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West Nile VirusWest Nile Virus

Lyle R. Petersen, M.D., M.P.H.Lyle R. Petersen, M.D., M.P.H.

Family Family FlaviviridaeFlaviviridae, Genus , Genus FlavivirusFlavivirus, ,

(~68 viruses)(~68 viruses)

•• ssRNAssRNA (positive(positive--sense), ~11,000 nucleotidessense), ~11,000 nucleotides

•• Human pathogensHuman pathogens•• Hemorrhagic fevers (Hemorrhagic fevers (flaviflavi=yellow)=yellow)•• EncephalitisEncephalitis•• Febrile illnessFebrile illness

•• 3 3 phylogeneticphylogenetic clustersclusters•• No known vectorNo known vector•• TickTick--borneborne•• Mosquito borneMosquito borne

•• Japanese encephalitis Japanese encephalitis serocomplexserocomplex•• Includes JEV, SLEV, WNVIncludes JEV, SLEV, WNV•• Primarily bird virusesPrimarily bird viruses•• Humans not “amplifying” hostHumans not “amplifying” host

•• Other Other serocomplexesserocomplexes include YFV, include YFV, DENVDENV

West Nile Virus before 1994West Nile Virus before 1994

•• Isolated in 1937 from blood of febrile woman in West Nile distriIsolated in 1937 from blood of febrile woman in West Nile district ct of Ugandaof Uganda

•• Commonly found in humans, birds, and other vertebrates in Asia, Commonly found in humans, birds, and other vertebrates in Asia, Eastern Europe, AfricaEastern Europe, Africa

•• Sporadic cases of febrile illness, meningitis, or encephalitis Sporadic cases of febrile illness, meningitis, or encephalitis reported in CAR, Egypt, France, India, Madagascar, Senegal, reported in CAR, Egypt, France, India, Madagascar, Senegal, Tunisia Tunisia

•• Outbreaks of varying sizeOutbreaks of varying size

•• Israel 1941, 1951Israel 1941, 1951--1954, 1954, 19571957, 1980 , 1980

•• South Africa, 1974South Africa, 1974

Outbreaks in yellow associated with many CNS disease cases

West Nile Virus Outbreaks in the Old World West Nile Virus Outbreaks in the Old World

since 1994since 1994

•• Algeria,Algeria, 19941994

•• Romania, Romania, 19961996

•• Tunisia, Tunisia, 19971997

•• Russia, Russia, 1999, 2000, 20011999, 2000, 2001

•• Israel, Israel, 20002000

•• Sudan,Sudan, 20022002

Outbreaks in yellow associated with many CNS disease cases

Outbreaks underlined associated with avian mortality

Egypt 1951France 1965

South AfricaIsrael 1952

Romania 1996 MKenya 1998Senegal 1993Morocco 1996Italy 1998Volgograd 1999New York 1999Israel 1998-ANY2000 3282NY2000 3356NY 1999 equineNY 1999 humConn 1999MD 2000NJ 2000Israel 1999 HC.Afr.Rep 1989Senegal 1979Algeria 1968C.Afr.Rep 1967Iv.Coast 1981Kunjin 1960Kunjin 1973Kunjin 1984bKunjin 1991Kunjin 1984aKunjin 1966Kunjin 1994India 1955aIndia 1980India 1958India 1955bKenyaUgandaSenegal 1990Uganda 1937C.Afr.Rep 1972aC.Afr.Rep 1983Uganda 1959C.Afr.Rep 1972bMadagascar 1988Madagascar 1986Madagascar 1978JE SA 14

India

Kunjin

US/Israel

Phylogenetic Tree Phylogenetic Tree

of West Nile of West Nile

VirusesViruses--20012001(Envelope gene)(Envelope gene)

LINLIN--11

LINLIN--222

1

Bird mortality,mouseneuroinvasive

West Nile Virus:Basic Transmission Cycle

Enzootic (Maintenance/Amplification)

Epizootic

Epidemic

Amplifying hosts

Incidental hosts

WNV Surveillance WNV Surveillance -- ArboNETArboNET

•• Only combined humanOnly combined human--veterinary, national veterinary, national surveillance systemsurveillance system

•• RealReal--time electronic reporting time electronic reporting

•• HumansHumans

•• Clinically illClinically ill

•• Viremic blood donors Viremic blood donors

•• Dead birds (especially crows and jays)Dead birds (especially crows and jays)

•• MosquitoesMosquitoes

•• EquinesEquines

•• Live captive sentinels (e.g., chickens)Live captive sentinels (e.g., chickens)

WNV Surveillance, United States, WNV Surveillance, United States,

19991999--2006*: Summary of Mosquito and 2006*: Summary of Mosquito and

Dead Bird DataDead Bird Data

• 1999-2006: 62 WNV-positive mosquito species reported

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

• Infection rates measured in percents, rather than per thousand

• 1999-2006: 317 spp. WNV-positive dead birds reported

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

* Reported as of 5/2/2007

Spatio-temporal Declines, American CrowNorth American Breeding Bird Survey

Source: S. LaDeau; Nature. 2007 Jun 7;447(7145):710-3

0

2000

4000

6000

8000

10000

12000

14000

16000

1999 2000 2001 2002 2003 2004 2005 2006

0

500

1000

1500

2000

2500

3000

3500

4000

Equine

Human

Equine and Human WNV Equine and Human WNV NeuroinvasiveNeuroinvasive

Disease Cases, United States, 1999Disease Cases, United States, 1999--20062006

Total Equine: 24,213 cases

Total Human: 9,906 cases

Eq

uin

e C

ase R

ep

ort

sH

um

an

Case R

ep

orts

Vaccine introduced

Reported WNV Disease Cases in Humans,Reported WNV Disease Cases in Humans,

United States, 1999United States, 1999--2006*2006*

9,9069,906

1,4951,495

1,3091,309

1,1481,148

2,8662,866

2,9462,946

6464

1919

5959

TotalTotal

WNNDWNND

23,97523,975

4,2694,269

3,0003,000

2,5392,539

9,8629,862

4,1564,156

6666

2121

6262

Total Total

casescases

637637

194194

9999

128128

166166

5050

00

00

00

OtherOther

clinical/clinical/

UnspecUnspec

DeathsDeathsFeverFeverYearYear

96296213,48913,489TotalTotal

1771772,6162,61620062006

1191191,6071,60720052005

1001001,2691,26920042004

2642646,8306,83020032003

2842841,1601,16020022002

992220012001

222220002000

773319991999


West Nile Virus Clinical SyndromesWest Nile Virus Clinical Syndromes

• Asymptomatic (Approx. 75%)

• West Nile fever (Approx. 25%)

• Neuroinvasive disease (Approx. 1/140)

• Encephalitis

• Meningitis

• Acute flaccid paralysis

Asymptomatic

1,040,300

Fever

322,800

Fever

13,484

Neuroinvasive,

Non-fatal

8,942

Fatal, 962

Reported

The Hidden EpidemicWNV Infections (n=1.4 million), 1999-2006

Not reported

WNV Neuroinvasive Disease Incidence, by County, US, 1999WNV Neuroinvasive Disease Incidence, by County, US, 1999

Incidence per million.01-9.99

10-99.99

>=100

Any WNV activity

N=54


10-99.99

>=100

Any WNV activity


N=19


10-99.99

>=100

Any WNV activity


N=64


10-99.99

>=100

Any WNV activity


N=2946


10-99.99

>=100

Any WNV activity


N=2866



10-99.99

>=100

Any WNV activity

N=1142

2004: Outbreaks in the Desert


N=1294


10-99.99

>=100

Any WNV activity


N=1495


10-99.99

>=100

Any WNV activity

Cumulative Incidence of WNND by State, 2002 to 2006

Cumulative Incidence of WNND By County, 2002 to 2006

Median Rank of Annual WNND Incidence,by State, 2002 to 2006

Median Rank of Annual WNND Incidence,by County, 2002 to 2006

0

500

1000

1500

2000

2500

3000

1932 1942 1952 1962 1972 1982 1992 2002

Reported Number of St. Louis and West Nile Reported Number of St. Louis and West Nile

Neuroinvasive Disease Cases, U.S., 1932Neuroinvasive Disease Cases, U.S., 1932-- 20062006

Human WNV Disease Cases, by Week of Human WNV Disease Cases, by Week of

Onset, United States, 2006*Onset, United States, 2006*

0

50

100

150

200

250

300

350

400

450

500

550

600

7-J

an21

-Jan

4-F

eb18

-Feb

4-M

ar18

-Mar

1-A

pr

15-A

pr

29-A

pr

13-M

ay27

-May

10-J

un

25-J

un

8-Ju

l22

-Jul

5-A

ug

19-A

ug

2-S

ep16

-Sep

30-S

ep14

-Oct

28-O

ct11

-Nov

25-N

ov

9-D

ec23

-Dec

Week ending

# c

ases


Reported Human West Nile Virus Cases, by Date of Reported Human West Nile Virus Cases, by Date of

Symptom Onset; and Date of First Positive Surveillance Symptom Onset; and Date of First Positive Surveillance

Event, Colorado, 2003Event, Colorado, 2003

0

10

20

30

40

50

60

70

80

90

100

110

6-Ju

n

20-J

un4-

Jul

18-J

ul

1-Aug

15-A

ug

29-A

ug

12-S

ep

26-S

ep

10-O

ct

24-O

ct

Symptom onset date

No.

of

ca

se

s

Fever(n=2323)Neuroinvasive(n=621)

mosquito

human

chicken

bird

horse

Source: John Pape, CO DOH

2002

2001

2002

2002 2002

2002

2004

2004

2003

WestWest NileNile Virus in Virus in LatinLatin AmericaAmerica

2004

2003

•2003

2004

2003

2004

2006 Argentina

ClinicalClinical Spectrum of WNV Illness: Spectrum of WNV Illness:

RevisedRevised

WN EncephalitisWN Encephalitis

WN “Poliomyelitis”WN “Poliomyelitis”GBSGBS--like syndromelike syndrome

RadiculopathyRadiculopathy / / plexopathyplexopathy

WN FeverWN FeverWN MeningitisWN Meningitis

Economic impact of acute costs for WNV

inpatients and governmental response in

Louisiana in 2002: $20.1 millionEID 2004;10:1735

Acute WNV Illness

WNV Long-term effects

WNV: The Other “Iceberg”

WN FeverWN Fever----OutcomesOutcomes

• Persistent symptoms common in 98 patients with WN Fever during Chicago 2002 outbreak*

• 63% self-reported persistent symptoms at 30 days; median duration of symptoms 60 days

• 30 hospitalized (median stay: 5 days)

• Colorado 2005: Quality of life measures (SF-36) significantly reduced among 16 WNF patients at 2 years post-infection#

• Fatigue, concentration problems, mood disorders frequently reported

• Significant enough to impact daily activities and functioning

•• (*Watson et al. Ann Intern Med, 141; 2004)(*Watson et al. Ann Intern Med, 141; 2004)

•• (#Sejvar et al., in press)(#Sejvar et al., in press)

WN EncephalitisWN Encephalitis——Outcomes Outcomes

• Persistent disabling neurologic sequelae

• Tremors, movement disorders in ~50% of WN Encephalitis survivors#

• Over 2 years after initial illness

• Neurocognitive outcomes

• Subjective memory, concentration difficulties frequent

• Objective cognitive dysfunction still unclear

• Increased all-cause mortality within 1 year following West Nile encephalitis^

# Sejvar et al., in press; Carson et al., CID 2006 ^Greenberg et al., EID 2005

WNVWNV--Associated “Poliomyelitis”Associated “Poliomyelitis”——

LongLong--Term OutcomesTerm Outcomes

• Range of outcomes— rule of ”thirds”

• 1/3 near-baseline recovery by 1 year

• 1/3 “significant” improvement (>1 increment on MMT* in all affected limbs)

• 1/3 little or no recovery by >2 years

• Persistent weakness, functional impairment the rule

*Manual muscle testing using Medical Research Council 1 – 5 scale

*Sejvar et al, EID 2006

West Nile virus neuroinvasive disease West Nile virus neuroinvasive disease

cases by age group and gender, 1999cases by age group and gender, 1999--

2006*2006*


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)

Inc

ide

nc

e p

er

10

0,0

00

MaleIncidence

FemaleIncidence

Risk Factors for Neuroinvasive DiseaseRisk Factors for Neuroinvasive Disease

•• Strong evidenceStrong evidence

•• AgeAge

•• Risk increases Risk increases ~~1.5 times per decade1.5 times per decade

•• Organ transplant recipientsOrgan transplant recipients

•• ~~40% develop neuroinvasive disease (>40 40% develop neuroinvasive disease (>40

times the risk as populationtimes the risk as population--atat--large)*large)*

•• Hematological malignanciesHematological malignancies

•• Experimental infection and individual case Experimental infection and individual case

reports (risk remains undefined)reports (risk remains undefined)

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

Risk Factors for Neuroinvasive DiseaseRisk Factors for Neuroinvasive Disease

• Weaker evidence

• Diabetes

• Hypertension

• Alcohol abuse

• Chronic renal disease

• Cardiovascular disease

Novel Modes of West Nile Virus Novel Modes of West Nile Virus

TransmissionTransmission

• Transfused blood

• Transplanted organs (2 instances)

• Breast milk (one case, infant asymptomatic)

• Transplacental transmission

• One instance severe outcome to infant

• F/U 72 infants: no conclusive evidence of WNV congenital malformation

• Percutaneous, occupational exposure

• Conjunctival exposure (1 instance)

• Dialysis?

West Nile Virus and Transfusion Safety: West Nile Virus and Transfusion Safety:

A New ParadigmA New Paradigm

• Blood supply screened with mini-pool nucleic acid amplification tests (MP-NAT) in 2003

• Only infectious agent screened solely by this method

• ~1800 viremic donors identified to date

• Viremia in humans very low (median 3500 copies/ml)

• 9 breakthrough transmissions documented because donor viremia below limit of detection of MP-NAT.

• Enormous hidden cost: >$4 million annually

Network analysis of E region of WNV by year

Source: E. Delwart, M Busch

Network analysis of E region of WNV by region

Source: E. Delwart, M Busch

Conclusions Conclusions –– Ecology and Ecology and

Geographic SpreadGeographic Spread

• Rapid spread across USA (4 years to Pacific Coast) and the Americas (7 years to Argentina)

• Bird migration and random bird movements

• Spread by human activity?

• Many possible important avian hosts and competent mosquito vectors (unprecedented infection prevalence).

• Significant impact on wildlife and domestic animals

• Ecologic surveillance provides indicators of impending human outbreaks several weeks in advance

• Combined human/veterinary surveillance essential for monitoring ecological impact and guiding prevention efforts

Conclusions Conclusions –– IncidenceIncidence

• Epidemic → Persistent epidemic/endemic pattern in USA

• Unprecedented pattern globally

• No clear temporal trend in incidence

• Highest incidence/persistence in Midwest

• Land use has facilitated persistence and spread

• Approximately 1.4 million infections to date

• Epidemiological pattern in areas of importation may have little relation to that in previously endemic regions

• Suburban/rural pattern with wide variation in annual incidence in any given area challenges traditional clinical trial approach for vaccines and therapeutics.

• Long-term approach required for surveillance and prevention

Conclusions Conclusions –– Clinical IllnessClinical Illness

• Severe underreporting of West Nile fever

• Chronic sequelae of both WN fever and neuroinvasive disease common

• Possible risk factors for neuroinvasive disease:

• Male, increasing age, immunosuppressive drugs, malignancy, diabetes, HTN, alcoholism, cardiovascular disease, chronic renal disease

• A hidden epidemic – long-term medical, economic, and social consequences of WN illness unknown, but likely huge

• Changing population demographics and medical care likely to greatly increase the population at risk for severe outcomes of infection

Conclusions Conclusions –– New Transmission ModesNew Transmission Modes

• Blood transfusion, organ transplantation, perinatal, breast milk transmission

• Within three years became the most common transfusion transmissible viral agent

• New paradigm• Risk conferred by high incidence rather than chronicity• Blood donor screening relies on MP-NAT screening

• Breakthroughs due to low viremia

• Vector-borne pathogens threat to blood safety due to high incidence of asymptomatic infection (model for dengue)

• Alternate transmission modes may have limited overall public health significance in relation to vector transmission, but may result in considerable cost and public concern

• New methods required to control them

Conclusions Conclusions –– VirologyVirology

• New closely related genetic variants associated with human outbreaks of unusual severity

• Single nucleotide change in non-structural gene resulted in avian mortality

• Original NY99 strain was replaced by a strain with apparent increased fitness in birds. Change due to one nucleotide difference in envelope gene.

• Subsequent temporal and regional viral evolution. Some new variants have appeared and then disappeared (South Texas).

• Multidisciplinary approach required to understand linkages between ecology, epidemiology, and viral genetics

AcknowledgementsAcknowledgements

• Division of Vector-borne Infectious Diseases staff

• State and local health department investigators

• Clinicians

• University-based investigators

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