Abstract

Since its introduction to the United States in 1999, West Nile virus (WNV) has become endemic in North America and has emerged as the most common cause of epidemic meningoencephalitis in North America and the leading cause of arboviral encephalitis in the United States. West Nile virus is maintained in nature by cycling between mosquito vectors and bird hosts; humans are incidental hosts. Transmission to humans occurs predominantly after a bite from an infected mosquito but has also occurred via transfusion of blood products, via organ transplantation from infected donors, transplacentally, and percutaneously through occupational exposure. Approximately one of 150 patients develops central nervous system manifestations, including meningitis, encephalitis, and acute flaccid paralysis/poliomyelitis. Risk factors for neuroinvasive disease include older age and immunosuppression. Imaging findings are nonspecific, and cerebrospinal fluid findings include pleocytosis, elevated protein, and normal to decreased glucose. The diagnosis is made in most patients on serological examination. Reverse transcription polymerase chain reaction tests are useful to screen blood products and for surveillance of birds and mosquitoes. The pathological findings are typical of a viral meningoencephalitis and include microglial nodules, perivascular chronic inflammation, and variable neuronal loss with necrosis or neuronophagia. Treatment is largely supportive, and control of the mosquito vectors may reduce the incidence of human infections.

Introduction

West Nile virus (WNV) was first isolated in 1937 from the blood of a woman with a febrile illness who lived in the West Nile region of Uganda (1). Until relatively recently, it was not considered to be a significant human pathogen. The virus was endemic throughout Africa, the Middle East, West and Central Asia, and the Mediterranean; however, most early epidemics occurred mainly in rural populations with few cases of severe neurological disease (2, 3).

Naturally occurring WNV infection first appeared in North America in 1999 when an outbreak in New York City resulted in encephalitis in 62 patients and 7 deaths (4). This epidemic and similar outbreaks in Romania in 1996 and Russia in 1999 were the first reported epidemics in large urban populations and involved hundreds of patients with severe neurological disease. An important factor common to these outbreaks was the first appearance of common house mosquitoes as a vector (3). Sequence studies of the earliest isolates from North America suggested that WNV was imported from the Middle East (5, 6), possibly via infected humans arriving from Israel (2), from infected migratory birds or illicitly imported exotic birds, or via infected mosquitoes inadvertently transported in an airplane or other carrier (7).

Since its introduction to the United States in 1999, WNV has become endemic in North America and expanded its geographic range to include the 48 contiguous US states, 7 Canadian provinces, Mexico, the Caribbean islands, and Colombia. It has emerged as the most common cause of epidemic meningoencephalitis in North America and the leading cause of arboviral encephalitis in the United States (7, 8).

BIOLOGY OF WNV

Virology

West Nile virus is an RNA arbovirus (arthropod-borne virus) in the family Flaviviridae. It is a member of the Japanese encephalitis serocomplex of the genus Flavivirus that also includes Japanese encephalitis virus, Murray Valley encephalitis virus, and St Louis encephalitis virus. West Nile virus isolates are grouped into 2 genetic lineages based on signature amino acid substitutions or deletions in their envelope proteins. West Nile virus isolates causing significant human disease belong to Lineage 1, which is subdivided into 4 clades (Indian, Kunjin, A, and B). West Nile virus isolates from the United States belong to Clade B (7, 9, 10).

West Nile virus virions are spherical, enveloped, approximately 50 nm in diameter, and have icosahedral symmetry. The WNV genome consists of a single-stranded RNA of positive polarity that produces 10 mature viral proteins via proteolytic processing of a single polyprotein by the viral serine protease and various cellular proteases. These include 3 viral structural proteins (capsid, premembrane/membrane, and envelope) and 7 nonstructural proteins (viral protease, NTPase, RNA helicase, and RNA-dependent RNA polymerase) (7, 9, 11-13). West Nile virus virions bind to an unknown cell receptor and enter cells via receptor-mediated endocytosis followed by low-pH fusion of the viral membrane with the endosomal vesicle membrane; the nucleocapsid is then released into the cytoplasm. Released genomic RNA is translated into a single polyprotein, and viral and cell proteases then cleave the polyprotein at multiple sites to generate mature viral proteins. Viral RNA-dependent RNA polymerase copies complementary minus strands from the genomic RNA template; these minus-strand RNAs serve as templates for the synthesis of new genomic RNAs. Virion assembly occurs in association with rough endoplasmic reticulum membranes. Intracellular immature virions accumulate in vesicles and are transported through the host secretory pathway; virions are then transported to the plasma membrane in vesicles and released by exocytosis (7, 9, 12, 13).

Transmission

West Nile virus is maintained by cycling between many species of mosquitoes, their preferred vectors, and more than 300 species of birds, their naturally amplifying hosts. Humans and other mammals, especially horses, are incidental hosts with low viremic levels and do not play a role in the transmission cycle (Fig. 1).

FIGURE 1.

Natural transmission cycle of West Nile virus. The virus cycles between mosquito vectors and bird hosts; humans and horses are incidental hosts.

FIGURE 1.

Natural transmission cycle of West Nile virus. The virus cycles between mosquito vectors and bird hosts; humans and horses are incidental hosts.

The mosquito vector species vary in their abundance in different geographic regions, their propensity to feed on mammals, and the efficiency with which they transmit infection. The species involved in transmission of WNV in the United States include Culex pipiens (northern house mosquito), Culex quinquefasciatus (southern house mosquito), Culex tarsalis, Culex restuans, Culex salinarius, and Culex nigripalpus (7, 14-16). The likelihood that a mosquito feeding on an infected host will become infected increases as the level of viremia increases. West Nile virus enters the mosquito in infected blood, penetrates the gut, replicates in tissues, and produces a noncytopathic effect that persists for the life of the insect (7). It must survive through winter to initiate new annual cycles of infection (overwintering). Possible mechanisms of overwintering include survival of the virus in hibernating female mosquitoes, vertical passage of the virus from infected females to their progeny, continued transmission in warmer latitudes, and chronic infections in migratory birds (7, 17).

Passerine birds (house sparrows, Corvid species [crows, magpies, and jays]), house finches, and grackles are the natural reservoir hosts for WNV. They are infected with WNV by mosquitoes; insectivorous birds can also acquire WNV after eating infected mosquitoes (7). The frequency of fatal infection varies between bird species but generally parallels the magnitude of their viremia. After infection, highly competent avian hosts develop elevated viremia for more than 100 days before succumbing to the virus, thus allowing for repeated cycles of mosquito infection (7, 17). A sudden die off of birds can be a sentinel event that presages subsequent human epidemics. The importance of birds in dispersing WNV is not entirely clear, but the movement of WNV westward in North America correlates well with the flyways of migratory birds. Therefore, it is hypothesized that infected migratory birds play a role in the spread of WNV to new geographic regions, and that the migration of uninfected susceptible birds may facilitate continued WNV transmission (2, 7, 15). In the southeastern United States, alligators may also serve as competent reservoirs (14-16). Most mammals except horses do not seem to generate viremia levels of sufficient titer to contribute to transmission. Like humans, however, they may be infected as incidental hosts, and fatal infections have been diagnosed in other species including cat, skunk, squirrel, chipmunk, rabbit, and bats (2, 3, 16).

EPIDEMIOLOGY AND PATHOGENESIS

Incidence

Through 2008, there were 28,763 cases of WNV infection reported to the US Centers for Disease Control and Prevention (http://www.cdc.gov/ncidod/dvbid/westnile/) (Fig. 2) (18), and it is estimated that more than 1 million people have been infected with the virus in this country with a seroprevalence rate of less than 3% (7, 8, 14, 16). Transmission of WNV to humans occurs predominantly after a bite from an infected mosquito. Peak transmission occurs between July and October (range, April-December), reflecting the seasonal activity cycle of the mosquito vectors. Persons of all ages are susceptible to WNV infection, but the incidence of central nervous system (CNS)/neuroinvasive disease and death increases with age. It is also higher in immunocompromised patients, and it is slightly higher in male patients (7, 14, 15, 19).

FIGURE 2.

Incidence of West Nile virus infection in the United States from 1999 to 2008.

FIGURE 2.

Incidence of West Nile virus infection in the United States from 1999 to 2008.

Risk Factors

The principal risk factor for WNV infection is exposure to infected mosquitoes, for example, living in areas with abundant vegetation, older housing, lower population density, a predominance of older residents, and in proximity to dead birds (16). Clinically significant disease is more common in elderly and immunocompromised individuals, including transplant patients (20-27), those with malignancies (4, 22, 28), those with human immunodeficiency virus infection/acquired immunodeficiency syndrome (4, 22, 29-32), patients receiving corticosteroids (4, 33, 34), and alcoholics (4, 35); it may also be more common in patients with hypertension, cerebrovascular disease, and diabetes (14-16, 35). The risk of meningoencephalitis in a solid organ transplant patient infected with WNV has been estimated to be as high as 40% (36). Interestingly, severe neurological and fatal disease is rare in WNV infections in tropical areas. Explanations proposed for this include the possibility that birds infected with more virulent strains may be too sick to migrate, experimental data that suggest that heterotypic cross-reactive Flavivirus antibodies can downregulate clinical illness and reduce virus loads, the possibility that other factors associated with hosts or the environment may select genetic variants of the virus that are less virulent, the possibility that WNV infections may be misdiagnosed as dengue in these regions, and the possibility that the capacity of surveillance systems to identify WNV disease differs from those in North America (2, 37). Children may also have a lower risk of developing neuroinvasive disease (38).

West Nile virus has also been transmitted via transfusion of blood products (red blood cells, platelets, and fresh-frozen plasma) (39-41), via organ transplantation from an infected donor (23, 24), transplacentally, and possibly via breast-feeding and dialysis (7, 8, 14-16, 42). Acquisition of WNV infection from occupational exposure has also been documented (43). Recent experimental evidence also suggests the potential for direct transmission of WNV. Experimentally infected birds shed infectious WNV in their feces, and fecal shedding of WNV has been detected in birds during winter when no mosquito activity was detected, suggesting that lateral transmission is possible through contact or fecal contamination. Therefore, handlers of sick or dead birds should take appropriate precautions to avoid exposure to potentially infectious material (16).

Viral Dissemination

After inoculation, WNV initially replicates in Langerhans dendritic cells, which migrate to draining lymph nodes; the virus then enters the bloodstream (primary viremia). Virus is then disseminated to the reticuloendothelial system where replication further augments viremia (secondary viremia). Experiments in mice indicate that the binding of double-stranded WNV RNA to toll-like receptor 3 induces production of tumor necrosis factor, which increases permeability of the blood-brain barrier and allows viral penetration of the CNS where WNV directly invades neurons (7, 10, 14). It is likely that WNV infects the CNS at least in part via hematogenous spread. Additional proposed mechanisms include infection or passive transport through the endothelium or choroid plexus epithelium, infection of olfactory neurons and spread to the olfactory bulb, transportation by infected immune cells that traffic to the CNS, and direct axonal retrograde transport from infected peripheral neurons (13). West Nile virus is cytolytic and induces apoptosis in a variety of cell types, including neurons. Tissue culture studies have shown that the acquisition of a neural phenotype confers susceptibility to WNV infection (44).

Host Response

Humoral/antibody-mediated responses are an essential aspect of immune system-mediated protection from WNV. Antibodies limit viral dissemination, particularly to the CNS, and it is thought that patients developing neurological symptoms may have a less robust IgM response to primary infection by WNV (11-13, 45). A T-cell response, which is mediated mostly by CD8-positive lymphocytes, also plays a role, particularly in viral clearance from infected neurons and in preventing viral persistence (46). T-lymphocyte chemokine receptor CCR5 deficiency increases the risk of symptomatic WNV infection, and homozygotes for a defective form of the receptor (CCR5delta32), present in approximately 1% of whites, have a higher incidence of a fatal outcome (47, 48). Innate immune responses (including interferon produced by dendritic cells) inhibit Flavivirus infection in cell culture and in animals, and complement may play a role in limiting WNV infection (12).

CLINICAL FEATURES

Clinical Syndromes

Approximately 80% of WNV infections are asymptomatic, and 20% result in a self-limited disease referred to as West Nile fever. Less than 1% of patients (approximately 1/150) develop CNS disease (West Nile neuroinvasive disease) including meningitis, encephalitis, and acute flaccid paralysis/poliomyelitis. The distinctions between these CNS disorders are somewhat arbitrary, and mixed patterns of disease are commonly encountered (7).

West Nile fever is an acute, self-limited, flulike illness that occurs 2 to 14 days after viral inoculation. The incubation period may be longer in immunocompromised patients because of prolonged viremia (23, 24, 26, 41). Common symptoms include fever, a maculopapular or morbilliform rash on the chest, back, and upper extremities, headache, muscle weakness or myalgias, gastrointestinal symptoms including anorexia, nausea, and vomiting, and difficulty concentrating (7, 8, 10, 14, 49). Most patients recover after approximately 3 to 6 days, but the median duration of illness was 60 days, and one third of patients were hospitalized in 1 series (50).

West Nile neuroinvasive disease has been defined by the US Centers for Disease Control and Prevention as fever, the absence of a more likely clinical explanation, and at least one of the following: acutely altered mental status, other acute signs of central or peripheral neurological dysfunction, or pleocytosis associated with an illness that is clinically compatible with meningitis (16). Approximately 40% of patients with neuroinvasive disease have meningitis, and 60% have encephalitis. Signs and symptoms of West Nile meningitis include fever, nausea and/or vomiting, myalgia, chills or rigors, nuchal rigidity with neck and/or back pain, Kernig and Brudzinski signs, headache, photophobia, and a cerebrospinal fluid (CSF) pleocytosis without altered mental status or focal weakness (7, 8, 14, 19, 34). Tremor and myoclonus are also common findings, and it has been suggested that the presence of a hyperkinetic movement disorder in a patient with otherwise classic aseptic meningitis should suggest the possibility of WNV infection (51). Patients with WNV encephalitis present with fever, diffuse weakness or fatigue, headache, confusion or altered mental status, dizziness or vertigo, and signs and symptoms of a systemic illness including gastrointestinal complaints, rash, arthralgia, and myalgia (7, 8, 19, 34, 49). Many patients also have tremor, myoclonus, or parkinsonian symptoms (rigidity, postural instability, or bradykinesia) or cranial nerve palsies including facial weakness (51).

In contrast to other arboviral encephalitides, neuromuscular weakness is often a prominent finding in WNV meningoencephalitis occurring in up to 50% of patients (8, 51). Clinical syndromes that have been described include an acute flaccid paralysis/poliomyelitis-like syndrome (7, 8, 34, 51-56), a Guillain-Barré-like syndrome, and a generalized myeloradiculitis (55). The acute flaccid paralysis/poliomyelitis-like syndrome has been the best characterized clinically and presents as acute monoplegia, asymmetric upper or lower extremity weakness, or generalized asymmetric tetraplegia or quadriplegia. Patients have diminished or absent deep tendon reflexes, and 70% have cranial nerve involvement including peripheral facial paralysis, extraocular muscle weakness/diplopia, dysarthria, or vocal cord paralysis. Sensory deficits and/or pain in affected limbs may precede the onset of weakness (55). Bladder and bowel dysfunction occurs in approximately one third of patients (14, 51). Respiratory failure requiring intubation is a common complication that is most likely to occur in immunocompromised patients and in those with encephalitis (55).

Rare clinical syndromes that have been reported in association with WNV infection include fulminant hepatitis (57), pancreatitis (58), myocarditis (22, 59), cardiac dysrhythmia/arrhythmia (new onset or exacerbation of existing atrial fibrillation, second- or third-degree heart block requiring temporary pacemakers) (35, 60), myositis (27), rhabdomyolysis (61), orchitis (27), nephritis (62), chorioretinitis, uveitis, vitreitis (7, 49), optic neuritis (63, 64), and fatal hemorrhagic fever with coagulopathy (57). West Nile virus encephalitis may also rarely relapse (65).

Radiographic Findings

Imaging studies in WNV infections are frequently normal. When they are abnormal (in approximately 40%-70% of cases), the findings are generally nonspecific (8, 66). When present, lesions are hyperintense on T2-weighted magnetic resonance and fluid-attenuated inversion recovery images, and they have a predilection for deep gray structures, mesial temporal structures, the brainstem, and the cerebellum (32, 34, 66, 67). In patients with WNV-associated muscle weakness, there may be signal abnormalities in the anterior horns, conus, cauda equina, and nerve roots (66). Diffusion-weighted images are useful in the early detection of inflammation (66). Other reported findings include periventricular hyperintensity and subcortical white matter abnormalities and variable leptomeningeal thickness and enhancement (51).

Diagnostic Tests

Electroencephalographic abnormalities may be found in approximately 60% to 100% of cases of WNV meningoencephalitis (51) and consist of diffuse slowing consistent with generalized encephalopathy (more prominent over the anterior regions) (34, 68), triphasic slow waves typical of those seen in metabolic encephalopathies, or periodic lateralized epileptiform discharges (25). In patients with WNV-associated acute flaccid paralysis/poliomyelitis-like syndrome, electromyographic and nerve conduction studies have shown findings consistent with a demyelinating sensorimotor neuropathy (marked slowing of conduction velocities, conduction block, temporal dispersion, and reduced sensory nerve action potentials) or a motor axonopathy and/or anterior horn cell process with preservation of voluntary motor unit potentials (reduced or absent compound muscle action potentials in paretic limbs with preserved sensory nerve action potentials and asymmetric denervation on needle electromyographic examination) (7, 25, 34, 54-56).

Cerebrospinal fluid findings are similar in cases of WNV meningitis and encephalitis and include increased leukocytes (>5 cells/μL with a mean of ∼225-230 cells/μL) (69), increased protein, and normal to slightly decreased glucose. Neutrophils are present early in infection followed by a shift to lymphocytosis (14, 25, 55). Plasmacytoid lymphocytes or large monocytic cells with cerebriform nuclei resembling Mollaret cells may be seen (7, 70). Other laboratory findings include leukocytosis, lymphocytopenia, thrombocytopenia, a slight decrease of hemoglobin, hyponatremia, abnormal liver function tests, elevated creatine kinase levels, transiently elevated serum lipase levels, and elevated serum ferritin (14).

West Nile virus is rarely isolated from clinical specimens because of biosafety issues; a Level 3 safety facility is required (11). Therefore, the diagnosis depends largely on serological examination. Diagnosis is typically based on the detection of WNV-specific antibodies in serum, CSF, or both using commercially available ELISAs (7, 51). Because of cross-reactivity with other flaviviruses, these assays are confirmed with plaque reduction neutralization assays performed by the US Centers for Disease Control and Prevention and many state public health laboratories (7, 11). A 4-fold or greater serial change in serum antibody titer may also be used to make a diagnosis of WNV infection (16). From Days 2 to 8 after infection, serum IgM but not IgG antibodies are present; IgG and IgM are present in serum from 8 to 20 days after infection (7). Serum IgM can persist for 500 days after onset of illness. Therefore, caution is required when interpreting early-season WNV IgM-positive samples (6). False-positive serum IgM antibody tests can occur in patients with rheumatoid factor or other inflammatory processes (7). In patients with an intact blood-brain barrier, WNV IgM in CSF is diagnostic of neuroinvasive disease because IgM antibodies do not readily cross the blood-brain barrier, and their presence in CSF indicates intrathecal synthesis (8, 51). It may be necessary to obtain serial samples, however, because the test may not be positive if CSF is collected less than 8 days after the illness onset (7). It is also important to recognize that a patient with meningoencephalitis may not have an intact blood-brain barrier. Detection of viral nucleic acid by real-time reverse transcription polymerase chain reaction is highly specific for WNV infection but is not as sensitive as serological testing, in part, because viremia may no longer be present at the onset of symptomatic disease (8, 51, 71). Reverse transcription polymerase chain reaction tests are used primarily in the screening of blood products and as a screening method for large-scale surveillance of birds and mosquitoes (11).

PATHOLOGICAL FINDINGS

Neuropathology

In most cases of WNV meningoencephalitis, the brain and spinal cord are grossly normal. Mild cerebral edema has been described as has a rare case of hemorrhagic necrosis affecting the thalamus and brainstem (27).

Microscopically, WNV meningoencephalitis is characterized by microglial nodules, perivascular cuffing with mononuclear cells, and variable neuronal loss (Figs. 3A, B). Neuronophagia and foci of necrosis are occasionally seen (33, 61). There is no evidence of vasculitis. In general, gray matter is affected more than white matter, and inflammation is typically more severe in the brainstem than in the cortex or cerebellum. The temporal lobes, basal ganglia, and thalamus may be severely involved (72). Dorsal root and sympathetic ganglia are involved in some cases (60). In patients with WNV-associated acute flaccid paralysis/poliomyelitis-like syndrome, the spinal cord shows a diffuse increase in microglial cells with ill-defined microglial nodules and neuronal loss/neuronophagia that is most prominent in anterior horns (60, 61, 73, 74). There is also inflammation with a loss of myelinated axons in anterior spinal nerve roots (Fig. 4) and neurogenic atrophy of skeletal muscle (73). Fragmentation of myelinated fibers into ovoid segments consistent with Wallerian degeneration has been described (33).

FIGURE 3.

West Nile virus infections of the central nervous system are characterized histologically by microglial nodules (A) and perivascular chronic inflammation (B).

FIGURE 3.

West Nile virus infections of the central nervous system are characterized histologically by microglial nodules (A) and perivascular chronic inflammation (B).

FIGURE 4.

Anterior spinal nerve roots show a loss of myelinated axons (Luxol fast blue stain).

FIGURE 4.

Anterior spinal nerve roots show a loss of myelinated axons (Luxol fast blue stain).

Immunohistochemistry for CD68 and glial fibrillary acidic protein demonstrates a diffuse microglial proliferation and global astrocytosis, respectively (60, 62). The inflammatory cells present in microglial nodules are largely CD8-positive T cells, whereas the cells present in perivascular cuffs consist of a combination of CD20-positive B cells and CD4-positive T cells (7, 59, 72, 75). West Nile virus antigens can also be identified by immunohistochemical methods in about half of cases and are most commonly found in the cytoplasm of neurons (22, 62, 76). They are rarely found in glial cells and are not present in meningothelial or endothelial cells (21, 28). Viral particles have been demonstrated by electron microscopy in rare cases (10, 21).

Extra-CNS Pathology

Pathological findings outside of the neuromuscular system include multifocal lymphocytic myocarditis (22, 62), chronic tubulointerstitial nephritis (62), acute (hemorrhagic) pancreatitis (4, 58, 75), an inflammatory myopathy, and orchitis (27). West Nile virus antigen has been demonstrated in kidney, lungs, pancreas, thyroid, intestine, stomach, esophagus, bile duct, skin, prostate, and testis in severely immunocompromised patients with minimal associated inflammation (20, 22). Microscopic examination of sections of pancreas, liver, heart, lung, spleen, kidney, brainstem including medulla, and spinal cord including dorsal and ventral roots in cases of WNV infection coming to autopsy has been recommended (59, 75).

Pathological changes in the nervous system of WNV-infected birds include gross brain hemorrhage, degeneration or necrosis of Purkinje cells, and lymphoplasmacytic encephalitis with glial nodules. Splenomegaly and myocarditis are also common findings (16, 77). Horses and experimentally infected monkeys develop a polioencephalomyelitis similar to that seen in human cases (11, 16).

PROGNOSIS AND THERAPY

Prognostic Factors

The overall case-fatality rate for WNV infections ranges from 2% to 18% (7, 8, 19, 49) but is higher (up to 25%) in transplant patients (23). Most patients with WNV meningitis and no associated focal neurological deficits make a full recovery (8, 14), but approximately 10% to 20% of patients with WNV encephalitis die (8). Up to 70% to 75% of survivors of WNV neuroinvasive disease experience persistent constitutional and neurological deficits from months to years after infection including fatigue, muscle weakness, insomnia or excessive sleepiness, difficulty walking, muscle pain, headache, persistent movement disorders (tremor, parkinsonism, and ataxia), memory loss, depression, irritability, lightheadedness, loss of concentration, and confusion (14, 34, 45, 78, 79). Patients frequently require placement in assisted living situations after hospitalization for acute illness or require physical, occupational, or speech therapy (35, 79). Patients with WNV-associated flaccid paralysis/poliomyelitis-like syndrome have the worst overall prognosis (8, 51). In those who survive, most strength recovery occurs in the first 6 to 8 months with a subsequent plateau (79). It has been speculated that a postpolio syndrome might become a significant complication in this patient population (79).

Risk factors for a fatal outcome include intubation, previous stroke, immunosuppression, and being older than 50 years (7, 19, 35). Conversely, a younger age at onset of infection is a significant predictor of recovery (8, 78). In 1 study, those with normal magnetic resonance images or with abnormalities noted only on diffusion-weighted images had better outcomes than those with abnormalities on fluid-attenuated inversion recovery and T2-weighed magnetic resonance images (67).

Treatment Options

At the present time, there is no treatment of proven efficacy for WNV infections. Current treatment is largely supportive, including pain control, antiemetic therapy and rehydration, monitoring for the development of elevated intracranial pressure, control of seizures, and prevention of secondary infections (8, 10, 26, 32). Acute inpatient rehabilitation leads to modest improvements in motor function in some cases (80). In transplant patients, reduction/early withdrawal of immunosuppression has been successful in some cases and is recommended in patients with presumed WNV meningoencephalitis (23, 26, 81). Other therapies used in patients with WNV infection or that are undergoing clinical trials include interferon α-2b, ribavirin, corticosteroids, intravenous immunoglobulin with high titers of anti-WNV IgG (Omr-IgG-am), humanized monoclonal antibodies, and antisense oligomers that bind to WNV RNA (7, 8, 14, 51, 82).

Prevention

Several vaccines are approved for equine use (11), and widespread vaccination of horses in the western United States has been responsible for a reduction in the numbers of equine cases (17). Vaccine candidates for use in humans include an inactivated WNV vaccine, an attenuated WNV vaccine, chimeric live virus vaccines that incorporate WNV genetic sequences into a yellow fever or dengue virus backbone, DNA vaccines that elicit WNV antigen expression, and a recombinant vaccine that uses measles vaccine as a vector for WNV antigens (8, 11, 12, 14). The use of existing and approved vaccines that target closely related flaviviruses has also been suggested (12, 51). The cost-effectiveness of WNV vaccination is uncertain, however, and vaccination strategies would have to target persons 50 years and older in all areas of the United States and Canada (2). Some do not consider vaccination of humans a viable option because of the low prevalence of human infection and the relatively low rate of clinical illness in infected individuals (45).

Control of WNV transmission by controlling the mosquito population may have some impact on transmission to humans. Proactive mosquito control programs focus on preventing human infection by suppressing mosquito populations below levels where the risk of tangential transmission from the enzootic mosquito-bird amplification cycle to humans is minimal. This is accomplished by eliminating mosquito breeding sites and applying larvicides to breeding areas (14, 16, 17). In areas where WNV is already established, reactive or emergency control of the adult mosquito population by application of pyrethrin or organophosphate formulations by ground or air is used (17). Individuals may reduce their risk by wearing long-sleeved shirts and pants while outdoors during the early evening and night hours and by using mosquito repellents containing N,N-diethyl-m-toluamide, picaridin, oil of lemon eucalyptus (p-menthane-3,8-diol), soybean oil, or permethrin (7, 14-16, 19, 51).

Finally, universal blood donor screening for WNV began in July 2003 (37), and the US Food and Drug Administration recommends that blood collection agencies ask donors about fever and headache occurring in the week before donation and not allow persons reporting such symptoms to donate blood (83). Screening deceased organ donors had not yet been implemented because of concern that life-saving organs in scarce supply will be inappropriately rejected (14).

Acknowledgment

The author thanks Richard A. Prayson, MD, for contributing case materials used in the preparation of this article.

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