Pediatrics

West Nile Virus

OVERVIEW: What every practitioner needs to know

Are you sure your patient has West Nile virus (WNV) disease? What are the typical findings for this disease?

West Nile virus (WNV) disease typically presents with the acute onset of nonspecific symptoms that variably can include fever, headache, myalgia, malaise, weakness, anorexia, back pain, abdominal pain, vomiting, diarrhea, and maculopapular rash.

Severe neurologic manifestations, which occur in less than 5% of all cases, can include mental status changes, asymmetric flaccid paralysis, cranial nerve palsies (causing dysarthria, dysphagia, vertigo, or facial paralysis), seizures, ataxia, or parkinsonian symptoms such as tremor, rigidity, bradykinesia or postural instability.

Immunocompromised children appear to be at higher risk of severe neurologic disease, but both encephalitis and flaccid paralysis due to WNV have been described in immunocompetent children.

Other manifestations of WNV disease include retinitis, optic neuritis, uveitis, cardiac dysrhythmia, myocarditis, rhabdomyalgia, hepatitis, pancreatitis, central diabetes insipidus, and orchitis, but most of these appear to be relatively uncommon in children.

Between 60% and 80% of all WNV infections are asymptomatic. From 20% to 40% of infected people develop the nonspecific symptoms described above in a self-limited viral syndrome called "WNV fever" (although not all patients with this syndrome are febrile) that is typically indistinguishable from many other viral illnesses including enteroviral illness, influenza and dengue.

The incubation period after initial exposure to the virus is 2 to 14 days in otherwise healthy people, but it can be longer in people who are immunocompromised

Fewer than 1% of infected people develop WNV neuroinvasive disease, which can present as WNV meningitis (the most common neuroinvasive presentation in children), encephalitis, or asymmetric flaccid paralysis. Acute onset of limb paralysis due to WNV infection can occur without antecedent fever or other symptoms.

WNV disease should be considered in any child who has acute onset of "viral syndrome" or neurologic illness with a history or likelihood of exposure to infected mosquitoes, blood transfusion, or organ transplantation; or in any infant with an acute nonspecific or neurologic illness whose mother was infected with WNV during pregnancy or breastfeeding.

What other disease/condition shares some of these symptoms?

In cases of acute paralysis, tick paralysis should be ruled out by carefully searching for any attached ticks.

WNV disease can be clinically confused with many other viral diseases such as enteroviral disease, influenza, and herpes encephalitis, as well as other arboviral diseases such as La Crosse virus disease, St. Louis encephalitis, eastern equine encephalitis, Japanese encephalitis, and dengue.

WNV is a flavivirus in the same family as yellow fever, dengue, Japanese encephalitis and St. Louis encephalitis viruses. The serologic tests for antibody to flaviviruses can cross-react (see below regarding diagnostic tests), which can complicate serologic differentiation of WNV infection from infection with other flaviviruses.

Eastern equine encephalitis is an alphavirus and La Crosse encephalitis is a bunyavirus; thus, standard serological assays effectively discriminate between these diseases and WNV disease.

The acute flaccid paralysis caused by WNV is clinically similar to poliomyelitis caused by polio viruses. Guillain Barre syndrome can occur with WNV infection and may require specific treatment.

What caused this disease to develop at this time?

WNV is transmitted to humans primarily through the bite of infected mosquitoes. Thus, in temperate areas, transmission is more common during the warmer months when mosquitoes are actively biting. The risk of WNV disease in temperate areas of the United States and Europe is highest in summer and early fall.

Focal WNV transmission has been described in most temperate and many tropical areas of the world. The virus was discovered in Africa in 1937 and over intervening years was recognized in Europe, Asia, the Mediterranean Basin, and Australia. It was detected in the Western Hemisphere for the first time in 1999 and has since spread across the North American continent and southward into Latin America and the Caribbean region.

In addition to mosquito-borne transmission, WNV can be transmitted through blood transfusions, organ transplantation, and dialysis. Possible aerosol transmission has been reported in laboratories and at a turkey farm. Both congenital WNV infection and transmission through breastfeeding have been described but appear to be rare.

Several studies have explored genetic predisposing factors for WNV infection and for severe WNV disease. The risk of acquiring WNV disease appears to be higher in people with homozygous CCR5delta32 genotype. The risk of WNV infection appears to be higher in people with a particular polymorphism in an oligoadenylate synthetase gene (see below). Information regarding genetic risk factors appears to be evolving rapidly.

Immunocompromised people, particularly solid organ transplant recipients, are at higher risk of severe neurologic manifestations.

The risk of WNV neuroinvasive disease increases with age and appears to be slightly higher among males. Encephalitis is more common in older age groups. Meningitis is the most common pediatric presentation of WNV neuroinvasive disease, but encephalitis and flaccid paralysis also occur in children.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

WNV infection is most commonly confirmed by serologic assays. WNV-specific IgM antibody can be detected in serum about 5 to 10 days after illness onset and generally persists for five to six months (persistence of IgM for more than 16 months after onset has been reported). A four-fold rise in WNV-specific antibody titer, or conversion from a negative to a positive antibody test, between paired acute and convalescent phase serum samples taken about two weeks apart, confirms WNV infection.

Ideally, the first serum sample should be obtained within the first few days after onset of symptoms, and a second serum sample obtained 2 to 3 weeks after onset. If establishing a definite diagnosis is urgent, an additional sample taken 8 to 10 days after onset can be tested for WNV-specific IgM antibody.

The standard tests for WNV-specific antibody may cross-react with antibody to other flaviviruses. Test results should be interpreted in light of any travel history that might have exposed the patient to dengue or other flaviruses, as well as any history of previous vaccinations against Japanese encephalitis, yellow fever, or tick-borne encephalitis. Plaque-reduction neutralization assays can help discriminate between antibody to different flaviviruses, but even these tests are often difficult to interpret if the patient has had more than one flavivirus infection.

Because even asymptomatic WNV infection can result in persistence of WNV-specific IgM for more than a year, a positive serum test for WNV IgM could possibly represent past infection unrelated to the patient's present illness.

Finding WNV-specific IgM antibody in cerebrospinal fluid is considered highly indicative of WNV neuroinvasive disease.

Detection of WNV viral nucleic acid in either serum or spinal fluid confirms WNV infection, but the sensitivity of nucleic acid tests for diagnosing neuroinvasive WNV disease is limited. Nucleic acid tests of blood are useful to screen blood donations for WNV infection and can increase diagnostic sensitivity for WNV fever during the first 8 days of illness. Although culturing live virus from diagnostic samples confirms WNV infection, the sensitivity and accessibility of viral culture for detecting WNV disease is limited.

WNV can be detected in tissue samples by nucleic acid tests or immunohistochemical staining for WNV antigens.

Patients with neuroinvasive WNV disease usually have pleocytosis in cerebrospinal fluid that can be either neutrophilic or lymphocytic. Cerebrospinal fluid protein is often elevated.

In cases of flaccid paralysis, the cerebrospinal fluid should be checked for albuminocytologic dissociation suggesting Guillain-Barre syndrome(GBS) , which might require specific treatment. Nerve conduction studies and careful physical examination can also help differentiate GBS, which typically is symmetric and reflects immune-mediated damage of peripheral nerves, from WNV poliomyelitis, which is usually asymmetric and typically due to viral damage of anterior horn cells.

Guidelines for the evaluation of infants born to mothers infected with WNV during pregnancy have been published by the U.S. Centers for Disease Control and Prevention (CDC). If maternal WNV infection is detected during pregnancy, ultrasound imaging of the fetus is recommended to search for congenital anomalies.

Infants born to mothers who were infected with WNV during pregnancy should have a careful newborn physical examination with attention to neurologic abnormalities, dysmorphic features, organomegaly, hearing, and rash or other skin lesions. Cord blood or infant serum should be tested for IgM and IgG antibody to WNV. If maternal WNV illness began 8 days or less before delivery, an additional infant sample should be tested for WNV antibody on or after 14 days of age.

If congenital WNV infection is suspected, the cord blood and infant serum can be tested for the presence of WNV nucleic acid after consultation with CDC or another reliable reference laboratory.

Would imaging studies be helpful? If so, which ones?

In cases of WNV neurologic disease, cranial imaging by computed tomography is usually unrevealing. Magnetic resonance imaging (MRI) may be normal or show nonspecific changes with areas of general or focal abnormal signal intensity or enhancement. Focal lesions in the deep brain nuclei and temporal lobes have been described. MRI of the spine may demonstrate abnormal signal intensity in anterior horn cells in patients with WNV flaccid paralysis.

If you are able to confirm that the patient has West Nile virus disease, what treatment should be initiated?

There is no specific treatment that has proven efficacy for WNV disease. Supportive care should be tailored to the patient's clinical condition.

In anecdotal reports, two adult patients with WNV neuroinvasive disease and deteriorating mental status had improvement of symptoms 2 days after initiation of treatment with interferon-alpha, but it remains uncertain whether improvement might have occurred without treatment.

Some anecdotal reports have suggested that intravenous administration of immune globulin with adequate titer against WNV might favor resolution of symptoms if given early in the clinical course, but thus far there is no solid evidence of effectiveness. In the United States some preparations of immune globulin do have measurable antibody against WNV.

Patients with residual neurologic deficits might benefit from physical therapy.

What are the adverse effects associated with each treatment option?

What are the possible outcomes of West Nile virus disease?

Most children with WNV disease have either WNV fever or WNV aseptic meningitis. Both these manifestations have a good prognosis and, in most reported cases, symptoms resolve completely without residual deficits within one to two weeks after the onset of illness. However, data on long-term outcomes of WNV disease in children is scarce. For many adults, recovery is often slow, with persistent symptoms, particularly fatigue, for several months after onset.

While some children with WNV encephalitis or flaccid paralysis also recover completely, others have long-term neurologic sequelae (see below regarding complications). The case fatality rate for children with WNV neuroinvasive disease in the United States is less than1%. A higher mortality rate (13%) was reported in an unusual outbreak of WNV neuroinvasive disease among children in Sudan.

What causes this disease and how frequent is it?

WNV is a flavivirus, in the same family as yellow fever, dengue, and Japanese encephalitis viruses. It is transmitted to humans through the bite of infected mosquitoes, mostly of the genus Culex, that acquire the virus from infected birds. In contrast to dengue and yellow fever, humans do not typically develop sufficiently high titer WNV viremia to infect mosquitoes.

WNV is endemically transmitted in Africa, Asia, Australia, and Europe, causing sporadic human infections and occasional outbreaks of human disease. In 1999, the virus was first detected in the Western Hemisphere and since then has spread across North America and southward into the Caribbean and Latin America.

Large epidemics in the United States caused thousands of cases of WNV neuroinvasive disease in 2002 and 2003. In recent years the numbers of reported cases have decreased, but hundreds of cases continue to be reported each year. There is risk of WNV disease throughout the United States, although human illness has not been reported from Maine, Alaska or Hawaii. The highest risk areas have been in the western plains, Rocky Mountain, and southwestern states.

Curiously, although spread of WNV to Latin America has been documented as far south as Argentina, cases of human disease in Latin America have been extremely rare.

About 600 cases of WNV neuroinvasive disease in adults and children were reported in the United States in 2010, for an incidence of about 0.2 per 100,000 population. From 1999 through 2007, 1,478 pediatric cases of WNV neuroinvasive disease were reported, for a median annual incidence of 0.07 per 100,000 children.

In Europe and the Mediterranean area, WNV outbreaks in 2010 were reported in Russia, Israel, Greece, Turkey, Romania, Hungary and Italy, and an equine outbreak was reported in Morocco. Data on the frequency of WNV disease in sub-Saharan Africa and Asia are scarce.

In temperate areas of the United States and Europe the risk of WNV disease is highest during the warmer months of the year when mosquitoes are most abundant. The incidence of severe neurologic disease is highest among people >= 50 years of age.

Unlike dengue or yellow fever viruses, which are transmitted between humans by mosquitoes, WNV is transmitted between birds by mosquitoes and only incidentally infects humans as "dead-end hosts" when infected mosquitoes bite humans. However, WNV can be transmitted between humans by blood transfusion, organ transplantation, and from mother to infant either in utero or through breastfeeding.

Immunocompromised people, including solid organ transplant recipients, and the elderly are at higher risk of severe WNV disease.

Some studies have indicated that other chronic conditions such as diabetes, hypertension or cardiovascular disease are more frequently present in people with WNV encephalitis than in those without WNV encephalitis. Data regarding risk factors for severe WNV disease in children are scarce.

In 2002 the first known case of congenital WNV infection was described. The affected infant had chorioretinitis and cystic lesions in the brain. Since then, intensive surveillance for additional congenital WNV infections has yielded only a handful of possible cases. The vast majority of babies born to mothers infected with WNV during pregnancy appear to be healthy, and most do not have any evidence of WNV infection.

Transmission of WNV through breastfeeding has been reported but appears to be rare.

There is some evidence that people who are homozygous for the CCR5delta32 allele are more susceptible to having WNV disease. In addition, variation in oligoadenytate synthetase genes might alter susceptibility to WNV infection. More evidence is needed to better define genetic risk factors for WNV infection, disease, and severe disease.

How do these pathogens/genes/exposures cause the disease?

Following an infected mosquito bite, it is believed that inoculated WNV initially infects Langerhans dendritic cells in the skin, then travels to lymph nodes and from there infects the blood stream and, in neuroinvasive cases, invades the central nervous system (CNS).

Invasion of the CNS might occur through one or more of the following mechanisms: 1) blood-borne dissemination of the virus to the CNS with viral migration or transport across the blood-brain barrier, perhaps at the choroid plexus, 2) transport of virus in immune cells that migrate to the CNS, or 3) transport of virus to the CNS through axons of peripheral nerves or via olfactory nerves through the cribriform plate.

One study suggested that, in mice, stimulation of Toll-like receptor (TLR) 3 by double-stranded WNV RNA promotes production of tumor necrosis factor-alpha which increases permeability of the blood barrier, thus facilitating neuroinvasion. Another study indicated that TLR-3 was protective against WNV mortality in mice by limiting viral replication in neurons. Thus the risk and severity of WNV neuroinvasive disease might be influenced in part by different "opposing" effects of TLR stimulation, one which facilitates neuroinvasion and the other which restricts viral replication.

Homozygous CCR5delta32 genotype appears to be more common among people with WNV disease than in the general population, but does not appear to be strongly associated with risk of severe disease. In mice CCR5 was shown to be important in promoting migration of T-lymphocytes to the CNS, where the T-lymphocytes helped clear WNV from neural tissue. Thus, once WNV has invaded the CNS it appears to trigger the release of chemokines that attract T-cells to clear the virus, and deficiency or mutation of CCR5 therefore could impair viral clearance. Nevertheless, less than 5% of people with WNV disease have been found to be homozygous for the CCR5delta32 mutation, so only a small proportion of the WNV disease burden can be attributed to this genotype.

Deficiency of oligoadenylate synthetase has been shown to influence susceptibility to flavivirus infection in mice. Oligoadenylate synthetase is an interferon-inducible enzyme that can activate other enzymes to degrade viral RNA. One study in humans indicated that a polymorphism in the human OAS1 gene was more common among people with WNV infection than among uninfected people, but there was no association with severity of disease.

Interferon alpha/beta appears to be important in limiting WNV pathogenesis. Host cells recognize intracellular WNV RNA through TLR 3 and 7 as well as melanoma-differentiation-associated 5 gene and retinoic acid-inducible gene helicases. Binding of viral RNA by these proteins induces cellular production of interferon, thereby reducing cell-to-cell spread of the virus. In turn, WNV has evolved mechanisms to counter these host defense systems. The evolution of WNV disease appears to depend on the balance between host defense mechanisms and viral countermeasures.

Other clinical manifestations that might help with diagnosis and management

What complications might you expect from the disease or treatment of the disease?

As noted above, long-term outcome data on WNV disease in children is scarce. However, it appears that the vast majority of children with WNV fever or uncomplicated WNV meningitis recover completely within one to two weeks after onset of illness.

Some children with WNV encephalitis or flaccid paralysis have persistent neurologic symptoms that last months or longer, including impaired mental function, ventilatory dependence, decreased visual acuity, balance disturbance, residual paralysis or limb weakness, athetotic movements, facial tics, swallowing difficulty, abnormal speech and auditory comprehension, need for assistance in daily activities, tinnitus, recurrent vomiting, and truncal weakness.

Recurrence of symptoms of meningitis two months after initial improvement has been described in a 5 year-old previously healthy child.

Are additional laboratory studies available; even some that are not widely available?

A lateral flow rapid diagnostic assay for IgM antibody to WNV was recently developed but is not currently commercially available.

How can West Nile virus disease be prevented?

Several vaccines against WNV have been developed to prevent WNV disease in animals. Vaccines for humans are in development, but none are commercially available thus far. Two vaccines have been evaluated in early-stage human clinical trials: a chimeric live vaccine using the backbone of 17D yellow fever vaccine with WNV premembrane and envelope genes inserted, and a single plasmid DNA vaccine encoding the premembrane and envelope proteins of WNV.

WNV disease can be prevented by avoiding exposure to infected mosquito bites. Wearing repellent when exposed to mosquitoes, and/or remaining inside screened or air-conditioned areas during times of peak mosquito-feeding activity (usually from dusk to dawn for the mosquitoes that transmit WNV) should reduce risk of infection. The most useful repellents are those that contain DEET, picaridin, oil of lemon eucalyptus (PMD), or IR3535. Permethrin is effective when used on clothing.

To prevent maternal and congenital WNV infection, pregnant women should practice the above measures to avoid mosquito bites.

Because transmission of WNV through breastfeeding appears to be rare, and the benefits of breastfeediing seem to outweigh the risks of WNV illness, mothers should be encouraged to breastfeed even in areas of ongoing WNV transmission. There is insufficient data regarding the risk of WNV transmission through breastfeeding to make definitive recommendations regarding discontinuing breastfeeding due to acute maternal WNV infection.

Screening of donated blood for WNV has reduced, but not completely eliminated, the risk of WNV infection through blood transfusion in the United States. Screening of organ donors is not routinely practiced because of concern that urgently needed organs in scarce supply might be inappropriately rejected in the event of a falsely positive screening test.

What is the evidence?

Lindsey, NP, Hayes, EB, Staples, JE, Fischer, M. "West Nile virus disease in children, United States, 1999-2007". Pediatrics. vol. 123. 2009. pp. e1084-9.

Reports the results of national surveillance in the United States for WNV disease in children, providing estimates of disease incidence and overall clinical manifestations.

Francisco, AM, Glaser, C, Frykman, E. "2004 California pediatric West Nile virus case series". Pediatr Infect Dis J. vol. 25. 2006. pp. 81-4.

One of the few recent case series of WNV disease in children; reports clinical and outcome information.

Civen, R, Villacorte, F, Robles, DT. "West Nile virus infection in the pediatric population". Pediatr Infect Dis J. vol. 25. 2006. pp. 75-8.

One of the few recent case series of WNV disease in children; reports clinical and outcome information.

Yim, R, Posfay-Barbe, KM, Nolt, D. "Spectrum of clinical manifestations of West Nile virus infection in children". Pediatrics. vol. 114. 2004. pp. 1673-5.

One of the few recent case series of WNV disease in children; reports clinical and outcome information.

Hayes, EB, O’Leary, DR. "West Nile virus infection: a pediatric perspective". Pediatrics. vol. 113. 2004. pp. 1375-81.

Historical review of WNV infection in children.

Hinckley, AF, O’ Leary, DR, Hayes, EB. "Transmission of West Nile virus through human breast milk seems to be rare". Pediatrics. vol. 119. 2007. pp. e666-71.

Assessment of frequency of WNV transmission through breastfeeding.

O’ Leary, DR, Kuhn, S, Kniss, KL. "Birth outcomes following West Nile Virus infection of pregnant women in the United States: 2003-2004". Pediatrics. vol. 117. 2006. pp. e537-45.

Reports the results of national surveillance for WNV infection in pregnant women with outcomes of pregnancy.

"Interim guidelines for the evaluation of infants born to mothers infected with West Nile virus during pregnancy". MMWR Morb Mortal Wkly Rep. vol. 53. 2004. pp. 154-7.

Consensus of a panel of experts providing guidance for clinical and diagnostic evaluation of these infants.

Kalil, AC, Devetten, MP, Singh, S. "Use of interferon-alpha in patients with West Nile encephalitis: report of 2 cases". Clin Infect Dis. vol. 40. 2005. pp. 764-6.

Case reports of treatment of WNV disease with interferon-alpha.

Rhee, C, Eaton, EF, Concepcion, W, Blackburn, BG. "West Nile virus encephalitis acquired via liver transplantation and clinical response to intravenous immunoglobulin: case report and review of the literature". Transpl Infect Dis. vol. 13. 2011. pp. 312-7.

A case report and literature review regarding treatment of WNV disease with immunoglobulin and risk of WNV infection in solid organ transplant recipients.

Ongoing controversies regarding etiology, diagnosis, treatment

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