West Nile Virus

Gary Green, MDInfectious Diseases

Santa Rosa Kaiser Medical Center

WNV CA DHS Pamphlet

History & Ecology• First isolated in febrile women in Uganda

(West Nile District) in 1937 (1)

• Endemic Geography– Historically: Africa, west/central Asia,

Middle East, Australia– Recently: Russia, Romania, France, Israel

• No previous case in Western Hemisphere < 1999• Natural Life Cycle: Culex mosquitoes birds(2)

(1) Smithburn KC et al. Am J Med Hygiene. 1940. 20: 471-92

(2) Goddard L. et al. Emerg Inf Dis. 2002. 8(12); 1385-1391.

Virology

• Neurotrophic ss RNA virus

• Family: Flaviviridae

• Genus: Flavivirus

• member of Japanese Encephalitis complex:– St Louis Virus

– Japanese Encephalitis virus

– West Nile virus

– Murral Valley virus

– Rocio virus (brazil)

– Kunjin virus

www.cdc.gov/ncidod/dvdib/westnile/cycle.htm

Other Incidental Hosts

• bats

• a chipmunk

• a squirrel

• a rabbit

• 5 dogs (Africa, USA-immunocompromised)

• a domestic cat

• goats and sheep (not confirmed)

list is growing

Historical Human Outbreaks

Israel 1951-54, 1957 , 2000France 1962, 2000South Africa 1974Algeria 1994Italy 1998Romania 1996 underlined: severe CNS cases

Czech Republic 1997Russia 1999United States 1999-2002

• since 1990’s, increase in severe CNS outbreaks• ? More neuro-virulent strains of WNV

1st US WNV casesAugust 1999, NYC. ID MD reported 2 severe cases encephalitis to

NYCDOH. NYCDOH initiated hospital survey: 6 more cases (7 severe muscular weakness, 3 w/flaccid paralysis)presumptive Dx SLE, but ... SLE PCR (-)Bronx Zoo reports lg # birds dying of encephalitisNYC residents report lg # dying crowsZoo birds and crows test (+) WNVhuman cases tested for WNV and (+)

WNV in USA1999-2002:

• 44 states reported human WNV activity

• >4000 cases reported to CDC

(3,893 lab confirmed)

• 281 deaths associated with WNV

(254 lab confirmed)

• ~ 6.25% mortality rate

• ~ 71% WNME, 21% WNF, 8% Unknown(As of 2/18/03)

Where did come from?

• WNV in NYC may be from Israel or Europe• >40 strains of WNV• WNV strain isolated in 1999 from NYC humans,

mosquitoes, horses, birds shares 99.9% nucleotide homology (RT-PCR) to 1998 WNV strain isolated from domestic geese in Israel (1)

• WNV isolated in Israel in migrating fledgling flock of white storks (Ciconia cionia) contracted WNV in Europe before flying south (2)

(1) Deubel V, et al. Emerg Infect Dis. 2001. 7(3):536(2) Malkinson M. 2001. Emerg Infect Dis. 2001. 7(3) 540.

WNV 1999

WNV 1999-2000

WNV 1999-2001

WNV 1999-2002

WNV 2002 Human Cases(report submitted 4-22-03)

Imported WNV cases to CA

PPT presentaion: Carol Glaser DVM, MD. CA DOH (VRDL)

Confirmed WN AFP

Los Angeles, CAKansasMale54

Confirmed WN encephalitis

Milwaukee, WISan MateoMale66

Confirmed WN fever

FloridaVenturaMale50

Female

Male

Male

Male

Gender

Confirmed WN fever

Washington, D.C.San Francisco20

Confirmed WN meningitis

NebraskaOrange70

Probable WN encephalitis

Chicago,Illinois

Contra Costa57

Confirmed WN encephalitis

Los Angeles, CAHouston, Texas45

DiagnosisTravelCounty of Residence

Age

WNV case in California, 2002mystery case …

• 31 year old female, Los Angeles County resident• Dx: aseptic meningitis early-mid August 2002• pt completely recovered• laboratory evaluation confirmed WNV• patient interviewed multiple times - no travel

outside CA, no other risk factors identified

• NO other human cases or other components of surveillance positive

• one theory: “hitchhiker” mosquito (eg., malaria)

WNV Wild Bird Activity 2002(report submitted 4-22-03)

WNV Mosquito Activity 2002(report submitted 4-22-03)

Sentinel Chicken Activity 2002(report submitted 4-22-03)

WNV Surveillance

ArboNet: system of reporting Arboviral pathogens (WNV, WEE, EEE, SLE, LCE) coordinated thruCDC, USGS, State DOH, county PH agencies

• Mosquito • Birds

–Sentinel Chickens –(dead) Wild Birds

• Equine• Human

ArboNet

• CDC “real-time” reporting system for WNV

year states human birds horses mosquitoes(deaths) pools

1999 4 62 (7) ? 25 16

2000 11+DC 21 (2) 4305 63 515

2001 27+DC 66 (9) 7332 731 919

2002 39+DC 4,007 (263) 8,533 14,717 4,931

Total 4,156 (281)

WNV Surveillance • Mosquito (Sonoma/Marin Mosquito & Vector Control District)

– environmental surveillance (phone: 285-2200)– mosquito pool testing (WNV, SLE, WEE)

• Birds– Sentinel Chickens (since 1979)

• >200 flocks strategically located throughout CA• monitored 2 x week for seroconversion

– (dead) Wild Birds phone: 877 WNV-BIRD• Equine case reporting (~40% mortality)• Human cases reporting

– California Encephalitis Project– Viral and Rickettsial Disease Laboratory

WNV Ecologic Activity(compliments of Leigh Hall MD, ppt presentation)

Dis

ease

Act

ivity

Aug

Oct

dead birds

chickens

mosquitoes

Veterinary cases

Human Cases

Clinical WNV

• Incubation period: 3-14 days

• ~80% people infected are ASYMPTOMATIC

• ~20% people infected develop “West Nile Fever”– sudden, onset mild dengue-like illness

– duration 3-6 days

– fever, HA, ocular pain, conjunctivitis, abd pain, N/V, anorexia, lymphadenopathy

• 1/150 (<1%) develop Meningitis/Encephalitis

~10% mortality (3-15%) for encephalitis

Risk Factors for CNS WNV

• Older age– x10 incidence age 50-59 vs age 0-19 years

– x43 incidence age >80 vs age 0-19 years

• Immune-suppressed– organ transplant

– HIV

– ? Recent chemotherapy, lymphoma, etc

WNV Hospitalized PatientsNYC, 1999

• Fever 90 %• weakness 56 %• nausea 53 %• vomiting 51 %• HA 47 %• change MS 46 %• diarrhea 27 %• rash 19 %• LN 2 %

Morbidity after CNS WNV disease

NY and NJ WNV patients (2000)• At hospital discharge:

>50% not at baseline functional level

only 33% ambulatory

NYC patients (1999 illness)• One year after discharge:

fatigue 67% memory loss 50%

difficulty walking 49% depression 38%

muscle weakness 44%

(CDC Training slide, Leigh Hall, MD PH Officer)

WNV Spectrum of Serious CNS Illness

• Aseptic Meningitis• Encephalitis• Acute Flaccid Paralysis (polio-like, GBS)• Acute demyelinating encephalomyelitis (ADEM)• Optic neuritis• ? Movement disorder• ? Parkinson-type syndrome• Rhabdomyalysis• Fetal WNV infection

(CNS developmental abnormalities)

WNV Diagnosis• West Nile Fever: IgM WNV IFA (PH lab)• CNS WNV: IgM WNV ELISA (CSF/Serum)

~90-95% (+) by day 8 of Sx’smay remain (+) 10-18 months; X-rxn YF, JEV

• IgG EIA Serology (x4 increase in titre)

• PCR WNV on CSF– poor sensitivity: 55% for CSF, 10% for Serum– of 19 cases WNV NY/NJ– 18 (+) CSF IgM, 1 of 13 (+) PCR on CSF

Emerg Infect Dis. 2001• Immunohistochemistry on neural tissue

WNV Treatment

West Nile Fever: outpt symptomatic Tx

(analgesics, rest, fluids)

West Nile Neurologic Illness:

• supportive Tx (ICU, MechVent, IVF, etc)

• ? Ribaviron

• ? IV IgG

WNV Transmission

Primary

• mosquito bites

(NOT human-human, horse, bird handling)

Secondary

• Transfusion

• Trans-placental

• Breast-feeding

• Organ Transplantation

• Occupational Exposure (lab)

Transfusion related WNV

2002. Georgia - Florida

• MVA victim, multiple transfusions, “brain dead”

• organ-donor candidate, serum PCR (+) WNV

• received multiple transfusions, all PCR (-)

• 4/4 recipients of donated organs developed Fever

• 3/4 recipients of donated organs Encephalitis

• 1/3 patients with Encephalitis died.MMWR. 2002. 51; 790

Transfusion related WNV

• WNV infection documented from:– PRBCs, FFP, Platelets

• Blood Banks

• after July 1, 2003 in Endemic Regions

• apply new Nucleic Acid technology to screen all blood products directly for West Nile Viral particles

• ? Sensitivity of Nucleic Acid Testing

WNV Intrauterine InfectionNovember 2002. First documented Intrauterine Infection20 year-old gravida female hospitalized for weakness in her legs. Dx Meningo-encephalitis. Fetal monitoring “normal”Maternal serology: WNV IgM (+) After Delivery: Infant Chorioretinitis by ophthalm. examInfant MRI: severe (B) temporal/occipital white-matter losscore & peripheral infant blood: WNV-IgM (+)

MMWR. 2002. 51(50):1135-1136CDC rec’s: (1) mosquito precautions for pregnant women,

(2) not to screen asymptomatic preg women or newborns.

WNV Transmission by Breast-feeding

• October, 2002

• documented WNV infection in infant after breast-feeding.

• MMWR. 2002

Occupational Transmission

• 2002• 2 reported cases of occupationally-acquired

infection among lab workers• Both percutaneous injury while performing

necropsy for WNV surveillance• Clinically “WNV fever” (not encephalitis)• Serology (+) WNV

MMWR 2002. 51:1133-1135.

Mosquito Vectors

Culex genus probably primary vector

“ornithophilic” mosquito (prefer feed on birds)

• Avian species: enzootic-epizootic VECTORS

• Mammals: epizootic “dead end” hosts (not vectors)

(primarily equine, dogs reported)

• Humans: epidemic (“dead end”) hosts

(not natural vectors)

Mosquito Vectors

Culex genus ~ primary vector

• Africa, Middle East Culex univatattus• Asia Culex vishnui complex • New York (1999) Culex pipiens complex

since NY outbreak, WNV has been recovered in >26 species of North American mosquitoes (from genus: Culex, Ochlerotatus, Aedes, Culiseta

Goddard L. et al. Emerg Infect Dis. 2002. 8(12); 13851391

California mosquito vectors

• Culex pipiens (complex) *• Culex tarsalis *• Culex erythrothorax

• Other accessory mosquito vectors (Fresh/Salt Water)

– Ochlerotatus dorsalis Anopheles punctipennis – Oc. squamiger Coquillettidia perturbans– Oc. washinoi Psorophora columbia– Oc. melanimon Cx quinquefasciatus– Aedes albopictus, vexans Cx restuans– Culiseta inornata Cx stigmatosoma

(*) also transmission vectors of SLE and WEE

Ochlerotatus (= Aedes) sierrensisTree hole Mosquito

• Primary vector of Dirofilaria immitis (dog heartworm) in Marin/Sonoma counties, NOT WNV

• Eggs deposited rot hole cavities in >50 species of trees

• Logistical problems treating larvae which develop for months before

• Difficult to control in the adult stage, emerging in the spring

• Males form mating swarm around the host – unlike any other species in California

Mosquito Precautions• Limit outdoor activity when mosquitoes are most

active: dawn and dusk

• wear long pants, long sleeve shirts when outside

• use insect repellant (according to label instruct.)

• tight fitting screens to doors/windows

(repair holes in screens, doors, windows)

• eliminate all sources of standing water

(rain gutter, old tires, ponds, old pots/cans, etc.)

• obtain (free) mosquito larvae-eating fish in ponds

Mosquito Control Actions• Eliminate aquatic breeding grounds (public/vector control)• Mosquito fish (Gambusia affinis)• disperse B.T.I. - Bacillus thuringiensis, subsp israelensis

H-14. Bacteria produces protein crystals (delta-toxin) that contain larvicidal activity against mosquitoes, black flies, midges.

• Spray ALTOSID (active ingredient Methoprene). Insect growth regulator that kills immature adult mosquitoes. Not classified as a toxin. Target specific - does not harm mammals, waterfowl or (beneficial) predatory insects. WHO recommends use in drinking H20 for mosquito control in developing countries.

Mosquito fish

Gambusia affinis

larva

egg raftpupa

Culex female

WNV in Birds

• birds are the primary amplifier hosts• migratory birds have expanded endemic region• WN isolated from >138 species wild birds

– both wetland and terrestrial species

• highly infectious for North American birds• high viremia and potential avian mortality

(0-90% mortality depending on bird species) avian encephalitis documented in NYC evaluation

Some Birds isolated with WNV

Native Bird Species Am erican Crow Budgerigar Fox Sparrow Northern Bobwhite Scarlet Ibis Am erican Goldfinch Canada Goose Golden Eagle Northern Cardinal Sharp-shinned Hawk Am erican Kestrel Canada W arbler Gray Catbird Northern Goshawk Short-eared Owl

Am erican Robin Carolina Chickadee Great B lack-backed Gull Northern Mockingbird Snowy Owl

Am erican Tree Sparrow Carolina W ren Great B lue Heron Northern Parula Song Sparrow

Am erican W hite Pelican Cedar W axwing Great Horned Owl Northern Saw-whet Owl Steller's Jay

Bald Eagle Chim ney Swift Great-tailed Grackle Northern W aterthrush Swainson's Hawk Baltim ore Oriole Com m on Grackle Green Heron Osprey Swallow-tailed Kite

Barn Owl Com m on Ground-Dove Harris' Hawk Ovenbird Traill's Flycatcher

Barred Owl Com m on Nighthawk Herm it Thrush Purple F inch Tufted Titm ouse Belted Kingfisher Com m on Raven Herring Gull Purple Martin Turkey Vulture

Black Skim m er Com m on Yellowthroat Hooded W arbler Red-headed W oodpecker Veery

Black Vulture Cooper's Hawk House Finch Red-shouldered Hawk Virginia Rail Black-billed Magpie Dickcissel House Sparrow Red-tailed Hawk W arbling Vireo Black-capped Chickadee

Double-crested Corm orant Kentucky W arbler Red-winged Blackbird W estern Scrub-Jay

Black-crowned Night Heron Downy W oodpecker Killdeer Ring-billed Gull W hite-breasted Nuthatch

Blackpoll W arbler Eastern Bluebird Laughing Gull Ring-necked Pheasant W hite-crowned Pigeon Black-throated Blue W arbler Eastern Kingbird Least B ittern Rock Dove W ild Turkey

Black-whiskered Vireo Eastern Phoebe Loggerhead Shrike Rough-legged Hawk W ood Duck

Blue Jay Eastern Screech-Owl Mallard Ruby-throated Hum m ingbird W ood Thrush

Boat-tailed Grackle Eurasian W igeon Merlin Ruddy Turnstone Yellow W arbler Brewer's B lackbird European Starling Mississippi K ite Ruffed Grouse Yellow-bellied Sapsucker Broad-winged Hawk Evening Grosbeak Mourning Dove Rusty Blackbird Yellow-billed Cuckoo Brown Thrasher Field Sparrow Mute Swan Sandhill Crane

Brown-headed Cowbird Fish Crow Nashville W arbler Savannah Sparrow

Yellow-rum ped W arbler

138 bird species reported to CDC’s West Nile Virus avian mortality database from 1999- 5/19/03

CDC: Seroprevalence Studies

NYC 1999 2.6% 19/677 (+) Ab samples(Queens, epi-center of 1999 outbreak)

NYC 2000 0.46% 4/871(Staten Island)

NYS 2000 0.12% 1/834(Suffolk County, no clinical cases reported)

CT 2000 0 0/731(Fairfield County)

Mosquito Status 6-03

WNV Wild Bird Status 6-03

WNV Sentinel Chicken Activity 6-03

WNV Equine Activity 6-03

WNV Vaccine ResearchTesh R. et al, Emerg Infectious Dis. 2002. 8(12);1392-1398

hamster model research (Mesocricetus auratus)

effective protective immunity– Hemagglutination Inhibition (HI)

– Complement Fixation (CF)

– Plaque Reduction Neutralization (PRN)

3 immunization strategies:

• WNV Encephalitis Vaccine (killed)

• Live-attenuated Chimeric WNV vaccine

• passive immunization (WNV immune serum)

WNV Vaccine ResearchTesh R. et al, Emerg Infectious Dis. 2002. 8(12);1392-1398

“Fort Dodge” WNV killed vaccine• formalin-inactivated whole virion preparation

– 8/9 hamsters HI and CF Ab’s 1 mo after vaccine

– 5/9 hamsters PRN Ab’s 1 mo after vaccine

– WNV challenge -> inc HI, CF titres, 2/9 viremic

– no animals appeared ill or died

• commercially available veterinary vaccine(Fort Dodge Animal Health; Fort Dodge IA)

• conditional approval for horses (US Dept Agricult)• ? duration of immunity, recom annual vaccination

WNV Vaccine ResearchTesh R. et al, Emerg Infectious Dis. 2002. 8(12);1392-1398

ChimeriVax-WNV Vaccine• Live-attenuated Chimeric vaccine• YFV 17D live vector for envelope genes of WNV

– 10/10 hamsters detectable HI, CF, PRN titres– WNV challenge -> no inc Ab titres, 1/10 viremic– no animals appeared ill or died

Passive immunization• hamster WNV-immune serum

– WNV challenge 24 hrs after immunization– 6/6 hamsters had low HI titres– no viremia, no animals ill or dead

many thanks...

• Leigh Hall MD

Deputy Officer, Sonoma County Public Health

Chairman, WNV Task Force

• Carol Glaser DVM, MD

CA DOH, Viral & Rickettsial Disease Lab

California Encephalitis Project

• Chris Canterbury and Ronald Keith

Marin/Sonoma Mosquito & Vector Control Dist.

More WNV info...

• CA Department of Health

www.westnile.ca.gov

• Marin/Sonoma Mosquito & Vector Control

www.msmosquito.com

• CDC

www.cdc.gov/ncidod/dvbid/westnile/index.htm

• UC Davis

www.vetmed.ucdavis.edu/ceh/wnv_info.html