APPENDIX-II-BO:  Sejvar, “West Nile Virus: An Historical Overview,” The Ochsner Journal,  Vol. 5, No. 3, pp. 6-10.


This appendix is copied from:‑5012‑005‑03‑0006.pdf


6 The Ochsner Journal

West Nile Virus: An Historical Overview

James J. Sejvar, MD

Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, GA

The emergence of West Nile virus (WNV), a

flavivirus within the Japanese encephalitis

antigenic complex, in New York City in the

summer of 1999 marked the first time that this Old

World virus had been identified outside of the Eastern

Hemisphere (1). Within a 3-year period, the virus

expanded its range in North America from a 6-county

area around metropolitan New York City to the West

Coast of the United States, establishing itself in 44

states and the District of Columbia, as well as in five

Canadian provinces. In particular, the 2002 season saw

an unprecedented number of human cases and

a dramatic geographic spread (2). While recent

assessments have led to a better understanding of the

clinical, ecological, and epidemiological facets of WNV,

an understanding of the historical patterns of WNV

may provide additional insight into the current

epidemic in North America.


WNV was first isolated from a febrile patient from the

West Nile district of Northern Uganda in 1937 (3). The

patient presented in the setting of a large epidemiologic

study of yellow fever virus; however, inoculations of

mice with the patient’s serum resulted in the isolation of

a virus with physical and pathologic properties similar

to those of two flaviviruses, St. Louis encephalitis virus

and Japanese B encephalitis virus, and sharing

immunological relationships with these viruses.

Although the index patient presented with fever only,

these first studies with the newly discovered virus

indicated that pathology primarily involved the

central nervous system (CNS), suggesting its neurotropic


The epidemiology and ecology of WNV was first

characterized in detail during several outbreaks in the

Mediterranean basin in the early 1950s and 1960s (4).

The first recognized epidemic of WNV occurred in

Israel in 1951 in a small town outside of Haifa, where a

total of 123 cases with no fatalities occurred among 303

inhabitants (5); young children represented the

majority of cases. During this outbreak the various

clinical features associated with infection were first

described in detail, with the main symptoms being

fever, headache, myalgias, anorexia, abdominal pain,

exanthems, and vomiting; lymphadenopathy, angina,

and diarrhea were somewhat less common.

Several large outbreaks in Egypt between 1951 and

1954 led to a further understanding of the ecology,

epidemiology, and clinical characteristics of WNV

(4,6). On the basis of the detection of WNV in the

blood of several children and a high seroprevalence rate

among residents of a village north of Cairo in 1950, an

extended study of WNV was begun in 1951 in the

upper Nile Delta region (6). The studies included

serosurveys among humans and animals; isolation

and identification of virus vectors; experimental

infection of birds, equines, arthropods, and humans;

and ecologic assessments. Findings from the studies

greatly increased the understanding of the various

clinical and epidemiologic aspects of the virus.

Serosurveys demonstrated that WNV was endemic

along the Nile, with seroprevalence rates approaching

60%. Older children and adults appeared to have

higher seroprevalence, while younger children seemed

to have more symptomatic illness, suggesting

that WNV was mainly an infection of early childhood.

Infections were characteristically self-limited, febrile

illnesses with rare occurrences of meningitis

or encephalitis.

Serosurveys conducted among animals suggested that

the virus was infectious in a wide range of species,

including birds and non-human mammals.

WNV-neutralizing antibodies were prevalent in birds,

particularly crows. WNV was found to be infectious


West Nile virus (WNV) has quickly established itself in North America since its recognition in New York

City in 1999. Historically, WNV has been associated with temporally dispersed outbreaks of mild febrile

illness. In recent years, the epidemiology and clinical features of the virus appear to have changed, with

more frequent outbreaks associated with more severe illness being noted. The 2002 outbreak in North

America was unprecedented in terms of the number of cases and geographic spread of the virus.

Historical patterns of WNV provide few indications as to the future behavior of WNV in North America.

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Volume 5, Number 3, Summer/Autumn2003 7

in a number of non-human mammals but was

particularly prevalent in equines, in which infection was

frequently symptomatic and often fatal. The vector-borne

nature of the virus had been suggested several years earlier (7)

on the basis of ecology and transmission studies. In addition,

the discovery in Egypt that the virus could be isolated only

from mosquitoes, and not from other arthropods, suggested

mosquitoes as the primary vector; this was substantiated by

the demonstration that only mosquitoes could maintain a

vector cycle by infection of a host through feeding, followed

by subsequent transmission through biting (6). Mosquitoes of

the culex species appeared to be the primary vectors.

During the Egyptian investigations, a series of experimental

infections of humans demonstrated important aspects of the

dynamics of human viremia (8, 9). At the time, persons with

incurable neoplasms were sometimes inoculated with viruses

causing pyrogenic infection in an effort to inhibit the growth

or spread of the cancer. Two separate series of patients were

assessed after inoculation with WNV; in the vast majority

of these patients, fever was the only clinical feature,

although some patients developed clinical encephalitis. These

experimental infections also suggested that the virus could be

detected in blood as soon as 24 hours after infection, and

viremia could persist for 6 to 12 days, and perhaps longer. It

also appeared that the persistence of viremia correlated with

the severity of illness.

In 1957, an outbreak of WNV occurred in Israel, where

severe neurologic manifestations among a group of elderly

nursing home residents became the first reports of

such neurologic events among humans (10). Prior to this,

neurologic illness had rarely been reported, and only among

patients undergoing experimental infection. However, during

subsequent outbreaks, including France in 1962 and

South Africa in 1974, patients developing meningitis

or encephalitis were recognized (11, 12). Neurologic

manifestations appeared to be infrequent, however, and the

vast majority of symptomatic patients still appeared to

develop mild, self-limited febrile disease. Of note is the South

African outbreak of 1974, during which thousands of febrile

illness cases were documented, with only one case of

encephalitis noted (13). Subsequent similar outbreaks

continued to occur sporadically, including epidemics in

Russia, Spain, South Africa, and India (13). Large outbreaks

of WNV were very infrequent throughout the late 1970s

and 1980s.


Beginning around 1996, the epidemiology and clinical

spectrum of WNV appeared to change. A large outbreak of

WNV occurred in the area around Bucharest, Romania, and

was notable for a number of reasons (14, 15). It was the first

WNV outbreak to be centered in a predominantly urban

area, and it was the first outbreak of the virus in which the

preponderance of symptomatic cases involved CNS infection

(15). The Romanian outbreak was extensively studied and

suggested several things about the changing epidemiology of

the virus. The overall seroprevalence rate among Bucharest

residents during the epidemic period was around 4%,

and little predilection for any particular age group, sex, or

geographic location in the city was noted (14). Serum

samples obtained from Bucharest residents that predated the

epidemic suggested that, for the most part, the population in

and around the city was serologically naive to WNV and

thus highly susceptible. Epidemiologic studies suggested

that certain factors prevalent in the rather deteriorated urban

infrastructure of Bucharest contributed to the epidemic,

including a profusion of areas conducive to mosquito

breeding, an abundance of amplifying hosts in the form of

domestic fowl, and the absence of protective barriers, such

as screens on windows and doors (15). Although cases of

milder febrile illness concomitant with the outbreak of

CNS infection were not observed, it was noted that

surveillance was rather insensitive and may have been unable

to detect such cases (15).

Following the 1996 outbreak in Romania, several subsequent

epidemics associated with relatively high rates of CNS

infection were observed throughout the Middle East and

Europe, including Morocco in 1996, Tunisia in 1997, and

large outbreaks in Italy and Israel in 1998 (13). Thus, it

appeared that outbreaks of WNV were occurring more

frequently; in addition, these outbreaks were associated

with higher rates of severe CNS disease and higher

fatality rates, predominantly among older individuals.

The Tunisian outbreak of 1997 involved 173 patients

hospitalized with meningitis or meningoencephalitis, and 8

deaths; more than half of all these patients were over 50

years of age (16). A large outbreak of WNV occurring in the

Volgograd region of Russia during the early Summer of 1999

involved 183 serologically confirmed cases, with 84 cases of

acute meningoencephalitis and 40 fatalities. In this outbreak,

over 75% of the fatalities occurred in patients older than 60

years (17).


By the time the virus was first detected in North America in

1999, it had already had a recent history of more frequent

outbreaks and more severe illness. In late August of 1999, a

cluster of severe cases of encephalitis was noted in an area

around Queens in New York City (18). An epidemiologic

investigation by the New York City Department of Health

identified eight such cases, and revealed that all of the patients

had been previously healthy, had resided within the same 16

square mile area, and had recently engaged in outdoor

activities. All but one had developed severe acute flaccid

paralysis in the setting of encephalitis. As the initial suspicion

West Nile Virus: An Historical Overview

The Ochsner Journal 8

was that of an arthropod-borne virus (arbovirus) encephalitis,

early testing was directed at common eastern North American

arboviruses. Early serologic testing displayed IgM antibodies

against St. Louis encephalitis virus by enzyme-linked

immunosorbent assay.

Both before and during the human encephalitis investigation,

an epizootic among birds associated with a high fatality rate

had been noted in and around New York City (19). These

were initially felt to be unrelated to the human epidemic.

Pathologic assessment of the dead birds displayed

involvement of multiple organs, including evidence of

encephalitis; however, common avian pathogens were not

detected (20). Genomic analyses using polymerase chain

reaction and genome sequencing with specimens from

New York City birds, infected mosquitoes collected in

Connecticut, and human brain tissue from a fatal case of

encephalitis, as well as expanded serological testing of

specimens from suspected human cases identified WNV as

the etiologic agent of this outbreak 4 weeks after the outbreak

in humans was first reported to New York City public health

officials (21-24). By the end of the Summer of 1999, 62

patients with serologic evidence of acute WNV infection,

including 59 hospitalized patients, had been identified.

Similar to more recent outbreaks of the virus, the epidemic

seemed to be associated with a high rate of CNS involvement

and a preponderance of cases in patients older than 60

years (25).

Although the mechanism of the introduction of the virus into

North America remains unknown, it seems clear that the

source of the WNV strain detected in New York City

originated in the Middle East. A similar avian epizootic

among domestic geese in Israel during 1997 and 1998 had

been attributed to WNV (21, 26). Human cases of WNV

occurred simultaneously in Israel and New York in August of

1999, and when the genomic sequences of WNV isolates or

infected human brain tissue from the New York City

outbreak were compared to various non-US strains, the

greatest homology was found with a WNV strain

isolated from a goose from the Israeli 1998 epizootic and

subsequently with a strain detected in the brain tissue of an

Israeli patient who died of West Nile encephalitis in 1999

(21). In addition, both the pattern of high avian mortality

previously not associated with WNV outbreaks and the

severity of human CNS disease seen in New York City and in

Israel were similar during the 1999 outbreaks.

The introduction of WNV in North America was followed by

progressive spread throughout the US. During the Summer of

2000, 21 cases of human WNV illness occurred among 10

counties in northeastern states (27). The following year, 66

cases were detected among a much more widespread

geographic area, involving 38 counties in 10 states.

The spread of human cases seemed to follow avian deaths;

thus, avian death surveillance and, to a lesser extent,

mosquito pool surveillance became important parts of public

health efforts to track the virus and predict potential human

cases (27). In addition to avian and human illness, a

substantial number of equine cases were documented

throughout the US, a pattern also being observed in other

parts of the world. Large epizootics, particularly among

equines, were noted in Italy in 1998 and 1999 (28) and in

France in 2000 (29). However, these outbreaks did not seem

to be associated with significant human disease. Human cases

appeared to be relegated to Israel, Russia, and the US.

During the summer of 2002, however, the number of

WNV cases in North America was unprecedented. This was

the largest outbreak of West Nile meningoencephalitis ever

recorded anywhere, and also the largest outbreak of arboviral

meningoencephalitis ever documented in the western

hemisphere. WNV expanded its geographic range from the

Mississippi River area at the conclusion of the 2001 season to

the Pacific Coast by the end of 2002. As of January 2003, the

provisional human case count from the 2002 season was

4156, including 2354 cases of meningoencephalitis and 284

deaths (2). Particular regions of the US including parts

of Louisiana, Mississippi, and the Chicago area, saw

particularly high numbers of cases. Severe CNS disease

continued to be predominantly seen in older individuals, but

more cases of milder febrile illness in younger patients were

detected, possibly as a result of enhanced surveillance efforts.

The factors contributing to the magnitude of the 2002

epidemic remain unclear, but it is interesting to note that in

several areas of the country, climatic and geographic factors

during the Spring and Summer of 2002 were very similar to

those in 1975, when a large epidemic of the related flavivirus,

St. Louis encephalitis virus, occurred in the US (30). The

particular factors and an understanding of how they may have

contributed to or facilitated these large arboviral outbreaks

require further elucidation.


The arrival and subsequent spread of WNV throughout

North America serves as an example of how an “emerging”

infectious disease may quickly and efficiently establish itself

in a new environment. The reason for the increase in frequency

and severity of outbreaks of WNV since 1996 remains

unclear. The movement of the virus into areas with large

immunologically naive populations, with an age structure

including many elderly and immunocompromised

individuals, may account in part for this observation (1);

however, a more virulent strain of the virus has been

suggested as well (31).

The future epidemiology of WNV in North America is

uncertain, and the historic pattern of the virus provides little

guidance as to its potential course in the US. Whether

continued infection among the population will lead to a


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Volume 5, Number 3, Summer/Autumn2003

decline in susceptible avian and human hosts, with a

subsequent decline in the number of cases, remains to be seen.

Following the large outbreak in 1996, Romania continued to

experience cases during following years, although at greatly

diminished rates, and seroprevalence rates among avians

appeared to remain high (15). Comparison with the

epidemiologic patterns of other related flaviviruses may be

illustrative: St. Louis encephalitis tends to occur sporadically

in various regions of the US, with the appearance of

occasional larger clusters and, rarely, large geographically

dispersed epidemics (32). On the other hand, Japanese

encephalitis tends to be a hyperendemic disease in areas

of Southeast Asia, where symptomatic illness predominates in

serologically naive children (33). The fact that WNV illness in

the US seems to predominate in adults and the elderly, with

children less frequently developing symptomatic illness, may

suggest that a substantial immune population will

develop over time; however, the future pattern cannot

be predicted.

During the period of WNV transmission in North

America, arbovirus surveillance capacity has been increased

substantially; however, the complex epidemiology of the

illness and the difficulties associated with serologic testing for

the virus continue to present challenges for surveillance and

prevention measures. Efforts to control and reduce vector

populations, reinforcement of public health messages of

personal protection from mosquitoes, and vigilant

surveillance and public awareness campaigns are likely to

remain the cornerstones of the public health response to

WNV. Through continued surveillance and further study,

it is hoped that the remaining questions regarding

the epidemiologic and clinical features of WNV may

be answered.


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