A Cautionary Tale: St. Louis in New York Was Really West Nile (-Like)
Special Report
The September 15th issue of Infectious Disease Alert summarized the then-current status of an outbreak of viral encephalitis in New York City. The outbreak had been confirmed, based on serological changes in blood and CSF, by the Centers for Disease Control (CDC) as being due to St. Louis encephalitis (SLE) virus. Wrong!1,2,9
An important clue to the fact that something unusual was going on was at first not recognized. Both before and during this outbreak, there had been increasing mortality among birds, particularly crows in New York City, as well as more exotic birds in the Bronx Zoo. Necropsied birds demonstrated evidence of encephalitis and myocarditis.
Virus was subsequently isolated from these birds by the National Veterinary Services Laboratory in Ames, Iowa; PCR testing and DNA sequencing of the virus at the CDC demonstrated the viral isolates to be closely related to the West Nile virus (WNV). In addition, examination of brain at the CDC and the University of California-Irvine from four human cases of encephalitis, previously identified as due to SLE, found WNV-like (WNVL) sequences identical to those found in the birds. Repeat serological studies on human blood and CSF found more intense positivity to WNV than to SLE and a number of specimens that were borderline or negative to SLE were positive to WNV. WNVL was subsequently detected in adult Culex pipiens and Aedes vexans mosquitoes as well as a diseased bird in Connecticut nearby to New York state’s Westchester and Nassau counties where human cases of encephalitis had occurred. On September 23, the CDC announced during a conference call that the encephalitis outbreak was due not to SLE but to a WNVL virus. On September 29, U.S. Geological Survey (USGS) biologists issued a Wildlife Health Alert to agencies east of the Mississippi River to report unusual bird fatalities, particularly among crows, which appear to have greater susceptibility to WNVL.3 WNVL genomic sequences were identified in bird tissue samples in Suffolk and Rockland counties in New York (in addition to Westchester and Nassau counties and New York City) and in Bergen, Union, Middlesex, and Essex counties in New Jersey (CDC). The New York City Department of Health reported that, as of October 7, there had been 39 laboratory-confirmed cases of WNVL infection with four deaths, as well as 168 cases under investigation.4 All human cases were from New York City or Westchester or Nassau counties.
WNV is a flavivirus of the Japanese encephalitis complex, a complex that also includes SLE, Murray Valley encephalitis, Kunjin, and several others (see Table 1).5 Other major flavivirus complexes include those of tick-borne encephalitis virus and the hepatitis C-like viruses. These complexes are an indication of antigenic relatedness in neutralization assays and serve as a warning that serological diagnoses that attempt to distinguish among members of a complex are fraught with the potential for error, a potential manifest in this instance. WNVL is only one of a number of flaviviruses that are known to cause encephalitis (see Table 2).
The vertebrate reservoirs of WNV, which is closely related to JE virus, are passerine and water birds; infection in these hosts is asymptomatic. This flavivirus is enzootic in Africa and the temperate regions of Europe and the Middle East. WNV-like JE and SLE cause epidemics in temperate zones, but only sporadic disease in the tropics. The disease caused by WNV is often more severe in temperate zones when compared to tropical zones, where background seroprevalence appears to be high.
| Table 1-Flaviviruses | |
| Complexes Defined by Neutralization | |
| Tick-borne encephalitis | |
| Japanese encephalitis | |
| Japanese encephalitis | St. Louis encephalitis |
| Murray Valley encephalitis | West Nile |
| Kunjin | Kokobera |
| Koutango | Usutu |
| Uganda S | |
| Dengue | |
| Rio Bravo | |
| Modoc | |
| Ungrouped | |
| Hepatitis C-like | |
WNV, first identified in the West Nile province of Uganda in 1937, was recently the cause of a large epidemic in southeastern Romania where, in the summer of 1996, 293 laboratory-confirmed cases were detected with almost three-fourths occurring in Bucharest.6,7 A serosurvey found that 4% of a sample of Bucharest residents had evidence of infection. As with SLE, the fatality rates were highest among the elderly.
Ilheus is a rarely encountered pathogen found in South America. Similarly, Rocio has been found only in Brazil and has not been detected for almost two decades. Kunjin and Murray Valley virus are found in Australia, Japanese encephalitis in Asia and islands of the Pacific. SLE is limited to the Americas, while WNV, even before its current identification in North America, had the widest distribution among these viruses with a presence in Europe, Africa, and Asia. Perhaps an additional 60 flaviviruses have been identified but have only rarely been seen.
| Table 2-Some Flaviviral Causes of Encephalitis6 |
| Ilheus |
| Japanese encephalitis |
| Kunjin |
| Murray Valley encephalitis |
| Rocio |
| St. Louis encephalitis |
Although birds serve as the vertebrate reservoir for both SLE and WNV, infection with this virus does not usually make them ill.8 The avian die-off observed in conjunction with this epidemic of WNV suggests, therefore, either introduction of virus into a WNV-naïve population or a shift in virulence of the virus. WNV is, like SLE, predominantly transmitted by Culex species mosquitoes, but also can be transmitted by Aedes, Anopheles, and other species. It is believed, based on their prevalence among trapped mosquitoes during the outbreak, that Culex mosquitoes played a dominant role in this epidemic. The similarity in transmission cycles of SLE and WNV resulted in the fact that the initial misidentification had little immediate practical effect, with the epidemic coming to a conclusion as the mosquito population was reduced by colder weather and application of adulticidal and larvicidal mosquito-control compounds (see Figure).
The CDC had not initially tested for the presence of WNV, since this virus had never been previously recognized in the Americas. It is possible, however, that it has not been identifed simply because it has not been looked for. Thus, it is possible that other past cases have been misidentified as SLE as a result of serological cross-reactivity, a problem that illustrates the importance of direct means of viral detection in diagnosis.
If, in fact, this epidemic was the result of a recent introduction of WNVL, a number of possible means by which this may have occurred have been proposed. The virus could have been transported in the blood of an infected human traveling from a known endemic area, in the blood of a migrating bird or a smuggled exotic bird, or in an infected mosquito which found its way here in, for instance, luggage. A more frightening possibility has been raised—that of bioterrorism. In fact, the New Yorker has recently reported that Iraq has worked with WNV as a possible biological warfare agent.
Thus, this outbreak provides a series of cautionary tales. 1) More effective vector control may have prevented the occurrence of this event. 2) Reliance on serological tests for diagnosis is potentially fraught with error; direct pathogen detection is the preferred means. 3) The threat of bioterrorism must always be considered in an outbreak situation. 4) Presumed geographic localization of transmissible infectious diseases has limited meaning in an age of speedy international travel or when infections could potentially be transmitted by migratory birds. Thus, the transmissible infectious diseases of, for example, Africa, must be considered a threat to the health of residents of more developed areas of the world. 5) Until we control the infectious diseases of lesser developed countries, we remain at risk.
References
1. CDC. Outbreak of West Nile-like viral encephalitis—New York, 1999. MMWR Morb Mortal Wkly Rep 1999; 48:871-874.
2. CDC. Update: West Nile-like viral encephalitis—New York, 1999. MMWR Morb Mortal Wkly Rep 1999;48: 890-892.
3. http://www.umesc.usgs.gov/http_data/nwhc/news/ whal9902.html.
4. http://www.ci.nyc.ny.us/html/doh/html/public/press99/ pr751007.html.
5. Monath TP, Tsai TF. Flaviviruses. In: Richman DD, Whitley RJ, Hayden FG, eds. Clinical Virology. New York: Churchill-Livingstone; 1997:1133-1186.
6. Smithburn KC, et al. A neurotropic virus isolated from the blood of a native of Uganda. Am J Trop Med Hyg 1940;20:471.
7. Tsai TF, et al. An epidemic of West Nile encephalitis in southeastern Romania. Lancet 1998;352:767-771.
8. Shope RE. Other flavivirus infections. In: Guerrant RL, Walker DH, Weller PF, eds. Tropical Infectious Diseases. Principles, Pathogens, & Practice. Philadelphia: Churchill-Livingstone; 1999:1275-1279.
9. http://www.healthnet.org/programs/promed.html.
10. A patient information sheet is available from the CDC at: http://www.cdc.gov/ncidod/dvbid/arbor/arboinfo.htm
Which of the following statements is correct?
a. Both WNV and SLE viruses are routinely lethal to birds.
b. WNV is a flavivirus of the Japanese encephalitis antigenic complex.
c. Both WNV and SLE are predominantly transmitted by Aedes and Anopheles mosquitoes.
d. WNV was first identified in Egypt.
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