Annals of Internal Medicine: Article

                      +-----------------------------------+
                      | 6 August 2002 Volume 137 Number 3 |
                      +-----------------------------------+
REVIEWS

West Nile Virus: A Primer for the Clinician
--------------------------------------------------------------------------------
Pages 173-179

This paper provides the clinician with an understanding of the epidemiologic
and biological characteristics of West Nile virus in North America, as well as
useful information on the diagnosis, reporting, and management of patients with
suspected West Nile virus infection and on advising patients about prevention.
Information was gathered from the medical literature and from national
surveillance data through May 2002. Since the identification of West Nile virus
in New York City in 1999, enzootic activity has been documented in 27 states
and the District of Columbia. Continued geographic expansion is likely.
Overall, one in 150 infections results in severe neurologic illness. Advanced
age is by far the most important risk factor for neurologic disease and, once
disease develops, for worse clinical outcome. Surveillance has identified 149
persons with West Nile virus-related illness in 10 states. Encephalitis is more
commonly reported than meningitis, and concomitant muscle weakness and flaccid
paralysis may provide a clinical clue to the presence of West Nile virus
infection. Peak incidence occurs in late summer, although onset has occurred
from July through December. Immunoglobulin M antibody testing of serum
specimens and cerebrospinal fluid is the most efficient method of diagnosis,
although cross-reactions are possible in patients recently vaccinated against
or recently infected with related flaviviruses. Testing can be arranged through
local, state, or provincial (in Canada) health departments. Prevention rests on
elimination of mosquito breeding sites; judicious use of pesticides; and
avoidance of mosquito bites, including mosquito repellent use.

Ann Intern Med. 2002;137:173-179.

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.

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).

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
bird-mosquito-bird 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"
mosquitoes--mosquitoes that bite both humans and birds--become 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).

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
http://www.cdc.gov/ncidod/dvbid/westnile/surv&control.htm and at
http://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
virus-host 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), encephalitis-meningoencephalitis 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).

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 complete flaccid paralysis. In fact,
several patients had such profound weakness that they were first thought to
have the Guillain-Barre syndrome (24, 25). However, most studied persons with
clinical presentations consistent with the Guillain-Barre syndrome had
pleocytosis as well as electromyography and nerve-conduction velocity studies
indicating both axonal and demyelinating lesions, with axonal changes most
prominent (26). These findings would be unusual for the Guillain-Barre
syndrome. Neurologic presentations other than encephalitis or meningitis, which
occur more rarely, include ataxia and extrapyramidal signs, cranial nerve
abnormalities, myelitis, optic neuritis, polyradiculitis, and seizures.
Myocarditis, pancreatitis, and fulminant hepatitis have been described in
outbreaks occurring before 1990.

Clinical Outcome and Treatment

Case fatality rates among patients hospitalized during recent outbreaks have
ranged from 4% in Romania (1996) to 12% in New York (1999) and 14% in Israel
(2000) (1, 9, 11). Case fatality rates have remained constant among U.S.
patients in 2000 and 2001 (13). Advanced age is the most important risk factor
for death, and patients older than 70 years of age are at particularly high
risk. For hospitalized persons older than 70 years of age, case fatality rates
were 15% in Romania and 29% in Israel; in New York, persons 75 years of age and
older were nearly nine times more likely to die than younger persons (1, 9,
11). Encephalitis with severe muscle weakness and change in the level of
consciousness were also prominent clinical risk factors predicting death.
Limited data suggest that certain preexisting conditions, such as diabetes
mellitus or immunosuppression, may be independent risk factors for death (1,
11). In one study of induced West Nile infections in patients with cancer,
prolonged viremia and severe illness were more common among those with
hematologic malignancies than among those with other types of cancer (27).

Few data exist regarding long-term morbidity after hospitalization for West
Nile infection; those that do suggest that many patients have substantial
morbidity. Among patients hospitalized in New York and New Jersey in 2000, more
than half did not return to their functional level by discharge and only one
third were fully ambulatory (23). One-year follow-up of the 1999 New York
patients by the New York City Department of Health found frequent persistent
symptoms (fatigue, 67%; memory loss, 50%; difficulty walking, 49%; muscle
weakness, 44%; and depression, 38%) (28).

Treatment for West Nile virus infection is supportive. Of 19 patients
hospitalized in New York and New Jersey in 2000, 5 were admitted to intensive
care units and 2 required mechanical ventilation (23). Ribavirin in high doses
and interferon-2b were efficacious against the West Nile virus in vitro;
however, controlled clinical trials have not been completed for either agent
(29). One comatose patient treated with both ribavirin and interferon- did not
improve (23). In Israel, patients treated with ribavirin had a higher mortality
rate than those who did not receive ribavirin, although this difference could
have been related to patient selection (11). No controlled studies have
examined the use of steroids, antiseizure medications, or osmotic agents in the
management of West Nile virus encephalitis.

Laboratory Findings and Diagnosis

During recent outbreaks, total leukocyte counts in peripheral blood were mostly
normal or elevated; lymphocytopenia and anemia also occurred (1, 11, 23).
Hyponatremia was sometimes present, particularly among patients with
encephalitis (11, 23). Examination of the cerebrospinal fluid showed
pleocytosis, with leukocyte counts ranging from 0 to 1782 cells/mm3, usually
with a predominance of lymphocytes (1, 11, 23, 25). Protein levels were
universally elevated (51 to 899 mg/dL), and glucose levels were normal.
Computed tomography of the brain usually showed no evidence of acute disease
(1, 11, 23). In approximately one third of patients, magnetic resonance imaging
showed enhancement of the leptomeninges, the periventricular areas, or both.

The diagnosis rests on a high index of clinical suspicion and on results of
specific laboratory tests. West Nile virus or other arboviral diseases, such as
St. Louis encephalitis, should be seriously considered in older adults who have
onset of unexplained encephalitis or meningitis in late summer or early fall.
The local presence of West Nile virus enzootic activity or other human cases
should further raise the index of suspicion. However, because severe neurologic
disease due to West Nile virus infection has occurred in persons of all ages
and because year-round transmission is possible in more southern states, West
Nile virus should always be considered in persons with unexplained encephalitis
and meningitis.

The most efficient diagnostic method is detection of IgM antibody to West Nile
virus in serum or cerebrospinal fluid. The IgM antibody-capture enzyme-linked
immunosorbent assay is optimal for IgM detection because it is simple,
sensitive, and applicable to serum samples and samples of cerebrospinal fluid.
Among the patients in New York City who were infected in 1999 and 2000 and for
whom a sample of cerebrospinal fluid was available, nearly all (95%) had
demonstrable IgM antibody (28). Since IgM antibody does not cross the
blood-brain barrier, IgM antibody in cerebrospinal fluid strongly suggests
central nervous system infection. Ninety percent of serum samples obtained
within 8 days of symptom onset were also positive for IgM antibody. Tests of
serum or cerebrospinal fluid are available commercially and can be obtained
through local, state, or province (in Canada) health departments for patients
with encephalitis or meningitis.

Two caveats must be considered when interpreting serologic tests. First,
because of close antigenic relationships among the flaviviruses, persons
recently vaccinated with yellow fever or Japanese encephalitis vaccines or
persons recently infected with a related flavivirus (for example, St. Louis
encephalitis or dengue) may have positive results on IgM antibody tests for
West Nile virus (18). The plaque reduction neutralization test, the most
specific test for the arthropod-borne flaviviruses, can be used to help
distinguish false-positive results on IgM antibody-capture enzyme-linked
immunosorbent assay or other assays (for example, indirect immunofluorescence
and hemagglutination inhibition). The plaque reduction neutralization test may
also help distinguish serologic cross-reactions among the flaviviruses,
although some degree of cross-reaction in neutralizing antibody may still cause
ambiguous results. Second, because most infected persons are asymptomatic and
because IgM antibody may persist for 6 months or longer, residents in endemic
areas may have persistent IgM antibody from a previous infection that is
unrelated to their current clinical illness (28). An increase in West Nile
virus-specific neutralizing antibody titer in serum specimens from persons with
acute and convalescent disease confirms acute infection.

It is also possible to isolate West Nile virus or to detect viral antigen or
nucleic acid in cerebrospinal fluid, tissue, blood, or other body fluids.
Although a positive culture or positive results on the nucleic acid
amplification test are diagnostic, low sensitivity precludes their use as
routine screening tests. Viral culture of cerebrospinal fluid or brain tissue
has had very low yield among U.S. patients; results on nucleic acid
amplification testing, such as real-time polymerase chain reaction, have been
positive in up to 55% of samples of cerebrospinal fluid and 10% of serum
samples (28). One autopsy series of four New York patients infected in the 1999
outbreak showed a mostly mononuclear inflammation that formed microglial
nodules and perivascular clusters in the white and gray matter. The brainstem,
particularly the medulla, was most extensively involved. Cranial nerve roots
had mononuclear inflammation in two patients (30).

Reporting

West Nile virus encephalitis has recently been added to the list of designated
nationally notifiable arboviral encephalitides; aseptic meningitis is
reportable in some jurisdictions (31). Recommended clinical and laboratory case
definitions for West Nile virus are available at
http://www.cdc.gov/ncidod/dvbid/westnile/resources/wnv-guidelines-apr-2001.pdf
and are summarized in Table 3. Submission of serum specimens or specimens of
cerebrospinal fluid to state and local public health laboratories for arboviral
diagnosis facilitates rapid diagnosis and reporting. The timely identification
of even a single person with acute West Nile virus or other arboviral infection
may have substantial public health implications and will probably augment the
public health response to reduce the risk for additional human infections. An
additional benefit of human West Nile virus surveillance has been increased
recognition of other arboviral encephalitides, such as Powassan encephalitis
virus in the northeastern United States and Canada (32, 33). Information on how
to report persons with suspected West Nile virus infection or how to submit
diagnostic samples in the United States is available at
http://www.cdc.gov/ncidod/dvbid/westnile/city_states.htm.

Prevention

Although human vaccines for West Nile virus are under development (34), for the
foreseeable future West Nile infection prevention will rest on two broad
general strategies: 1) reducing the number of vector mosquitoes through actions
taken by the public or by municipal authorities, and 2) preventing vector
mosquitoes from biting humans by using mosquito repellents; avoiding locations
where vector mosquitoes are biting; and using barrier methods, such as window
screens or long-sleeved clothing.

Reducing the Number of Mosquitoes

Many vector mosquitoes have a limited flight range and readily breed in
containers or other objects containing small pools of water. Thus, homeowners
or municipal authorities can greatly reduce mosquitoes in residential or urban
areas by draining water from or eliminating mosquito breeding sites. Larvicides
can also be applied to still or stagnant waters that are potential mosquito
breeding sites. Bacillus thuringiensis var. israelensis and Bacillus sphaericus
are two larvicides in which the active ingredient is a biological organism.
Municipal authorities commonly use these products with methoprene, a
biochemical regulator that interferes with mosquito maturation, for West Nile
virus prevention. None of these products is associated with serious acute or
chronic health effects.

The U.S. Environmental Protection Agency-approved organophosphate or pyrethroid
formulations are applied in very small volumes by ground or aerial spraying for
control of adult mosquitoes. Public health authorities use these "adulticides"
for prevention of human West Nile virus infection when epidemiologic evidence
suggests impending or continuing human transmission. Serious adverse health
events associated with pesticide spraying for West Nile virus control seem rare
(28). Minor eye and skin irritation, as well as breathing problems, have rarely
been reported with spraying of organophosphates and pyrethroids. Cholinergic
symptoms (for example, nausea, vomiting, diarrhea, sweating, and bronchospasm)
are associated with high-dose occupational or accidental organophosphate
exposure. A cholinesterase level can be obtained to confirm organophosphate
poisoning. Exposure to high doses of pyrethroids may cause abnormal facial
sensation, dizziness, salivation, headache, vomiting, diarrhea, irritability,
pulmonary edema, and seizures. More detailed information about pesticides and
other mosquito control measures can be obtained from the U.S. National
Pesticide Information Center at http://www.ace.orst.edu/info/npic/wnv/.
Backyard "bug zappers" or carbon dioxide-baited devices have not been proven to
significantly reduce exposure to mosquito bites.

Using Mosquito Repellents

An excellent clinician's guide for mosquito repellents has recently been
published (35). The most widely used repellent, DEET
(N,N-diethyl-3-methylbenzamide), is available in many formulations; however,
concentrations higher than 50% show little incremental increase in efficacy and
only slightly longer durations of action. Extended-release preparations are
available. Products containing 10% to 50% DEET are sufficient under most
conditions and can be reapplied according to the manufacturer's instructions.
The American Academy of Pediatrics recommends that repellents containing no
more than 10% DEET be used on children. DEET is registered for direct
application to skin, pets, clothing, tents, bedrolls, and screens. It has a
remarkable safety profile, and serious toxicity has been limited to
encephalopathy in a few children, most of whom had a history of long-term,
excessive use of DEET repellents. DEET is not recommended for infants younger
than 2 months of age.

Permethrin, a pyrethroid with repellent and insecticidal characteristics, is
found in Environmental Protection Agency-approved repellents that can be
applied to clothing, tent walls, mosquito nets, or other fabrics, but not to
skin. Many other repellents, such as citronella, are marketed but are not as
effective as DEET.

Author and Article Information

From U.S. National Center for Infectious Diseases, Division of Vector-borne
Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins,
Colorado.

Current Author Addresses: Drs. Petersen and Marfin: Division of Vector-borne
Infectious Diseases, Centers for Disease Control and Prevention, PO Box 2087
(Foothills Campus), Fort Collins, CO 80522.

References

1. Nash D, Mostashari F, Fine A, Miller J, O'Leary D, Murray K, et al. The
outbreak of West Nile virus infection in the New York City area in 1999. N Engl
J Med. 2001;344:1807-14. [PMID: 11407341]  | PubMed |

2. Smithburn KC, Hughes TP, Burke AW, Paul JH. A neurotropic virus isolated
from the blood of a native of Uganda. American Journal of Tropical Medicine.
1940;20:471-92.

3. Hubalek Z, Halouzka J. West Nile fever--a reemerging mosquito-borne viral
disease in Europe. Emerg Infect Dis. 1999;5:643-50. [PMID: 10511520]  | PubMed |

4. Petersen LR, Roehrig JT. West Nile virus: a reemerging global pathogen.
Emerg Infect Dis. 2001;7:611-4. [PMID: 11585520]  | PubMed |

5. Weinberger M, Pitlik SD, Gandacu D, Lang R, Nassar F, Ben David D, et al.
West Nile fever outbreak, Israel, 2000: epidemiologic aspects. Emerg Infect
Dis. 2001;7:686-91. [PMID: 11585533]  | PubMed |

6. Murgue B, Murri S, Triki H, Deubel V, Zeller HG. West Nile in the
Mediterranean basin: 1950-2000. Ann N Y Acad Sci. 2001;951:117-26. [PMID:
11797769]  | PubMed |

7. Jupp PG. The ecology of West Nile virus in South Africa and the occurrence
of outbreaks in humans. Ann N Y Acad Sci. 2001;951:143-52. [PMID: 11797772]  |
PubMed |

8. Spigland I, Jasinska-Klinberg W, Hofshi E, Goldblum N. Clinical and
laboratory observations in an outbreak of West Nile fever in Israel. Harefuah.
1958;54:275-81.

9. Tsai TF, Popovici F, Cernescu C, Campbell GL, Nedelcu NI. West Nile
encephalitis epidemic in southeastern Romania. Lancet. 1998;352:767-71. [PMID:
9737281]  | PubMed |

10. Platonov AE, Shipulin GA, Shipulina OY, Tyutyunnik EN, Frolochkina TI,
Lanciotti RS, et al. Outbreak of West Nile virus infection, Volgograd Region,
Russia, 1999. Emerg Infect Dis. 2001;7:128-32. [PMID: 11266303]  | PubMed |

11. Chowers MY, Lang R, Nassar F, Ben-David D, Giladi M, Rubinshtein E, et al.
Clinical characteristics of the West Nile fever outbreak, Israel, 2000. Emerg
Infect Dis. 2001;7:675-8. [PMID: 11585531]  | PubMed |

12. Hubalek Z. Comparative symptomatology of West Nile fever. Lancet.
2001;358:254-5. [PMID: 11498205]  | PubMed |

13. West Nile virus activity--United States, 2001. MMWR Morb Mortal Wkly Rep.
2002;51:497-501. [PMID: 12079245]  | PubMed |

14. Hayes CG. West Nile virus: Uganda, 1937, to New York City, 1999. Ann N Y
Acad Sci. 2001;951:25-37. [PMID: 11797781]  | PubMed |

15. Turell MJ, Sardelis MR, Dohm DJ, O'Guinn ML. Potential North American
vectors of West Nile virus. Ann N Y Acad Sci. 2001;951:317-24. [PMID: 11797788]
 | PubMed |

16. Swayne DE, Beck JR, Smith CS, Shieh WJ, Zaki SR. Fatal encephalitis and
myocarditis in young domestic geese (Anser anser domesticus) caused by West
Nile virus. Emerg Infect Dis. 2001;7:751-3. [PMID: 11585545]  | PubMed |

17. Eidson M, Miller J, Kramer L, Cherry B, Hagiwara Y. Dead crow densities and
human cases of West Nile virus, New York State, 2000. Emerg Infect Dis.
2001;7:662-4. [PMID: 11585529]  | PubMed |

18. Martin DA, Biggerstaff BJ, Allen B, Johnson AJ, Lanciotti RS, Roehrig JT.
Use of immunoglobulin m cross-reactions in differential diagnosis of human
flaviviral encephalitis infections in the United States. Clin Diagn Lab
Immunol. 2002;9:544-9. [PMID: 11986257]  | PubMed |

19. Lanciotti RS, Roehrig JT, Deubel V, Smith J, Parker M, Steele K, et al.
Origin of the West Nile virus responsible for an outbreak of encephalitis in
the northeastern United States. Science. 1999;286:2333-7. [PMID: 10600742]  |
PubMed |

20. Giladi M, Metzkor-Cotter E, Martin DA, Siegman-Igra Y, Korczyn AD, Rosso R,
et al. West Nile encephalitis in Israel, 1999: the New York connection. Emerg
Infect Dis. 2001;7:659-61. [PMID: 11585528]  | PubMed |

21. Mostashari F, Bunning ML, Kitsutani PT, Singer DA, Nash D, Cooper MJ, et
al. Epidemic West Nile encephalitis, New York, 1999: results of a
household-based seroepidemiological survey. Lancet. 2001;358:261-4. [PMID:
11498211]  | PubMed |

22. Serosurveys for West Nile virus infection--New York and Connecticut
Counties, 2000. MMWR Morb Mortal Wkly Rep. 2001;50:37-9. [PMID: 11215880]  |
PubMed |

23. Weiss D, Carr D, Kellachan J, Tan C, Phillips M, Bresnitz E, et al.
Clinical findings of West Nile virus infection in hospitalized patients, New
York and New Jersey, 2000. Emerg Infect Dis. 2001;7:654-8. [PMID: 11589170]  |
PubMed |

24. Ahmed S, Libman R, Wesson K, Ahmed F, Einberg K. Guillain-Barre syndrome:
an unusual presentation of West Nile virus infection. Neurology. 2000;55:144-6.
[PMID: 10891928]  | PubMed |

25. Asnis DS, Conetta R, Teixeira AA, Waldman G, Sampson BA. The West Nile
Virus outbreak of 1999 in New York: the Flushing Hospital experience. Clin
Infect Dis. 2000;30:413-8. [PMID: 10722421]  | PubMed |

26. Asnis DS, Conetta R, Waldman G, Teixeira AA. The West Nile virus
encephalitis outbreak in the United States (1999-2000): from Flushing, New
York, to beyond its borders. Ann N Y Acad Sci. 2001;951:161-71. [PMID:
11797774]  | PubMed |

27. Southam CM, Moore AE. Induced virus infections in man by the Egypt isolates
of West Nile virus. Am J Trop Med Hyg. 1954;3:19-50.

28. West Nile virus surveillance and control: an update for healthcare
providers in New York City. New York Department of Health. City Health
Information. 2001;20.

29. Anderson JF, Rahal JJ. Efficacy of interferon alpha-2b and ribavirin
against West Nile virus in vitro [Letter]. Emerg Infect Dis. 2002;8:107-8.
[PMID: 11749765]  | PubMed |

30. Sampson BA, Armbrustmacher V. West Nile encephalitis: the neuropathology of
four fatalities. Ann N Y Acad Sci. 2001;951:172-8. [PMID: 11797775]  | PubMed |

31. Case definitions for infectious conditions under public health
surveillance. MMWR Morb Mortal Wkly Rep. 1997;46(RR-10):12-3, 43-4.

32. Outbreak of Powassan encephalitis--Maine and Vermont, 1999-2001. MMWR Morb
Mortal Wkly Rep. 2001;50:761-4. [PMID: 11787585]  | PubMed |

33. Ford-Jones EL, Fearon M, Leber C, Dwight P, Myszak M, Cole B, et al. Human
surveillance for West Nile virus infection in Ontario in 2000. CMAJ.
2002;166:29-35. [PMID: 11800244]  | PubMed |

34. Monath TP. Prospects for development of a vaccine against the West Nile
virus. Ann N Y Acad Sci. 2001;951:1-12. [PMID: 11797767]  | PubMed |

35. Fradin MS. Mosquitoes and mosquito repellents: a clinician's guide. Ann
Intern Med. 1998;128:931-40. [PMID: 9634433]  | PubMed |

Copyright (c)2003 American College of Physicians