West nile virus infection overview
Synonyms and keywords: WNV

# Overview
West Nile virus (WNV) is an enveloped positive-sense ssRNA virus that is considered a member of the Japanese encephalitis serocomplex. It belongs to the family Flaviviridae. It was first isolated in 1937 in Uganda; and since then has disseminated to become a worldwide infection. The natural reservoir of the virus is mainly birds, but it is usually transmitted by Culex mosquito bites to humans and other animals, and less commonly transmitted from human to human by blood transfusions or tissue transplantation. WNV infection is a spectrum of clinical disease that may have an asymptomatic course, a mild "West Nile fever" characterized by fever and constitutional symptoms, or a more severe "neuroinvasive disease" that includes severe neurological deficits. If left untreated, the virus usually self-resolves among immunocompetent patients, but may progress to lead a complicated course among the elderly, immunosuppressed patients, or those with malignancies, advanced cardiovascular, and renal disease. Diagnosis is often made by serological testing, plaque reduction neutralization test (PRNT), reverse transcription polymerase chain reaction (RT-PCR), immunofluoresence, or immunohistochemistry. Management is generally aimed at supportive care only, but antiviral pharmacologic therapy has been frequently administered in neuroinvasive cases. Universal screening is not recommended, but screening donors of blood products and tissue transplants for WNV using nucleic acid testing (NAT) is mandatory. Prognosis is excellent in mild cases, but the disease may cause permanent neurological impairment or even death if neuroinvasive disease develops.

# 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 documented outbreak occurred 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 virus 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 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.

# Epidemiology & Demographics
WNV is considered a worldwide infective agent. Since most cases are asymptomatic and self-limited, the true incidence and prevalence of West Nile fever are often underestimated. Between the years 1999 and 2013, a total of 39557 cases were reported by the CDC in USA alone. The 2002 outbreak in USA marks the WNV outbreak with the most recorded rates of neuroinvasive disease. Nonetheless, only 1/140 to 1/256 cases of West Nile fever are complicated by encephalitis or meningitis. WNV infection occurs predominantly during the end of summer and beginning of fall. Females are more likely to develop WNV infection. The prevalence of the disease is not affected by ethnicity or age, but elderly patients are more likely to experience a complicated clinical course.

# 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 WNV is not recommended. As blood and transplant-related transmissions of the virus have been reported, nucleic acid tests (NAT) may be used to screen for WNV among potential blood and solid organ donors. In blood donation, individual screening is not recommended either. 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
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.

# 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 indicated 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
Human vaccines are not available for WNV infection. With 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.