West nile virus infection overview
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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
Overview
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]
Historical Perspective
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]
Causes
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]
Pathophysiology
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]
Epidemiology & Demographics
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 Factors
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.
Screening
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]
Differentiating West Nile Virus from Other Diseases
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.
Natural History, Complications, & Prognosis
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.
History & Symptoms
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
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]
Lab Tests
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]
Medical Therapy
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.
Primary Prevention
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]
Future or Investigational Therapies
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]
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 1.30 1.31 1.32 1.33 1.34 1.35 1.36 1.37 1.38 1.39 1.40 1.41 1.42 1.43 1.44 1.45 Gould CV, Staples JE, Guagliardo SAJ; et al. (2025). "West Nile Virus: A Review". JAMA. 334 (7): 618–628. doi:10.1001/jama.2025.8737.
- ↑ Petersen LR, Brault AC, Nasci RS (2013). "West Nile virus: review of the literature". JAMA. 310 (3): 308–15. doi:10.1001/jama.2013.8042. PMID 23860989.
- ↑ Campbell, Grant L; Marfin, Anthony A; Lanciotti, Robert S; Gubler, Duane J (2002). "West Nile virus". The Lancet Infectious Diseases. 2 (9): 519–529. doi:10.1016/S1473-3099(02)00368-7. ISSN 1473-3099.
- ↑ 4.0 4.1 4.2 "West Nile Virus" (PDF).
- ↑ Miller DL, Mauel MJ, Baldwin C, Burtle G, Ingram D, Hines ME; et al. (2003). "West Nile virus in farmed alligators". Emerg Infect Dis. 9 (7): 794–9. doi:10.3201/eid0907.030085. PMC 3023431. PMID 12890319.
- ↑ Bakonyi T, Ivanics E, Erdélyi K, Ursu K, Ferenczi E, Weissenböck H; et al. (2006). "Lineage 1 and 2 strains of encephalitic West Nile virus, central Europe". Emerg Infect Dis. 12 (4): 618–23. doi:10.3201/eid1204.051379. PMC 3294705. PMID 16704810.
- ↑ Charrel RN, Brault AC, Gallian P, Lemasson JJ, Murgue B, Murri S; et al. (2003). "Evolutionary relationship between Old World West Nile virus strains. Evidence for viral gene flow between Africa, the Middle East, and Europe". Virology. 315 (2): 381–8. PMID 14585341.
- ↑ Lanciotti RS, Ebel GD, Deubel V, Kerst AJ, Murri S, Meyer R; et al. (2002). "Complete genome sequences and phylogenetic analysis of West Nile virus strains isolated from the United States, Europe, and the Middle East". Virology. 298 (1): 96–105. PMID 12093177.
- ↑ Papa A, Xanthopoulou K, Gewehr S, Mourelatos S (2011). "Detection of West Nile virus lineage 2 in mosquitoes during a human outbreak in Greece". Clin Microbiol Infect. 17 (8): 1176–80. doi:10.1111/j.1469-0691.2010.03438.x. PMID 21781205.
- ↑ Savini G, Capelli G, Monaco F, Polci A, Russo F, Di Gennaro A; et al. (2012). "Evidence of West Nile virus lineage 2 circulation in Northern Italy". Vet Microbiol. 158 (3–4): 267–73. doi:10.1016/j.vetmic.2012.02.018. PMID 22406344.
- ↑ Valiakos G, Touloudi A, Iacovakis C, Athanasiou L, Birtsas P, Spyrou V; et al. (2011). "Molecular detection and phylogenetic analysis of West Nile virus lineage 2 in sedentary wild birds (Eurasian magpie), Greece, 2010". Euro Surveill. 16 (18). PMID 21586266.
- ↑ "CDC West Nile Virus Prevention & Control".