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West Nile Virus Update


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July 2008

West Nile virus (WNV) is a mosquito-borne flavivirus (single-stranded RNA) that primarily infects birds, but occasionally infects horses and humans. The virus was first isolated in 1937 from a person in the West Nile district of Uganda. Until the viral infection was recognized in 1999 in birds in New York City, WNV was found only in the Eastern Hemisphere, with wide distribution in Africa, Asia, the Middle East, and Europe.1-3 The virus continued to spread across the United States until it reached epidemic proportions in 2002, with 37 states reporting a total of 3,389 human cases of WNV infection.2 (See Figure 1) As of 2008 (March), every state except Maine, Alaska, and Hawaii has reported the presence of WNV (either human or nonhuman infections). (Figure 2)

Figure 1.

Figure 1. Human cases of West Nile virus infection in the United States4

WNV occurs as a seasonal epidemic, with cases usually seen in late summer or early fall in temperate zones, while year-round transmission is possible in southern climates. The virus exhibits a bird-mosquito-bird transmission cycle (Figure 3) and undergoes amplification during that process, with environmental factors such as the length of the warm season and rain levels impacting the level of amplification.6
WNV is transmitted from birds to humans by mosquitoes; specifically the Culex species, but possibly also other species. While it is not transmitted from person to person by mosquitoes, 5 other modes of transmission have been identified in humans: blood product transfusion, organ transplantation, breast-feeding, transplacental, and occupational exposure in laboratory workers.

Figure 2.

Figure 2. 2007 West Nile virus activity in the United States
(Reported to CDC as of March 4, 2008)5

The greatest risk for WNV infection is from exposure to infected mosquitos; the easiest way to avoid infection is by using mosquito repellents and wearing long sleeves and pants when outside, especially during periods of high insect activity (dusk and dawn).

Symptoms

Most people who are infected with WNV do not develop symptoms and are unaware that they have been infected. Only about 20% of those who become infected develop symptomatic West Nile fever. Most patients with West Nile fever experience mild symptoms including fever, headache, myalgia, swollen lymph nodes, and occasionally a skin rash on the trunk of the body. These symptoms are nonspecific and are seen with many different conditions and diseases. The incubation period for West Nile fever ranges from 2 to 15 days, while the symptoms may last for days, weeks, or even months.7,8

Neurologic disease, seen at much lower levels (Figure 4), has been estimated to develop in 1 of 150 WNV infections (<1%) and includes meningitis, encephalitis, and poliomyelitis-like features (flaccid paralysis). Meningitis and encephalitis symptoms include severe headaches, high fever, visual disturbances, numbness, confusion, coma, or death.9 West Nile acute flaccid paralysis presents as sudden onset weakness and is usually related to only 1 side of the body or 1 limb. As well, the weakness can affect breathing and may potentially result in respiratory failure.

Figure 3.

Figure 3. WNV vector-borne disease transmission cycle

Case fatality rates among patients hospitalized during recent outbreaks ranged from 4% to 14%. Advanced age is the most important risk factor for death from West Nile infection, and patients >70 years old are at particularly high risk.1 A 2005 study in California further identified male gender and the presence of diabetes or hypertension as additional risk factors for developing neuroinvasive disease.11 There is no treatment for WNV disease; care is supportive. Some patients may require hospitalization.

Laboratory Diagnosis

Serology

Laboratory diagnosis of WNV is best achieved by demonstration of specific IgG and IgM class antibodies in serum specimens (eg, #84186 West Nile Virus (WNV) Antibody, IgG and IgM, Serum).

A member of the Flavivirus genus, WNV (Family Flaviviridae) is a member of the Japanese encephalitis antigenic complex, which includes St. Louis encephalitis, a virus also found in the United States. False-positive serology results may occur with persons infected with or vaccinated for other flaviviruses (eg, yellow fever, dengue). WNV serology test results may also be positive in persons previously infected with WNV.

Because these closely related arboviruses (viruses transmitted by mosquitoes and ticks) exhibit serologic cross-reactivity, it sometimes may be epidemiologically important to attempt to pinpoint the infecting virus by conducting cross-neutralization tests using an appropriate battery of closely related viruses. In those situations, physicians can order #87814 Arbovirus and West Nile Antibody Panel, Serum, which tests for IgM and IgG antibodies to the following viruses:

California (LaCrosse)
St. Louis
Eastern equine
Western equine
West Nile

Figure 4.

Figure 4. 2007 WNV human neuro invasive disease incidence in the United States
(Reported to CDC as of March 4, 2008)10

IgM Antibodies

By the eighth day of illness, most infected persons will have serologically detectable IgM antibody to WNV; in most cases it will be detectable for at least 1 to 2 months after the onset of illness, and in some cases it will remain detectable for 12 months or longer. (Figure 5)

The absence of IgM class antibodies to WNV is consistent with the lack of acute-phase infection with this virus. However, specimens drawn too early in the acute phase (eg, before 8 days postinfection) may be negative for IgM-specific antibodies to WNV. If WNV infection is still suspected, a second specimen drawn approximately 14 days postinfection should be tested. In the very early stages of acute WNV infection, IgM may be detectable in cerebrospinal fluid (CSF) before it becomes detectable in serum.

IgG Antibodies

The presence of specific IgG class antibodies in a serum specimen indicates infection with WNV sometime in the past. By 3 weeks postinfection, virtually all infected persons should have developed IgG antibodies to WNV. If an acute-phase infection is suspected, serum specimens drawn within approximately 7 days postinfection should be compared with a specimen drawn approximately 14 to 21 days after infection to demonstrate rising IgG antibody levels between the 2 serum specimens.

Central Nervous System Disease

The detection of WNV IgM antibodies in CSF is the recommended test to document central nervous system disease. IgM class antibody to WNV is generally detected in CSF from 3 to 5 days after the onset of symptoms. Mayo Medical Laboratories offers #88680 West Nile Virus [WNV] Antibody, IgG and IgM, Spinal Fluid, which tests for both the acute phase IgM antibodies and the later occurring IgG antibodies. WNV antibody results for CSF should be interpreted with caution, and a serum specimen obtained at the time of CSF collection should be tested in parallel. The test may not detect IgG class antibodies in CSF collected <8 days after the onset of symptoms. Other complicating factors include low antibody levels found in CSF, passive transfer of antibody from blood, and contamination of CSF with antibodies in sera via bloody taps.

In those situations where risk factors specific for WNV are not established, physicians can order #87813 Arbovirus and West Nile Antibody Panel, Spinal Fluid, which tests for IgM and IgG antibodies to the California (LaCrosse), St. Louis, Eastern equine, Western equine, and West Nile viruses.

Figure 5.

Figure 5. Development of detectable RNA and antibodies to WNV
*Detection of WNV RNA by PCR
†IgM antibodies may persist for up to 12 months in some cases

RNA Detection by PCR

As previously discussed, the most appropriate tests for detection of WNV infection are the serologic tests, in either serum or CSF specimens. However, PCR can be used to detect WNV RNA in specimens from patients with WNV infection when specific antibodies to the virus are not present (ie, between 2-8 days after onset of symptoms).12,13 As seen in Figure 5, the WNV RNA is present at detectable levels only during the time immediately following infection, and for up to an estimated 6 days postinfection.14 As the illness progresses, IgM- and IgG-class antibodies increase, while viral RNA levels decrease. Because PCR can detect the viral RNA prior to onset of symptoms, the test is very useful for screening blood donations. In fact, as of 2003, all blood donations in the United States are screened for WNV.

PCR testing (#86197 West Nile Virus [WNV] RNA Detection by Rapid PCR) is most useful as an adjunct in the diagnosis of early WNV infection, or in situations that require rapid testing. However, the likelihood of detection is relatively low. Even when testing patients with known WNV infection, the sensitivity of PCR is approximately 55% in CSF and even lower (approximately 10%) in blood. The sensitivity of the assay depends on the viral load in the specimen, as well as the quality of the specimen submitted. Because a negative test does not exclude infection with WNV and because the assay detects both active and nonreplicating virus (WNV RNA), results must be used in conjunction with clinical findings to make an accurate diagnosis.

Summary

While WNV has demonstrated a rapid spread across the United States since its detection here in 1999, most people who are infected will not develop symptoms. Because the signs and symptoms of WNV infections are nonspecific, testing is available to assist in the evaluation of patients to identify WNV as the infecting virus. While PCR may be indicated in certain situations, serology remains the preferred method for identification of WNV infection.

Authored by: Masoner DE, Dale JC, Binnicker MJ

References

  1. Petersen LR, Marafin AA: West Nile Virus: a primer for the clinician. Ann Intern Med 2002;137:173-179
  2. Petersen LR, Roehrig JT: West Nile Virus: a reemerging global pathogen. Emerg Infect Dis 2001;7(4):611-614
  3. Brinton MA: The molecular biology of West Nile Virus: a new invader of the western hemisphere. Ann Rev Microbiol 2002;56:371-402
  4. CDC: Division of Vector-Borne Infectious Diseases: West Nile Virus: Statistics, Surveillance, and Control. Available at www.cdc.gov/ncidod/dvbid/westnile/surv&control.htm. Retrieved 4/18/08
  5. CDC: West Nile Virus-Statistics, Surveillance, and Control. Available at www.cdc.gov.ncidod/dvbid/westnile. Retrieved 4/1/08
  6. Petersen LR, Marfin AA: West Nile Virus: A Primer for the Clinician. Ann Intern Med 2002;137:173-179
  7. CDC: West Nile Virus QA. Available at www.cdc.gov/ncidod/dvbid/westnile/qa. Retrieved 4/9/08
  8. CDC: Department of Health and Human Services: WNV Fact Sheet. Available at www.cdc.gov. Reviewed 9/27/05. Retrieved 4/9/08
  9. FDA.gov: West Nile Virus. Office of Women’s Health. Available at www.fda.gov. Retrieved 4/1/08
  10. CDC: West Nile Virus Questions and Answers. Division of Vector-Borne Infectious Diseases. Available at www.cdc.gov/ncidod/dvbid. Retrieved 4/1/2008
  11. Jean CM, Honarmand S, Louie JK, Glaser CA: Risk factors for West Nile virus neuroinvasive disease, California, 2005. Emerg Infect Dis [serial on the Internet]. 2007 Dec. Available at www.cdc.gov/EID/content/13/12/1918.htm. Retrieved 4/4/08
  12. Busch MP, Tobler LH, Saldanha J, et al: Analytical and clinical sensitivity of West Nile virus RNA screening and supplemental assays available in 2003. Transfusion 2005;5(4):492-499
  13. Epstein JS: Insights on donor screening for West Nile virus. Transfusion 2005;45(4):460-462
  14. CDC: Detection of West Nile Virus in Blood Donations—United States, 2003. MMWR Morb Mortal Wkly Rep 2003 Aug 15;52(32);769-772

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