West Nile Virus

West Nile virus is an enveloped, positive-sense, single-stranded RNA virus of the genus Flavivirus. Birds are the primary hosts and the disease is most often transmitted by Culex mosquitoes. Most people infected with West Nile virus are asymptomatic. Some patients develop West Nile fever (a self-limited, febrile illness) and a very small proportion of patients develop West Nile neuroinvasive disease. West Nile neuroinvasive disease includes meningitis, encephalitis, and acute flaccid paralysis. The diagnosis is confirmed with serum serology, CSF serology, or PCR. Antiviral therapy is not available; therefore, management is supportive. Prevention is aimed at local mosquito control and donated blood and organ screening.

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Classification

RNA Viruses Flowchart Classification

RNA virus identification:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA or RNA. RNA genome viruses can be further characterized by either a single- or double-stranded RNA. “Enveloped” viruses are covered by a thin coat of cell membrane (usually taken from the host cell). If the coat is absent, the viruses are called “naked” viruses. Viruses with single-stranded genomes are “positive-sense” viruses if the genome is directly employed as messenger RNA (mRNA), which is translated into proteins. “Negative-sense,” single-stranded viruses employ RNA dependent RNA polymerase, a viral enzyme, to transcribe their genome into messenger RNA.

Image by Lecturio. License: CC BY-NC-SA 4.0

General Characteristics and Epidemiology

Basic features of West Nile virus

  • Taxonomy:
    • Flaviviridae family
    • Flavivirus genus
  • RNA virus:
    • Single stranded
    • Positive sense
    • Linear
  • Spherical
  • Icosahedral symmetry
  • Enveloped
  • Size: approximately 50 nm
West Nile virus

A colorized transmission electron microscopic (TEM) image of West Nile virions

Image: “West Nile virus” by CDC/P.E. Rollin. License: Public Domain

Associated disease

Two phylogenic lineages of West Nile virus cause the following diseases:

  • West Nile fever
  • Neuroinvasive disease:
    • Meningitis
    • Encephalitis
    • Acute flaccid paralysis

Epidemiology

  • Number of cases in the United States 1999–2015:
    • 44,000 total
    • 20,000 with neuroinvasive disease
  • Develop severe disease: < 1%
  • Patient death rate if severe disease: 3%–15%
  • One of the most widely distributed arbovirus diseases 
  • Geographic distribution: 
    • Africa
    • Middle East
    • Europe
    • South Asia
    • Australia
    • North America
    • South America

Pathogenesis

Reservoir

  • Primary host: birds
  • Accidental hosts:
    • Horses 
    • Humans
    • Other mammals

Transmission

  • Vector: Culex mosquitoes
  • Blood transfusion
  • Organ transplant
  • Transplacental
Culex mosquito

A female Culex mosquito responsible for transmission of West Nile virus

Image: “Culex mosquito” by CDC/James Gathany. License: Public Domain

Host risk factors

Higher risk for infection:

  • Living in areas with high temperature and rainfall
  • Living near stagnant water
  • Living near immunologically naive, avian-host population

Higher risk for neuroinvasive disease:

  • Age > 75 years old
  • Immunosuppression:
    • Hematologic malignancy
    • Organ transplantation
    • Medications
    • Diabetes
  • Other medical conditions:
    • Chronic renal disease
    • Hypertension

Viral replication

  • Virion interacts with cell surface receptors → endocytosis
  • ↓ pH in the endosome → fusion of viral and endosomal membranes → uncoating of the virus
  • Viral protein synthesis occurs in the rough endoplasmic reticulum (RER).
  • Genomic replication occurs in invaginations of the RER → virions are repackaged and assembled
  • Mature virions leave the cell.

Pathophysiology

  • West Nile virus is injected into a host by a mosquito.
  • Replication occurs in keratinocytes and dendritic cells.
  • Spread through lymphatics → replication in lymph nodes
  • Viremia occurs → spread to visceral organs → further replication
  • Eventual spread to the CNS (mode of entry is unclear) → inflammatory response → neuron damage → neurologic manifestations

Clinical Presentation

The majority of patients are asymptomatic. Symptomatic disease can vary in severity and presentation.

West Nile fever

Approximately 20% of infected patients will develop a mild, self-limited disease.

  • Fever
  • Headache
  • Nausea and vomiting
  • Anorexia
  • Malaise
  • Myalgia
  • Eye pain
  • Backache
  • Rash:
    • Features:
      • Erythematous
      • Maculopapular
      • Morbilliform
      • May be pruritic
    • Distribution:
      • Chest
      • Back
      • Arms

Neuroinvasive disease

Approximately 1% of infected patients may experience:

  • Meningitis:
    • Fever
    • Headache
    • Nuchal rigidity
    • Photophobia
  • Encephalitis: 
    • Altered mental status
    • Severe muscle weakness
    • Parkinsonism:
      • Rigidity
      • Bradykinesia
      • Postural instability 
    • Tremor
    • Myoclonus
    • Seizures
  • Acute flaccid paralysis:
    • Usually isolated, asymmetric limb paralysis
    • Respiratory paralysis may occur.
  • Other manifestations:
    • Guillain-Barré syndrome
    • Polyneuropathy
    • Cranial nerve palsy

Diagnosis

Definitive studies:

  • Serology of serum or CSF
  • PCR to detect viral RNA
  • Viral culture

Supporting evaluation:

  • Blood testing:
    • Leukocytosis
    • Hyponatremia → SIADH due to encephalitis
  • CSF examination:
    • Pleocytosis with lymphocyte predominance (neutrophil predominance early in the course)
    • Normal glucose levels
    • ↑ Protein
  • MRI of the brain: enhancement in the leptomeninges, basal ganglia, and thalami

Management

No antiviral therapy is currently available; management is supportive. In patients with neuroinvasive disease, the following may be needed:

  • ICU care
  • Intracranial pressure monitoring
  • Seizure management
  • Ventilator support for respiratory failure or inability to protect the airway
  • Occupational and physical therapy

Prevention

  • Local mosquito control
  • Insect repellent
  • Protective clothing
  • Blood and organ donor screening

Comparison of Similar Flavivirus Species

Table: Features and diseases of several Flavivirus species
OrganismTick-borne encephalitis virusJapanese encephalitis virusSt. Louis encephalitis virusWest Nile virus
CharacteristicsThe structural features are almost identical.
Region
  • Europe
  • Siberia
  • Asia
  • Asia
  • Western Pacific
North America
  • Africa
  • Middle East
  • Europe
  • South Asia
  • Australia
  • North America
TransmissionTickMosquitoMosquitoMosquito
Clinical
  • Most are asymptomatic.
  • Initially nonspecific symptoms
  • Neurologic phase:
    • Meningitis
    • Encephalitis
    • Meningoencephalitis
  • Nonspecific febrile illness
  • Meningitis
  • Encephalitis
  • Acute flaccid paralysis
  • Guillain-Barré
  • Most are asymptomatic.
  • Nonspecific febrile illness
  • Meningitis
  • Encephalitis
  • Meningoencephalitis
  • Most are asymptomatic.
  • West Nile fever
  • Neuroinvasive disease:
    • Meningitis
    • Encephalitis
    • Acute flaccid paralysis
Diagnosis
  • Serology
  • PCR
SerologySerology
  • Serology
  • PCR
ManagementSupportiveSupportiveSupportiveSupportive
Prevention
  • Tick avoidance measures
  • Vaccination (in endemic areas)
  • Mosquito avoidance measures
  • Vaccination
Mosquito avoidance measuresMosquito avoidance measures

Differential Diagnosis

  • Lyme disease: a tick-borne infection caused by the gram-negative spirochete Borrelia burgdorferi. The presentation can vary depending on the stage of the disease and may include the characteristic erythema migrans rash. Neurologic, cardiac, ocular, and joint manifestations are also common in later stages. The diagnosis relies on clinical findings and tick exposure, and is supported by serological testing. Antibiotics are used for treatment. 
  • Ehrlichiosis and anaplasmosis: tick-borne infections caused by Ehrlichia chaffeensis and Anaplasmosis phagocytophilum, respectively. Symptoms of ehrlichiosis and anaplasmosis include fever, headache, and malaise. Meningoencephalitis can also occur with severe disease. The diagnosis is made using PCR. Treatment of both diseases is with doxycycline.
  • Rocky Mountain spotted fever: a disease caused by Rickettsia rickettsii. Presentation includes fever, fatigue, headache, and rash following a tick bite. Diagnosis is made based on clinical features, rash biopsy, and serologic testing. Treatment involves antibiotics, including doxycycline.  
  • Toxoplasmosis: an infectious disease caused by Toxoplasma gondii. Immunocompetent patients usually have no symptoms; immunocompromised patients may develop CNS toxoplasmosis or chorioretinitis. The diagnosis is made with serology or PCR testing. Immunocompetent patients may not need any treatment. The immunocompromised or patients with severe disease may require combination therapy with pyrimethamine, sulfadiazine, and leucovorin. 
  • Herpes simplex encephalitis: a severe CNS infection caused by herpes simplex viruses. Patients develop rapid onset of fever, headache, an altered level of consciousness, focal neurologic deficits, and seizures. The diagnosis is confirmed with PCR testing of CSF. Hyperintense lesions in the temporal lobes may be seen on MRI. The treatment of choice is IV acyclovir.
  • Poliomyelitis: an infectious disease caused by the poliovirus. The majority of patients are asymptomatic or have mild, abortive presentation with flu-like symptoms. Nonparalytic poliomyelitis may present with aseptic meningitis. A minor proportion of patients will progress to paralytic poliomyelitis with neurologic progression, including asymmetric flaccid paralysis. The diagnosis is determined by clinical presentation and supported by viral culture, PCR, and serology.  Management is supportive.
  • Bacterial meningitis: an acute infection of the meninges. Patients present with headache, fever, nuchal rigidity, and rapid clinical deterioration. A lumbar puncture is performed to make the diagnosis. Unlike viral meningitis, CSF studies will show turbid fluid, hypoglycemia, and a high WBC count with neutrophil predominance. Gram stain and culture determine the causative bacteria. Treatment includes antibiotics and corticosteroids. 
  • Intracranial tumors: a benign or malignant growth of cells in the brain. Presentation includes headache, unexplained nausea or vomiting, blurred vision, and difficulty in speech or hearing. The diagnosis is made with a neurologic examination, imaging (MRI or CT), and sometimes biopsy. Management includes radiation, chemotherapy, and/or surgery.
  • Brain abscess: a collection of pus in the brain parenchyma due to infection. Presentation includes fever, headache, seizures, nausea, and vomiting. A definitive diagnosis from clinical presentation alone is difficult; therefore, the diagnosis is mainly based on imaging. Management includes antibiotic therapy and surgery to drain the abscess.

References

  1. Petersen LR, Marfin AA. West Nile virus: a primer for the clinician. Ann Intern Med. 2002. 137(3):173–9. http://reference.medscape.com/medline/abstract/12160365
  2. Brinton MA. Host factors involved in West Nile virus replication. Ann N Y Acad Sci. 2001. 51:207–19. http://reference.medscape.com/medline/abstract/11797778
  3. Asnis DS, Conetta R, Teixeira AA, et al. The West Nile Virus outbreak of 1999 in New York: the Flushing Hospital experience. Clin Infect Dis. 2000. (3):413–8. http://reference.medscape.com/medline/abstract/10722421
  4. Centers for Disease Control and Prevention. Acute flaccid paralysis syndrome associated with West Nile virus infection–Mississippi and Louisiana, July-August 2002. MMWR Morb Mortal Wkly Rep. 2002. 51(37):825–8. http://reference.medscape.com/medline/abstract/12353741
  5. Guarner J, Shieh WJ, Hunter S, Paddock CD, Morken T, Campbell GL, Marfin AA, Zaki SR. Clinicopathologic study and laboratory diagnosis of 23 cases with West Nile virus encephalomyelitis. Hum Pathol. 2004. 35(8):983–90. https://www.ncbi.nlm.nih.gov/pubmed/15297965
  6. Hart J, Tillman G, Kraut MA, Chiang HS, Strain JF, Li Y, Agrawal AG, Jester P, Gnann JW, Whitley RJ., NIAID Collaborative Antiviral Study Group West Nile Virus 210 Protocol Team. West Nile virus neuroinvasive disease: neurological manifestations and prospective longitudinal outcomes. BMC Infect Dis. 2014. 14:248. https://www.ncbi.nlm.nih.gov/pubmed/24884681
  7. Yuill, T.M. (2020). West Nile virus. [online] MSD Manual Professional Version. Retrieved May 6, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/arboviruses-arenaviridae-and-filoviridae/west-nile-virus
  8. Clark, M.B., and Schaefer, T.J. (2020). West Nile virus. [online] StatPearls. Retrieved May 6, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK544246/
  9. Salinas, J.D., and Steiner, M.L. (2020). West Nile virus. In Moberg-Wolff, E.A. (Ed.), Medscape. Retrieved May 6, 2021, from https://emedicine.medscape.com/article/312210-overview
  10. Petersen, L.R. (2020). Epidemiology and pathogenesis of West Nile virus infection. In Mitty, J. (Ed.), UpToDate. Retrieved May 6, 2021, from https://www.uptodate.com/contents/epidemiology-and-pathogenesis-of-west-nile-virus-infection
  11. Petersen, L.R. (2021). Clinical manifestations and diagnosis of West Nile virus infection. In Mitty, J. (Ed.), UpToDate. Retrieved May 6, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-west-nile-virus-infection
  12. Petersen, L.R. (2020). Treatment and Prevention of West Nile virus infection. In Mitty, J. (Ed.), UpToDate. Retrieved May 6, 2021, from https://www.uptodate.com/contents/treatment-and-prevention-of-west-nile-virus-infection

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