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West Nile Virus: An Emerging West Nile Virus: An Emerging ZoonosisZoonosisin the United Statesin the United States

Slides borrowed from: Lyle R. Petersen, M.D., M.P.H.: Lyle R. Petersen, M.D., M.P.H.and and HerveHerve Zeller, PhDZeller, PhD

Photo of Culex quinquefasciatuscourtesy of Dr. Stephen Higgs, UTMB/Galveston

Source: L. Petersen

West Nile Virus• Flaviviridae (~80 viruses)

• Single-stranded, + sense, RNA• ~11,000 nucleotides• Tick- & mosquito-borne human pathogens

• Related to yellow fever & dengue

• Distantly related to hepatitis C virus

• Japanese encephalitis serocomplex• Closely related to SLE virus• Primarily bird viruses• Humans not “amplifying” host / reservoir

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Source: L. Petersen

*O

St. Louis encephalitisRocio and St. Louis (Brazil)*West Nile VirusJapanese encephalitis

West Nile and Japanese encephalitisJapanese and Murray ValleyMurray Valley and KunjinO

Distribution of the Japanese Encephalitis Sero- complex of West Nile-Related Flaviviruses before 1999

Source: L. Petersen

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Source: L. Petersen

West Nile Virus before 1996

• Isolation in 1937, West Nile district of Uganda

• Mild dengue-like illness• CNS involvement rare

• Wide distribution in Asia, Eastern Europe, Africa

Source: L. Petersen

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Source: L. Petersen

West Nile Outbreaks• Israel: 1941, 1951-1954, 1957, 1980, 20002000

• France: 1962, 20002000

• South Africa: 1974

• Romania: 19961996

• Italy: 19981998

• Russia: 19991999

• United States: 19991999--20022002

Source: L. Petersen

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Source: L. Petersen

Source: L. Petersen

West Nile Virus Since 1996

• More frequent outbreaks

• Apparent increased severity of human illness• Encephalitis/meningitis• Weakness and/or flaccid paralysis:

poliomyelitis syndrome

• Avian mortality

• Virus introduced into North America (NYC)

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Source: L. Petersen

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Arrival in North

America

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An exotic arbovirus in NYC was surprising and unexpected:

Should it have been?

Source: L. Petersen

WEST NILE VIRUS ENCEPHALITIS CASES WEST NILE VIRUS ENCEPHALITIS CASES & DEATHS IN HUMANS, U. S. A., 1999& DEATHS IN HUMANS, U. S. A., 1999--20022002

YEARYEAR CasesCases Deaths (%)Deaths (%) LOCATIONLOCATION

1999 62 7 (11.3%) New York2000 21 2 (9.5%) New York (14), New Jersey (6),

Connecticut (1)2001 66 9 (14%) New York (15), Florida (12),

New Jersey (12), Connecticut (6) Maryland (6), Pennsylvania (3) Massachussets (2), Georgia (1), Louisiana (1). Mainly in elderly(mean age:70 years old, range 36-90 years); 27 (56%) males.

2002 4,008 263 (6.6%) 37 states + DC. Mainly Illinois, Michigan, Ohio and Louisiana.

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West Nile Virus in the United Statesas of January 28, 2004*

Source: L. Petersen

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West Nile Virus Transmission CycleMosquito vector

Incidental infections

Bird reservoir hosts

Incidental infections

West NileVirus

West NileVirus

Source: L. Petersen

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Source: L. Petersen

Madagascar

Uganda 1937

Central African Republic2

Egypt 1951France 1962 South Africa 1974

NE United StatesIsrael 98/99/2000

India

Kunjin

Romania 1996Italy 1998Volgograd 1999

1

LINEAGEClade

Eg 101

U.S./Israel

Europe/Russia

India

Kunjin

Phylogenetic Tree of West Nile

Viruses

Israel 2000

Source: L. Petersen

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Source: L. Petersen

International Animal Importations Into New York International Animal Importations Into New York August 1998 August 1998 –– July 1999July 1999

N = 2,873,144

none1 – 60006001 - 2000020001 - 5000050001 - 350000350001 -

Animals

Source: L. Petersen

Top Ten Countries of Origin Passengers arriving into NY Airports, July 1998 – June 1999

N = 4,850,090Country Passengers Percent

DOMINICAN REPUBLIC 539,740 11%UNITED KINGDOM 456,540 9%CANADA 350,510 7%FRANCE 312,400 6%MEXICO 310,330 6%ITALY 215,040 4%JAPAN 177,810 4%BRAZIL 157,220 3%ISRAEL 153,540 3%BAHAMAS 143,390 3%GERMANY 129,690 3%BERMUDA 114,750 2%

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Source: L. Petersen

WEST-NILE Virus: Clinical Epidemiology

• Incubation period: 2-14 days• Advanced age primary risk factor for severe

neurological disease and death• Immunosuppressive drugs and hematological

malignancies probable risk factors for severe disease and death

• Approximate 10% mortality among persons with meningo-encephalitis

• Long-term morbidity common

Source: L. Petersen

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Source: L. Petersen

West Nile Fever: Classical Clinical DescriptionWest Nile Fever: Classical Clinical Description

• Mild dengue-like illness of sudden onset

• Duration 3-6 days

• Fever, lymphadenopathy, headache, abdominal pain, vomiting, rash, conjunctivitis, eye pain, anorexia

• Symptoms of West Nile fever in contemporary outbreaks not fully studied

Source: L. Petersen

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Source: L. Petersen

Experimental Infection of Dogs and cats with WEST Experimental Infection of Dogs and cats with WEST NILE VIRUSNILE VIRUS

•Mosquito bite: Low viremia of short duration developed in four dogs but they did not display signs of disease.

Four cats became viremic, with peak titers ranging from 103.0 to 104.0 PFU/mL. Three of the cats showed mild,

non-neurologic signs of disease. WNV was not isolated from saliva of either dogs or cats during the period of viremia.

•Oral infection: four cats exposed to WNV through ingestion of infected mice. Two cats consumed an infected mouse on

three consecutive days, and two cats ate a single infected mouse.Viremia developed in all four cats with a magnitude and

duration similar to that seen in cats infected by mosquito bite, but none of the four showed clinical signs.

Source: Austgen et al., Emerg Infect. Dis., 2004;10:82-86

Source: L. Petersen

Experimental Infection of Dogs and cats with WEST Experimental Infection of Dogs and cats with WEST NILE VIRUSNILE VIRUS

•These results suggest that dogs and cats are readily infected by WNV.

•The high efficiency of oral transmission observed with cats suggests that infected prey animals may serve as an important source of infection to carnivores.

•Neither species is likely to function as an epidemiologicallyimportant amplifying host, although the peak viremiaobserved in cats may be high enough to infect mosquitoes at low efficiency.

Source: Austgen et al., Emerg Infect. Dis., 2004;10:82-86

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Source: L. Petersen

SYMPTOMS ASSOCIATED WITH WEST NILE SYMPTOMS ASSOCIATED WITH WEST NILE VIRUS INFECTION IN HORSESVIRUS INFECTION IN HORSES

•• Usually, asymptomatic. Clinical signs (neurological) in about 10% of all infections (Camargue, 1962), to about 20% of all infections (Tuscany, 1998) and to less than 40% of all infections in Long Island, New York, (1999).

•• Neurological disease in Horses: Posterior ataxia, proprioception deficits, altered behaviour. Severe cases: Paralysis of the hind legs, recumbency, terminal convulsion and death.

Source: L. Petersen

Clinical signs in horses with West Nile Clinical signs in horses with West Nile encephalitis, USA, 2000.encephalitis, USA, 2000.

SymptomSymptom Percentage of horses with signPercentage of horses with sign

Ataxia 85Weakness of limbs 48Recumbency, difficulty rising, or both 45Muscle fasciculation 40Fever 23Paralyzed or drooping lip 18Twitching face or muzzle 13Teeth grinding 7Blindness 5

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Source: L. Petersen

WEST NILE VIRUS OUTBREAKS IN HORSESWEST NILE VIRUS OUTBREAKS IN HORSESYEARYEAR LOCATIONLOCATION # CASES# CASES # DEATHS# DEATHS

1960s Egypt ? ?

1962 France (Camargue) about 80 10%

1996 Morocco 94 42 (44.7%)

1998 Italy 14 6 (42.8%)

1999 USA (2 States) 25 9 (36%)

2000 France 76 21 (27.6%)(8.5%; 432/5,107 sero+)

Source: L. Petersen

WEST NILE VIRUS OUTBREAKS IN HORSES:WEST NILE VIRUS OUTBREAKS IN HORSES:Beginning of an epidemic?Beginning of an epidemic?

YEARYEAR LOCATIONLOCATION # CASES# CASES # DEATHS# DEATHS

1999 USA (1State) 25 9 (36%)

2000 USA (7 States) 60 23 (38%)

2001 USA (20 States) 752 (651*) 156/470 (33%)

2002 USA (40 states) 14,717 1/3 to 1/4

* Confirmed by USDA

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Source: L. Petersen

1999 and 2000 WNV Serosurvey Results

0.00731CT 2000Fairfield Co.

0.121834NYS 2000Suffolk Co.

0.464871NYC 2000Staten Is.

2.619677NYC 1999Queens

Sero-prevalence

(%)PositivesParticipantsLocation

Source: L. Petersen

~80%Asymptomatic

~20%“West Nile Fever”

<1%CNS

disease

~10% fatal(<0.1% of total infections)

WNV Human Infection “Iceberg”

1 CNS disease case=

~150 total infectionsVery crude estimates

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Source: L. Petersen

Neurological Presentations of West Nile Virus Infection

• New York City 1999• Meningitis/meningoencephalitis 62%• Meningitis 32%• Complete flaccid paralysis 10%

• Confused with Guillain-Barre syndrome• Poliomyelitis-like syndrome

• Other reports• Ataxia, extrapyramidal signs, cranial nerve

abnormalities, myelitis, optic neuritis, seizures

Source: L. Petersen

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Source: L. Petersen

InfectionIllness onset

D4 – D6 illness 1Y after illness

Viremia

IgM

IgG & Nt

D14 – D21 illness

Con

cent

ratio

n

Timing of WNV Viremia and Antibody Response

Source: L. Petersen

Diagnostic methods

• Serology• IgM-capture ELISA (MAC-ELISA); 95% positive within

8 days of symptom onset• IgG ELISA• Plaque-reduction neutralization assay

• Amplification• TaqMAN (Detection: 0.1 pfu/0.1ml; ~ 50 copies / mL)• rt PCR (10 pfu)

• Virus isolation on Vero cells (1pfu)• Immunohistochemistry• WNV antigen detection

• ELISA/dipstick (10 pfu)

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Source: L. Petersen

Geographic spread:

1999-2001

Source: L. Petersen

WNV SurveillanceWNV Surveillance

• Dead birds (especially crows)• Human surveillance• Horse surveillance• Mosquitoes• Live captive sentinels (e.g. chickens)• Live wild birds• Zoo animals

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1999-2002 Verified WNV Surveillance Results Reported to ArboNet

7319197,33266/927+DC2001

44 + DC

11 + DC

4

States

14,717

63

25

Horses

4,943*14,122*4,008/2632002

5154,30521/22000

16?62/61999

MosquitoPools

Birds(dead)

Humans/Fatalities

Year

* As of November 30, 2002

Source: L. Petersen

Human WNV Disease Cases, by Week of Onset, Human WNV Disease Cases, by Week of Onset, Northern vs. Southern United States, 2002*Northern vs. Southern United States, 2002*

050

100150200250300350400450

6/15 7/

6

8/3

9/7

9/28

Week ending

# ca

ses

NorthSouth

* As of 10/08/2002

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Source: L. Petersen

U.S. Counties Reporting WNV-Positive Birds

1999

28 counties

Source: L. Petersen

U.S. counties reporting humanhuman WNV illness19991999 (N = 6 counties)

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2000JAN - DEC136 counties

U.S. Counties Reporting WNV-Positive Birds

Source: L. Petersen

U.S. counties reporting humanhuman WNV illness20002000 (N = 10 counties)

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2001JAN - DEC319 counties

U.S. Counties Reporting WNV-Positive Birds

Source: L. Petersen

U.S. Counties Reporting Human WNV Disease Cases

20012001JAN JAN –– DECDEC

39 counties39 counties

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WEST NILE VIRUS IN HORSES, USA, 1999WEST NILE VIRUS IN HORSES, USA, 1999--20022002

YEARYEAR STATESSTATES

1999 New York (2 counties, 25 horses).

2000 Connecticut , Delaware, Massachusetts, New Jersey, New York, Pennsylvania, Rhode Island.

2001 Alabama, Connecticut (5 counties, 11 horses), Delaware, Florida (42 counties, 492 horses), Georgia (26 counties, 68 horses), Illinois, Indiana, Kentucky, Louisiana, Maryland, Massachusetts (4 counties, 45 horses), Mississippi, New Hampshire, New Jersey (10 counties, 33 horses), New York, North Carolina, Pennsylvania, Rhode Island, Tennessee, Virginia.

2002 40 States, 14,717 horses

Source: L. Petersen

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Novel Modes of West Nile Virus Novel Modes of West Nile Virus Transmission, 2002Transmission, 2002

• Transplanted organs• Transfused blood• Breast milk• Percutaneous, occupational exposure

Source: L. Petersen

West Nile Virus Infection in an Organ Donor West Nile Virus Infection in an Organ Donor and Four Transplant Recipients, August 2002and Four Transplant Recipients, August 2002

Organ Donor

WNV PCR –IgM –

Organ Donor

WNV PCR +

Culture +IgM –

Kidney recipientWNME (fatal)

Kidney recipientWNME

Liver recipientWNF

Heart recipientWNME

Blood Blood components components

from 63 donorsfrom 63 donors

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Source: L. Petersen

Patients with Confirmed Patients with Confirmed TransfusionTransfusion--Related WNV InfectionRelated WNV Infection

CasesCasesPatient 1 Patient 1 Patient 2 Patient 2 Patient 3Patient 3Patient 4 Patient 4 Patient 5 Patient 5 Patient 6Patient 6Patient 7 Patient 7 Patient 8Patient 8Patient 9Patient 9Patient 10Patient 10

Underlying Underlying conditioncondition

Post partumPost partumLiver transplantLiver transplant

Post partumPost partumAMLAML

CancerCancerCancerCancer

AMLAMLPendingPending

BMTBMTCancerCancer

OutcomeOutcomeAliveAliveAliveAliveAliveAliveAliveAliveFatalFatalAliveAliveFatalFatalAliveAliveAliveAliveAliveAlive

MosquitoMosquitoExposureExposure

YesYesPossiblePossible

YesYesNoNo

UnlikelyUnlikelyPossiblePossiblePossiblePossibleUnlikelyUnlikelyPossiblePossiblePossiblePossible

Source: L. Petersen

TransfusionTransfusion--associated WNV Infectionassociated WNV InfectionPatients 2 (s/p Liver Transplant) and 3 (PostPatients 2 (s/p Liver Transplant) and 3 (Post--partumpartum))

9/29/2 9/59/5

IllnessIllnessonsetonset

CSFIgM +

8/208/208/158/15 10/710/78/178/17

Serum Serum IgMIgM ++

DONOR

PATIENT 2 (39 donors)

PRBC PRBC transfusedtransfused

9/39/3 9/139/13

Illness Illness onsetonset

PATIENT 3 (2 donors)

9/189/18

CSFCSFIgMIgM ++

DonationDonation

DONORFever; weakness 8/19Fever; weakness 8/19

rash 8/20rash 8/20

PLTS transfused

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Source: L. Petersen

Ten Confirmed Cases of TransfusionTen Confirmed Cases of Transfusion--Associated Associated West Nile Virus Infection: SummaryWest Nile Virus Infection: Summary

•• Illness onset: August 1 Illness onset: August 1 –– October 9October 9

•• Days from transfusion to illness onsetDays from transfusion to illness onsetRange: 3 Range: 3 –– 2222Median: 10.4Median: 10.4

•• Duration of PCR+: at least 17 days after symptom Duration of PCR+: at least 17 days after symptom onset for 1 patientonset for 1 patient

•• Implicated componentsImplicated componentsRed blood cells (4)Red blood cells (4)Platelets (4)Platelets (4)FFP (2)FFP (2)

Source: L. Petersen

Summary of Six Implicated DonorsSummary of Six Implicated Donors

•• Dates of Donation: July 22 Dates of Donation: July 22 –– September 6September 6

•• WNV symptom onsetsWNV symptom onsets1 donor: pre1 donor: pre--donation (URI symptoms donation (URI symptoms –– onset onset unclear)unclear)1 donor: 5 days pre1 donor: 5 days pre--donationdonation2 donors: 2 days 2 donors: 2 days –– 4 days post donation4 days post donation1 donor: 11 days post1 donor: 11 days post--donationdonation1 donor: within 3 weeks after donation1 donor: within 3 weeks after donation

•• Maximum interval from donation to transfusion Maximum interval from donation to transfusion PLT 5 days; RBC 26 days; FFP 44 daysPLT 5 days; RBC 26 days; FFP 44 days

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Source: L. Petersen

Source: L. Petersen

Prevention

• Repellants• DEET (up to 50% concentration); 10% in

children• Permethrin on clothing and fabrics

• Reduce mosquito breeding sites• Long sleeves and pants• Stay indoors when mosquitoes are biting (dawn

and dusk)• Bug zappers, CO2 devices (mosquito magnet):

save your money

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Source: L. Petersen

Summary

• Mosquito-borne infection of birds • Continued geographic spread likely• In humans:

• Incubation period short• Most (approx 80%) infections asymptomatic• Severe neurological disease more likely in

elderly and persons with hematological malignancies and on immunosuppressive drugs

Source: L. Petersen

Summary

• Human incidence peaks in late summer• Year-round transmission possible in south• Late fall transmission possible in north

• Human incidence variable by year• Probably >400,000 persons infected in 2002• Proven transmission through organ donation and

blood transmission; probable transmission through breast milk