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93
Newly Recognized Focus of La Crosse Encephalitis in Tennessee
Timothy F. Jones, Allen S. Craig, Roger S. Nasci,
Lori E. R. Patterson, Paul C. Erwin, Reid R. Gerhardt,
Xilla T. Ussery, and William Schaffner
From the Epidemic Intelligence Service, Centers for Disease Control
and Prevention, Atlanta, Georgia; Tennessee Department of Health, and
Departments of Preventive Medicine and Medicine, Vanderbilt
University School of Medicine, Nashville, Tennessee; Division of VectorBorne Diseases, Centers for Disease Control and Prevention, Fort
Collins, Colorado; and East Tennessee Children’s Hospital, East
Tennessee Regional Department of Health, and University of Tennessee,
Knoxville, Tennessee
La Crosse virus is a mosquito-borne arbovirus that causes encephalitis in children. Only nine
cases were reported in Tennessee during the 33-year period from 1964 – 1996. We investigated a
cluster of La Crosse encephalitis cases in eastern Tennessee in 1997. Medical records of all suspected
cases of La Crosse virus infection at a pediatric referral hospital were reviewed, and surveillance
was enhanced in the region. Previous unreported cases were identified by surveying 20 hospitals in
the surrounding 16 counties. Mosquito eggs were collected from five sites. Ten cases of La Crosse
encephalitis were serologically confirmed. None of the patients had been discharged from hospitals
in the region with diagnosed La Crosse encephalitis in the preceding 5 years. Aedes triseriatus and
Aedes albopictus were collected at the case sites; none of the mosquitos had detectable La Crosse
virus. This cluster may represent an extension of a recently identified endemic focus of La Crosse
virus infection in West Virginia.
La Crosse virus, one of the California serogroup bunyaviruses,
is the primary cause of pediatric arboviral encephalitis in the
United States [1]. In areas of endemicity, incidence rates for La
Crosse encephalitis approximate those of bacterial meningitis of
all causes [2, 3]. In Minnesota from 1967 to 1972, La Crosse virus
accounted for 18% of acute CNS infections of known etiology [4].
La Crosse encephalitis occurs in an endemic pattern. Since 1964,
an average of 73 cases per year (range, 29–139 cases per year)
have been reported to the Centers for Disease Control and Prevention (CDC) from 23 different states (G. L. Campbell, Arbovirus
Diseases Branch, Division of Vector-Borne Infectious Diseases,
National Center for Infectious Diseases, CDC; personal communication). Over this same 33-year period, only nine cases were
reported in Tennessee.
In September 1997, an apparent cluster of La Crosse encephalitis was reported by a children’s hospital in eastern Tennessee,
and an investigation was undertaken by the state and regional
health departments.
Patients and Methods
Hospital A served as the primary pediatric referral center in
eastern Tennessee. Medical records of all children at hospital
A with suspected viral encephalitis from 15 July through 15
Received 27 May 1998; revised 31 August 1998.
Reprints or correspondence: Dr. Timothy Jones, Tennessee Department of
Health, CEDS, 4th Floor, Cordell Hull Building, 425 5th Avenue North, Nashville, Tennessee 37247 ([email protected]).
Clinical Infectious Diseases 1999;28:93–7
q 1999 by the Infectious Diseases Society of America. All rights reserved.
1058–4838/99/2801–0014$03.00
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October 1997 were reviewed. Serum specimens from some
patients were tested with a ‘‘meningoencephalitis panel’’ that
measured antibodies to 28 viruses; this was performed at a
private referral laboratory. All available serum and CSF specimens were sent to the CDC Arbovirus Diseases Laboratory
(Fort Collins, Colorado) for arbovirus antibody testing. Convalescent serum specimens were collected 3 to 6 weeks after
hospitalization.
The CDC surveillance case definition for arboviral encephalitis was used to classify cases [5]. Patients with a symptomatic,
physician-diagnosed, nonbacterial infection of the CNS and
with serological evidence of recent La Crosse virus infection
were included as cases. Confirmed diagnoses required a fourfold or greater change in serum antibody titers by use of indirect
fluorescent antibody test (IFA) [6] between acute and convalescent sera, or single specimens of CSF or serum with specific
IgM antibody by ELISA [7]. Serum and CSF IgM antibodies
were confirmed by demonstration of antibodies with use of
serum dilution – plaque reduction neutralization testing [8, 9].
Enhanced surveillance for potential cases of La Crosse
encephalitis was undertaken from mid-September through
mid-October, 1997. Emergency room personnel and medical
staff at hospital A were asked to report all possible cases
of viral CNS infection to the institution’s infection control
personnel. Laboratory records were reviewed for all CSF or
serum specimens tested for viral antibodies or sent to a referral laboratory for a ‘‘meningoencephalitis panel’’ in the preceding 3 months. Diagnoses of all patients who underwent
lumbar puncture at the hospital were reviewed. Infection
control personnel at all hospitals in the metropolitan area
and the surrounding 16 counties were asked to immediately
report any possible cases of viral encephalitis to the regional
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Jones et al.
CID 1999;28 (January)
Figure 1. Confirmed cases of La
Crosse encephalitis according to
week of onset, eastern Tennessee,
1997.
health department. They were also asked to review hospital
records for possible unreported cases in the preceding 3
months.
To assess possible previously unreported cases, 20 hospitals
in the region surrounding and including hospital A were asked
to provide information concerning all hospital discharges of
children and adults with viral encephalitis or related diagnoses
in the preceding 5 years. The discharge diagnoses requested
included La Crosse, California, mosquito-borne, or arboviral
encephalitis; arboviral meningitis, encephalitis, viral encephalitis, viral meningoencephalitis, and aseptic meningitis.
Mosquito eggs were collected from five sites in areas where
patients were likely to have been exposed before their illnesses.
Ten standard ovitraps [10] were placed Ç10 m apart at each
site and collected after 7 to 10 days. Homesites of three patients
were formally evaluated for potential mosquito-breeding habitats, including counting permanent and temporary manmade
containers on the property and measuring the distance from
the home to forested areas. Mosquito eggs were sent to the
CDC for counting, identification, hatching, rearing, and examination for viruses by Vero-cell plaque assay [9].
Results
During the period from 15 July to 15 October 1997, a total
of 27 patients admitted to hospital A had illnesses consistent
with possible La Crosse encephalitis on initial presentation.
After further evaluation, nine patients were given other diagnoses by their physicians, including viral meningitis (7 patients),
idiopathic seizures (1), and severe nonspecific headache (1),
and had no further testing for arboviral antibodies. Of the remaining 18 patients, 10 had confirmed La Crosse encephalitis
(figure 1) and eight patients with compatible symptoms were
negative for La Crosse virus antibodies (table 1).
Of the 10 patients with La Crosse virus infections, diagnoses
were confirmed for seven patients by demonstration of a four-
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fold or greater increase in antibody titers between acute and
convalescent sera. One patient had IgM demonstrated in CSF
and a twofold change in serum IgM titer. The other two patients
had serum specimens positive for IgM antibodies by use of
IgM-capture ELISA, with positive plaque reduction neutralization tests; one of these patients had a twofold change in serum
titers, and the other had only one specimen available for testing.
All 10 of these patients had negative CSF viral cultures. A
panel of 28 antibody tests was performed on single-serum spec-
Table 1. Clinical characteristics of patients with viral CNS infections who were evaluated for La Crosse infection, eastern Tennessee,
1997.
Characteristic
Mean age, y (range)
Male sex
Fever (temperature, ú100.07F)
Headache
Vomiting
Photophobia
Behavioral change
Altered consciousness
Seizures
Meningismus
Neurologic sequelae
Abnormal electroencephalogram
Mean duration of symptoms
before hospitalization, d
(range)
Mean CSF WBC count
per mm3 (range)
Serologically
confirmed La
Crosse
(n Å 10)
No La Crosse*
(n Å 8)
6.9 (3 – 14)
7 (70)
10 (100)
9 (90)
7 (70)
4 (40)
7 (70)
7 (70)
8 (80)
1 (10)
1 (10)
9 (90)
7 (1 – 12)
6 (75)
8 (100)
6 (75)
7 (89)
2 (25)
5 (63)
3 (38)
3 (38)
1 (13)
1 (13)
3/5 (60)
3.1 (1 – 7)
2.8 (1 – 7)
205 (42 – 590)
203 (21 – 880)
NOTE. Data are no. (%) of patients unless otherwise indicated.
* There were no statistically significant differences between the two groups
for any of the variables listed.
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La Cross Encephalitis in Tennessee
imens from 10 and on CSF specimens from 6 of the 17 patients
who did not have serologically documented La Crosse virus
infections, and no other specific viral etiologies of their illnesses were identified serologically. Subsequently, viral cultures of CSF from two of the patients who did not have complete La Crosse virus antibody testing yielded coxsackievirus.
Seven of the 10 patients with La Crosse virus infections
were boys (table 1). The 10 patients were ages 3 to 14 years.
Signs and symptoms were consistent with previous reports of
La Crosse encephalitis: nine had headache, eight had seizures,
seven had altered consciousness, and nine had abnormal electroencephalograms (EEGs). At the time of discharge from the
hospital, diagnoses included viral meningoencephalitis (6 patients), viral meningitis (2), and encephalitis (2). None of the
patients were discharged with a diagnosis indicating La Crosse
virus as the etiologic agent. One patient was discharged from
the hospital with persistent deficits including ptosis, right abducens palsy, slowed speech, residual gait ataxia, and intention
tremors at 12 days after presentation. None of the clinical
characteristics examined differed significantly between the patients with confirmed La Crosse encephalitis and those who
did not have antibodies to La Crosse virus.
On the basis of the patients’ histories and a reported incubation period of 5 to 15 days, of the 10 confirmed cases of La
Crosse encephalitis, 9 were thought likely to have been infected
within 50 miles of hospital A. No other hospitals in the area
reported cases of pediatric or adult La Crosse encephalitis during this period.
Evaluation of the homes of three patients with confirmed La
Crosse encephalitis revealed 2, 7, and 16 permanent and 5, 16,
and 22 disposable containers that could hold standing water in
the yards. Two houses were within 50 to 100 feet of a forest
line, and one was also 100 feet from a large pond of standing
water.
A total of 7,279 mosquito eggs were collected from 50 traps
at five sites, including the yards of three patients with confirmed
La Crosse virus infections. Of the 4,493 mosquitos that were
successfully reared, 3,591 (80%) were identified as A. triseriatus, and 902 (20%) as A. albopictus. None of the mosquitos
reared were found to harbor La Crosse virus.
All 20 hospitals in the counties surrounding hospital A responded to the survey of discharge diagnoses in the preceding
5 years. There were no cases with discharge diagnoses of mosquito-borne, arboviral, La Crosse, or California encephalitis
reported from these hospitals during this period. The highest
number of cases of nonspecific viral CNS disease were seen
in the third quarter (July through September) of each year, with
20 to 49 cases reported annually during that quarter.
Discussion
This cluster of 10 cases of La Crosse encephalitis is the
largest ever reported in Tennessee, surpassing the total number
of cases reported in the entire state over the preceding 33 years.
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Because not all patients with suspected La Crosse encephalitis
had complete testing, these 10 cases represent a minimum estimate of the number of cases seen at this hospital. In the past, La
Crosse encephalitis has been primarily an infection occurring in
the upper midwestern United States, with most cases reported
from Illinois, Indiana, Iowa, Minnesota, Ohio, and Wisconsin.
Since 1993, however, West Virginia has had more reported
cases than any other state, and, in 1996, West Virginia accounted for more than half of all cases reported in the country
(figure 2) (G. L. Campbell, Arboviruses Disease Branch, Division of Vector-Borne Infectious Diseases, National Center for
Infectious Diseases, CDC; personal communication). This is
the first report of a possible extension of the West Virginia
endemic focus.
Studies have suggested that there may be 300,000 human
La Crosse virus infections per year in the United States, with
more than 1,000 asymptomatic or mildly symptomatic infections per reported case [1,11, 12]. Estimates of ratios of inapparent-to-apparent infections in children have ranged from 26:1
[12] to 1,571:1 [11]. In highly endemic areas, seropositivity
increases with age, and antibody prevalence can reach 35% by
adulthood [12 – 18].
La Crosse virus infections are difficult to distinguish from
other viral infections of the CNS. Most infections are not recognized clinically, and those that are can have diverse manifestations, ranging from nonspecific viral illness to aseptic meningitis or frank encephalitis. Specific laboratory testing is required
to differentiate La Crosse virus from other causes of CNS
infection. Viral-specific IgM antibody in the CSF is diagnostic
of La Crosse virus infection, but the serum IgM antibody levels
may remain elevated for ú9 months in over half of patients
[3]. Serological diagnosis, therefore, requires demonstration of
a fourfold or greater change in serum antibody titer or confirmation of serum IgM antibodies by demonstration of IgG antibodies with use of another serological assay [5].
Reliance on laboratory confirmation for diagnosis precludes
the quantification of the extent of undetected illness before this
outbreak. Some of the patients discharged in previous years
with diagnoses of viral encephalitis or encephalitis of unknown
etiology may have had La Crosse virus infections. All of the
patients in this cluster who eventually were shown to have La
Crosse virus infections were discharged from the hospital with
diagnoses of nonspecific viral CNS illnesses during the period
when annual peaks are seen for these diagnoses. Our review
of hospital discharge data did not reveal specific examples of
underreporting of documented La Crosse virus infections. This
cluster of infections could represent a new southern endemic
focus or a newly recognized focus elucidated by increased
surveillance and testing.
The La Crosse virus is transmitted to humans by the eastern treehole mosquito, A. triseriatus (Say). The virus is
passed transovarially (vertically) in mosquitos and can survive the winter in eggs [19, 20], although it is amplified
horizontally in small mammals as well [3]. Several previous
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CID 1999;28 (January)
Figure 2. Geographic distribution
according to county of La Crosse encephalitis cases reported to the Centers for Disease Control and Prevention, 1990 – 1997. Data are from:
G. L. Campbell, Arbovirus Diseases
Branch, Division of Vector-Borne
Infectious Diseases, National Center
for Infectious Diseases, Centers for
Disease Control and Prevention, personal communication; and personal
communications from departments
of health in states reporting cases
during these years. 1997 data reflect
cases reported to the CDC as of 8
January 1998.
studies have isolated La Crosse virus from only 0.2% to
0.6% of mosquitos collected in the field in areas of endemicity [19 – 21]. Endemic foci may be quite localized [18, 22],
with possible ‘‘island’’ populations of mosquitos in shaded
areas surrounding human habitats and discarded containers
[23]. A. triseriatus typically breeds in treeholes or manmade
containers and is difficult to control with the pesticide spraying usually used to eliminate pestiferous species [21]. Programs to prevent disease by filling treeholes, removing discarded tires, and educating the community have met with
mixed success [17, 24]. A. triseriatus is generally a daytime
biter [23, 25]. Persons potentially at risk in areas of endemicity should be encouraged to use adequate personal protective
measures including insect repellents, protective clothing, and
avoidance of infested areas when possible.
This is the largest cluster of La Crosse encephalitis ever
reported in Tennessee. Since 1994, West Virginia has reported
more cases of La Crosse encephalitis than any other state. This
cluster may represent a newly recognized endemic focus in the
southeastern United States. Underdiagnosis is probably common. In endemic areas, physicians should be alerted to the
broad spectrum of clinical manifestations of La Crosse virus
infection and report all cases to local health departments. Further surveillance is warranted to help define shifts in endemicity
of the disease.
Acknowledgments
The authors thank Alan Dupuis, Denise Martin, and Nick Karabatsos of the CDCs Arbovirus Disease Laboratory for laboratory
testing of specimens; Grant L. Campbell, MD, PhD, at the CDC
(Fort Collins) for updated surveillance information; Sandy Halford,
Frank Bristow, Jan Fowler, Stephanie Hall, MD, Dan Jorgensen,
MD, and the staffs of the Knoxville/Knox County and East Tennes-
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see Regional Health Departments for help with the investigation
and patient follow-up; Kristy Gottfried of the University of Tennessee for assistance with mosquito surveillance; Jim Moore for
information on A. albopictus in Tennessee; Pat Turri of the Tennessee Department of Health for assistance with mapping; and Laura
Fehrs, MD, MPH, of the Epidemiology Program Office at the CDC
for her thoughtful review of the manuscript.
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