APPENDIX-II-BO: Sejvar, “
This appendix is copied from:
http://www.ochsnerjournal.org/pdfserv/i1524‑5012‑005‑03‑0006.pdf
6 The Ochsner
Journal
James J. Sejvar, MD
Division of Viral and Rickettsial Diseases,
Centers for Disease Control and Prevention,
The emergence of
flavivirus within the Japanese encephalitis
antigenic complex, in
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
area around metropolitan
Coast of the
states and the District of
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
BACKGROUND
WNV was first
isolated from a febrile patient from 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
nature.
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
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
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
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
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
ABSTRACT
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
Historical patterns
of WNV provide few indications as to the future behavior of WNV in
Sevjar JJ
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
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
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
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
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
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
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
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
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
epidemics associated with
relatively high rates of CNS
infection were observed
throughout the
large outbreaks in
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
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).
ARRIVAL OF WNV IN
By the time the
virus was first detected 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
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
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
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
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
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
source of the WNV strain
detected in
originated in the
among domestic geese in
been attributed to WNV
(21, 26). Human cases of WNV
occurred simultaneously in
1999, and when the
genomic sequences of WNV isolates or
infected human brain tissue
from the
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
(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
The introduction of
WNV in
progressive spread throughout
the
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
parts of the world. Large
epizootics, particularly among
equines, were noted in
to be associated with
significant human disease. Human cases
appeared to be relegated to
During the summer of
2002, however, the number of
WNV
cases in
the largest outbreak of
recorded anywhere, and also
the largest outbreak of arboviral
meningoencephalitis ever documented in the western
hemisphere. WNV expanded its
geographic range from the
the
provisional human case count
from the 2002 season was
4156, including 2354
cases of meningoencephalitis and 284
deaths (2). Particular
regions of the
of
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
particular factors and an
understanding of how they may have
contributed to or facilitated
these large arboviral outbreaks
require further
elucidation.
COMMENT
The arrival and
subsequent spread of WNV throughout
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
uncertain, and the historic
pattern of the virus provides little
guidance as to its potential
course in the
continued infection among the
population will lead to a
9
Sevjar JJ
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,
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
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
serologically naive children
(33). The fact that WNV illness in
the
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
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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