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West Nile Encephalitis: An Emerging Disease in the United States

  1. Larry J. Strausbaugh, Section Editor
  1. Anthony A Marfin and
  2. Duane J Gubler
  1. Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado
  1. Reprints or correspondence: Dr. Anthony A. Marfin, Centers for Disease Control and Prevention, PO Box 2087, Foothills Research Campus, Fort Collins, CO 80522-2087 (aam0{at}cdc.gov).
 
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Abstract

In 1999, an epidemic of West Nile virus (WNV) encephalitis occurred in New York City (NYC) and 2 surrounding New York counties. Simultaneously, an epizootic among American crows and other bird species occurred in 4 states. Indigenous transmission of WNV had never been documented in the western hemisphere until this epidemic. In 2000, the epizootic expanded to 12 states and the District of Columbia, and the epidemic continued in NYC, 5 New Jersey counties, and 1 Connecticut county. In addition to these outbreaks, several large epidemics of WNV have occurred in other regions of the world where this disease was absent or rare >5 years ago. Many of the WNV strains isolated during recent outbreaks demonstrate an extremely high degree of homology that strongly suggests widespread circulation of potentially epidemic strains of WNV. The high rates of severe neurologic illness and death among humans, horses, and birds in these outbreaks are unprecedented and unexplained. We review the current status of WNV in the United States.

In August 1999, an epidemic of West Nile virus (WNV) encephalitis and aseptic meningitis began in New York City (NYC) [1–3]. Over 8 weeks, 59 people were hospitalized with severe neurologic illnesses; 7 died. Concurrent epizootics with high mortality occurred in birds, particularly American crows (Corvus brachyrhynchos), and in horses on Long Island.

Until recently, WNV was known to occur in Africa, the Middle East, and western Asia, causing sporadic epidemics with mild illness. Since the mid-1990s, however, numerous WNV epidemics and epizootics have occurred in Europe, the Middle East, northern and western Africa, and North America, all of which were associated with higher rates of neurologic illness and case fatality in humans, horses, and, in 2 cases, birds.

In 2000, the United States WNV epizootic spread to 12 states and the District of Columbia [4]. Doctors, especially those along the East Coast and Gulf Coast, should include WNV infection in the differential diagnosis of summertime febrile illnesses and unexplained encephalitis or aseptic meningitis. Here, we review the status of WNV in the United States.

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Virology

WNV is a flavivirus within the Japanese encephalitis (JE) antigenic complex that includes 4 related viruses that cause CNS infections—JE in Asia; St. Louis encephalitis in North and South America; and Kunjin (considered a subtype of WNV) and Murray Valley encephalitis viruses in Australia [5, 6]. The WNV genome is a single-stranded RNA that encodes 3 structural proteins (capsid, premembrane, and envelope [E]) and 7 nonstructural proteins. The mature virion is a nucleocapsid enveloped in a lipid bilayer with projecting E proteins that mediate cellular attachment and membrane fusion and appear to be important virulence factors [7].

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Transmission Cycle

Birds usually become infected from the bite of an infected mosquito. Infected ticks have been reported, and direct bird-to-bird transmission has been experimentally demonstrated in crows sharing common cages (R. McLean, personal communication). Although some transmission may be due to ticks or direct transmission, the large number of infected ornithophilic mosquitoes found during outbreaks strongly suggests that most transmission is between mosquitoes and birds. The amplifying vertebrate hosts are birds, and Culex mosquitoes have been the primary vectors in most major outbreaks [5, 8–10].

After female mosquitoes ingest blood from infected birds, virus replicates in the mosquito gut and salivary glands and is transmitted in salivary fluid during subsequent bites. After the bite of an infected mosquito, humans can develop viremia, but it is not known what role they and other mammals contribute to amplification and transmission. This is an area that requires more research. Although only one study has shown that infected people have greater exposure to infected mosquitoes than uninfected people [11], no data suggest that human infections result from direct contact with ill humans or vertebrates or from infectious aerosols in natural settings. Laboratory infections due to percutaneous inoculation and to infectious aerosol exposure have been reported [12].

In addition to the Culex mosquitoes, many naturally infected species have been found, including 14 species in the United States. In 2000, 38 counties in 5 northeastern states reported 515 pools of WNV-infected mosquitoes [4]. Most were pools containing 2 ornithophilic mosquito species, Culex pipiens and Cx. restuans, but also included species that may feed on humans: Aedes albopictus, Ae. vexans, Cx. salinarius, Ochlerotatus triseriatus, and Oc. trivittatus. Some of these species aggressively bite humans, play a role in transmission of other domestic arboviruses, and bite during the day. WNV was also recovered from multiple pools containing Oc. japonicus, a species not seen in the United States until 1998 and whose role in WNV transmission is unclear.

Epidemiology. WNV was first isolated in 1937 in Uganda, and it is enzootic in many parts of Africa, the Middle East, west Asia, and Australia [5]. In the Middle East, WNV antibody prevalence among children was 3.5%–8% [13, 14]. Epidemics are rare in populations with high background immunity. From 1951 to 1957, Israel experienced outbreaks, and in 1974, South Africa experienced an epidemic with thousands of symptomatic infections [15]. After 20 years with no epidemic activity, outbreaks of WNV illness in humans, horses, or both have occurred in Algeria (1994), Morocco (1996), Romania (1996), Tunisia (1997), the Czech Republic (1997), Congo (1998), Italy (1998), Israel (1997–2000), Russia (1999), France (2000), and the United States (1999–2000) [10, 11, 16–18].

Northeastern United States epidemic/epizootic, 1999–2000. Of 62 WNV cases reported in 1999, 59 patients were hospitalized with encephalitis, meningitis, or both in 4 NYC boroughs and 2 adjacent counties (figure 1). Of 59 hospitalized people, 32 (54%) were residents of Queens (rate, 1.6 cases/105 population). In 2000, a total of 21 people were reported with acute illness due to WNV infection; 19 were hospitalized with encephalitis or meningitis. Of 19 hospitalized people, 10 (53%) were residents of Staten Island (rate, 2.4 cases/105 population). Illnesses also occurred in residents of other NYC boroughs, in Hudson, Bergen, Morris, Passaic, and Monmouth Counties in New Jersey and in 1 resident of Fairfield County, Connecticut (figure 1) [4]. The onset of most human illnesses occurred during August and September (figure 2). Although hospitalized people with severe neurologic disease ranged in age from 5 to 95 years, older people were at increased risk for severe illness and death. Of 78 hospitalized people, 12 (15%) were <50 years old, 28 (36%) were aged 50–69 years, and 38 (49%) were aged ⩾70 years. Nine of these 78 people died (case fatality rate, 12%); all were aged >65 years old.

Figure 1
Figure 1

Counties reporting West Nile viral illnesses in humans, 1999 and 2000, United States

Figure 2
Figure 2

Date of onset of symptoms for 83 people with West Nile viral illnesses, 1999 and 2000, United States.

Neurologic illness was infrequent among people infected with WNV. In 1999, a community-based survey to identify infected people was performed in the epicenter of the outbreak, north Queens, where 9 residents had confirmed West Nile encephalitis; 2.6% of survey participants had been recently infected but did not develop clinical illness, an illness-to-infection ratio of 1 : 134 [19]. In Staten Island, where 10 human cases occurred in 2000, an October 2000 survey showed that 0.5% of residents aged >12 years (∼1570 residents) had evidence of recent WNV infection without clinical illness, an illness-to-infection ratio of 1 : 157 [20].

In 1999, many WNV-infected crows died throughout metropolitan NYC, preceding the report of human cases [19, 21]. In 2000, a newly established WNV surveillance system operated by the Centers for Disease Control and Prevention (CDC) and 22 cooperating state and local jurisdictions [22], also documented an expanding geographic distribution as well as widespread WNV epizootic activity before human illness was reported [4]. A total of 4305 WNV-infected birds were reported from 136 counties in 12 states and the District of Columbia (figure 3). Although American crows and blue jays (Cyanocitta cristata) were the most frequently infected species reported, WNV morbidity and mortality have been identified in 78 avian species in the United States since 1999.

Figure 3
Figure 3

Counties reporting West Nile virus (WNV)—infected birds, 2000, United States

In 2000, 63 horses with neurologic and other illnesses due to WNV infection were reported from 26 counties in 7 states (New Jersey, New York, Connecticut, Delaware, Massachusetts, Pennsylvania, and Rhode Island) [4]. In follow-up studies of ill horses, the US Department of Agriculture documented a case fatality rate of 38% (unpublished data). These cases in horses suggested that the risk for human infection, including the presence of infected mammal-biting mosquitoes, were more widespread than the 10 counties reporting human cases.

Romania, 1996. The first WNV epidemic in Europe in 34 years occurred in 1996, when 393 laboratory-confirmed WNV encephalitis cases were identified in southeast Romania [10]. The illness-to-infection ratio was estimated to be 1 : 140 to 1 : 320, but unlike earlier epidemics in which illness was mild and mortality was low, this outbreak had high rates of severe neurologic disease and mortality (case fatality rate, 4.3%). Surveillance during 1997–1998 documented sporadic human WNV infections, suggesting persistent local enzootic transmission [23].

Russia, 1999. An estimated 480 people infected with WNV were identified in studies of hospitalized people with encephalitis, meningitis, or severe febrile illness in Volgograd in July—September 1999 [24]. Among 84 people with encephalitis, 40 (48%) died. By use of nucleic acid amplification techniques (NAAT), the WNV genome was demonstrated in the brain of 14 fatal cases.

Israel, 2000. The first documented WNV epidemics occurred in Israel in 1951–1957. Sporadic illnesses occurred from 1975–1980 among soldiers, but no outbreaks were reported until anecdotal reports of deaths among domestic geese in 1997–2000 and 2 fatal human cases of WNV encephalitis in 1999 (M. Giladi, unpublished data). In the summer of 2000, a total of 417 people with serologically confirmed WNV illnesses were reported; of these, 28 (6.7%) died [25, 26]. The conditions that allowed the increase in human cases in 2000 are unknown. As in the US outbreak, severe neurologic illness and death primarily occurred in people aged 70 years and older. The WNV strains in Israel and the United States are the only ones found to be associated with increased avian mortality.

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Molecular Epidemiology

The envelope (E) gene of selected WNV isolates was sequenced to investigate the relationships between virus strains that have caused recent epidemics. The phylogenetic tree of WNV strains is divided into 2 main groups, lineage 1 and lineage 2 [6, 27]. Lineage 1 viruses include most of the epidemic strains isolated since 1996, including the 1999 and 2000 United States, 1996 Romania, 1998 and 1999 Israel, and 1999 Volgograd strains. Lineage 2 includes many strains that are enzootic in equatorial Africa.

Among genomic sequences amplified from NYC isolates from animals and from human brain during 1999, there was a high degree of homology, indicating that a single virus strain caused the US outbreak. In addition, E gene sequencing showed that the WNV from the 1999 NYC outbreak was essentially identical to a virus isolated from a dead goose in Israel in 1998 [6]. Because of the unexpectedly high degree of homology among lineage 1 strains, complete genome sequences were performed on selected WNV strains. These analyses confirmed the similarity between the 1999 NYC and 1998 Israel strains and supported the hypothesis that the 1999–2000 outbreaks in the United States resulted from the introduction of a virus that has been circulating in the Mediterranean region since at least 1998.

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Clinical Presentation And Pathologic Findings

After WNV infection, the viral incubation period in humans ranges 3–15 days [5, 28]. Most human infections are clinically inapparent, but febrile illnesses, ranging from nonspecific viral syndrome to fatal encephalitis, are not uncommon [5]. Mild illness includes 3–6 days of fever, headache, backache, myalgia, and anorexia. A roseolar or maculopapular rash occurs in about half of the patients and lasts up to a week, but it resolves without scaling. Generalized lymphadenopathy is common.

On the basis of animal and human studies, WNV replicates in local tissues and lymph nodes and is transported via lymphatics to the blood. In normally healthy people who are infected, virus can be isolated from the blood from 2 days before the onset of illness through the fourth day of illness [5], but the rate of successful isolation drops rapidly after the first day of illness.

Although the exact mechanism is uncertain, CNS infection presumably occurs when virus crosses the blood-brain barrier by endothelial replication or axonal transport through olfactory neurons. Factors that enhance progression of CNS infections among the elderly may include those that disrupt the blood-brain barrier (e.g., hypertension) or increase the duration and level of viremia (e.g., immune senescence). Severe neurologic syndromes occur principally in the elderly, but numerous cases have also been reported in children [5].

MRI appears more helpful than CT in distinguishing the presence of CNS inflammation. In 1999, a third of CT scans performed on hospitalized patients showed preexisting chronic changes, but none showed acute changes suggestive of encephalitis. Among patients who received MRI scans, roughly a third showed acute meningeal enhancement consistent with encephalitis [29]. CSF analyses showed a normal glucose level, elevated protein level (up to 900 mg%), and a lymphocytic pleocytosis with counts of 10–100 cells/mm3.

Pathology in fatal cases shows diffuse inflammation of the brain and spinal cord with small hemorrhages, perivascular cuffing, and extensive neuronal degeneration [30, 31]. These findings are the result of injury due to WNV replication, cytotoxic immune response to infected neural cells, and resulting inflammation. Recovery is usually complete and rapid, but the potential for clinical relapse occurring weeks to months after recovery remains a question. Experimental infection of monkeys has been associated with chronic, progressive CNS infection [32], suggesting the possibility of viral persistence in the CNS. Other serious, nonneurologic complications in humans rarely occur but include myocarditis, pancreatitis, and fulminant hepatitis [29, 33].

Both humoral and cellular immune responses contribute to recovery. Neutralizing antibodies directed against specific epitopes on the E protein appear to provide long-lived protection against reinfection. As with other flaviviruses [34–37], infection may elicit antibody and cytotoxic T lymphocyte responses to nonstructural proteins that mediate recovery and protect against reinfection, but this remains an important research question.

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Disease Management

In WNV encephalitis, the most frequent cause of death is cerebral edema after neuronal death and degeneration. There is no WNV-specific therapy to reduce the injury or resulting edema. Although preliminary studies of ribavirin in cell culture systems suggest a potential benefit [38], in vivo studies with other flaviviruses suggest no effect [39]. Even if effective agents are developed, supportive care—respiratory support, management of cerebral swelling, and prevention of secondary bacterial infections—will remain the primary treatment.

Because steroids and osmotic agents have been shown to control brain swelling in some viral encephalitides, the benefits of a short course of steroids in instances of cerebral edema and impending herniation should be weighed against the risk of potentiating WNV infection. There are no controlled studies regarding prophylactic use of steroids, antiseizure medications, or osmotic agents (e.g., mannitol) in the management of people with WNV encephalitis.

Clinicians should consider treatable infections and syndromes, including the following: other viruses that cause severe neurologic illnesses (i.e., herpesviruses and enteroviruses); neurologic syndromes often interpreted as viral infections (e.g., Guillain-Barré syndrome); rheumatologic conditions that cause neurologic syndromes including encephalitis (e.g., lupus cerebritis); and early bacterial meningoencephalitides (e.g., Neisseria meningitidis).

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Diagnostic Methods

Because WNV encephalitis or meningitis cannot be clinically distinguished from other viral CNS infections, specific diagnostic testing should be sought. The most commonly used method is the IgM capture ELISA, which measures WNV-specific IgM antibody and has a sensitivity approaching 100% in appropriately timed CSF and serum samples [40]. WNV-specific IgM antibody is generally not detectable until the end of viremia, which may last through the fourth day of illness [5]. A high level of WNV-specific IgM antibody in a single acute-phase serum sample from a person with encephalitis or meningitis strongly suggests infection. Unfortunately, follow-up serologic testing of people with confirmed WNV infections shows that IgM may remain detectable for several months [40]. Definitive serologic diagnosis can only be obtained when an acute sample and convalescent sample (collected at least 10 days later) are compared by means of the plaque-reduction neutralization test to document a 4-fold rise in antibody titer. A single negative assay of a sample collected early in the clinical course does not exclude infection.

Because IgM antibody does not cross the blood-brain barrier, intrathecal IgM strongly suggests a CNS infection. However, because the kinetics of WNV-specific CSF IgM are not known, one must consider whether its presence reflects IgM persistence in blood or signifies an acute, chronic, or relapsing infection. Persistent or relapsing infection has been seen as a result of natural and experimental infections of humans and nonhuman primates by WNV and other members of the JE complex [32, 41]. In such cases, the use of NAATs has become valuable.

Cross-reactions with other flaviviruses, including yellow fever, dengue, and members of the JE antigenic complex, limit the utility of the WNV ELISA. Some laboratories have established diagnostic ELISA absorbance ratios that compare reactivity to potentially cross-reacting flavivirus antigens. However, a 4-fold change in neutralizing antibody titer should still be sought to provide a specific diagnosis of WNV infection. Currently, commercial testing for WNV-specific antibody is limited, and because of the potential cross-reactions with antibodies to other flaviviruses, previous experience in performing and interpreting these tests is crucial. CDC-defined IgM and IgG ELISAs that use specified antigens are preferred and performed by many state public health laboratories. Plaque-reduction neutralization tests comparing the titers to WNV, St. Louis encephalitis virus, and, when indicated, dengue and JE should be used for the serologic confirmation of infection in the initial cases of an outbreak.

NAATs have the potential to simplify and improve the diagnosis of flavivirus CNS infections [42, 43]. PCR that use degenerate primers that detect regions conserved across a wide variety of flaviviruses and primers that are WNV specific should provide a sensitive and specific diagnostic method, but its value relative to IgM assays needs further evaluation. Development of “real-time” or TaqMan PCR may provide a rapid diagnostic test for evidence of WNV in CSF. Currently, neither NAATs nor virus isolation from CSF are as sensitive as ELISA for identifying an acute WNV infection. But a positive test may distinguish WNV encephalitis or meningitis from infections due to treatable pathogens. Because these methods would be done in hospital-based microbiology laboratories that routinely use NAATs for other infectious diseases, clinicians could make a specific diagnosis within hours of collecting CSF samples. In contrast, traditional serology-based diagnostic methods may take one to several weeks to perform and are only available at a few experienced laboratories. Although the WNV IgM ELISA and NAAT are not approved by the US Food and Drug Administration for patient management, they are useful in identifying the cause of epidemic encephalitis after more treatable causes of encephalitis are ruled out.

WNV may be isolated from human serum, blood, and CSF early in the febrile stage and from brain obtained during biopsy or autopsy. Virus isolation is made by inoculation of multiple substrates, including neonatal mice and both mammalian and mosquito cell lines. Only laboratories with extensive experience in flavivirus isolation and a biosafety level 3 containment facility should attempt virus isolation. If virus isolation is to be attempted, or if clinicians are uncertain about the type of testing needed, specimens should be frozen at -70°C or placed on dry ice immediately. Storage and shipment at this temperature will prevent degradation of the virus and nucleic acids. To date, no WNV isolates have been recovered from humans during the 1999–2000 epidemics. If serum is to be tested for antibody only, it may be shipped or stored at ambient temperatures for up to 48 h, provided it is kept free of microbiologic contamination. Repeated freezing and thawing of samples may degrade antibody and should be avoided.

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Disease Prevention And Control

Reducing contact between humans and potentially infected mosquitoes is the only way to reduce infection rates, morbidity, and mortality due to WNV infection. This can be done with specific personal protection behaviors and with mosquito control activities conducted by agencies with the authority and expertise to apply biologic or chemical control of mosquito larvae and adult populations. Only personal protection is reviewed here.

Personal protection behaviors that reduce the risk of infection in areas where WNV activity is present include the following: avoiding activity in areas when potentially infected mosquitoes are present; eliminating peridomestic conditions that support mosquito breeding (e.g., eliminate standing water, clean rain gutters); maintaining window and door screens; wearing long-sleeved shirts and long pants when outdoors; applying insect repellents containing DEET (N,N,-diethyl-m-toluamide) or permethrin to clothes; and applying DEET-containing repellents to exposed skin. DEET should not be used on children <2 years of age or on the hands of older children who may rub their eyes or mouth. For further information on the effective and safe use of DEET, see Fradin [44] or contact the National Pesticide Telecommunications Network (800/858-7378 or http://ace.orst.edu/info/nptn).

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Conclusion

WNV outbreaks have emerged and persisted in the eastern United States and other regions of the world where WNV infections were never or rarely found before 5 years ago. These outbreaks have been caused by genetically similar virus strains and suggest wide geographic circulation of potentially epidemic WNV strains associated with high rates of neurologic illness and death. The WNV epidemic in 3 eastern states in the United States in 1999 and 2000 and the expansion of the avian epizootic throughout the northeastern United States underscore the ease with which emerging infectious pathogens can become established and spread in new geographic areas. In the next decade, residents of and doctors in many states will face potential outbreaks due to WNV. States should monitor avian, mosquito, equine, and human infections in order for vector control activities to be implemented in a timely fashion to prevent human disease.

Doctors in areas with enzootic WNV transmission play a critical role in the recognition of cases of encephalitis, aseptic meningitis, and other illnesses caused by WNV. Given the persistence of virus activity in areas affected in 1999 and the expansion of activity in 2000, doctors in the East Coast, Gulf Coast, and Midwest should consider WNV infection in their assessment of adults with summertime febrile illnesses, especially those with profound motor dysfunction, aseptic meningitis, or encephalitis. Recognizing such cases is important because identification of just one case demonstrates that the components of a widespread epidemic are present, that hundreds of other human infections may have already occurred, and that more aggressive forms of vector control are needed.

In areas without effective vertebrate and mosquito surveillance, a human case may be the only clue that WNV is being locally transmitted and that humans are at risk. Although a person's clinical care is unlikely to be changed by a specific WNV diagnosis, knowledge of the etiology is important in preventing further human infection and illness in the patient's community. Thus, development and performance of tests that rapidly identify WNV may allow public health authorities to take immediate measures to prevent other arboviral infections.

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Acknowledgments

We thank Drs. Grant “Roy” Campbell, Marci Layton, Bob McLean, Michael Giladi, Amy Bode, Kathleen Julian, Larry Strausbaugh, David Withum, and John Roehrig. In addition, we thank Jennifer Lehman, Kimlea Medlin, Mindy Perilla, Suzanne Sutliffe, Tami Hilger, Tim Morris, and John Jones and the many state-based contributors to ArboNET, for the WNV surveillance data.

  • Received February 27, 2001.
  • Revision received May 10, 2001.
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  1. Clin Infect Dis. (2001) 33 (10): 1713-1719. doi: 10.1086/322700
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