the 1890s

Filterable agent (=virus) as cause of animal disease

Malaria transmission by mosquito

Discovery of extrinsic incubation period

18

y p

Yellow fever transmission by Ae. aegypti

Spanish-American War


Duane J Gubler


19

Urban yellow fever epidemics in the United States 1793-1905

1. Philadelphia, 1793; 5,000 dead

2. New York City, 1795; 730 dead

3. Boston, New York City and Philadelphia; 1798; more than 5,000 dead

4. Baltimore, 1800; 1,200 dead

5. New Orleans, 1853; 8000 or more dead

20

6. Norfolk, 1855; 2,000 dead

7. Mississippi Valley, 1878; 20,000 dead

8. Cuba, 1898; hundreds dead

9. New Orleans, 1905; more than 900 dead

Currently:

Rare imported cases with travel history

No local transmission

21


Duane J Gubler


Reported cases of yellow fever 1948-98

22WHO Report, 2000

19701930's 2010

Aedes aegypti distribution in the Americas

23Adapted from Gubler, 1998

Dengue: a historical perspectiveMore important epidemics of dengue-like illness

China - 992

Caribbean - 1635

Panama - 1699

Spain/Africa - 1700s

Batavia, Indonesia - 1779

24

Cairo, Egypt - 1779

Philadelphia, PA, USA - 1780

Spain - 1801

Cuba - 1828

Americas and Asia-Pacific - 1800s & early 1900s

World War II - 1941-45

Aedes aegypti eradication program in Americas, 1946

Post war era - 20th Century re-emergence


Duane J Gubler


Epidemic dengue hemorrhagic fever / dengue shock syndrome emerged as newly recognized

disease in Southeast Asia in the 1950s

At the end of WWII all four serotypes of dengue were widespread in Asia

25

1950-1969 1970-1979

Expanding geographic distribution of epidemic dengue/dengue hemorrhagic

fever in Asia

26

1980-2010

Adapted from Gubler, 1998

19701930's 2010




Duane J Gubler


The emergence of dengue hemorrhagicfever in the Americas

Prior to 1981 1981-2010


Re emergence of dengue in the US 1980

29

Re-emergence of dengue in the US 1980

Year

1980

1986

1995

1997

1998

Location

Texas

Texas

Texas

Texas

Texas

No. Cases

27

9

7

3

1

Autochthonous dengue in the United States

30

1998

1999

2001

2005

2007

2009

2010

Texas

Texas

Hawaii

Texas

Texas

Florida

Florida

1

17

122

25

?

27

16


Duane J Gubler


Dengue fever in AfricaPrior to 1980 1981-2010

31Areas at riskAdapted from Gubler, 1998Epidemic transmission

Expanding geographic distribution

Increased epidemic activity

Hyperendemicity

The 20th century re-emergence of epidemic dengue

1,151,300

50

60

70

1000000

1200000

1400000

Average annual number of DF/DHF cases reported to WHO, 1955 - 2008

ries

ses

32Source: DengueNet2008 data provisional

Emergence of DHF

908 15,497

122,174

295,554

479,848

0

10

20

30

40

0

200000

400000

600000

800000

1955-1959 1960-1969 1970-1979 1980-1989 1990-1999 2000-2008

Number of cases

Num

ber o

f cou

ntr

Num

ber o

f cas

Approximate global distribution of dengue and Aedes aegypti, by state/province, 2010

33Areas with recent dengue transmissionAreas infested with Aedes aegyptiAdapted from Gubler, 1998


Duane J Gubler


Public health impact of dengue

2.5-3 billion people live in areas of risk

50-100 million cases/infections/year

Millions hospitalized

500,000 cases of dengue hemorrhagic fever

34

20,000 plus deaths

Incidence and geographic range are increasing

Economic impact

No vaccine or antiviral drugs

Mosquito control has been largely ineffective

Why have we seen such a dramatic increase in epidemic dengue/dengue

hemorrhagic fever?

Complacency, Lack of political will

Policy changes

35

Changes in public health

Changing life styles/behavior

Microbial adaptation

Technology

Climate change?

Why have we seen such a dramatic increase in epidemic dengue/dengue

hemorrhagic fever?

Demographic changes (Pop. growth and distribution)

Environmental change

Major drivers

36

Environmental change

Uncontrolled urbanization

Modern transportation (Globalization)

Increased movement of people, animals, commodities

Lack of effective mosquito control


Duane J Gubler


33.5

44.5

5

of p

eopl

e

Estimated number of people living in urban areas

37

00.5

11.5

22.5

3

1950 1985 2000 2030

Bill

ions

o

Source: UN

The urban and rural population of the world 1950-2030

38

UrbanizationThe case of Dhaka, Bangladesh

e (M

illio

ns) 14,000,000

10 000 00012,000,00014,000,00016,000,000

39

Num

ber o

f peo

ple

Source: UN

1,500,000

02,000,0004,000,0006,000,0008,000,000

10,000,000

1970 2008


Duane J Gubler


Emergence of dengue/dengue hemorrhagic fever

Uncontrolled urbanization

Crowding

Living conditions

Lack of basic services:

40

Lack of basic services: inadequate housing, piped water, sewage and waste management

From: PAHO, 1997; Gubler, 1998

Urban agglomerations, 1950, 2000, 2015

41Source: UN, World Urbanization Prospects, The 1999 Revision

5 million & over since 1950

5 million & over since 2000

5 million & over in 2015 (projected)

0

204060

80100120

1950 2000 2015

Asia

S. America

Sub-Sahara Africa

ulat

ion

(Milli

ons)

Urban population growth and reported dengue cases

Dengue C1500

2000

2500

3000

600000

800000

1000000

1200000

42Population data, UN; Dengue data, WHO, to April, 2008Estimated Number of People Living in Urban Areas - World

Urb

an P

opu ases

Dengue/DHF - Average Annual Number of Cases Reported to WHO - World

0

500

1000

1950s 1960s 1970s 1980s 1990s 2000s0

200000

400000


Duane J Gubler


Dengue viruses & mosquitoes:

43

hitching a ride on modern transportation

The global airline network

44PNAS, 2004

500

600

700

seng

ers

Mean annual number of airline passengers by decade, United States, 1954-2007

45

0

100

200

300

400

1950s 1960s 1970s 1980s 1990s 2000s

Mill

ions

of p

as

Source: RITA, DOT


Duane J Gubler


46

Global movement of dengue (1971-1980)

47DENV 1; DENV 2; DENV 3; DENV 4

1980

1979



1985


Duane J Gubler



1994


1994

Global distribution of dengue virus serotypes, 1970

50Gubler, 1998

DEN-2DEN-1

DEN-1DEN-2

DEN-1DEN-2DEN-3DEN-4

Global distributionof dengue virus serotypes, 2010

DEN-1

51Adapted from Gubler,1998




DEN-2DEN-3DEN-4

DEN-1DEN-2DEN-3

DEN-1DEN-2DEN-3DEN-4DEN-1

DEN-2DEN-3DEN-4




Duane J Gubler


Yellow fever: re-emergence?

Low YF vaccine coverage rates

Increased global travel

52

Reinfestation by Aedes aegyptiof urban areas threatens major population centers

Encroachment of humans into sylvatic cycleHuman migration and urbanization

Number of yellow fever cases and deaths reported to WHO, by decade, 1950-1999

12000140001600018000

53

02000400060008000

10000

1950-59 1960-69 1970-79 1980-89 1990-99

Cases Deaths

19701930's 2010




Duane J Gubler


Potential for urban yellow fever epidemics

55

in the Americas

Imported yellow fever

Texas 2002

Belgium 2000

California 1999

G 1999

56

Germany 1999

Switzerland 1996

Tennessee 1996

Urban yellow fever, Santa Cruz, BoliviaDec 1997 - June 1998

Six acute cases confirmed

Two clusters of transmission

57

Five died

(Three cases likely contracted infection in the city)

Serosurvey - 281

16 (6%) had YF antibody

5 - no previous immunization


Duane J Gubler


Dados Gerais:

Endemic areas:States: 12

Epidemiologic distribution of yellow fever, Brazil

AM

AC RO TOAL

PE

MA

PI

CERN

PB

RR

PA

AP

58

Population: 27,014,229

Epizootic area :States parts of 3Population 10,443,215

YF free area :States: 15

Fonte: SUCAM/MS Vasconcelos, P.F. (1997)

Enzootic Area

Epizootic Area

YF Free Area

RO

MT

MS

TOBA SE

MG

RS

SP

PR

SC

ES

RJ

GODF

Feb 1

Feb 6

Feb 15

Distribution of confirmed cases of yellow fever by date of onset of symptoms, Laurelty, Paraguay, 2008

59

Jan 11

Feb 2

Feb 4

Feb 8

Feb 1Feb 17

Feb 28

Hypothesis to explain the absence of urbanyellow fever epidemics in the Americas

Cross-protective flavivirus immunity Evidence through monkey experiments

Vi Ad t ti

60

Virus Adaptation Humans

Aedes aegypti

Evolutionary exclusion


Duane J Gubler


Hypothesis to explain the absence of yellow fever in Asia

A matter of logistics

Cross-protective flavivirus immunity

Low vector competence of Asian Aedes aegypti

61

Low vector competence of Asian Aedes aegypti

Geographic and demographic obstacles to spread yellow fever virus

Evolutionary exclusion

Potential global spread of urban yellow fever

62

Dengue and yellow fever viruses

Summary

Both old diseases

Both effectively controlled

63

Dengue re-emerged; yellow fever did not

Dengue viruses evolved with urbanization

Yellow fever remained in the jungle

Current global threat


Duane J Gubler


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Dengue and Yellow Fever: the Anatomy of Decline and ... · • Typhoid fever • Leptospirosis •...

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