West Nile Virus: An Emerging Disease

1
West Nile Virus An Emerging Disease
Linda C. Glaser, DVM Wisconsin Division of
Public Health
2
West Nile Virus -Background

• First isolated in 1937 in Uganda
• First recorded human epidemics in Israel in the
  1950s
• Since mid-1990s
• 10 human outbreaks in 7 counties since 1994
• Increase in frequency of human outbreaks
• Increase in severity of human disease
• High avian death rates w/human outbreaks in
  Israel, US
• The New York 1999 strain of WNV most similar to
  an isolate from a domestic goose in Israel

3
West Nile Virus -Background

• Birds are the primary hosts
• Most classes of vertebrates susceptible to
  infection - mammals, birds, reptiles, amphibians
• Humans are incidental hosts with typical
  infection causing mild flu-like symptoms
• High-titer viremia sufficient to transmit a virus
  is rare in species other than birds.

4
West Nile Virus - Mosquitoes

• 175 mosquito species found in the U.S.
• Over 50 species of mosquitoes in Wisconsin
• Not all of them bite people
• Only female mosquitoes seek blood meals
• Very few mosquitoes are infected with virus
• Typically lt1 mosquitoes of any species found
  with virus

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West Nile Virus - Transmission Cycle
Transmission Cycle
Incidental infections
Reservoir hosts
6
West Nile Virus - Worldwide Distribution
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West Nile Virus 2002 Distribution in the U.S.
8
West Nile Virus Distribution of 2002 Human
Epidemic
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West Nile Virus 2002 Human Epidemic in the U.S.

• Western hemispheres largest arboviral ME
  epidemic
• 2,741 WNME cases
• 1,267 WNF / unspecified
• 263 deaths
• 39 states D.C
• Largest WNME epidemic EVER
• New clinical syndromes
• Five new transmission modes

West Nile virus New modes of transmission Dr.
Anthony Marfin, M.D, MPH 4th WNV Natl
Conference
As of 2/5/2003
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West Nile Virus In Wisconsin
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West Nile Virus In Wisconsin

• WNV Dead Bird Surveillance
• Sensitive indicator of viral activity in the
  environment
• Monitor the spread of the virus
• Crudely estimates intensity of epizootic
• Does not predict human risk

12
West Nile Virus In Wisconsin

• Data collection
• Recorded reports of sick and dead corvids (crow,
  raven, and blue jay)
• Report located to zip code for mapping
• Report identified a date found
• 5873 reports from 5/1-10/31/02
• 532 of 791 birds tested were positive (between
  6/25/02 and 10/08/02)

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West Nile Virus In Wisconsin
2002 Statewide Corvid Data
Corvids Reported (N5873)
Corvids Positive for WNV(N532)
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West Nile Virus In Wisconsin
2002 Statewide Corvid Data
Corvids Positive (N532)
Corvids Negative (N257)
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West Nile Virus In Wisconsin
16
West Nile Virus In Wisconsin

• 52 people with illness from WNV in 2002 (Age
  range 20-93 yo)
• 3 fatalities
• Date of illness onset from 7/13-10/20/02 (N48)
• 29 of 47 people were hospitalized
• 16 of 42 people had severe illness (neurological
  involvement)

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WNV Human Infection Iceberg
1 CNS disease case 150 total infections
10 fatal (lt0.1 of total infections)
lt1 CNS disease
Very crude estimates
20 West Nile Fever
Emerging Clinical Syndromes of West Nile Virus
Infection Dr. J. Sevjar, M.D 4th WNV Natl
Conference
80 Asymptomatic
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West Nile Virus - Human Infections

• Incubation period of 2-15 days
• Most illness is West Nile Fever
• self-limited
• headache with fever
• rash, lymphadenopathy
• nausea, vomiting
• Rarely pancreatitis, hepatitis, myocarditis

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West Nile Virus - Human Infections

• Severe neurologic illness categories
• Meningitis - fever, neck stiffness, CSF
  pleocytosis
• Encephalitis - altered mental status
• Meningoencephalitis
• Acute flaccid paralysis

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West Nile Virus - Human Infections Clinical
Investigations in 2002

• Prospective clinical case series
• Detailed serial neurologic exams
• 16 patients identified
• WNV Fever Study
• Detailed neurodiagnostic studies on large numbers
  of patients
• House-to-house serosurvey

Emerging Clinical Syndromes of West Nile Virus
Infection Dr. J. Sevjar, M.D, 4th WNV Natl
Conference
21
West Nile Virus - Human InfectionsClinical
Syndromes-The Scope of Illness

• West Nile fever
• Emerging clinical syndromes
• Movement disorders
• Parkinsonism
• Flaccid paralysis
• Rhabdomyolysis
• Outcomes / prognosis
• Future directions

Emerging Clinical Syndromes of West Nile Virus
Infection Dr. J. Sevjar, M.D, 4th WNV Natl
Conference
22
West Nile Virus-Human InfectionsWest Nile Fever

• Felt to represent the majority of symptomatic
  infections
• Subacute progression to severe CNS disease
  unlikely
• Development of meningitis / encephalitis /
  paralysis within 24-48 hours of fever onset
• No subsequent hospitalization among fever
  outpatients
• Increased detectionfewer cases truly
  asymptomatic??

Emerging Clinical Syndromes of West Nile Virus
Infection Dr. J. Sevjar, M.D, 4th WNV Natl
Conference
23
West Nile Virus-Human Infections Movement
Disorders

• Tremor - 15 (94) of prospective series patients
  
• Occasionally disabling
• Myoclonus - 10 (63)
• Upper extremity, facial involvement
• Nocturnal myoclonus
• Onset of both generally gt 5 days following
  initial symptoms

Emerging Clinical Syndromes of West Nile Virus
Infection Dr. J. Sevjar, M.D, 4th WNV Natl
Conference
24
West Nile Virus-Human Infections Parkinsonism

• Parkinsonism - Observed in 11 (68)
• Seen both in encephalitis and meningitis cases

Emerging Clinical Syndromes of West Nile Virus
Infection Dr. J. Sevjar, M.D, 4th WNV Natl
Conference
25
West Nile Virus-Human Infections WNV Associated
Flaccid Paralysis

• Previously described
• Relatively young lack of premorbid conditions
• May have absence of feverheadache
• Onset during acute infection
• Multiple alternative diagnoses
• Little or no improvement short-term

Emerging Clinical Syndromes of West Nile Virus
Infection Dr. J. Sevjar, M.D, 4th WNV Natl
Conference
26
West Nile Virus-Human Infections Rhabdomyolysis

• Rhabdomyolysis - acute destruction of skeletal
  muscle cells
• Reported in 14 people from the Chicago area
  infected with WNV
• Trauma, medication effect unlikely

Emerging Clinical Syndromes of West Nile Virus
Infection Dr. J. Sevjar, M.D, 4th WNV Natl
Conference
27
West Nile Virus-Human InfectionsClinical
Outcomes Data

• Current data limited
• 10 fatality rate with CNS disease
• Long term outcomes in NYC patients
• gt50 w/continued impairment at 1 year
• 37 considered fully recovered

Emerging Clinical Syndromes of West Nile Virus
Infection Dr. J. Sevjar, M.D, 4th WNV Natl
Conference
28
West Nile Virus-Human InfectionsClinical
Outcomes Data

• Short-term prospective data
• No deaths
• Most patients (14/16 88) eventually went home
• Follow-up
• Persistent / chronic headache
• Concentration, memory difficulties
• Overwhelming fatigue
• Persistence of tremor, parkinsonism
• Paralysis - no short-term improvement

Emerging Clinical Syndromes of West Nile Virus
Infection Dr. J. Sevjar, M.D, 4th WNV Natl
Conference
29
West Nile Virus-Human InfectionsModes of
Transmission

• Transplantation
• Transfusion
• Breastfeeding
• Transplacental transmission
• Occupational exposure

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West Nile Virus-Human InfectionsTransfusion
Associated Transmission

• 60 investigations, Aug 2002 - Jan 2003
• 20 confirmed cases
• 14 infectious unit donors identified
• 21 on-going investigations
• 19 no transmission evidence
• gt 2500 samples tested (NAAT serology)

West Nile virus New modes of transmission Dr.
Anthony Marfin, M.D, MPH 4th WNV Natl Conference
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West Nile Virus-Human InfectionsCases of TFX
Transmission
PATIENT A (39 donors)
Illness onset
CSF IgM
Platelets transfused
PATIENT B (2 donors)
RBCs transfused
Illness onset
CSFIgM
9/2
9/5
8/20
9/3
9/13
9/18
West Nile virus New modes of transmission Dr.
Anthony Marfin, M.D, MPH 4th WNV Natl Conference
32
West Nile Virus-Human InfectionsTFX Associated
Transmission

• Transmitted in RBCs, plasma, platelets
• Virus isolated from one stored plasma unit
• 5 of 14 infectious donors asymptomatic
• 7 of 20 confirmed cases asymptomatic

West Nile virus New modes of transmission Dr.
Anthony Marfin, M.D, MPH 4th WNV Natl Conference
33
West Nile Virus-Human InfectionsTFX Associated
Transmission

• Reduce risk of TFX-associated transmission
• Defer unsuitable blood donors
• Report post-donation illness suggesting WNV
  infection
• Withdraw/quarantine blood products from ill
  donors
• Diagnostics industry developing screening tests
• Testing strategies, deferral policies TBA
• Investigate transfusion cases in 2003 to evaluate
  strategies and policies

West Nile virus New modes of transmission Dr.
Anthony Marfin, M.D, MPH 4th WNV Natl Conference
34
Wisconsin WNV Surveillance in 2003
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Wisconsin WNV Surveillance In 2003

• Surveillance Objective - to predict/prevent major
  human epidemics
• Environmental Surveillance Wild Bird Surveillance
• Veterinary Surveillance
• Mosquito Surveillance
• Human Surveillance

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Wisconsin WNV Surveillance In 2003Wild Bird
Surveillance

• Goal - Utilize WNV bird mortality as a means of
  detecting WNV activity in a location
• Some wild bird species in North America, such as
  crows, are highly susceptible to WNV
• Crows can be used as a sentinel species
• Detection of WNV in wild birds not a predictor of
  human risk of WNV

37
Wisconsin WNV Surveillance In 2003Wild Bird
Surveillance

• Request reports of sick/dead corvids
• Test a subset of dead corvids for WNV by RT-PCR
  from a cloacal swab sample
• Once 5 positive birds identified in a county,
  discontinue testing
• Continue to record reports of sick/dead corvids

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Wisconsin WNV Surveillance In 2003Veterinary
Surveillance

• Goals
• Equine health impact of WNV and other arboviruses
• ID risk factors for high-risk population groups
  or geographic areas
• Identify movement of arboviruses, particularly
  WNV and EEE, into mammal populations

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Wisconsin WNV Surveillance In 2003Veterinary
Surveillance

• Veterinary Surveillance
• Reporting horses with signs of encephalitis
• Testing horses for WNV and other arboviruses
• Considerations
• WNV now considered endemic by USDA
• Vaccine vs. natural exposure
• Report test results to local health depts.

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Wisconsin WNV Surveillance In 2003Mosquito
Surveillance

• Goals
• assess threat of human disease
• ID geographic areas of high risk
• assess need for and timing of intervention events

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Wisconsin WNV Surveillance In 2003Mosquito
Surveillance

• Trap mosquitoes on regular basis through season
• Identify mosquito species trapped
• Test pools of same species for presence of WNV
  and other arboviruses

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Wisconsin WNV Surveillance In 2003Human
Surveillance

• Goals
• assess local, state, and national public health
  impact of WNV disease and other arboviruses
• demonstrate need for public health intervention
  and allocate resources
• ID risk factors for infection and high-risk
  population groups

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Wisconsin WNV Surveillance In 2003Human
Surveillance

• Test human samples of CSF or serum for IgM
  antibody to WNV and SLE
• clinical criteria no longer required for sample
  submission to WSLH
• fee-for-service testing
• Reporting human arboviral infections to the DPH

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Laboratory Testing for West Nile Virus

• Dr. David Warshauer Ph.D. ABMM
• Assistant Director
• Communicable Disease Division
• Wisconsin State Laboratory of Hygiene

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CDC Tests for WN Virus
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WN Virus Testing at WSLH

• Avian Testing
• LightCycler Real-Time RT-PCR
• Brain/Kidney
• Cloacal Swabs
• Human Testing
• IgM ELISA
• Serum dilution neutralization assay
• Marshfield Clinic Research Foundation

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ELISA P/N
pfu/ml
IgM
150
IgG
WN viremia
1 2 3 4 5 6 7 8 9 10
-5 -4 -3 -2 -1 0
DAYS POST ONSET
illness
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IgM Capture ELISA

• Coat With Goat anti-Human IgM
• 4 Overnight

• Add Patient Serum _at_ 1400
• 37 1 Hour

• Add West Nile Recombinant Antigen
• 4 Overnight

• Add HRP anti-Flavivirus McAb
• 37 1 Hour

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Interpretation of Results

• P/N O.D. patient serum/O.D. negative control
  serum.
• P/N gt 3 positive
• P/N lt 2 negative
• P/N 2-3 equivocal
• ELISA Assay must be standardized in each lab

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WN Serological Data
Typical Human WN Case

• In primary flavivirus infections
• Martin et al 2002 IgM P/N to WN is 3-5X greater
  than SLE.
• 2002 data Use 2X criteria WN to SLE ratio only
  1 exception in 417 WN confirmed cases.

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Longevity of Human WN Virus-Reactive IgM in Serum
53
CDC IgM ELISA Assay

• Good Points
• Sensitive
• Relatively Specific (WN SLE P/N ratio)
• Technology Transferable

• Bad Points
• Cross-reactivity among flaviviruses
• Limited utility in secondary infections
• Two day test
• IgM persistence

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Serological Testing Algorithm for West Nile Virus
human serum/csf
National Case Definition Confirmed IgM pos
csf IgM pos serum PRNT gt4-fold increase PRNT
titer
IgM ELISA WN SLE
NEG
POS
STOP
Plaque reduction Neutralization test (PRNT)
with SLE, WN, (other flaviviruses)
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WN Human Serological Data
Lessons Learned 1999-2002

• IgM Detectable in serum csf by onset (99)
• 6 exceptions------ serum from 800 cases
• 10 exceptions----- csf from 800
• IgG Positive by day 7 Post-Onset
• P/N 3-5X Higher to WN than SLE
• IgM Persistence gt 1 Year
• Secondary Flavivirus Infections are Problematic

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WSLH Arbovirus Serology

• Arbovirus IgM CEIA Ab Diagnostic Panel
• West Nile Virus
• St. Louis Encephalitis
• LaCrosse Encephalitis
• Eastern Equine Encephalitis
• Panel Cost
• 89.32
• CDD Requisition Form B

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Thank you to Dr. Rob Lanciotti and CDC for the
use of their slides and data