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West Nile Virus in the United States
Author: Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center; Editor-in-Chief, Infectious Disease Alert.
Editor’s Note—West Nile virus was of no concern to residents of North America until the summer of 1999, when it seemingly inexplicably struck in Queens, NY.1 The cases of encephalitis were thought to be due to a pathogen well known in the United States, St. Louis encephalitis (SLE) virus. SLE infection, like other arboviral diseases, occurs in the summer months when mosquitoes are active and, also like the outbreak in Queens, is most severe in the elderly. In addition, many of the patients had detectable antibody against SLE antigens. There was at least one puzzling observation, however, that did not fit with SLE—dead birds, especially crows and exotic birds in the Bronx Zoo. While birds are the natural reservoir for SLE virus, avian infection is seldom lethal. An initial thought was that SLE had perhaps mutated to a form more virulent to avians. Eventually, however, the startling discovery was made that the infections occurring that summer, both human and avian, were caused by a flavivirus related to SLE, West Nile virus (WNV). This relatedness was close enough to cause antigenic cross-reactivity and, thus, accounting for the falsely positive serological tests.
The discovery that the infections were caused by WNV was both surprising and disquieting. Naturally acquired WNV infection had never before been detected in North America, a continent presumed to be protected by its surrounding oceans from the wayward flight of a migratory bird from across the Atlantic (patients with advanced cancer were deliberately infected with WNV at the Sloan-Kettering Institute in New York in the early 1950s, and several of these patients developed encephalitis [Southern]). In fact, we still do not know how the WNV made its way to this continent. Suggested means of transport have included a stowaway mosquito on an overseas transport, an infected migratory or storm-blown bird, in a viremic human, in an infected bird or mammalian pet, or by an (unlikely) act of bioterrorism.2 Whatever the means, the virus had arrived in North America, a land mass heavily populated with birds and humans, none of which had previous immunologic experience with the virus. This immunologic naivete had predictably devastating consequences for wild and captive avian populations. While the birds were dying, so were humans, albeit in much smaller, but increasing numbers—from 7 deaths in 1999 to 284 in 2002. The approximately 2700 cases of WNV meningoencephalitis reported through 2002 made it the largest such epidemic ever documented anywhere in the world.
WNV is a member of the Flaviviridae, of which more than 70 have been described, with at least 13 capable of causing disease in humans. Other flaviviruses include the etiologic agents of tick-borne encephalitis, dengue, yellow fever, hepatitis C, and the closely related Japanese encephalitis and SLE viruses. Flaviviruses that affect humans are, with the exception of hepatitis C virus and GB virus, transmitted by the bite of mosquitoes or ticks.
WNV and other flaviviruses contain linear, positive-sense single-stranded DNA comprised of approximately 11,000 nucleotides.3 The open reading frame encodes 3 structural proteins and 7 nonstructural proteins. Electron micrography of the mature virion reveals an enveloped spherical capsid 40 nM to 60 nM in diameter, with icosahedral symmetry and small surface projections of E glycoprotein anchored in the viral membrane. The projecting E glycoproteins contain antigenic determinants recognized by hemagglutinating and neutralizing antibodies. It is believed that the E protein also interacts with host cell receptors during virion attachment. Penetration of the cell probably occurs by receptor-mediated endocytosis. Virion uncoating releases genomic RNA that then functions as messenger RNA, as well as a template for further RNA synthesis, via a minus-strand RNA intermediary. The open reading frame of the genomic RNA generates a large polyprotein that is then cleaved into constituent proteins. Assembled mature virions are transported to the cell membrane where they undergo vesicle fusion and are released from the cell.
Analysis of full-length genomes demonstrate 2 distinct WNV lineages.4 One of these consists of enzootic strains present in Africa, while the other has wide distribution, including Africa, the Middle East, Eastern Europe and, now, North America. The Kunjin virus, present in Australia, closely related to WNV, is a subtype of the latter lineage.5
Epidemiology and Transmission (see Tables 1 and 2, below)
|Table 2. West Nile Virus: Possible Modes of Transmission|
WNV was first isolated from the blood of a woman with an uncomplicated febrile illness residing in Uganda, near the West Nile, in 1937.6 WNV infection has been described in Africa, Europe, the Middle East, west and central Asia, Oceania (subtype Kunjin) and, most recently, North America.7 Outbreaks of WNV infection in humans have occurred in recent years in Algeria in 1994, Romania in 1996-1997, the Czech Republic in 1997, the Democratic Republic of the Congo in 1998, Russia in 1999, the United States in 1999-2001, and Israel in 2000. Epizootics of disease in horses occurred in Morocco in 1996, Italy in 1998, the United States in 1999-2001, France in 2000, and in birds in Israel in 1997-2001 and in the United States in 1999-2002.
When WNV made its dramatic first appearance in North America in the summer of 1999, it accounted for 59 hospitalizations and 7 deaths.1 Although the virus is transmitted vertically in mosquitoes, it was hoped that infected arthropods would not survive the cold northern winter. Unfortunately, this was not true, and the virus has caused infection in 4 consecutive transmission seasons in North America. Most human infections occur in summer or early autumn in temperate and subtropical zones, but year-round transmission has been documented in Florida.8
The transmission cycle of WNV involves mosquitoes and passerine birds (birds with the ability to hold on using claws), with mammals being accidental hosts.9-12 While a variety of mosquitoes have been found to be infected by WNV (29 infected species have been identified in the United States through 2002), the most important vectors are those of the genus Culex, especially C pipiens, C quinquefasciatus, and C restuans, species that have an affinity for feeding on birds. The birds act as amplifying hosts and as reservoirs of virus. High-level viremia occurring during the course of the avian infection provides a reservoir, leading to infection of mosquitoes that feed on the firds. Some mosquitoes that bite both birds and humans serve as a bridge to the latter. More than 100 North American bird species have been found to be infected, with avian mortality highest in crows and other corvids, such as ravens and jays. Birds that survive the infection may acquire life-long immunity in the process.
Infection of migrating birds accounts for transport of the virus between distant geographic areas. The means by which WNV was first introduced into North America in 1999, however, remains a matter of conjecture. The WNV first detected in New York is genetically almost identical (99.8% nucleic acid and amino acid homology) to a virus isolated from a dead goose in Israel in 1998.13
In urban outbreaks, including that in New York City, risk factors for human infection were predictable: prolonged time spent out-of-doors, lack of regular use of mosquito repellent, having noticed mosquitoes in the home, and living in an apartment with a flooded basement.14 In addition to its usual means of mosquito-borne transmission, WNV has also been transmitted by blood component transfusion, organ transplantation, direct percutaneous inoculation in laboratory accidents, and by transplacental passage.15-19 During 2002, it was estimated that the maximum and mean risk of WNV transmission from donors in Queens were 2.7 (95% CI, 0.9-5.6) and 1.8 (95% CI, 1.4-2.2) per 10,000 donors, respectively, with the peak risk in late August and very low risk before August and after September.16 A single case report has raised the possibility of transmission via breast milk.17 Transmission as a result of needle sharing by injection drugs users is also considered a potential danger. There is otherwise no evidence of direct person-to-person transmission.
Clinical Aspects (see Figure 1, below)
|Figure 1. Clinical Spectrum of WNV Infection. CDC.|
Most human cases of WNV infection are clinically inapparent, with only approximately one-fifth becoming symptomatic.9-11 The incubation period for symptomatic cases is 2-14 days, although it is most often 2-4 days for febrile cases. Symptoms generally last 3-6 days. The onset of fever is typically abrupt, often reaching > 39° C, with mylagia and headache or ocular pain. Gastrointestinal symptoms, including anorexia, nausea, and vomiting may also occur. Rash may occur in up to one-fifth of cases and generalized lymphadenopathy in only approximately 5% of US cases. The rash is maculopapular or morbilliform and may involve the neck, trunk, arms, and legs. Both fever and lymphadenopathy occurred more frequently during previous outbreaks in Israel.
In the United States, approximately 1 in 150 patients have developed infection of the central nervous system (CNS). In patients with neurologic disease, the illness is often biphasic, with 1-7 prodromal days of febrile illness followed by manifestations of CNS infection. The risk of neurological involvement rises with increasing age, especially after the age of 50 years. In the initial New York experience, the risk of severe neurologic disease was 43 times greater in those 80 years or older compared to those younger than 20 years of age.1 Encephalitis or meningoencephalitis is observed in approximately 60% of those with CNS involvement, while 16-40% have meningitis without an encephalitic component.9-11
The onset of CNS symptoms may occur simultaneously with, or within a few days after the onset of fever. Patients with mental status changes may progress to coma, a complication that may occur in 15% of those with encephalitis. Muscle weakness, resulting from myelitis, may be observed in one-half of patients, in some cases severe enough to suggest the presence of acute poliomyelitis or Guillian-Barré syndrome.20 Respiratory failure may result. Less frequently observed have been ataxia, extrapyramidal signs, cranial neuropathies and polyradiculitis, and rhabdomyolysis. Tremors and myoclonus may be more frequent than previously reported.21 Seizures may occur. Also uncommonly observed are optic neuritis, chorioretinitis, uveitis, and vitritis.22-25
Differentiation from Guillian-Barré syndrome may be made by clinical findings, electromyography, and nerve conduction velocity studies, as well as by the presence of cerebrospinal fluid (CSF) pleocytosis in WNV infection (see Table 3). WNV infection may produce flaccid paralysis clinically indistinguishable from that caused by polioviruses, as a consequence of direct involvement of anterior horn cells.26 Resultant weakness of thoracic muscles may lead to respiratory failure and need for mechanical ventilation.
The case fatality rate among patients hospitalized in New York City in 1999 was 12%.1 In New York, patients affected severely enough to warrant hospitalization during the initial outbreak in 1999, persisting morbidity was frequent. One year later, 67% reported persisting fatigue, 50% memory loss, 49% difficulty walking, 44% muscle weakness, and 38% suffered depression.27
Diagnosis (see Table 4 and Figure 2, below)
|Figure 2. Serological Testing Algorithm for West Nile Virus. CDC.|
In North America, arbovirus infection, especially WNV and SLE, should be suspected in patients who develop otherwise unexplained encephalitis or meningitis during the summer or early autumn, especially if these infections are active in the community, or if the patient has traveled to an area with suspected or known arboviral activity.7,10-12 This suspicion should be heightened in patients older than 50 years of age. The presence of significant muscular weakness should also suggest the diagnosis. The presence of WNV infection should also be considered in patients with nonspecific febrile illness in a setting of WNV activity.
The white blood count may be normal or elevated or low and anemia may also be present.7,10-12 Hyponatremia, possibly due to inappropriate secretion of antidiuretic hormone may be seen, especially when encephalitis is present. When CNS infection is present, CSF examination generally demonstrates a lymphocyte-predominant pleocytosis, modest protein elevation, and normal glucose. The CSF may, however, have a neutrophilic predominance or may be acellular. Magnetic resonance imaging may demonstrate leptomeningeal and/or periventricular enhancement and, in some cases, high signal intensity lesions on T2 weighted images involving basal ganglia, findings consistent with the high frequency of movement disorders.7
The diagnosis of infection due to WNV may be made by detection of serum IgM antibody, by enzyme-linked immunosorbent assay, to viral antigens in serum or cerebrospinal fluid (CSF).27-30 Detection in the CSF of IgM antibody against WNV antigens is highly consistent with acute CNS infection due to the virus. A negative test on a serum sample obtained within the first 14 days of illness should be repeated on a later sample. Falsely positive serum IgM antibody tests may occur in individuals recently infected with or vaccinated against related flaviviruses such as dengue, yellow fever, or Japanese encephalitis viruses. The use of the highly specific plaque reduction neutralization assay may assist in distinguishing between false and true positives. Care must also be taken because IgM antibody to antigens of WNV may persist for 6 or more months and, as a consequence, a positive test may only indicate a prior, probably asymptomatic infection.28,30 The serological diagnosis of WNV infection is most confidently made in the presence of a fourfold or greater increase in serum neutralizing antibody titers upon testing acute and convalescent sera. Specimens are ideally obtained on the first day of illness and again after an interval of at least 3 weeks. In addition, the titers detected against WNV antigens should be at least four-fold higher than those to antigens of other appropriately selected flaviviruses, in order to assure specificity.
Successful cultivation of WNV from CSF or brain tissue has had a very low yield in US cases. In New York City cases, a polymerase chain reaction (PCR) assay has been reported to be positive in as many as 55% of CSF but in only 10% of serum samples.28,30 PCR assays may be more successful when applied to brain tissue, in which viral antigen may also be detected by immunohistochemistry.
The neurological changes appear to result from CNS invasion, with viral proliferation in glial cells and neurons, together with a cytotoxic immunological response to viral antigens.10 Tissue responses include diffuse perivascular lymphocytic inflammation and formation of microglial nodules, together with neuronal degeneration. Areas of involvement include the thalamus, the brain stem, and proximal spinal cord. Cases clinically resembling paralytic polio are characterized by death of anterior horn cells.26
Treatment is symptomatic and supportive. No controlled trials of either adjunctive measures, such as the use of osmotic agents or corticosteroids in the presence of cerebral edema, or of antiviral agents have been reported. Passive immunization with WNV-immune serum protected hamsters from clinical illness and death when subsequently challenged with WNV.31 Pooled intravenous immunoglobulin collected in Israel has been administered to WNV infected patients, but there is no data demonstrating its efficacy.32,33
Ribavirin and interferon α-2b each inhibit WNV replication and inhibit cytopathic effect in neural cells in vitro.34,35 A multivariate analysis of 233 Israeli patients infected with WNV,37 of whom received interferon α, found no evidence of survival benefit from this agent.36 Interferon α-2a was ineffective in a randomized, placebo-controlled trial of treatment of Japanese encephalitis.37 WNV is, as mentioned previously, very closely related to Japanese encephalitis virus. A randomized trial of interferon α therapy is underway, however. Several other small molecules, including mycophenolic acid, have been demonstrated to have in vitro activity against WNV.38,39
While no vaccine is available for use in humans, an inactivated virus vaccine has received a license in the United States for use in horses.40,41 A variety of experimental approaches to vaccine development have been reported, including the use of live attenuated chimeric vaccine backbone derived from yellow fever virus.31,42 One of the patients who developed WNV infection by a laboratory accident had previously had dengue and had been vaccinated against yellow fever.18 This suggests that immunity to these related viruses does not provide protection against WNV infection.
The most effective, and critical, means of prevention of WNV infection is a program of surveillance for arboviral surveillance and aggressive control of the mosquito serving as vectors within a region, together with education of the public. ArboNET is a cooperative WNV surveillance program involving CDC, 48 states, 5 cities, and the District of Columbia. This network accumulates and analyzes reports of WNV-infected mosquitoes, sentinel animals, dead birds, and ill humans and horses.40,41,43 The lethality of WNV infection in crows and jays makes observations of die-offs of these Corvidae a potential early warning system for WNV activity. It has been reported that the detection of WNV infected dead birds prior to August 15 of both 2001 and 2002, was an early harbinger of the subsequent appearance of WNV disease in humans.44
Critical prevention measures include elimination of larval habitats, including such things as old tires, tin cans, and other containers that may accumulate water. Also considered in some instances is the spraying of insecticides to kill juvenile larvae and adult mosquitoes.40 The combination of mosquito control methods selected for use in a control program depends on the type of mosquitoes to be controlled and the habitat structure. In emergency situations, wide area aerial spraying is used to quickly reduce the number of adult mosquitoes.
Personal protective measures are also of great importance (see Table 5). To avoid mosquito bites, one should wear long sleeves, long pants, and socks and apply DEET (N,N-diethyl-meta-toluamide) to exposed skin when outdoors, especially in the period from dawn to dusk. Extra protection may be gained by treating clothes with repellents containing permethrin or DEET. It is also important to limit mosquito breeding grounds by eliminating standing water around the home
Standard procedure has always required that donors of blood components be in good health at the time of donation, thus excluding the 20% of individuals with WNV infection who become symptomatic. Individuals with diagnosed WNV infection should defer donation until at least 14 days after resolution of the illness and at least 28 days after the onset of symptoms, whichever is the later date. In the absence of current or recent symptoms, an IgM positive antibody test result alone should not be grounds for deferral. Other Flaviviridae are known to be inactivated by heat or solvent detergent treatments used to prepare plasma derivatives.
The FDA has provided recommendations for donor deferral, and for product quarantine and retrieval related to reports of post-donation illnesses in the donor, or WNV infection in recipients of blood.45 Because four-fifths of infections are asymptomatic, such measures may have limited effectiveness and there is a need for effective screening tests. Such tests would also be applied to organ donors. Finally, WNV is classified as a BSL3 agent and appropriate protective measures must be used in laboratories processing potentially affected specimens.
Cases of WNV infection must be reported to their local public health authority.
The introduction of WNV into North America provided a striking lesson in the globalization of infectious diseases. It can be expected that the infection will continue to spread through large parts of the western hemisphere, causing increasing disability and death. This highlights the need for improved public health structures in both developed and lesser developed countries, as well as the need for development of therapeutics.
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