A Global Perspective on Emerging Mosquito-Borne

Diseases

Laura D. Kramer Wadsworth Center

New York State Dept Health

JV Irons / RR Parker Memorial Lecture

Ft. Worth, Texas June 3, 2009

Emerging Infections: Microbial Threats to Health in the United States. Joshua Lederberg, Robert E. Shope, and Stanley C.Oaks, Jr., Editors; Committee on Emerging Microbial Threats to Health, Institute of Medicine (1992)

• Defined the concept of EID

• Identified factors contributing to disease emergence

• Pointed to challenges posed by infectious diseases

Emerging Infections: Microbial Threats to Health in the United States. Joshua Lederberg, Robert E. Shope, and Stanley C.Oaks, Jr., Editors; Committee on Emerging Microbial Threats to Health, Institute of Medicine (1992)

“…the United States has no comprehensive national system for detecting outbreaks of infectious disease. Outbreaks of any disease that is not on CDC's current list of notifiable illnesses may go undetected or may be detected only after an outbreak is well under way.”

“Although many local and regional vector-control programs can effectively combat small and even medium-size outbreaks of vector-borne disease, they are not equipped to deal with outbreaks that are national in scope.”

“The significance of zoonoses in the emergence of human infections cannot be overstated.”

Outline

• Drivers of emerging / re-emerging diseases

• Re/emerging flavivirus – West Nile

• Re/emerging alphavirus – Chikungunya

Atlantic Monthly, 1997

Re/emerging infectious diseases

• Define the concept. EIDs are infections that have newly appeared in a population, or have existed but are rapidly increasing in incidence or geographic range (Morse 1995)

• Process

– Introduction of agent

– Establishment and dissemination

Introduction: The ‘Zoonotic Pool’

Assuming 50,000 vertebrates, each with 20 endemic viruses. There are likely 1,000,000 vertebrate viruses.

99.8% of vertebrate viruses remain to be discovered

Large potential for future zoonotic emergence!

S Morse 1993

Question

What leads to selection

or

emergence

a new agent?

Genetic and biological factors

Socal, political and economic factors

Physical and environmental

factors

Ecological factors

Modified from Jones et al 2008 Nature 451:990.

Vectors

Underlying factors in emergence:

• Genetic and biologic factors Microbial genetics and adaptation Host susceptibility to infection

Modified from King L CDC 2008

• Physical environmental factor Climate and weather Economic development and land use

• Ecological factors Changing ecosystems Human demographics and behavior

• Social, political, and economic factors International travel and commerce Poverty and society inequity War and famine Intent to harm

Po

pu

lati

on

in

mil

lio

ns

http://esa.un.org/unpp/

Global Aviation Network

Least frequent no. passengers / day Most frequentHufnagel et al, 2004 PNAS

There is nowhere that is too remote to reach

Speed of Global Travel in Relation toWorld Population Growth

Wor

ld P

opula

tion in

bill

ions

(

)

Day

s to

Circ

umn a

viga

te (

)

th

e G

lob e

Year1850

0

400

350

300

250

200

150

100

50

2000

0

1900 1950

1

2

3

4

5

6

Murphy and Nathanson Sems Virol 5, 87, 1994

Percentage of Population Without Reasonable Access to Safe Drinking Water

Earth Dispatch

What is an Arbovirus?

• Arthropod-borne• Group of viruses spread by arthropods• Many are zoonotic• Infection spread to incidental hosts that are not

essential to the life cycle.

Outline• Drivers in emerging diseases• Re/emerging flaviviruses

– West Nile – Dengue– Japanese encephalitis– Yellow fever– Kyassanur Forest

• Re/emerging alphavirus– Chikungunya

WNV modified from Kuhn RJ in Kramer LD et al. Lancet Neurology 2007

Flavivirus: Flaviviridae (~70 members)

11 kb

– Human pathogens• Hemorrhagic fevers (flavi=yellow)• Encephalitis• Febrile illness

– 3 phylogenetic clusters• No known vector• Tick-borne• Mosquito borne

– Japanese encephalitis serocomplex» Includes JEV, SLEV, WNV» Primarily bird viruses» Humans not “amplifying” host

– Other serocomplexes include YFV, DENV

Flavivirus: Flaviviridae (~70 members)

Japanese encephalitis serogroup

WNV SLEV JEVKUNV MVEV

Smithburn JS, Hughes TP, Burke AW, Paul JH. A neurotropic virus isolated from the blood of a native of Uganda. Am J Trop Med Hyg. 1940;20:471–92.

Medical Department of the Uganda ProtectorateInternational Health Division of The Rockefeller Foundation.

West Nile 1994-2003

19962003

1996

1999

1994

1997 2003

ItalyItaly1998

20002003

2000

2000

2002

Horses Humans Birds

1998

BucarestBucarest

FranceFrance

2003

MoroccoMorocco

Modified from the French National Reference Center for Arboviruses, Pasteur Institute,Lyon, France

TunisiaIsrael

2003

WNV geographic distribution

Pre-1999 distribution

Post-1999 distribution

West Nile Virus in North America: Background

• Discovered in 1999 in New York City during an outbreak of meningitis and encephalitis in humans and an accompanying epizootic in birds– Emergence during heat wave

West Nile Virus In New York - 1999 West Nile Virus In New York - 1999

NYC - 1795NYC - 1795

Yellow Fever OutbreakYellow Fever Outbreak

730 Deaths730 Deaths

“I love the smell of malathion in the morning”

The New YorkerSept. 27, 2000

Buzz City

by

Barry Blitt

The New YorkerApril 17, 2000

The Bite of Spring

by

Peter de Seve

• Infected Human

• Human-transported vertebrate host

– Legal

– Illegal

• Human-transported mosquito vector

• Storm-transported vertebrate host (bird)

• Intentional introduction (terrorist event)

Possible pathways of introduction of WNV into the USA

Lanciotti et al. 1999. Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern U.S. [Science 286:2333-337.]

West Nile Virus Transmission Cycle

Mosquito vectors Culex species

AAmplification hosts

Epizootic

Secondary HSecondary Hosts

Epidemic

WNV Surveillance, United States,1999-2008*: Summary of Mosquito and Dead Bird Data

• 64 WNV-positive mosquito species reported

–Culex species account for >98% of the total reported

* Reported as of 3/2009A Hitchcock, The Birds

317 WNV-positive dead bird spp. reported

2006: American crows and blue jays accounted for 62% of the dead birds reported

Spatio-temporal Declines, American CrowNorth American Breeding Bird Survey

S LaDeau; Nature. 2007. 447(7145):710-3

Equine Cases, United States, 1999-2007

Total Equine: 24,681cases

Eq

uin

e C

ase

Rep

ort

s

Vaccine introduced

0

2000

4000

6000

8000

10000

12000

14000

16000

1999 2000 2001 2002 2003 2004 2005 2006 2007Year CDC/NCID/DVBID

WN disease

Reported incidence of West Nile virus disease by county, United States, 1999–2007

(62) (21)

(66) (4156)

(9862) (2539)

(Total cases)

Hayes EB et al. EID 2006

(1294)

2005

(1495)

2006

(1173)

2007

Risk of WN disease in humansseroprevalence studies in US (CDC)

Most mosquito bites not

by infected mosquito

4 of 5 infections subclinical

1 of 5 infections febrile illness

1 of 140 infections neurologic disease

WNV neuroinvasive disease cases in United States (by year)

0

500

1000

1500

2000

2500

30001

99

9

20

00

20

01

20

02

20

03

20

04

20

05

20

06

20

07

20

08

WNND Cases

Avg = 1295/year

Regional epidemics

Year

No

. N

ID c

ases

WNV neuroinvasive disease cases and deathsN

o.

of

NID

cas

es

0

500

1000

1500

2000

2500

3000

3500

1999 2000 2001 2002 2003 2004 2005 2006 2007

0%

20%

40%

60%

80%

100%

NID cases mortality

% m

ortality

Reported WNND Cases and WNV Deaths in Humans,

United States, 1999-2008*

Year

Encephalitis/

Meningitis

(includes some AFP)

Non-Encephalitis/

Meningitis AFP

Total AFP

Total WNND

Deaths

1999-2002

3,088 -- -- 3,088 303

2003 2,866 -- -- 2,866 264

2004 1,142 6 33 1,148 100

2005 1,294 15 82 1,309 119

2006 1,459 36 101 1,495 177

2007 1,217 10 63 1,227 124

2008 665 1 21 687 44

Total 11,616 68 300 11,820 1,114* Reported as of 11/04/2008

11,820 WNND Cases

x 140 infections/WNND

~ 1.65 Million Infections

WNV Widespread and Pervasive in Environment

Produced Widespread and Pervasive Impact

West Nile virus neuroinvasive disease cases by age group and gender, 1999-

2006*

* Reported as of 5/2/2007

0

5

10

15

20

25

0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99

Age Group (yr)

Inci

den

ce p

er 1

00,0

00

MaleIncidence

FemaleIncidence

Sejvar J CDC

Proportion of viremic blood donorsdeveloping West Nile fever

Colorado, 2003

Vector Borne Zoonotic Dis 2007;7:479

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

18-29 30-39 40-49 50-59 60-69 70-79

Age Group

Pro

po

rtio

n w

ith

WN

F

Risk factors for neuroinvasive disease

• Strong evidence– Age

Risk increases ~1.5 times per decade

– Organ transplant recipients ~40% develop neuroinvasive disease (>40 times the

risk as population-at-large)*

– Hematological malignancies Experimental infection and individual case reports

(risk remains undefined)

* Kumar et al. Am J Transplant 2004;4:1883-8

Risk factors for neuroinvasive disease

• Weaker evidence–Diabetes

–Hypertension

–Alcohol abuse

–Chronic renal disease

–Cardiovascular disease

Acute WNV

WNV long term effects

The West Nile Virus “Iceberg” - 2

Sejvar CDC

Temporal profile of recovery—WNV “Poliomyelitis”

Baseline Strength100

80

40

60

20

0

Level of recovery (18)

Sejvar J CDC

Novel modes of virus transmission• Transfused blood

–Blood supply screening began in 2003–More than 1000 viremic blood donors identified 2003 - 2004

• Transplanted organs • Breast milk

–One case, infant asymptomatic• Transplacental transmission

–Single case 2002 with severe outcome to infant• Percutaneous, occupational exposure• Dialysis?

Greatest risk – exposure to mosquito bite !!

Conclusions 1 – North America• Rapid spread across USA (<4 years to Pacific Coast)

• Bird migration and random bird movements• Many possible important avian hosts and competent

mosquito vectors (unprecedented infection prevalence) • Significant impact on wildlife and domestic animals.• Persistent seasonal outbreaks. Incidence varies

regionally.• High infection incidence in humans has led to unusual

modes of transmission.• Age and immunosuppression highly significant risk

factors for neuroinvasive disease. Role of other risk factors unclear, but possibly important.

West Nile Virus in Latin America

2006

2002 –

2004

Little evidence of human and animal disease in Latin America

• Less virulent virus circulating?

• Poor surveillance?

• Serological cross reactivity with other flaviviruses?

• Previous exposure to other circulating flaviviruses modulating disease expression?

• Other causes?

West Nile Virus Puerto Rico, 2007

• Sentinel chicken surveillance: up to 50% chickens seroconverted per week for over two months

• 3 viremic human blood donors

• 7 sick horses; 1 death

• Active human surveillance: only one human with West Nile fever; no neuroinvasive disease

• WNV isolated from chickens and Culex mosquitoes

• Strain identical to that circulating in United States

Future issuesWest Nile virus is endemic in the western hemisphere

• Vaccines successful for equines but need to weigh cost effectiveness for humans

• Therapeutics / antivirals

• Long term sequelae

• Control and risk prediction

Pools at foreclosed homes raise West Nile threat in Dallas County 10:38 PM CDT on Friday, May 22, 2009

By THEODORE KIM / The Dallas Morning Newstkim@dallasnews.com

braceforimpactnow.blogspot.com

Outline

• Drivers of emerging diseases

• Re/emerging flavivirus – West Nile

• Re/emerging alphavirus– Chikungunya

Atlantic Monthly, 1997

Togaviridae: Alphaviruses

Genome: Single stranded, positive sense RNA5’ capped , 3’ polyadenylatedCytoplasmic replication Structural proeins encoded at 3’ end in subgenomic message

Insect transmitted

3 disease patterns: Arthropathy (Sindbis, Ross River, Chikungunya) Systemic febrile illness (Semliki forest, VEE) Encephalitis (EEE, WEE, VEE)

Chikungunya

In Swahili, “chikungunya” : “ that which contorts or bends “up”Disease:

High fever (103-104 F) Rash Severe incapacitating arthritis/arthralgia

–Generalized –Usually acute

Hemorrhagic manifestations have been reported Rarely fatal

A.M. Powers and C.H. Logue, 2007 J Gen Virol,

G. Pialoux et al., 2007, Lancet Infect Dis

CHIKV Transmission Cycleforested areas in West & Central Africa

Forest Aedes spp.

eg. Forest redtail monkeyAe africanusAe luteocephalusAe furcifer-taylori

Modified from Gould EA and Higgs S 2009 Trans Royal Soc Trop Med Hyg

CHIKV Transmission Cycleurban in Asia

Aedes aegypti & Ae. albopictus

Powers AM, Logue CH J Gen Virol. 2007 88:2363.

Recent outbreaks of Chikungunya 2004-2007

Enserink, M. (2007) Science 318: 1860-1861

266,000 cases

Chikungunya Virus Outbreak878 imported cases to France

Pialoux et. al 2007 Lancet Inf Dis, 7:319-327

Recent outbreaks of Chikungunya 2004-2007

>1.4 million cases

Enserink, M. (2007) Science 318: 1860-1861

Recent outbreaks of Chikungunya 2004-2007

New emergence in 2007: >200 cases

Enserink, M. (2007) Science 318: 1860-1861

Mosquito species were different in various outbreaks

Enserink, M. (2007) Science 318: 1860-1861

Ae. aegypti

Ae. albopictus

Re-emergence in the 2000sDomestic epidemic cycles

Ae albopictus on islands and ItalyAe. aegypti in India

Mosquito-borne virus hits 20,000HEALTH MINISTRY ISSUES ALERT OVER CHIKUNGUNYA DISEASE

By: APIRADEE TREERUTKUARKUL

Bangkok Post 05/24/09

Charrel et al. 2007. N Engl J Med 356;8

ECDC/WHO Mission report Sept 2007

Presence of Aedes albopictus in Europe, 2007

Expansion of world distribution of Aedes albopictus

Charrel et al. 2007. N Engl J Med 356;8

Factors involved in re-emergence of Chikungunya virus

• Biologic and genetic– Non-immune population

– Adaptation of virus to new mosquito: Ae. albopictus

• Ecologic conditions– Standing water due to droughts

– Warm European summer

– Mosquito abundance

• Social, economic, political– International travel

– Previous introduction of Ae. albopictus into Reunion Island & Italy

– Delayed identification and control of initial outbreaks

• Physical environment– Stored water/atificial breeding sites

Modified from Chretien JP, Linthicum KJ. Lancet. 2007

Can Chikungunya virus emerge in US?

• 37 imported cases in 2005-2006 No autochthonous transmission so far

• Components of the transmission cycle? Climate in southern states Humans Monkeys X Mosquitoes ????

www.cdc.gov/ncidod/dvbid/dengue/map-ae-aegypti-distribution.htm

Distribution of Ae. aegypti in Americas

1970 – after mosquito eradication

2002

http://www.cdc.gov/ncidod/dvbid/Arbor/albopic_97_sm.htm

Distribution of Ae. albopictusin US, year 2000

• 37 imported cases in 2005-2006

• Components of the transmission cycle? Climate in southern states Humans Monkeys X Mosquitoes

• Human behavior ???

Can Chikungunya virus emerge in US?

Can we predict the next new emerging zoonosis?

“In general, there is no way to predict when or where the next important new zoonotic pathogen will emerge or what its ultimate importance might be.”

F.A. Murphy, ICEID 1998

Emerg. Infect. Dis. 1998 4: 429-435

Malaria, yellow fever, dengue, West Nile virus, chikungunya,

WHAT’S NEXT?

QUESTIONS???????Thank you!