West Nile Virus: An Update with Pearls and Pitfalls

West Nile Virus: An Update with Pearls and Pitfalls

by Brit Long MD
EM Resident Physician at SAUSHEC; USAF

Edited by Alex Koyfman MD (@EMHighAK) and Stephen Alerhand MD (@SAlerhand)

A patient presents to a Texas ED with reports of severe headache, myalgias, and ascending weakness. She has no past medical history. Over the last several days, she has experienced difficulty concentrating, a gradually worsening headache, diffuse aches, and trouble getting up from a seated position.

Your exam reveals normal vital signs. Neurologic exam reveals decreased reflexes in the lower extremities with +3/5 strength. The rest of your exam is normal. Due to concern for Guillain–Barré syndrome (GBS), cerebral spinal fluid (CSF) is obtained, revealing elevated protein and lymphocytes, but negative RBCs. What should you consider with this presentation?

Introduction

West Nile Virus (WNV) is a flavivirus, spread by the bite of female Culex mosquitoes. The virus is predominantly in temperate and tropical regions. This RNA virus is widely distributed, with birds as the host where the virus primarily amplifies. Humans are dead-end hosts.1,2

Epidemiology

WNV is widely distributed across Africa, the Middle East, Europe, Asia, North America, and Australia. The first outbreak in the U.S. occurred in 1999 in New York City. It is now endemic in the U.S. Neurologic disease has occurred all over the world. This disease is likely underreported, as most patients do not present for medical care. A large U.S. outbreak occurred in 2012, with 43 states reporting cases, and 29% of cases in Texas. Presentations peak in late summer and early fall at the height of mosquito season, as these insects emerge in the spring with viral amplification requiring weeks to reach peak levels via the bird-mosquito-bird cycle. Birds are the primary amplifying host (and normally asymptomatic), with humans and livestock as incidental hosts. Mosquitoes are of the Culex species, with only females able to transmit the disease to humans. Unfortunately, the virus can also be passed via blood transfusion and from mother to baby via the placenta.1-3

transmission cycle

Presentation

Only 20-25% of those patients infected with the virus actually experience symptoms, predominantly fever and myalgias. This is called West Nile fever. Abdominal pain, malaise, headache, vomiting, and diarrhea can also occur. Symptoms last two to ten days, with full recovery the norm. However, a small percentage can experience a prolonged recovery with fatigue, general weakness, and headache. A viral maculopapular rash can also present in half of patients.1-5

Neuroinvasive disease

WNV presenting with fever and meningitis, encephalitis, paralysis, or mixed pattern characterizes this subset of patients. Fortunately, less than one percent of patients infected with WNV suffer from neuroinvasive disease. The mortality rate is 10% of those with this disease. The incubation period is up to two weeks. Encephalitis is more common than meningitis in neuroinvasive disease, with symptoms ranging from confusion and headache to coma. Extrapyramidal symptoms such as tremor, clonus, rigidity, and bradykinesia are also common. Acute flaccid paralysis may occur, called West Nile poliomyelitis, with anterior horn cells affected in the spinal cord.1,6

Symptoms rapidly progress over 48 hours, with asymmetric ascending weakness. Recovery follows the rule of 1/3’s: a third of patients recover with no complications, a third partially recover, and a third have no improvement. In these patients, dysarthria and dysphagia mandate ICU admission for respiratory monitoring, as these patients can have respiratory failure.1,6

Other Complications

Patients can present with ocular manifestations (vitreitis, retinitis, retinal hemorrhages), rhabdomyolysis, fatal hemorrhagic fever (case reports), hepatitis, pancreatitis, myocarditis, myositis, and orchitis.1

Risk factors

Advanced age is the most commonly found risk factor for neuroinvasive disease. Malignancy, organ transplantation, and female gender also increase the risk of more severe presentations.1,7

Differential Diagnosis

This differential is broad with patients presenting in late summer and early fall with fever and myalgias. Tick-borne illnesses, influenza, bacterial meningitis, and other viral encephalitides (such as HSV or Zoster) all present similarly. Tick-borne illnesses include Lyme disease, Rocky Mounted spotted fever, human ehrlichiosis, and anaplasmosis. Other viruses spread via mosquitoes including St. Louis encephalitis, Japanese encephalitis, dengue fever, and malaria must be considered as well.1,2 If the patient presents with ascending weakness (often asymmetric), be concerned for GBS or polio.

Diagnosis

If the disease is suspected, WNV IgM antibody testing is completed. This ELISA test evaluates IgM production and can be used on serum and CSF. It has sensitivities greater than 95%, but initial testing may be negative for the first 4-10 days of illness. Ultimately, in patients with WNV neuroinvasive disease, CSF demonstrates elevated protein with pleocytosis, with lymphocyte predominance. CSF testing with WNV specific antibodies (IgM) or RNA PCR testing is required for diagnosis. Serum and CSF IgM testing is done with MAC-ELISA assay. This test can be completed at most major medical centers. The most specific antibody tests, plaque reduction neutralization test (PRNT) can only be performed at reference labs (such as the CDC). Nucleic acid testing using PCR is better for immunocompromised patients, as these patients are less apt to form antibodies to the virus, as well as patients requiring urgent diagnosis, blood donors, and prior WNV exposure. PCR testing is approximately 15% and 55% sensitive for serum and CSF testing respectively.1-3,8-10

CDC diagnostic criteria include isolation of virus from tissue/serum/CSF, fourfold increase in WNV antibody titers, or presence of IgM antibodies in a region where exposure occurred.1,2

Treatment

Treatment is supportive. Treatment with alfa-interferon, ribavirin, and IVIG has not been supported in human studies. Various in vitro and animal studies have shown support. If CSF studies reveal pleocytosis with lymphocyte predominance and PCR studies have not returned, acyclovir should be provided to treat HSV encephalitis, though this is not effective in WNV.1,11-15

Prognosis

Adverse outcomes are primarily limited to patients with neuroinvasive disease. Older age and immunosuppressed patients also experience increased morbidity. Studies show mortality rates of 12% with encephalitis and 2% with meningitis. Unfortunately, for those who suffer from neuroinvasive disease, only approximately 40% of patients are able to fully recover. Fatigue, weakness, paresthesias, tremor, and headaches can be chronic after WNV.1,11,16,17

New

Vaccines are currently under development, with a live attenuated recombinant vaccine, plasmid DNA vaccine, and inactivated virus vaccine all showing promise.1,17

Despite the new vaccines and supportive treatment, the most important aspect is prevention with insect repellent, destruction of mosquito breeding grounds, covering skin when outside, and sleeping in enclosed areas.

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References/Further Reading

  1. Petersen LR, Brault AC, Nasci RS. West Nile virus: review of the literature. JAMA 2013; 310:308.
  2. Centers for Disease Control and Prevention (CDC). West Nile virus and other arboviral diseases–United States, 2012. MMWR Morb Mortal Wkly Rep 2013; 62:513.
  3. Petersen LR, Hayes EB. West Nile virus in the Americas. Med Clin North Am 2008; 92:1307.
  4. Zou S, Foster GA, Dodd RY, et al. West Nile fever characteristics among viremic persons identified through blood donor screening. J Infect Dis 2010; 202:1354.
  5. Orton SL, Stramer SL, Dodd RY. Self-reported symptoms associated with West Nile virus infection in RNA-positive blood donors. Transfusion 2006; 46:272.
  6. Davis LE, DeBiasi R, Goade DE, et al. West Nile virus neuroinvasive disease. Ann Neurol 2006; 60:286.
  7. Lindsey NP, Staples JE, Lehman JA, et al. Surveillance for human West Nile virus disease – United States, 1999-2008. MMWR Surveill Summ 2010; 59:1.
  8. Prince HE, Tobler LH, Lapé-Nixon M, et al. Development and persistence of West Nile virus-specific immunoglobulin M (IgM), IgA, and IgG in viremic blood donors. J Clin Microbiol 2005; 43:4316.
  9. Busch MP, Kleinman SH, Tobler LH, et al. Virus and antibody dynamics in acute west nile virus infection. J Infect Dis 2008; 198:984.
  10. Busch MP, Caglioti S, Robertson EF, et al. Screening the blood supply for West Nile virus RNA by nucleic acid amplification testing. N Engl J Med 2005; 353:460.
  11. Sejvar JJ, Haddad MB, Tierney BC, et al. Neurologic manifestations and outcome of West Nile virus infection. JAMA 2003; 290:511.
  12. Gea-Banacloche J, Johnson RT, Bagic A, et al. West Nile virus: pathogenesis and therapeutic options. Ann Intern Med 2004; 140:545.
  13. Morrey JD, Day CW, Julander JG, et al. Effect of interferon-alpha and interferon-inducers on West Nile virus in mouse and hamster animal models. Antivir Chem Chemother 2004; 15:101.
  14. Anderson JF, Rahal JJ. Efficacy of interferon alpha-2b and ribavirin against West Nile virus in vitro. Emerg Infect Dis 2002; 8:107.
  15. Agrawal AG, Petersen LR. Human immunoglobulin as a treatment for West Nile virus infection. J Infect Dis 2003; 188:1.
  16. Hart J Jr, Tillman G, Kraut MA, et al. West Nile virus neuroinvasive disease: neurological manifestations and prospective longitudinal outcomes. BMC Infect Dis 2014; 14:248.
  17. Petersen LR, Marfin AA. West Nile virus: a primer for the clinician. Ann Intern Med 2002; 137:173.
  18. http://www.ncbi.nlm.nih.gov/pubmed/21865003
  19. http://www.ncbi.nlm.nih.gov/pubmed/16982350

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