West nile virus infection

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D. Alberto Castro Molina, M.D.
Synonyms and keywords: WNV

West Nile virus (WNV) is an enveloped positive-sense ssRNA virus in the family Flaviviridae and a member of the Japanese encephalitis serocomplex. It was first isolated in 1937 in Uganda and has since become widely distributed across Africa, the Middle East, Europe, and the Americas. WNV is now the leading cause of domestically acquired mosquito-borne disease in the contiguous United States.^[1]

The primary transmission route to humans is the bite of infected Culex mosquitoes that have fed on viremic birds. Less common modes include transfusion of blood products, solid organ transplantation, transplacental and peripartum transmission, and laboratory or occupational exposure.^[1] WNV infection represents a clinical spectrum: approximately 80 percent of infections are asymptomatic, around 20 percent present with a self-limited febrile illness often termed West Nile fever, and fewer than 1 percent progress to neuroinvasive disease, including meningitis, encephalitis, or acute flaccid myelitis.^[1]

Most immunocompetent patients recover completely or with minor residual symptoms; however, older adults and immunocompromised individuals have a substantially higher risk of neuroinvasive disease, long-term neurologic sequelae, and death. Diagnosis is primarily based on serologic testing, with WNV-specific IgM in serum or cerebrospinal fluid (CSF), supplemented in selected situations by plaque reduction neutralization testing (PRNT) or nucleic acid testing (NAT). There is no proven antiviral therapy, and management is supportive. Prevention is centered on personal protective measures against mosquitoes, community vector control, and screening of blood and organ donors.^[1]

WNV was first isolated in 1937 from the blood of a febrile patient in the West Nile district of Uganda. In the following decades, outbreaks were described in the Mediterranean basin and parts of Africa and the Middle East, which allowed characterization of the virus, its transmission cycle, and its clinical manifestations.

The virus emerged in North America in 1999, with an outbreak of encephalitis and meningitis in New York City. Over subsequent years, WNV spread across the continental United States and into Canada, the Caribbean, and parts of Central and South America. The 2002 outbreak in the United States was notable for a large number of neuroinvasive cases and deaths, highlighting the potential severity of WNV disease.^[2]

Since then, recurrent outbreaks have occurred in Europe, North Africa, Israel, and North America, including large recent outbreaks in southern and central Europe and focal but intense outbreaks in western US states.^[1]

WNV is an enveloped positive-sense ssRNA virus of approximately 11000 base pairs that belongs to the genus Flavivirus and family Flaviviridae. Its genome encodes a single polyprotein that is co- and post-translationally processed into three structural proteins (capsid, membrane, and envelope) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5). These proteins mediate virion assembly, replication, and immune evasion.^[3]

Seven phylogenetic lineages have been described; however, only lineages 1 and 2 are clearly associated with human disease and considered clinically important.^{[4][5][6][7][8][9][10][11]}

The natural reservoir of WNV is birds, particularly passerine species that develop high-level viremia. Mosquitoes, mainly Culex species, become infected when feeding on these birds and subsequently transmit the virus to humans and other mammals. Humans, horses, and most other mammals develop lower and shorter viremia and are regarded as dead-end hosts because they rarely infect feeding mosquitoes.^[1]

After inoculation via a mosquito bite, WNV initially replicates in skin-resident dendritic cells, then disseminates to regional lymph nodes and into the bloodstream. In immunocompetent hosts, innate and adaptive immune responses including type I interferon signaling, complement activation, and virus-specific B and T cell responses usually limit viremia and prevent central nervous system (CNS) invasion.^[1]

Neuroinvasive disease occurs when the virus gains access to the CNS, likely through a combination of mechanisms such as disruption of the blood–brain barrier, transcytosis across endothelial cells, infection of olfactory neurons, or “Trojan horse” entry within infected immune cells. Within the CNS, WNV shows tropism for neurons, particularly in the brainstem, basal ganglia, thalamus, cerebellum, and anterior horn cells of the spinal cord, leading to meningitis, encephalitis, and acute flaccid myelitis.^[1]

Host factors including advanced age, immunosuppression, hematologic malignancy, solid organ transplantation, and therapies that deplete B cells (such as rituximab or ocrelizumab) impair viral clearance and substantially increase the risk of neuroinvasive disease and death.^[1]

WNV is widely distributed in Africa, the Middle East, Europe, Australia, and the Americas. In the United States, all 48 contiguous states, the District of Columbia, and Puerto Rico have reported human disease.^[1] Because most infections are asymptomatic or mild and non-neuroinvasive cases are underreported, the true incidence of WNV infection is much higher than that reflected in surveillance data.

From 2014 to 2023, a mean of approximately 1300 WNV neuroinvasive disease cases and 130 deaths were reported annually in the United States.^[1] Neuroinvasive disease rates are a more reliable indicator of WNV activity than total reported cases. Cumulative neuroinvasive disease incidence has remained highest in western and some central states, with marked geographic heterogeneity within and between seasons.^[1]

Transmission is highly seasonal in temperate regions, with most cases occurring from July through October, paralleling periods of highest mosquito abundance and WNV activity in mosquito and avian surveillance programs.^[1]

Globally, large outbreaks have been reported in southern and central Europe, North Africa, and Israel, including an extensive European outbreak in 2018 largely driven by lineage 2 WNV.^[1] Climatic factors such as milder winters, longer summers, and increased precipitation may favor mosquito survival, reproduction, and viral amplification, but outbreaks remain difficult to predict based on climate alone.^[1]

Risk of WNV infection in humans is determined by ecological and behavioral factors that influence exposure to infected mosquitoes, as well as host susceptibility to severe disease. Warm temperatures, high mosquito densities, outdoor activities at dawn and dusk, lack of window or door screens, homelessness, and occupational exposure in agriculture or outdoor work increase the likelihood of infection.^[1]

Among infected persons, the strongest risk factor for neuroinvasive disease is advanced age. Approximately 2 percent of infected individuals aged 65 years or older develop neuroinvasive disease compared with 0.1 to 0.4 percent of those younger than 65 years.^[1] Additional risk factors for severe disease and death include:

• Male sex
• Diabetes mellitus
• Hypertension
• Chronic kidney disease
• Hematologic malignancies
• Solid organ or hematopoietic stem cell transplantation
• Receipt of B-cell–depleting monoclonal antibodies
• Other substantial forms of immunosuppression^[1]

These conditions are associated with higher rates of neuroinvasive disease, prolonged viremia, and increased mortality.

Universal screening for WNV infection in the general population is not recommended. Because transfusion and transplant-associated transmission have been documented, nucleic acid testing is used to screen blood donations in many countries. In the United States, blood donors undergo nucleic acid testing, often initially using minipool strategies with reflex individual donation testing when pools are positive.^[1] This approach has markedly reduced transfusion-related transmission since its implementation in 2003.

For organ and tissue donors, policies are less uniform. Some organ procurement organizations perform seasonal WNV NAT screening of living donors, but there is no single nationwide requirement for deceased donor testing. Nonetheless, transplant programs should consider WNV in donors or recipients with compatible illness, particularly during the vector season.^[1]

Donors with confirmed WNV infection should be deferred from blood or organ donation for at least 120 days, and repeat testing is advised before re-eligibility, consistent with historical CDC guidance.^[4][1]

West Nile fever must be differentiated from other causes of acute undifferentiated febrile illness with myalgias, arthralgias, and rash, including infections due to enteroviruses, coxsackievirus, influenza virus, echovirus, rhinovirus, and other arboviruses.

Neuroinvasive WNV disease, presenting as meningitis, encephalitis, or acute flaccid myelitis, should be distinguished from:

• Other viral encephalitides (for example, herpes simplex virus encephalitis, enterovirus encephalitis)
• Bacterial meningitis or encephalitis
• Autoimmune or metabolic encephalopathies
• Poliomyelitis
• Guillain-Barre syndrome and other acute inflammatory polyradiculoneuropathies
• Other causes of acute flaccid paralysis or myelitis^[1]

Neuroimaging, CSF analysis, and electrodiagnostic studies, together with appropriate virologic testing, help differentiate WNV from these other entities.

Following an incubation period of approximately 2 to 6 days (and up to about 14 days), most WNV infections are asymptomatic. About 20 percent of infected individuals develop West Nile fever, characterized by acute onset fever and constitutional symptoms, while fewer than 1 percent progress to neuroinvasive disease.^[1]

Neuroinvasive disease manifests as meningitis, encephalitis, or acute flaccid myelitis. Complications include:

• Seizures
• Raised intracranial pressure
• Respiratory failure due to bulbar involvement or diaphragmatic weakness
• Long-term cognitive and motor deficits
• Functional impairment requiring prolonged rehabilitation or long-term care^[1]

Mortality among patients with neuroinvasive disease is approximately 10 percent overall but increases substantially with age and in persons with significant immunosuppression, reaching around 20 percent or higher in older adults and up to 30 to 40 percent in some high-risk groups such as transplant recipients and patients with hematologic malignancies.^[1]

Long-term sequelae are common. More than half of hospitalized patients report persistent symptoms such as fatigue, weakness, and cognitive difficulties months to years after acute illness, and some remain unable to return to baseline activities of daily living.^[1] In contrast, prognosis for patients with mild West Nile fever is excellent, with full recovery in most cases.

WNV infection spans a broad clinical spectrum.

• Asymptomatic infection

Most infections are clinically inapparent and identified only by serologic studies.^[1]

• West Nile fever (non-neuroinvasive disease)

About 20 percent of infected individuals develop a self-limited febrile illness. Typical features include:

• Acute onset fever
• Headache
• Fatigue and malaise
• Myalgias and arthralgias
• Gastrointestinal symptoms, such as nausea, vomiting, or diarrhea
• A non-specific maculopapular rash, often involving the trunk and extremities^[1]

Symptoms may persist for weeks, particularly fatigue and weakness.

• Neuroinvasive disease

Less than 1 percent of infections progress to meningitis, encephalitis, or acute flaccid myelitis.^[1] Patients may present with:

• Severe headache and neck stiffness (meningitis)
• Fever, altered mental status, confusion, or coma (encephalitis)
• Focal neurologic deficits
• Movement disorders such as tremor, myoclonus, parkinsonian features, or ataxia
• Acute onset flaccid limb weakness, often asymmetric, with depressed reflexes and minimal sensory findings (acute flaccid myelitis)
• Bulbar symptoms including dysarthria and dysphagia, with risk of respiratory compromise^[1]

A focused history should assess seasonality, recent mosquito exposure, residence or travel in endemic areas, blood transfusions or organ transplantation, pregnancy, and underlying immunosuppressive conditions.

Physical examination findings in WNV infection vary with disease severity.

In West Nile fever, exam may reveal fever, mild tachycardia, and a maculopapular rash, typically non-pruritic and transient. Meningeal signs are absent in non-neuroinvasive disease.^[1]

In neuroinvasive disease, findings may include:

• Fever and signs of systemic illness
• Neck stiffness and other meningeal signs in meningitis
• Altered level of consciousness, disorientation, or agitation in encephalitis
• Focal neurologic deficits, movement disorders, or cerebellar signs
• Asymmetric flaccid limb weakness with reduced or absent deep tendon reflexes in acute flaccid myelitis
• Cranial nerve deficits and bulbar dysfunction
• Signs of respiratory distress or hypoventilation in cases with diaphragmatic or intercostal muscle involvement^[1]

The primary laboratory test for diagnosis of WNV infection is detection of WNV-specific IgM antibodies by enzyme-linked immunosorbent assay (ELISA) or microsphere-based immunoassay in serum or CSF.^[1] IgM antibodies typically appear by the end of the first week of illness. If early testing is negative but clinical suspicion remains high, repeat testing after 7 to 10 days is recommended. Detection of WNV IgM in non-bloody CSF strongly supports CNS infection because IgM does not cross an intact blood–brain barrier.^[1]

Because IgM and IgG antibodies to flaviviruses can cross-react, positive screening tests should be confirmed with plaque reduction neutralization testing (PRNT) for WNV and other co-circulating flaviviruses when:

• There is possible exposure to multiple flaviviruses or recent flavivirus vaccination
• Illness is atypical or severe
• Unusual transmission routes (for example, transfusion or transplantation) are suspected
• Illness occurs outside the typical WNV transmission season^[1]

Nucleic acid amplification tests (RT-PCR or other NAT) for WNV RNA in serum, plasma, whole blood, CSF, urine, or tissue have limited sensitivity in immunocompetent patients with neuroinvasive disease because viremia is usually brief and precedes neurologic manifestations. NAT is most useful:

• Early in the course of disease
• In severely immunocompromised patients who may not mount an IgM response
• In investigating suspected transfusion or transplant-associated cases^[1]

Viral antigen or RNA can also be detected in tissue specimens by immunohistochemistry or molecular methods, particularly in brain and spinal cord tissue from fatal cases.^[1]

Historically, CDC guidelines have emphasized IgM ELISA, confirmatory PRNT, and NAT in selected circumstances for surveillance and clinical diagnosis of WNV disease.^[4]

There is no antiviral therapy of proven clinical benefit for WNV infection. Management is primarily supportive and depends on disease severity.^[1]

Patients with neuroinvasive disease should be hospitalized and often require intensive care. Key aspects of management include:

• Monitoring and treatment of increased intracranial pressure
• Control of seizures
• Management of agitation and delirium
• Early recognition of respiratory compromise and timely ventilatory support in patients with bulbar involvement or acute flaccid myelitis
• Prevention of secondary complications such as aspiration pneumonia, venous thromboembolism, pressure injuries, and deconditioning^[1]

Several therapies have been evaluated in case reports, small series, or early-phase trials, including:

• Standard or high-titer intravenous immunoglobulin (IVIG)
• Monoclonal antibodies targeting WNV
• Interferon-based regimens
• Ribavirin
• Corticosteroids^[1]

Evidence remains insufficient to support routine use of these agents, and current expert guidance does not recommend them as standard therapy outside of clinical trials. Patients with mild West Nile fever can usually be managed in the outpatient setting with symptomatic care and close follow-up.

There is currently no licensed human vaccine against WNV. Prevention therefore relies on personal protective behaviors, vector control, and safety measures in blood and organ donation.^[1][12]

Personal protective measures include:

• Use of Environmental Protection Agency–registered insect repellents
• Wearing long sleeves and long pants, especially from dusk to dawn
• Ensuring that window and door screens are intact
• Reducing standing water around homes and communities
• Limiting outdoor exposure during peak mosquito activity when feasible^[1]

Community-level vector control programs may deploy larvicides and adulticides, guided by mosquito and avian surveillance data, to reduce WNV transmission risk.^[1] Screening of blood donors by NAT has dramatically decreased the risk of transfusion-transmitted WNV, and targeted screening strategies for organ donors help mitigate transplant-associated transmission.^[1]

Multiple human WNV vaccine candidates, including inactivated, live attenuated, recombinant viral vector, and subunit vaccines, have demonstrated immunogenicity and acceptable safety in early-phase clinical trials but none has yet progressed to licensure, in part because of challenges in conducting large efficacy trials for a sporadic, seasonal disease.^[1]

Prophylactic monoclonal antibodies directed against WNV have shown protection in animal models and are under consideration as potential preventive tools for high-risk populations, such as transplant recipients, during periods of intense WNV transmission. Antiviral agents and immunomodulatory therapies continue to be evaluated, but no investigational therapy has yet demonstrated clear clinical benefit in randomized controlled trials.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.

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.

WNV was first discovered following its isolation in 1937 from a hospitalized patient presenting with isolated fever in the West Nile district of Northern Uganda.^[1] Initial reports described a virus whose physical and pathological characteristics resemble that of St. Louis encephalitis virus and Japanese B encephalitis virus. Early studies noted the frequent involvement of the CNS among infected patients, suggesting neurotropism of the virus. It was not until the 1950-1960 Mediterranean basin outbreaks in small towns that clinical and pathological features of West Nile virus were really revealed.

The first epidemic was documented in 1951 in Isreal, when Bernkopf and colleagues isolated WNV among 123 cases.^[2][3] Further understanding of the viral pattern, mode of transmission, and pathogenesis was conducted by studies in 1951-1954 following outbreaks in Cairo, Egypt.^[2][4][5] The first report of neurological sequelae following WNV infection was documented in 1957 during an outbreak in Israel.^[1] Other outbreaks in other regions, such as Europe, India, South Africa, were later described in the 1970s and 1980s.^[1] In 1996, an outbreak of WNV in Romania in Europe spiraled a series of outbreaks in the Middle East, North Africa, and Europe region.^[6][7] Unlike early reports that mostly included children, these outbreaks unveiled adult preponderance and an increased rate of CNS complications associated with the disease.^[6][7]

In 1999, the first outbreak in USA initially described 8 cases, most of which had neurological symptoms, in Queens, New York City.^[8] The 1999 outbreak in USA finally marked the global spread of the virus. The outbreak eventually infected a total of 62 individuals, whose symptoms were mostly severe and necessitated hospitalization. Although initially believed to be caused by an endemic arbovirus, WNV was eventually demonstrated to be the agent responsible for the outbreak after the discovery of a coinciding outbreak among infected birds within the same geographical region and during the same time frame^{[9][10][11][12][13]} Only 3 years after its documented presence in USA, the clinically most severe WNV outbreak occurred in North America in 2002, where the largest number of meningoencephalitis from a single outbreak was recorded. In the same year, the first human-to-human transmission was discovered; it was attributed to transmission via blood transfusion and tissue transplantation.^[14]

• The first WNV MAC-ELISA-based commercial diagnostic test for arboviruses was also developed and later commercialized to assays that may be used in the field.^[15]

• Following the 1999 outbreak in USA, the first animal vaccine was developed and later approved by the U.S. department of agriculture (USDA). The WNV-DNA virus is considered the only USDA-approved vaccine.^[15][16]

• The 1999 outbreak in New York in USA drove the Center of Disease Control (CDC) to fund its own Zoo Surveillance Program at Cornell University School of Veterinary Medicine. During the outbreak, CDC assigned other channels to test infected bird species that might help in identifying the virus. The delay in diagnosis was presumed to be a significant element for the outbreak’s detrimental outcomes.^[17]

• Following the 1999 outbreak, WNV was considered a nationally reportable disease in USA. Annual meetings were held in USA to provide public health information about WNV, and guidelines for surveillance, prevention, and control of WNV were developed and frequently updated.^[15]

• ArboNET, a real-time disease reporting network developed by CDC, was first launched in 2000 after the 1999 outbreak to follow WNV disease in humans and animals.^[15]
• Funding to the CDC – Enhanced Laboratory Capacity (ELC) cooperative agreement program reached $2.7 million dollars in 2000. In a few years, the program’s funding was higher than $20 million dollars. Grants were utilized to train arbovirologists and to fund research programs, lab diagnosis, and surveillance programs.^[15]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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.

Viruses; ssRNA viruses; ssRNA positive-strand viruses, no DNA stage; Flaviviridae; Flavivirus; Japanese encephalitis virus group^[1]

WNV is a member of Japanese encephalitis serocomplex and belongs to the genus Flavivirus, family Flaviviridae. Other species of the this serocomplex include the St Louis encephalitis virus and the Japanese encephalitis virus.^[3]

The WNV has an icosahedral symmetry, with a smooth surface.^[4] It is an enveloped virus with a nucleocapsid core built of RNA and capsid proteins. Its genome is contained in a single-stranded RNA of about 11000 bp.^[5] It contains a single open reading frame (ORF), a 5′ untranslated region (UTR), and another 3′ region which is also not translated. The ORF contains a single polyprotein that produces 3 smaller types of structure proteins and 7 of non-structural proteins following processing and translation.

• Structural proteins are responsible for the formation of the viral particle and include:

• Envelope proteins
• Membrane proteins
• C proteins

• Non-structural proteins are responsible for viral replication, evasion of the immune system, and assembly of virions. They include:

• NS1
• NS2A
• NS2B
• NS3
• NS4A
• NS4B
• NS5

The WNV may be classified in 7 phylogenetic lineages. Of these, only 1 and 2 have been identified as causative agents of disease in humans and are considered clinically significant.^{[6][7][8][9][10][11][12][13]}

• Lineage 1: Widespread, isolates from Europe, America, Middle East, India, Africa, and Australia
• Lingeage 2: Southern Africa, Madagascar, and Europe

Although WNV can infect humans and numerous animals, birds are its main natural reservoir.^[3][5]

• 
  West Nile virus is a flavivirus commonly found in Africa, West Asia, and the Middle East. From Public Health Image Library (PHIL). ^[14]
• 
  This is a transmission electron micrograph (TEM) of the West Nile virus (WNV). From Public Health Image Library (PHIL). ^[14]
• 
  Digitally-colorized transmission electron micrograph (TEM) of the West Nile virus (WNV). From Public Health Image Library (PHIL). ^[14]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.

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 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.

The West Nile virus has an enzootic life cycle, being primarily transmitted between some species of birds and different species of mosquito vectors.^[1]

Birds are the main reservoir of West Nile virus (WNV). Transmission of the virus is by a mosquito bite of an infected bird with high-level viremia, such as birds of the family Passeriformes.^[2] Thus, transmission is frequently denoted as “bird-mosquito-bird” transmission. Other forms of transmission have been speculated, such as direct bird-to-bird transmission, but further validation is still required.^[3] Other species may also be infected, such as horses, cats, and dogs. Humans are considered dead-end hosts because the disease rarely progresses to viremia in humans, making transmission of the virus from a human unlikely except in some reported cases of transmission by blood transfusion, breastfeeding, or organ transplantation.^[4][5][6]

Mosquitoes responsible for viral transmission belong to different families, varying based on geographical location:^[7]

• Culex pipiens: Northern half and West of USA
• Culex quinquefasciatus: Southeast and West of USA
• Culex tarsalis: West of USA

[[

image:WNV Mosquito.png|600px|thumb|center|Approximate geographic distribution of the primary WNV vectors, Cx. pipiens, Cx. quinquefasciatus and Cx. tarsalis– Center for Disease Control and Prevention(CDC)^[2]]]

Other transmission routes, not involving vectors, have also been described:^[1]

• Blood transfusions^[8]
• Breast milk^[8]
• Organ transplants (patients with organ transplants also carry an increased risk of neuroinvasive disease)^[9]
• Intrauterine transmission^[8]
• Exposure in a laboratory setting^[2]

Following inoculation, replication of WNV takes place in the Langerhans epidermal dendritic cells, which are antigen-presenting immune cells.^[10] These cells then migrate to lymph nodes, resulting in lymph node drainage, followed by viremia and dissemination of the virus into other organs, namely the spleen and the kidneys. Within one week, the virus is successfully cleared from the serum and tissue compartments among immunocompetent individuals. Interferons (IFN) have a crucial role in upregulating genes that carry antiviral functions and in stimulating the maturation of dendritic cells that eventually combine both the innate and the adaptive immune responses.^[11] Viral sensors, such as Toll-like receptor 3, help in activation of transcription factors and IFN-stimulated genes.^[12][13] Additionally, complement activation through classical, lectin, and alternative pathways offers significant immunity against WNV by opsonization, cytolysis, and chemotaxis. Innate immune cells, such as macrophages, along with humoral, primary, and memory adaptive immune cells are also activated during viral infection; these cells also contribute to the clearance of the virus and the prevention of its dissemination to the CNS.^[14]

Mice models have demonstrated that persistent infection, including CNS infiltration, is possible, especially in immunosuppressed states. TNF-alpha has been hypothesized to allow viral migration across the blood-brain barrier (BBB) by promoting the permeability of endothelial cell.^[15][16][17] Other reports showed that the virus may cross the BBB either by using the olfactory bulb in a “Trojan horse” mechanism to cross to the CNS, or utilizing passive transport mechanisms, or following a retrograde transport mechanism from peripheral neurons.^[18][19][20]

WNV may be disseminated to include all organ systems. Animal models demonstrated that WNV infection typically first appears in the lymphatic tissue and the spleen before it migrates to other organs, namely the kidneys, lungs, liver, the cardiovascular system, and the nervous system.^[21] In animals, tropism of WNV has been described in the following organs:

• Eyes
• Peripheral and central nervous system
• Heart
• Blood vessels
• Spleen and other lymphoid organs
• Liver
• Kidneys
• Lungs
• GI tract
• Endocrine system, including gonads
• Skeletal muscles
• Skin
• Bone marrow

Genetic factors may be associated with WNV susceptibility. In mice strains, a truncated isoform mutation of the gene encoding OAS1b may lead to susceptibility of infections by WNV and other flaviviruses. Similarly, human subjects with CCR5-Δ32, a mutant allele of the gene encoding chemokine receptor, were more likely to be symptomatic with worse WNV clinical disease. Nonetheless, the true role of genetics in the susceptibility and resistance to WNV is yet to be elucidated.^[22][23]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]; Michael Maddaleni, B.S.

WNV is considered a worldwide infective agent. Since most cases are asymptomatic and self-limited, the true incidence and prevalence of West Nile virus 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.

WNV is widely distributed across Australia, Middle East, Western Russia, Southwestern Asia, Africa and Southern Europe. A series of outbreaks in the Mediterranean basin between 1950 and 1960 and in Europe and Africa between 1970 and 1980, marking a continuously waxing and waning incidence during the second half of the 20th century.^[1] In America, the virus was first isolated in 1999 in New York City. The WNV disseminated rapidly across the American continent to the West coast in just 4 years and to Argentina in 6 years.^[2][3] The 2002 outbreak in USA marked the highest rate of neuroinvasive disease of a single WNV outbreak. The total number of infected patients reached 4156, with 2942 (71%) of those suffering severe neuroinvasive disease.^[4]

Most patients with WNV infection are asymptomatic. Accordingly, West Nile fever is considered to be underreported, either because infected patients do not seek medical attention or because they are not tested for the virus.^[3] Between 1999 and 2013, a total 39557 probable and confirmed cases of West Nile fever were reported to the CDC from across the US.^[5][2] The outbreak of 2012, in which 2873 cases of neuroinvasive disease were reported, occurred during a period of increased mosquito infection rate. A possible explanation for this was the severe precipitation felt during the previous winter.^[6][7]

Image:WNV cumulative human disease cases.png|thumb|center|500 px|USA cumulative human disease cases of WNV in 2014. Data as of September 2014– Center for Disease Control and Prevention(CDC)^[8]]]

Image:WNV Cumulative 2014 Data.png|thumb|center|500 px| WNV Cumulative 2014 Data. Data as of September 2014– Center for Disease Control and Prevention(CDC)^[8]]]

• The prevalence of WNV does not change with age.
• Elderly patients have a higher risk of developing severe forms of the disease.^[1][9]

WNV is more prevalent in women.^[1][9]

The prevalence of WNV does not vary by race or ethnicity.

Infection with WNV commonly occurs during warmer seasons, such as the period between late summer and beginning of fall.^[5]

WNV is considered a global virus. Outbreaks of the virus have been documented since its initial isolation in 1937 in approximately all regions of the world.

Image:West Nile Virus Disease Cases.png|thumb|center|1000 px| US West Nile Virus Disease Cases– Center for Disease Control and Prevention( CDC)^[8]]]

Image:West Nile Virus Activity by State.png|thumb|center|1000 px| US West Nile Virus Disease Cases– Center for Disease Control and Prevention (CDC)^[8]]]

Image:West Nile Virus Neuroinvasive Disease Incidence by State.png|center|500px|thumb|Average annual incidence of West Nile Virus neuroinvasive disease 1999-2012– Center for Disease Control and Prevention (CDC)^[8]]]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

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.

Risk factors for infection with West Nile virus include:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.

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.

Universal screening for WNV is not recommended. Screening is only recommended for blood and solid organ transplant donors.

Following the discovery of WNV transmission by blood transfusions, WNV blood donor screening is performed using nucleic acid testing (NAT). A “minipool” nucleic acid testing program (MP NAT) is currently implemented to detect WNV viremia among donors. In contrast, serological testing is not feasible for screening purposes because IgM seroconversion may be detectable approximately 5 months following infection.^[1] Pools with positive NAT results warrant further investigation for individual screening. Individual patients with positive NAT may not donate blood for at least 120 days.^[2][3][4][1]

Although the only data on human-to-human transmission by organ transplantation is derived from reports that included deceased donors, transmission to recipients may still occur if donors have NAT-negative IgM-positive results. These findings suggest that clearance of the WNV from solid organs may be delayed compared to its clearance from plasma. Accordingly, screening for WNV among transplant donors is recommended using NAT. There is no evidence to demonstrate the optimal time for solid organ donation in cases of positive NAT, but re-testing after 120 days to confirm negative NAT has become common practice. Patients with negative results after 120 days may donate solid organs.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

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.

Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

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.

WNV is a member of Japanese encephalitis antigenic complex of the family Flaviviridae. It is transmitted by a mosquito bite, most commonly Culex pipiens. Birds are the natural reservoir of the virus and the disease is generally transmitted to humans when a mosquito that previously fed on a bird with high-level viremia bites a human.^[1]

The incubation period for WNV disease is typically 2 to 6 days. It ranges from 2 to 14 days and can be several weeks in immunocompromised patients. An estimated 70-80% of human WNV infections are subclinical or asymptomatic. Less than 1% of infected individuals develop neuroinvasive disease, which typically manifests as meningitis, encephalitis, or acute flaccid paralysis.^[2]

When left untreated, approximately 80% of the people infected by virus remain asymptomatic.

Around 20% of the patients infected with WNV develop West Nile fever and usually present with fever and other constitutional symptoms. If left untreated, the infection generally self-resolves with no complications or sequelae.

Approximately 1 in 150 persons infected with WNV will develop a severe form of disease if left untreated. Serious illness can occur in patients of any age. However, advanced age, systemic diseases such as malignancy and cardiovascular disease, and immunosuppressed patients are considered high risk for developing neuroinvasive disease.

• Complications from mild West Nile virus infection are very rare.
• Complications from severe West Nile virus infection are as follows

• Meningitis
• Encephalitis
• Parkinsonism
• Rhomboencephalitis
• Cerebellar dysfunction
• West nile poliomyelitis ^[3]
• Dysphagia
• Permanent motor weakness
• Cranial nerve palsy

• Chorioretinitis
• Papilledema
• Hearing loss

• Ataxic breathing
• Apnea

• Deep venous thrombosis
• Pressure ulcers

• Hepatitis
• Myocarditis
• Nephritis
• Pancreatitis
• Splenomegaly^[4][5][6]

• In general, the prognosis of a mild WNV infection is excellent. Most patients with non-neuroinvasive WNV disease or WNV meningitis recover completely. However, fatigue, malaise, and weakness can linger for weeks or months.
• Patients who recover from WNV encephalitis often have residual neurologic deficits. Among patients with neuroinvasive disease, the overall case-fatality ratio is approximately 10%. The rate is significantly higher among patients with WNV encephalitis compared to patients with WNV meningitis.