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West Nile Virus

West Nile Virus. Jane A. Rooney, D.V.M. State Public Health Veterinarian WV DHHR Infectious Disease Epidemiology Program. Arboviruses. Arboviruses that cause human encephalitis are members of three virus families: Togaviridae (genus Alphavirus) Eastern Equine encephalitis

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West Nile Virus

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  1. West Nile Virus Jane A. Rooney, D.V.M. State Public Health Veterinarian WV DHHR Infectious Disease Epidemiology Program

  2. Arboviruses • Arboviruses that cause human encephalitis are members of three virus families: • Togaviridae (genus Alphavirus) • Eastern Equine encephalitis • Western Equine encephalitis • Venezuelan equine encephalitis • Flaviviridae • West Nile • St. Louis encephalitis • Japanese encephalitis • Yellow fever • Dengue • Bunyaviridae • La Crosse encephalitis (California group) • Reoviruses • Colorado tick fever

  3. Distribution of Important Arboviruses in the U. S. Distribution of Important Arboviruses in the U. S. Eastern Equine Encephalitis California serogroup viruses Western Equine Encephalitis St. Louis Encephalitis West Nile Probably Highlands J

  4. Human SLE Case Distribution by State1964 - 2001 3 19 2 8 9 2 5 3 3 21 1 36 CT 1 25 14 440 DC 9 368 3 695 12 1 7 88 NJ 131 125 67 75 123 DE 1 3 141 MD 9 11 29 65 6 5 150 337 970 80 379 1990s 2000 2001

  5. WNV 2002 in USA4/17/03 • Human • 4156 infections • 284 deaths (median age 77, range 19 – 99. Gender 64% male) • Median age 55 yrs (range 0 – 99) • Gender distribution 53% male • Avian • 16,739 • Veterinary • >14,571 • 1 cat, 7 dogs, 24 other species, remainder equine

  6. West Nile Virus 2002 Season (77 bird, 3 horse, and 3 human cases) HANCOCK BROOKE OHIO MARSHALL MORGAN BERKELEY MONONGALIA WETZEL MARION MINERAL PRESTON TYLER PLEASANTS HAMPSHIRE TAYLOR 2 DODD- HARRISON WOOD RIDGE RITCHIE BARBOUR TUCKER GRANT JEFFERSON HARDY WIRT LEWIS UP- GILMER CAL- SHUR JACK- RANDOLPH HOUN SON MASON ROANE PENDLETON BRAXTON WEBSTER PUTNAM CLAY CABELL Positive birds KANAWHA POCAHONTAS NICHOLAS Positive horses + birds LINCOLN WAYNE BOONE Positive humans + birds FAYETTE GREENBRIER Negative counties LOGAN MINGO RALEIGH SUM- WYOMING MERS MONROE MERCER McDOWELL WVDHHR/BPH/OEHP/Division of Surveillance and Disease Control/Infectious Disease Epidemiology Program

  7. Public Health Action • Educate, Educate, Educate • Elimination of mosquito breeding sites & personal protective measures • Report dead bird sightings to LHD • Health Care community to: • Recognize clinical syndromes that warrant arboviral testing during summer and fall • Febrile headache • Aseptic meningitis • Encephalitis • Veterinarians to consider WNV as a possible etiology of summertime neurologic disease in horses • Government officials regarding mosquito surveillance and Integrated Pest Management (IPM) for control

  8. Public Health Action cont. • LHD report total dead bird sightings to WV IDEP on weekly basis • Report and test recently dead (< 24 hours) birds • Investigate cases of human WNV and perform home visit • LHD report all confirmed/probable/suspect human, equine or avian WNV urgently to IDEP • Generate public, physician and veterinarian alerts when cases are identified • Establish mosquito surveillance, testing and control capacity

  9. Disease and Prevention Objectives • Reduce disease risk through public education • Use of personal protective measures • Elimination of mosquito breeding sights • Reduce disease risk through development of mosquito surveillance and control capacity

  10. Surveillance Objectives • Determine where West Nile virus is present in West Virginia and the extent of spread • accomplished through dead bird testing • Estimate the intensity of West Nile virus activity, if present • accomplished through dead bird testing and dead bird reports • Detect human and equine cases of West Nile virus, if present • Determine where West Nile virus is present in West Virginia and the extent of spread • accomplished through adult mosquito surveillance using both CDC gravid and CDC miniature light traps

  11. Public Health Significance • Fourth year in a row, WNV has continued to expand its territory, spreading over much of the United States, including WV in 2002 • Purpose of surveillance is to identify whether human cases are likely so that appropriate prevention measures can be taken • Public health has a major role in prevention and control of this disease through surveillance, public and provider education, and through promotion of mosquito control activities

  12. Surveillance Activities • Dead Bird Surveillance • Establish whether West Nile virus is present within the jurisdiction under surveillance • Accomplished by testing freshly dead birds for WNV • Intensity of viral activity can be estimated • By tracking the number of dead bird reports • more dead bird reports suggests more viral activity and a higher likelihood of human cases • Information used to inform the public about the level of risk within the jurisdiction so they can take action to protect themselves

  13. Surveillance Activities cont. • Mosquito Surveillance • Identify mosquito breeding sites and prioritize sites for abatement • Determine if disease-carrying adult mosquitoes are present • used for mosquito control so that human cases of arboviral infection can be prevented • PH Entomologist, field biologists and LHD’s will conduct adult and larval mosquito surveillance throughout WV

  14. Surveillance Activities cont. • Equine Surveillance • The full role of equine surveillance is yet to be determined • Horses do serve as an important indicator of WNV activity in the jurisdiction • Information on equine cases should be used to prevent human cases • Human Surveillance • Purpose of human surveillance is to detect human WNV infection within the jurisdiction • This information should be used to prevent additional cases

  15. West Nile Virus • Reservoir • Wild birds are the primary reservoir • American Crow, Blue Jay, and other corvids and raptors (hawks, owls, and eagles) are particularly susceptible • Horses, humans, and other animals are considered to be dead-end hosts • Do not develop infectious-level of viremia • Incubation Period • usually 3 to 15 days • Infectious Period • no direct person-to-person transmission • Refer to Modes of Transmission section below

  16. WNV Human Infection “Iceberg” 1 CNS disease case = ~150 total infections ~10% fatal (<0.1% of total infections) <1% CNS disease Very crude estimates ~20% “West Nile Fever” ~80% Asymptomatic

  17. Clinical Description • Most WNV infections are mild or unapparent • Approximately 80% asymptomatic • About 20% develop West Nile fever • sudden onset mild febrile illness • often accompanied by: malaise, anorexia, nausea, vomiting, eye pain, headache, myalgia, rash and lymphadenopathy • Symptoms are normally self-limiting and last 3 to 6 days

  18. Clinical Description cont. • Less than 1% of infections result in severe neurological disease • Most significant risk factor for developing severe neurological disease is advanced age • Case fatality rate is estimated at 10% of those with severe neurological symptoms • this equates to < 0.1% of total infections

  19. West Nile Virus—”Classical” Clinical Description • Severe neurologic illness categories • Meningitis • Fever, nuchal rigidity, CSF pleocytosis • Encephalitis • Altered mental status • Meningoencephalitis • Acute flaccid paralysis

  20. Emerging and Evolving Clinical Syndromes • Preliminary data from clinical investigations conducted during 2002 are elucidating an expanding spectrum of neurological disease • Movement disorders • Parkinsonism • Rhabdomyolysis (disintegration of muscle fibers with excretion of myoglobin in the urine) • Acute flaccid paralysis

  21. Modes of Transmission • Transplantation • Transfusion • Breastfeeding • Transplacental transmission • Occupational exposure

  22. Case Definition • Arboviral Meningitis or Encephalitis Clinical Description Arboviral infections may be asymptomatic or may result in illnesses of variable severity sometimes associated with central nervous system (CNS) involvement. When the CNS is affected, clinical syndromes ranging from febrile headache to aseptic meningitis to encephalitis may occur, and these are usually indistinguishable from similar syndromes caused by other viruses

  23. Arboviral Meningitis and Encephalitis • Arboviral meningitis is characterized by fever, headache, stiff neck, and pleocytosis (> 5 white blood cells in CSF) • Arboviral encephalitis is characterized by fever, headache, and altered mental status ranging from confusion to coma with or without additional signs of brain dysfunction • paresis or paralysis, cranial nerve palsies, sensory deficits, abnormal reflexes, generalized convulsions, and abnormal movements)

  24. Laboratory Diagnosis • Fourfold or greater change in virus‑specific serum antibody titer, or • Isolation of virus from or demonstration of specific viral antigen or genomic sequences in tissue, blood, cerebrospinal fluid (CSF), or other body fluid, or • Virus‑specific immunoglobulin M (IgM) antibodies demonstrated in CSF by antibody‑capture enzyme immunoassay (EIA), or • Virus‑specific IgM antibodies demonstrated in serum by antibody‑capture EIA and confirmed by demonstration of virus‑specific serum immunoglobulin G (IgG) antibodies in the same or a later specimen by another serologic assay (e.g. neutralization or hemagglutination inhibition

  25. Laboratory Diagnosis cont. • It is impossible to clinically distinguish one type of encephalitis from another • Individuals in West Virginia who presents with encephalitis/meningitis during mosquito season (May - November) should be tested for La Crosse encephalitis (LAC), eastern equine encephalitis (EEE), St. Louis encephalitis (SLE), and West Nile virus (WNV) • Serum or CSF should be sent to the West Virginia Office of Laboratory Services (OLS), 167 11th Ave, South Charleston, WV 25303 for testing or confirmation • Sherry Nestor (304-558-3530) should be contacted to arrange testing. Specimens should be accompanied by a completed Arbovirus Test Submission Form when sent to the OLS

  26. Laboratory Diagnosis cont. • Detection of IgM using the antibody-capture enzyme-linked immunosorbent assay (MAC-ELISA) is the preferred diagnostic method • 90% of serum and CSF specimens tested at CDC from 1999 - 2002 had detectable IgM antibody to WNV in serum or CSF by the time of symptom onset • Detection of IgM antibody to West Nile virus in serum or CSF collected within eight (8) days of symptom onset is the most efficient diagnostic method • Patients who are negative for IgM antibodies in CSF or serum specimens drawn eight (8) to 21 days after illness onset are considered negative • Patients with specimens drawn within 7 days of onset of symptoms that are found negative by MAC-ELISA should have a convalescent specimen drawn at least two weeks later

  27. Laboratory Diagnosis cont. • IgM antibodies may persist for greater than one year • residents in endemic areas may have persistent IgM antibodies from a previous infection that is unrelated to their current illness • Since West Nile virus was present in our state last year acute (drawn within 7 days of symptom onset) and convalescent (drawn 14 - 21 days after symptom onset) serum specimen collection and submission are recommended to confirm acute infection • Single serum specimens positive for WNV IgM by MAC-ELISA require confirmation by demonstration of IgG antibodies using another serologic assay (e.g. neutralization or hemagglutination inhibition) • Specimens found to be positive for IgM by MAC-ELISA at OLS will be followed-up with confirmatory PRNT testing

  28. Surveillance Case Classification • Probable: an encephalitis or meningitis case occurring during a period when arboviral transmission is likely, and with the following supportive serology: • a single or stable (less than or equal to twofold change) but elevated titer of virus‑specific serum antibodies; or • serum IgM antibodies detected by antibody‑capture EIA but with no available results of a confirmatory test for virus‑specific serum IgG antibodies in the same or a later specimen. • Confirmed: an encephalitis or meningitis case that is laboratory confirmed.

  29. Surveillance Indicators • Number of dead birds (crow and non-crow) submitted per county for testing for WNV • Proportion of weeks May to November that counties submit dead bird reports to IDEP • Proportion of humans with a diagnosis of encephalitis that are tested for EEE, SLE, LAC, and WNV May to November • Proportion of cases with complete clinical investigation: • Patient demographics, involvement in outdoor activities, travel history and clinical symptoms • Part 1 of Arbovirus Investigation Form completed

  30. Surveillance Indicators • Proportion of cases with home visit completed for environmental evaluation, including GIS coordinates of location, patient and family education • Part 2 of Arbovirus Investigation Form completed • Proportion of cases investigations that are totally complete: • WV BPH Confidential Reportable Disease Case report (yellow card) • Arbovirus Investigation form and copies of supporting laboratory results i.e. confirmatory WNV serologic or antigen results and CSF test results

  31. Laboratory Diagnosis of West Nile Virus Infections

  32. Diagnostic Assays for Arboviruses Diagnostic Assays for Arboviruses Serum, CSF Mosquito pools, Tissues WN virus is a BSL-3 pathogen Serological Assays Virus Detection Assays IgM ELISA IgG ELISA PRNT CF HI IFA Dipsticks Virus isolation (cell culture, mice) IFA TaqMan RT-PCR Ag-capture ELISA RT-PCR / sequencing Dipsticks NASBA

  33. CDC Tests for WN Virus

  34. Appropriate Use of Nucleic Acid Detection Assays For human specimens, nucleic acid detection assays should not be used as the sole diagnostic test, especially for serum samples.

  35. Laboratory Safety Issues CDC Implementation of Biosafety in Microbiological & Biomedical Laboratories; 4th Ed. • West Nile is a BSL3 virus • ELISA: Biosafety Cabinet (BSC) until serum is washed, then BSL2 • PRNT: BSL3 • Virus Isolation: BSL3 • PCR: BSC until viral lysis buffer is added, then BSL2 • Antigen (Dipstick) Assays: BSC until detergent lysis buffer is added, then BSL2 • Animal Necropsy: BSL3

  36. Information needed for serological testing and interpretation Information Needed for Serological Testing and Interpretation Date of onset of disease Dates of sample collection Travel history Vaccination history Clinical history

  37. Serological Testing Algorithm for West Nile Virus human serum/csf National Case Definition Confirmed: IgM pos csf IgM pos serum + PRNT >4-fold increase PRNT titer IgM ELISA WN & SLE IgG ELISA WN & SLE NEG POS STOP Plaque reduction Neutralization test (PRNT) with: SLE, WN, (other flaviviruses)

  38. IgM Capture ELISA HRP HRP • Coat With Goat anti-Human IgM • 4° Overnight • Add Patient Serum @ 1:400 • 37° 1 Hour • Add West Nile Recombinant Antigen • 4° Overnight • Add HRP anti-Flavivirus McAb • 37° 1 Hour

  39. Interpretation of Results • P/N: O.D. patient serum/O.D. negative control serum. • P/N > 3 = positive • P/N < 2 = negative • P/N 2-3 = equivocal ELISA Assay must be standardized in each lab

  40. 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.

  41. Long Term WN Virus IgM Activity in Human Serum 30 25 20 P/N 15 10 5 0 0 50 100 150 200 250 300 350 400 Days Post-onset Long-term WN Virus IgM Activity in Human Serum NYCDOH-CDC Collaborative Study N=29 N = 29 7/12 (60%) of WN Encephalitis Virus Patients were IgM Positive at 500 Days Post-onset

  42. 40 N=31 35 30 25 P/N 20 15 10 5 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 Days Post-onset WN Virus IgM Response in CSF WN Virus IgM Response in CSF

  43. WN Human Serological Data Lessons Learned 1999-2002 • IgM Detectable in serum & csf by symptom onset (99%) • 6 exceptions serum of 800 – 1999 - 2002 cases • 10 exceptions csf of 800 - 1999 - 2002 cases • IgG Positive by day 7 Post-Onset • P/N 3-5X Higher to WN than SLE • IgM Persistence > 1 Year • Secondary Flavivirus Infections are Problematic

  44. 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

  45. Virus Isolation Antigen Detection IFA – Mabs Ag – Capture Dipsticks Immunohistochemistry WN Virus/Antigen Detection Assays

  46. WNHuman Viremia Data Summary • Human viremia is low • Transfusion studies: 1-130 pfu/ml • Average 24 pfu/ml • Virus isolation is rare (asymptomatic IgM neg donors) • Human viremia is short-lived • Rarely detectable by Day 1 of onset • 2 TaqMan Positives/ 100 Acute IgM positives • Viremia is absent when IgM is detectable • 2 IgM & TaqMan positives in transfusion studies • Israel study • 2002 LA Fever Study

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

  48. Control SLE WNV VecTest™ WNV/SLE Dipstick assay Procedure: VecTest strip 15 min 250 l mosquito pool suspension

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