Chapter IV. Clinical Deblockedion

Clinical Features of Severe Disease

• Fever
• Gastrointestinal symptoms
• Ataxia and extrapyramidal signs
• Optic neuritis
• Seizures
• Weakness
• Change in mental status
• Myelitis
• Polyradiculitis
• A minority of patients with severe disease develop a maculopapular or morbilliform rash involving the neck, trunk, arms, or legs.
• Flaccid paralysis is sometimes seen.
• Although not observed in recent outbreaks, myocarditis, pancreatitis, and fulminant hepatitis have been described.

Common Laboratory Findings of Severe Disease

• Total leukocyte counts in peripheral blood is mostly normal or elevated with lymphocytopenia and anemia also occurring.
• Hyponatremia is sometimes present, particularly among patients with encephalitis.
• Examination of the cerebrospinal fluid (CSF) shows pleocytosis, usually with a predominance of lymphocytes. Protein is universally elevated. Glucose is normal.
• Computed tomography is not useful in the diagnosis of WNV infection, but is useful in excluding other etiologies of acute meningoencephalitis. Brain MRI is often normal, but will sometimes display leptomeningeal enhancement or parenchymal signal changes.

Diagnostic Tests for Severe Disease

• WNV infection can be suspected in a person based on clinical symptoms and patient history. Laboratory testing is required for a confirmed diagnosis.
• The most efficient diagnostic method is detection of IgM antibody to WNV in serum collected within 8 to 14 days of illness onset or CSF collected within 8 days of illness onset using the IgM antibody-capture, enzyme-linked immunosorbent assay (MAC-ELISA).
• Since IgM antibody does not cross the blood-brain barrier, presence of IgM in CSF strongly suggests central nervous system infection. Patients who have been recently vaccinated against or recently infected with related flaviviruses (e.g., yellow fever, Japanese encephalitis, dengue) may have positive WNV MAC-ELISA results, although vaccination or non-CNS infections should not give CSF IgM, and killed vaccines (e.g., JE-VAX) should not produce IgM at all.
• One caveat is that serological tests for WN virus cross react with other closely related flaviviruses (Japanese encephalitis, St. Louis encephalitis, yellow fever, dengue). Neutralization assays (plaque reduction neutralization tests) are more specific and should be considered if any of these other infections are suspected.
• The plaque-reduction neutralization test (PRNT), the most specific test for the arthropod-borne flaviviruses, can be used to help distinguish false-positive results in an IgM antibody-capture enzyme-linked immunosorbent assay or other assays (for example, indirect immunofluorescence and hemagglutination inhibition). The plaque-reduction neutralization test may also help distinguish serologic cross-reactions among the flaviviruses, although some degree of cross-reaction in neutralizing antibody may still cause ambiguous results, especially if the current infection is not the first flavivirus infection the patient ever experienced. Because most infected persons are asymptomatic and because IgM antibody may persist for six months or longer, residents in endemic areas may have persistent IgM antibody from a previous infection that is unrelated to their current clinical illness.
• There are cross-reactivity issues with the neutralizing antibody test as well.
• PCR is used in the diagnosis of WNV infections in humans, although it has limited usefulness because of the transient and low viremias. With PCR, WNV genetic material can be detected in CSF in up to 50% of patients who present with acute West Nile meningoencephalitis. Because this is not a very good sensitivity, a negative test does not rule out a WNV infection. Serology should be used in these patients.
• Virus culture is the gold standard, but it is rarely positive except in autopsy material, generally from the brain and other solid organs.
• Serum or CSF can be refrigerated or frozen if submitting samples to a reference laboratory for testing for WNV.
• Autopsy specimens can be subjected to a variety of tests for detecting the presence of WNV: PCR tests on fresh-frozen material, virus culture on fresh-frozen material, and histology and immunohistochemistry on formalin-fixed tissue.
• A significant increase in WNV specific neutralizing antibody titer between acute- and convalescent-phase serum specimens confirms acute infection. These additional tests require growth of the virus and may take a week or longer (plus shipping time) to conduct.
• The CT scan has not been effective in identifying any signs that are consistent or unique for WNV encephalitis in particular or for flaviviral encephalitis in general. MRI is more effective but will yield abnormal results in only 25% to 35% of cases, and the MRI abnormalities are nonspecific.