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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [3]; Rim Halaby, M.D. [4]

Overview

WNV infection is considered a clinical spectrum. Infection due to WNV may have any of 3 different clinical presentations: Asymptomatic (~70-80%), mild febrile syndrome termed West Nile fever (~20%), and neuroinvasive disease termed West Nile meningitis or encephalitis (<1%). Patients who are suspected to have WNV infection should specifically be inquired about recent mosquito bites.

History

Patients who are suspected to have West Nile virus infection should be inquired about recent mosquito bites. In addition, important clues in the history include the time of the year, geographical location, recent travel, and outdoor activities. Patients should also be asked about virus-associated symptoms and their progression.

Symptoms

Asymptomatic

An asymptomatic course of the disease is observed among approximately 80% of individuals infected with WNV.

West Nile fever

Constitutional symptoms

HEENT symptoms

Gastrointestinal symptoms

Genitourinary symptoms

Cutaneous manifestations

Neuroinvasive disease

Neuroinvasive disease is the most severe form of WNV infection. Patients can present with fever associated with a wide range of neurological manifestations, such as flaccid paralysis, symptoms of meningitis or encephelatitis, or a combination of these conditions.

Constitutional symptoms

Neurological symptoms

Shown below is a table of the most common neurological symptoms of neuroinvasive WNV disease with their corresponding frequencies.[1]

Symptom Percentage
Facial palsy 13%
Dysphagia 33%
Dysarthria 33%
Diplopia 33%
Tremor 22%
Parkinsonism 16%
Ataxia 31%
Motor seizures 5%
Myoclonus 31%
West Nile meningitis
West Nile meningoencephalitis
Acute flaccid paralysis
  • Lower limb weakness

Multiorgan involvement

References

  1. ↑ "Neurologic Complications of West Nile Virus".
  2. ↑ Abroug F, Ouanes-Besbes L, Letaief M, Ben Romdhane F, Khairallah M, Triki H, Bouzouiaia N. "A cluster study of predictors of severe West Nile virus infection." Mayo Clinic Proceedings 2006; 81: 12-16.
  3. ↑ Perelman A, Stern J. "Acute pancreatitis in West Nile Fever." American Journal of Tropical Medicine and Hygiene 1974; 23: 1150-1152.
  4. ↑ Omalu B I, Shakir A A, Wang G, Lipkin W I, Wiley C A. "Fatal fulminant pan-meningo-polioencephalitis due to West Nile virus." Brain Pathology 2003; 13: 465-472
  5. ↑ Mathiot C C, Georges A J, Deubel V. "Comparative analysis of West Nile virus strains isolated from human and animal hosts using monoclonal antibodies and cDNA restriction digest profiles." Res Virol 1990; 141: 533-543.


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5]

Overview

On physical examination, patients with WNV infection may have no specific signs. Physical examination findings may range from an isolated fever to signs of severe neurological impairment, meningeal irritation, stupor, and coma.

Physical exam

Most patients with WNV are asymptomatic or experience a mild disease that may often have no signs on physical examination.[1]

Vital signs

Skin

HEENT

Chest

  • Ataxic or apneustic breathing

Abdomen

Neurologic

References

  1. ↑ Sejvar JJ, Haddad MB, Tierney BC, Campbell GL, Marfin AA, Van Gerpen JA; et al. (2003). "Neurologic manifestations and outcome of West Nile virus infection". JAMA. 290 (4): 511–5. doi:10.1001/jama.290.4.511. PMID 12876094. Review in: ACP J Club. 2004 May-Jun;140(3):78


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [6]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [7]

Overview

The front-line assay for laboratory diagnosis of WNV infection is the IgM assay. IgM and IgG ELISA tests can cross-react between flaviviruses; therefore, serum samples that are antibody-positive on initial screening should be evaluated by a more specific test. Currently the plaque reduction neutralization test (PRNT) is the recommended test for differentiating between flavivirus infections. Specimens submitted for WNV testing should also be tested by ELISA and PRNT against other arboviruses known to be active or be present in the area or in the region where the patient traveled. Numerous procedures have been developed for detecting viable WNV, WNV antigen or WNV RNA in human diagnostic samples. These procedures vary in their sensitivity, specificity, and time required to conduct the test. Among the most sensitive procedures for detecting WNV in samples are those using RT-PCR to detect WNV RNA in human CSF, serum, and other tissues. Confirmation of virus isolate identity can be accomplished by indirect immunofluorescence assay (IFA) using virus-specific monoclonal antibodies or nucleic acid detection. Immunohistochemistry (IHC) using virus-specific MAbs on brain tissue has been very useful in identifying cases of WNV infection.[1]

Laboratory Tests

Appropriate selection of diagnostic procedures and accurate interpretation of findings requires information describing the patient and the diagnostic specimen. For human specimens, the following data must accompany sera, CSF, or tissue specimens for results to be properly interpreted and reported:[1] 1) Symptom onset date (when known) 2) Date of sample collection 3) Unusual immunological status of patient (e.g., immunosuppression) 4) State and county of residence 5) Travel history (especially in flavivirus-endemic areas) 6) History of prior vaccination (e.g., yellow fever, Japanese encephalitis, or Tick-borne encephalitis viruses) 7) Brief clinical summary including clinical diagnosis (e.g., encephalitis, aseptic meningitis).

Minimally, onset and sample collection dates are required to perform and interpret initial screening tests. The remaining information is required to evaluate any specimens positive on initial screening. If possible, a convalescent serum sample taken at least 14 days following the acute sample should be obtained to enable confirmation by serological testing.[1]

Serology

IgM and IgG ELISA tests

The front-line screening assay for laboratory diagnosis of human WNV infection is the IgM assay. WNV-specific IgM antibodies are usually detectable 3 to 8 days after onset of illness and persist for 30 to 90 days, but longer persistence has been documented. Therefore, positive IgM antibodies occasionally may reflect a past infection. If serum is collected within 8 days of illness onset, the absence of detectable virus-specific IgM does not rule out the diagnosis of WNV infection, and the test may need to be repeated on a later sample.

The presence of WNV-specific IgM in blood or CSF provides good evidence of recent infection but may also result from cross-reactive antibodies after infection with other flaviviruses or from non-specific reactivity. According to product inserts for commercially available WNV IgM assays, all positive results obtained with these assays should be confirmed by neutralizing antibody testing of acute- and convalescent-phase serum specimens at a state public health laboratory or CDC.

WNV IgG antibodies generally are detected shortly after IgM antibodies and persist for many years following a symptomatic or asymptomatic infection. Therefore, the presence of IgG antibodies alone is only evidence of previous infection and clinically compatible cases with the presence of IgG, but not IgM, should be evaluated for other etiologic agents.

Currently, the FDA has cleared four commercially-available test kits from different manufacturers, for detection of WNV IgM antibodies. These four kits are used in many commercial and public health laboratories in the United States. In addition the CDC-defined IgM and IgG ELISA can be used; protocols and reagents are available from the CDC DVBD Diagnostic Laboratory. There is also a microsphere-based immunoassay for the detection of IgM antibodies that can differentiate WNV from SLE.[1]

Plaque reduction neutralization test

Because the IgM and IgG ELISA tests can cross-react between flaviviruses (e.g., SLE, dengue, yellow fever, WN), they should be viewed as screening tests only. For a case to be considered confirmed, serum samples that are antibody-positive on initial screening should be evaluated by a more specific test; currently the plaque reduction neutralization test (PRNT) is the recommended test for differentiating between flavivirus infections. Though WNV is the most common cause of arboviral encephalitis in the United States, there are several other arboviral encephalitides present in the country and in other regions of the world. Specimens submitted for WNV testing should also be tested by ELISA and PRNT against other arboviruses known to be active or be present in the area or in the region where the patient traveled.[1]

Virus detection assay

Numerous procedures have been developed for detecting viable WNV, WNV antigen or WNV RNA in human diagnostic samples. These procedures vary in their sensitivity, specificity, and time required to conduct the test.[1]

RT-PCR

Among the most sensitive procedures for detecting WNV in samples are those using RT-PCR to detect WNV RNA in human CSF, serum and other tissues. Fluorogenic 5' nuclease techniques (real-time PCR) and nucleic acid sequence-based amplification (NASBA) methods have been developed and validated for specific human diagnostic applications and for detecting WNV RNA in blood donations.[1]

WNV presence can be demonstrated by isolation of viable virus from samples taken from clinically ill humans. Appropriate samples include CSF (serum samples may be useful very early in infection) and brain tissue (taken at biopsy or postmortem). Virus isolation should be performed in known susceptible mammalian (e.g., Vero) or mosquito cell lines (e.g., C6/36). Mosquito origin cells may not show obvious cytopathic effect and must be screened by immunofluorescence or RT-PCR. Appropriate samples for virus isolation from clinically ill humans include CSF (serum samples may be useful very early in infection) and brain tissue (taken at biopsy or postmortem).[1]

Indirect immunofluorescence assay

Confirmation of virus isolate identity can be accomplished by indirect immunofluorescence assay (IFA) using virus-specific monoclonal antibodies or nucleic acid detection. The IFA using well-defined murine monoclonal antibodies (MAbs) is an efficient, economical, and rapid method to identify flaviviruses. MAbs are available that can differentiate WNV and SLE virus from each other and from other flaviviruses. Incorporating MAbs specific for other arboviruses known to circulate in various regions will increase the rapid diagnostic capacities of state and local laboratories. Nucleic acid detection methods including RT-PCR, TaqMan and nucleic acid sequence based amplification (NASBA) methods may be used to confirm virus isolates as WNV.[1]

While these tests can be quite sensitive, virus isolation and RT-PCR to detect WNV RNA in sera or CSF of clinically ill patients have limited utility in diagnosing human WNV neuroinvasive disease due to the low level viremia present in most cases at the time of clinical presentation. However, one study demonstrated that combining detection of IgM with detection of WNV RNA in plasma significantly increased the number of WNV non-neuroinvasive (i.e., fever) cases detected. Virus isolation or RT-PCR on serum may be helpful in confirming human WNV infection in immunocompromised patients when antibody development is delayed or absent.[1]

Immunohistochemistry

Immunohistochemistry (IHC) using virus-specific MAbs on brain tissue has been very useful in identifying both human and avian cases of WNV infection. In suspected fatal cases, IHC should be performed on formalin fixed autopsy, biopsy, and necropsy material, ideally collected from multiple anatomic regions of the brain, including the brainstem, midbrain, and cortex.[1]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 <West Nile Virus in the United States: Guidelines for Surveillance, Prevention, and Control. 4th revision, 2013. [1]


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