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