West nile virus overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Overview

West Nile virus (WNV) is a virus of the family Flaviviridae; part of the Japanese encephalitis (JE) antigenic complex of viruses, it is found in both tropical and temperate regions. It mainly infects birds, but is known to infect humans, horses, dogs, cats, bats, chipmunks, skunks, squirrels, and domestic rabbits. The main route of human infection is through the bite of an infected mosquito. Image reconstructions and cryoelectron microscopy reveal a 45-50 nm virion covered with a relatively smooth protein surface. This structure is similar to the dengue fever virus; both belong to the genus flavivirus within the family Flaviviridae. WNV is a positive-sense, single strand of RNA, it is between 11,000 and 12,000 nucleotides long which encode seven non-structural proteins and three structural proteins. The RNA strand is held within a nucleocapsid formed from 12 kDa protein blocks; the capsid is contained within a host-derived membrane altered by two viral glycoproteins.

Historical Perspective

WNV was first isolated in 1937 in Uganda from a hospitalized patient who presented with isolated fever. Between 1950 and 1960, small villages in the Mediterranean basin had repeated outbreaks, especially in Israel and Egypt. These outbreaks allowed researchers to study the molecular and clinical features of the disease and further understand its mode of transmission and natural history. Several WNV outbreaks were recorded in the second half of the 20th century in Europe, Middle East, Far East, and Africa. It was not until 1999 when the first WNV outbreak was documented in USA, making WNV a worldwide infection. Perhaps the most severe outbreak documented was in 2002 in USA, recording the highest number of meningoencephalitis from a single WNV outbreak. The first description of a person-to-person transmission was reported in 2002 among patients with blood transfusions and tissue transplantation.

Causes

WNV is an enveloped positive-sense ssRNA of 11000 base pairs (bp) that is considered a member of the Japanese encephalitis serocomplex. It belongs to the genus Flavivirus and family Flaviviridae. Its RNA encodes structural and non-structural proteins. Although 7 lineages of WNV have been described, only lineage 1 and 2 are clinically significant. The viral natural reservoir includes many species, such as humans, horses, dogs, and cats; but the main natural reservoir is birds.

Pathophysiology

The natural reservoir of West Nile virus (WNV) is birds, particularly species with high-level viremia. In contrast, viremia is relatively rare among infected humans, who are considered dead-end hosts of the virus. WNV is transmitted by bites of various species of mosquitoes. Following inoculation, replication of the virus occurs in the Langerhans epidermal dendritic cell. Among immunocompetent hosts, the replication process is immediately followed by activation of the immune system, including complement system pathways, and humoral and adaptive immune responses that act simultaneously to clear the infection. On the other hand, immunocompromised patients may suffer CNS dissemination and fatal outcomes due to the failure to activate proper immunological pathways. Finally, the role of genetics in WNV susceptibility is not fully understood; but mice models and a few human experiments have described genetic mutations that may predispose individuals to worse clinical disease of WNV infections.

Risk Factors

Certain factors may increase the risk of infection with WNV by a mosquito bite, such as warm temperatures, extensive outdoor exposure, homelessness, and absence of window screens. Occupational risk factors include in-field occupations, such as agriculture. Severe clinical disease is often associated with advanced age, immunosuppression, malignancy, diabetes mellitus, hypertension, and renal disease. An increased risk of death is observed among immunosuppressed patients and those presenting with altered level of consciousness. Certain conditions such as encephalitis, advanced cardiovascular disease, and hepatitis C virus may also carry an increased risk of death among patients infected with WNV.

Screening

Universal screening for West Nile virus is not recommended. As bloodand transplant-related transmission of the virus has been reported, nucleic acid tests (NAT) may be used to screening for WNV among potential blood and solid organ donors. In blood donation, individual screening is not recommended. Instead, a "minipool" nucleic acid testing program (MP NAT) is implemented. Positive pools warrant further investigation for individuals. Patients with positive NAT may not donate blood or solid organs for at least 120 days. Re-testing after 120 days is indicated.

Differentiating West Nile Virus from Other Diseases

West Nile fever must be differentiated from other diseases that cause fever, skin rash, myalgias, and back pain, such as other viral infections due to rhinovirus, enterovirus D68, coxsackievirus, influenza, echovirus. Patients with severe WNV infection may present with meningitis, encephalitis, or flaccid paralysis. These diseases must be differentiated from other diseases that cause severe headache, altered mental status, seizures, and paralysis, such as herpes virus encephalitis, enterovirus encephalitis, bacterial encephalitis, metabolic encephalitis, poliomyelitis, and Guillain-Barre syndrome.

Natural History, Complications, & Prognosis

WNV is usually transmitted to humans by the culex mosquito after feeding on infected birds with high-level viremia. Following an incubation period of 2-14 day, untreated patients can remain asymptomatic or present with West Nile fever or with life-threatening neuroinvasive disease. Common complications of WNV infections include neurological impairment. The prognosis of mild disease is excellent; whereas West Nile meningitis and encephalitis may have residual neurologic deficits.

History & Symptoms

West Nile fever infection is considered a clinical spectrum. West Nile fever infection has 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.

Physical Examination

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.

Lab Tests

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.

Medical Therapy

There is currently no specific antiviral pharmacologic therapy for patients with WNV infection, but interferon-alpha-2b or ribavirin have been used. Patients with mild disease may be followed-up as outpatients; whereas patients with severe disease require hospitalization and close monitoring. Current management of infected patients is based on supportive care aimed at symptom relief and prevention of complications.

Primary Prevention

Vaccines are not available for WNV infection. In the absence of a vaccine, prevention of WNV disease depends on community-level mosquito control programs to reduce vector densities, personal protective measures to decrease exposure to infected mosquitoes, and screening of blood and organ donors.

Future or Investigational Therapies

Human vaccines against WNV are under development, and they have shown promising results in phase I and II trials. Ribavirin and interferon alfa-2b are currently being studied for the treatment of WNV CNS infections, as both drugs have demonstrated benefit in in vitro studies.

References

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