West Nile Virus: A Primer for the Clinician

By L. Petersen, A. Marfin. Annals of Internal Medicine, 2002

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Four centuries of travel and commerce have led to the North American importation of several important vector-borne human pathogens, including dengue, yellow fever, malaria, and plague. The 1999 appearance of the West Nile virus in New York City may prove to be the best-documented introduction of a new, vector-borne human pathogen into the United States in the past century (1). It remains unknown how the West Nile virus came to North America. However, because it first appeared in a major international gateway, travel and commerce may have played a role. The virus's rapid geographic expansion and subsequent persistence in newly established enzootic areas in North America indicate that West Nile virus has become a permanent fixture of the U.S. medical landscape. Key features of the West Nile virus in North America are indicated in Table 1. Table 1. Key Clinical Facts about West Nile Virus in North America Epidemiology West Nile virus was first isolated and identified in 1937 from an infected person in the West Nile district of Uganda (2). Until 1999, the virus was found only in the Eastern Hemisphere, with wide distribution in Africa, Asia, the Middle East, and Europe (3). Since 1937, infrequent human outbreaks, mainly associated with mild febrile illnesses, were reported mostly in groups of soldiers, children, and healthy adults in Israel and Africa (4-7). However, one notable outbreak in Israeli nursing homes in 1957 was associated with severe neurologic disease and death (8). Since the mid-1990s, the frequency and apparent clinical severity of West Nile virus outbreaks have increased (4). Outbreaks in Romania (1996) (9), Russia (1999) (10), and Israel (2000) (11) involved hundreds of persons with severe neurologic disease. It is unclear if this apparent change in disease severity and frequency is due to differences in the circulating virus's virulence or to changes in the age structure, background immunity, or prevalence of other predisposing chronic conditions in the affected populations (12). A large outbreak of West Nile virus infection has yet to occur in the United States. However, national surveillance has documented persons with illness caused by West Nile virus, mostly encephalitis and meningitis, each year since 1999 (62 persons in 1999, 21 in 2000, and 66 in 2001) (13). These persons have been identified over an expanding geographic area (1 state in 1999, 3 in 2000, and 10 in 2001) (Figure 1). From 1999 to 2001, illness onset ranged from 13 July to 7 December, with peak incidence in late August and early September (Figure 2). Figure 1. States reporting epizootic activity and human infections of the West Nile virus, 19992001. Figure 2. Week of symptom onset for persons reported to have West Nile virus infection, 19992001. Ecology In the Eastern Hemisphere, West Nile virus is maintained in an enzootic cycle involving culicine mosquitoes and birds (3, 14). Evidence to date suggests a similar cycle in North America (Figure 3) (4). After passing through three aquatic stages (egg, larva, pupa), adult mosquitoes begin to emerge in the spring in temperate regions. Viral amplification occurs in the birdmosquitobird cycle until early fall, when female mosquitoes begin diapause and infrequently bite. Many environmental factors affect this viral amplification cycle (for example, weather or climate, host and vector predators and parasites, and host immune status). When environmental conditions promote significant amplification, sufficient numbers of bridge vector mosquitoesmosquitoes that bite both humans and birdsbecome infected in late summer and then pose an infection threat to humans. Year-round transmission is possible in more tropical climates. Through spring 2002, West Nile virus had been detected in 29 North American mosquito species; this number will undoubtedly increase as the virus spreads into new ecologic habitats. Although Culex pipiens, Culex restuans, and Culex quinquefasciatus are probably the most important maintenance vectors in the eastern United States, it is unknown which species are most responsible for transmission to humans (15). Figure 3. Transmission cycle of West Nile virus. While arboviral maintenance cycles are normally not apparent, dramatic avian mortality rates have accompanied outbreaks in humans in Israel and the United States (4, 16). Particularly high mortality rates have been noted among American crows (Corvus brachyrhynchos) and other North American corvids (ravens, jays, and other crows). In the northeastern United States, deaths in crows have increased markedly shortly before human cases have developed (17). Surveillance systems involving testing dead birds, sentinel chickens, and ill horses for West Nile virus have demonstrated rapid geographic spread in the United States (4 states in 1999, 12 states and the District of Columbia in 2000, 27 states and the District of Columbia in 2001) and into Canada (southern Ontario in 2001) (Figure 1). Up-to-date maps showing the U.S. distribution of West Nile virus are available at www.cdc.gov/ncidod/dvbid/westnile/surv&control.htm and at cindi.usgs.gov/hazard/event/west_nile/west_nile.html. Virology West Nile virus is a single-stranded RNA virus of the family Flaviviridae, genus Flavivirus. The E-glycoprotein is the viral hemagglutinin and mediates virushost cell binding. As the most immunologically important structural protein, the E-glycoprotein elicits most virus-neutralizing antibodies. West Nile virus is a member of the Japanese encephalitis virus serocomplex, which contains several medically important viruses associated with human encephalitis: Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, and Kunjin virus (an Australian subtype of West Nile virus). The close antigenic relationship of the flaviviruses, particularly those belonging to the Japanese encephalitis complex, accounts for the serologic cross-reactions observed in the diagnostic laboratory (18). West Nile virus can be divided genetically into two lineages. Only viruses of lineage 1 have been definitely associated with human disease. The West Nile virus responsible for the 1999 outbreak in New York City was a lineage 1 virus that circulated in Israel from 1997 to 2000, suggesting viral importation into North America from the Middle East (19, 20). Of interest, both birds and humans have died of West Nile virus infection only in the United States and Israel to date; the reason for this is not known. Since 1999, very few genetic changes have occurred in the variant of West Nile virus circulating in the United States. Clinical Features The incubation period of West Nile virus, although not precisely known, probably ranges from 3 to 14 days. Most human infections are not clinically apparent. A serosurvey conducted during the 1999 New York City epidemic indicated that approximately 20% of persons infected with West Nile virus had developed West Nile fever and only half of these had visited a physician for this illness (21). The frequencies of various symptoms and signs associated with West Nile fever during recent outbreaks are poorly defined because surveillance has focused on patients with neurologic disease. In earlier outbreaks, the disease was described as a febrile illness of sudden onset, often accompanied by malaise, anorexia, nausea, vomiting, eye pain, headache, myalgia, rash, and lymphadenopathy; these symptoms generally lasted 3 to 6 days. Among the 6 symptomatic persons positive for IgM antibody who were identified in the 1999 New York City serosurvey, all reported myalgia, 5 reported fatigue, 5 had headache, and 4 had arthralgia (21). Although recent outbreaks of West Nile virus seem to be associated with increased morbidity and mortality, severe neurologic disease remains uncommon. Two serosurveys conducted in New York City in 1999 and 2000 showed that approximately 1 in 150 infections resulted in meningitis or encephalitis, a result consistent with a 1996 Romanian serosurvey indicating that 1 in 140 to 320 infections led to these diseases (9, 21, 22). Advanced age is by far the most significant risk factor for severe neurologic disease after infection; risk increases markedly among persons 50 years of age and older. An analysis of attack rates per million persons during the 1999 New York City outbreak showed that compared with persons 0 to 19 years of age, the incidence of severe neurologic disease was 10 times higher in persons 50 to 59 years of age and 43 times higher in those at least 80 years of age (1). In addition, the household-based serosurvey in New York City showed that incidence of West Nile virus infection was fairly uniform according to age (21). These results indicated that the higher incidences of severe neurologic disease among older persons were not attributable simply to differences in mosquito exposure. A similar finding was noted during the 1996 Romanian outbreak (9). Among hospitalized persons with West Nile virus infection in the United States (1999), Romania (1996), and Israel (2000), encephalitismeningoencephalitis was more frequently reported than meningitis (62%, 60%, and 58% compared with 32%, 40%, and 16%, respectively) (1, 9, 11). More than 90% of patients hospitalized during these outbreaks had fever; weakness, gastrointestinal symptoms, headache, and changes in mental status were common reported symptoms (Table 2). A skin rash, present in a minority of patients, was described as an erythematous macular, papular, or morbilliform eruption involving the neck, trunk, arms, or legs (1, 23). Table 2. Symptoms of West Nile Virus Reported among Hospitalized Patients during Outbreaks in New York State (1999), Romania (1996), and Israel (2000) Approximately half of the hospitalized U.S. patients had severe muscle weakness. This symptom may provide a clinical clue to the presence of West Nile virus, particularly in the setting of encephalopathy (1, 23). Approximately 10% of patients in the New York outbreak had

Subfields: Infectious Diseases, Public Health, Environmental and Occupational Health

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