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1284
BRIEF REPORTS
Serological Survey and Active Surveillance for La
Crosse Virus Infections among Children in Tennessee
In 1998 and 1999, we performed a serosurvey and active
surveillance for La Crosse encephalitis at a children’s hospital in eastern Tennessee. Fifteen cases of La Crosse encephalitis were confirmed. Only 5 (0.5%) of 1000 serum
samples being tested at the state laboratory for other diseases had evidence of antibodies to La Crosse virus. These
findings suggest that La Crosse virus is newly endemic to
eastern Tennessee.
La Crosse virus is the primary cause of pediatric encephalitis
in the United States, with well-recognized foci in upper midwestern states [1]. However, since 1993, West Virginia has had
more reported cases than any other state, and in 1997, a focus
of La Crosse encephalitis was newly recognized in eastern Tennessee [2]. La Crosse encephalitis occurs in an endemic pattern,
and knowledge is limited regarding recent changes in patterns of
endemicity of the virus. The Tennessee Department of Health
undertook a study to further characterize the epidemiology of
La Crosse encephalitis in that state. This study included active
surveillance for acute La Crosse encephalitis, a serosurvey for
evidence of remote infection, and analysis of the relative sensitivity of serological testing for IgG and IgM antibodies to La
Crosse virus during acute infection.
Active surveillance for La Crosse encephalitis was performed
at a large children’s hospital in eastern Tennessee. That hospital
is the primary pediatric referral center in the area, and all persons
with cases of La Crosse encephalitis reported in Tennessee in
1997 were treated there. In 1998 and 1999, active surveillance
was performed from 1 June through 30 September. Medical records of the following patients were reviewed: all pediatric patients aged 16 months who had physician-diagnosed febrile CNS
infection, underwent lumbar puncture, and did not have bacterial
CNS infection or another documented diagnosis to explain their
illness. In addition, any patient whose physician suspected possible La Crosse virus infection was included. Physicians were
encouraged to send acute-phase serological specimens for testing
for antibodies to La Crosse virus. Caregivers were given information on the disease and contacted 3–4 weeks after the onset
of illness for convalescent-phase serum specimens. In addition,
improved awareness of La Crosse encephalitis was encouraged
through news media releases, letters to physicians, newsletters,
and seminars for medical personnel in the region.
Laboratory testing was performed at the Tennessee DepartReprints or correspondence: Dr. Timothy Jones, Communicable and Environmental Disease Services, Tennessee Dept. of Health, 4th Floor, Cordell
Hull Building, 425 5th Ave. North, Nashville, TN 37247 (tjones4@mail
.state.tn.us).
Clinical Infectious Diseases 2000; 31:1284–7
q 2000 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2000/3105-0030$03.00
ment of Health Laboratories without charge. Paired acute-phase
and convalescent-phase serum samples were tested for titers of
IgM and IgG antibodies to La Crosse, St. Louis encephalitis,
eastern equine encephalitis, and western equine encephalitis viruses by use of a commercially available indirect immunofluorescent antibody (IFA) test for arboviruses (MRL Diagnostics,
Cypress, CA). IgG antibodies were inactivated before testing for
IgM antibodies by means of Gullsorb IgG inactivation reagent
(Gull Laboratories, Salt Lake City). For the serosurvey, single
specimens were tested.
A case of La Crosse encephalitis was defined according to the
surveillance case definition of the Centers for Disease Control
and Prevention [3]. Patients with symptomatic, physician-diagnosed CNS infection for which there was no other confirmed
cause and serological evidence of recent La Crosse virus infection
were included as cases. Diagnoses were confirmed by a 4-fold or
greater change in serum titers of antibody between acute-phase
and convalescent-phase serum testing.
A serosurvey was performed by using serum specimens received at the Tennessee Department of Health Regional Laboratory in eastern Tennessee for testing for antibodies to Treponema pallidum, HIV, and rubella virus. Serum samples from
patients residing in Knoxville or the surrounding 15 counties were
examined. No personal identifiers were used for any specimens.
All serum samples received from patients aged !16 or 145 years
were tested for antibodies to La Crosse virus. For both male and
female patients 16–25, 26–35, and 36–45 years of age, every third
specimen received was tested. A total of 1000 serum samples
were screened for titers of IgG antibody; we set the cutoff level
to 4. Any specimen with positive screening was tested at serial
dilutions to determine the antibody titer in the specimen. Specimens with a final antibody titer of >8 were considered positive.
Data were analyzed by using x2 tests calculated with Epi-Info
software [4].
During 1998, a total of 55 patients were identified at the referral
hospital who had illnesses consistent with possible La Crosse
encephalitis at the time of initial presentation. Of these patients,
9 had confirmed La Crosse encephalitis (figure 1). Convalescentphase serum specimens from 9 patients were negative for La
Crosse virus, and 10 patients subsequently had confirmed enterovirus meningitis. Convalescent-phase serum specimens were
not obtained from 24 patients; hence, these patients did not have
final confirmed diagnoses. Two patients had probable La Crosse
encephalitis: for one, acute-phase serum titers of IgM antibody
and IgG antibody were 80 and 320, respectively, but the patient
declined convalescent-phase serum testing; for the other, acutephase serum titers of IgG and IgM antibodies were 80, with a
2-fold increase in the convalescent-phase serum titer of IgG antibody. A third patient had a 4-fold drop in serum titers of IgG
antibody between acute-phase serum testing and convalescentphase testing; this patient’s case would technically be a confirmed
diagnosis according to the definition of the Centers for Disease
CID 2000;31 (November)
Brief Reports
Figure 1. Cases of confirmed La Crosse encephalitis in Tennessee,
1998–1999. Black box, 1998; hatched box, 1999.
Control and Prevention [3], although in the absence of IgM antibody or an increase in the serum titer of IgG antibody this case
was not counted as a confirmed diagnosis in this analysis.
In 1999, of 36 patients identified as having possible La Crosse
encephalitis, 6 had this diagnosis confirmed. Twelve patients did
not have a 4-fold increase in antibody titers; convalescent-phase
serum samples were not obtained from 14 patients, and 4 patients
subsequently had other diagnoses confirmed.
Of the 15 patients with confirmed acute La Crosse virus infections, the mean age was 8 years (range, 8 months to 13 years).
Eleven (73%) of the patients were male. All patients able to give
a history had headache; all but 1 had documented fever. Ten
patients (67%) reported vomiting; 4 (27%) had seizures. The mean
WBC count in CSF was 242 cells/mm3. The proportion of males,
mean age, and other clinical characteristics did not differ significantly between the group of patients with confirmed La Crosse
virus infection and the group from whom convalescent-phase
serum specimens were not obtained. The mean WBC count in
CSF (191 cells/mm3) was significantly lower in the group from
whom convalescent-phase serum samples were not obtained
(P p .009).
The 15 patients with confirmed La Crosse virus infections had
4-fold or greater increases in antibody titers between acute-phase
serum testing and convalescent-phase testing (table 1). For all
patients, there was at least a 4-fold change in titers of IgG antibody. In 5 cases, there was a 4-fold change in titers of IgM
antibody as well. In none of these acute cases was the diagnosis
dependent on changes in titers of IgM antibody alone.
The results of the serosurvey are shown in table 2. Of 1000
serum samples tested, only 5 had antibody titers >8 (range, 8–32).
Of the 5 patients from whom these specimens were obtained, 4
(80%) were female. The mean age of persons with positive antibody titers was 29 years (range, 14–49 years). Each positive
specimen was obtained from a person residing in a different
county in the Knoxville area.
The first large cluster of La Crosse encephalitis in Tennessee
was reported at a pediatric referral hospital in Knoxville in 1997,
when 10 cases were diagnosed. Subsequent active surveillance
identified 9 cases of acute La Crosse encephalitis in 1998 and 6
cases in 1999 at the same hospital. In contrast, over the preceding
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33 years, only 9 cases of La Crosse encephalitis had been reported
in the entire state [2]. Studies suggest that there may be 300,000
human cases of La Crosse virus infections per year in the United
States, most of which are asymptomatic or mildly symptomatic
[5–7]. An average of only 73 cases per year are reported to the
Centers for Disease Control and Prevention [2]. The clinical manifestations of La Crosse virus infection are nonspecific, and given
the need for specific antibody testing and convalescent-phase
serum testing to confirm the diagnosis, most infections likely go
unrecognized or undiagnosed [1].
The true number of cases of acute La Crosse virus infection
at this hospital during the study period was likely underestimated.
Because treatment is not affected by the results of testing, convincing parents to agree to convalescent-phase serum testing can
be difficult, particularly after a patient has recovered. For example, in this study, 42% of patients suspected of having the
illness refused follow-up testing, despite being contacted directly
by the health department. This group included 3 persons with
acute-phase serum titers of antibody of >80 who likely had acute
infections that could not be confirmed. Testing serum samples
obtained on the day of admission and the day of discharge,
regardless of the interval, might allow confirmation of additional
cases.
This study used the only commercially available, US Food
and Drug Administration–approved test for detecting antibodies
to La Crosse virus in serum specimens. IFA testing has been
shown to be as sensitive and specific as hemagglutination inhibition and neutralization testing of acute-phase serum specimens
[8]. The lack of a confirmed increase in titers of IgM antibody
in many of the cases in this series is interesting; further study
should be directed at determining whether this finding reflects
problems with the sensitivity of the commercially available IFA
assay for detection of IgM antibody or the natural history of
antibody development in La Crosse virus infections.
Previously reported data on the development of antibodies
after acute infection with La Crosse virus are meager. It has been
shown that serum levels of IgM antibody might remain elevated
for 19 months in over one-half of patients [1]. In this study, all
cases of La Crosse encephalitis that were ultimately diagnosed
based on a 4-fold or greater change in antibody titers could have
been confirmed with titers of IgG antibody alone. Testing for
IgG antibody is simpler than testing for IgM antibody, which
requires inactivation of IgG antibody. In addition, the cost of
testing for both antibodies is double that for testing for IgG
antibody alone by means of the currently available IFA test kits.
Unfortunately, relying solely on changes in titers of IgG antibody
is problematic given the high number of persons who do not
return for convalescent-phase serum testing.
Demonstration of specific IgM antibody in CSF by IgM antibody–capture ELISA is a sufficient laboratory criterion for confirmation of the diagnosis of La Crosse encephalitis [3]. This test
was not available at the Tennessee State Laboratory, although
it can be a sensitive and rapid tool for the diagnosis of La Crosse
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Brief Reports
Table 1.
Patient
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Summary of data for children with confirmed La Crosse encephalitis in eastern Tennessee in 1998.
Age in y,
sex
10, M
12, F
3, F
0.75, M
4, M
3, M
13, M
9, M
11, F
8, M
13, M
9, M
9, F
6, M
1, M
a
CID 2000;31 (November)
Acute-phase serum titer
Onset date
05/28/98
06/05/98
06/09/98
06/23/98
06/28/98
07/20/98
07/27/98
08/01/98
08/21/98
06/20/99
07/10/99
08/18/99
08/20/99
08/21/99
08/29/99
Date
05/28/98
06/09/98
06/15/98
06/25/98
07/01/98
07/25/98
07/29/98
08/04/98
08/23/98
06/24/99
07/13/99
08/18/99
08/20/99
08/21/99
09/02/99
IgM
IgG
a
!16
!20
!20
!20
!20
!20
!20
!20
!20
!20
20
!20
!20
!20
!20
!20
!20
!20
!20
!20
!20
40
20
640
160
!20
!20
320
160
Convalescent-phase
serum titer
Date
06/16/98
07/01/98
07/15/98
07/14/98
08/11/98
08/18/99
09/22/98
09/08/98
09/15/98
07/29/99
08/05/99
09/21/99
09/23/99
09/23/99
09/24/99
IgM
Subsequent serum titer
IgG
Date
IgM
IgG
09/23/98
!20
160
10/08/99
80
2560
a
320
20
20
!20
80
80
160
40
!20
!20
1160
160
640
80
256
640
>320
80
>320
>640
>160
>320
160
320
640
12560
640
2560
640
Patient 1 had only titers of total antibodies measured.
virus infections [9] and therefore might be valuable to have readily
available in areas of endemicity. Hemagglutination inhibition and
neutralization tests may be more sensitive than IFA testing for
detecting remote infection [8], and further retrospective serosurveys with these tests might be valuable.
The first confirmed case of La Crosse encephalitis in Tennessee
in 1998 occurred at the end of May, which is earlier than the
first cases documented in 1997 [2] or 1999. A mild winter and
wet spring were believed to have contributed to an early mosquito
season in the area that year. Local conditions can have a substantial effect on the timing of La Crosse virus infections, and
La Crosse virus infection should be considered in the differential
diagnosis of febrile CNS infections throughout the period of
potential exposure.
Unlike St. Louis encephalitis virus and other arboviruses that
cause epidemic disease, La Crosse virus infections exhibit an
endemic pattern. Few data exist regarding shifts in areas in which
this disease is endemic. For 3 successive years, enhanced surveillance has confirmed cases of human disease diagnosed at a
single referral hospital in eastern Tennessee. It is possible that
these findings represent recent recognition of a long-standing
problem, resulting from increased awareness of health care providers, easier access to testing, and improved surveillance. If this
were the case, however, and unrecognized infections had been
common for a long period, it would be expected that a substantial
proportion of the general population in the area would have
antibodies to the virus due to past exposure.
In this study, the prevalence of antibodies to La Crosse virus
was strikingly low, indicating that La Crosse virus infection might
be a relatively new phenomenon in eastern Tennessee. Previous
serosurveys performed in well-established areas of endemicity
have shown that the prevalence of seropositivity increases with
age and can reach levels as high as 35% in an adult population
[7, 10–15]. In contrast, only 0.5% of the persons tested in this
serosurvey had antibodies even at titers as low as 8. On the basis
of prior estimates of >1000 asymptomatic or mildly symptomatic
infections per reported case [5–7], substantially higher rates of
seropositivity would be expected among the general population
if the disease had been endemic for a long period. The fact that
3 of the 5 positive specimens in this serosurvey were from persons
aged <26 years reinforces the idea that this might be a newly
introduced infection in the area. Although this study used serum
specimens from a convenient sample of persons being tested for
other diseases, there is little reason to expect that persons whose
serum samples are tested at the state laboratory would be substantially different from the general population in terms of prevalence of risk factors for exposure to La Crosse virus. A larger,
systematic serosurvey over a wider geographic area would provide more information regarding the distribution of this infection
over time in this and surrounding areas.
This study confirms that La Crosse virus is now endemic in
eastern Tennessee, and La Crosse encephalitis appears to be a
newly emergent disease there. Physicians now should consider
La Crosse virus infection in the differential diagnosis of summertime febrile disease in children in this region. Continued surveillance is warranted to monitor further shifts in endemicity of
this disease and to assess potential causes or correlates of such
changes.
Table 2. Results of serosurvey for antibodies to La Crosse virus in
eastern Tennessee.
No. tested
Age group, y
!16
16–25
26–35
36–45
46–55
56–65
165
Total
Specimens
Men
Women
137
233
188
174
158
84
26
1000
27
109
106
94
94
46
17
493
110
124
82
80
64
38
9
507
No. of positive
patients (titer[s])
2
1
0
1
1
0
0
5
(32, 32)
(16)
(8)
(32)
CID 2000;31 (November)
Brief Reports
Acknowledgments
We thank Sandy Halford, RN, and the staff of the East Tennessee
Regional Department of Health; Jan Fowler, RN, and the staff of the
Knoxville Department of Health; Caroline Graber, RN, and the staff
of the East Tennessee Children’s Hospital; Judy Tharpe, Lynn Hilstrom, Jerry Hindman, Jim Gibson, Michael Kimberly, DPH, and the
staff of the Tennessee Department of Health Laboratories; and Laura
Fehrs, MD, of the Centers for Disease Control and Prevention for
assistance with this investigation.
Timothy F. Jones, 1 , 2 Paul C. Erwin, 4 Allen S. Craig, 2 , 3
Philip Baker, 5 Kristen E. Touhey, 4 Lori E. R. Patterson, 6
and William Schaffner 3
1
Epidemic Intelligence Service, Centers for Disease Control
and Prevention, Atlanta, Georgia; 2Tennessee Department of Health
and 3Department of Preventive Medicine, Vanderbilt University School
of Medicine, Nashville, 4Tennessee Department of Health, 5Tennessee
Department of Health Regional Laboratory, and 6East Tennessee
Children’s Hospital, Knoxville
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1991; 5:73–103.
2. Jones TF, Craig AS, Nasci RS, et al. Newly recognized focus of La Crosse
encephalitis in Tennessee. Clin Infect Dis 1999; 28:93–7.
3. Centers for Disease Control and Prevention. Case definitions for infectious
conditions under public health surveillance. MMWR Morb Mortal Wkly
Rep 1997; 46:1–55.
Recurrent Pneumococcal Arthritis as the Presenting
Manifestation of X-Linked Agammaglobulinemia
Pneumococcal arthritis in children older than 24 months
is unusual and can suggest underlying immunodeficiency.
We report a case of recurrent pneumococcal arthritis as
the presenting manifestation of X-linked agammaglobulinemia.
X-linked agammaglobulinemia is characterized by a profound deficiency of circulating B cells and serum immunoglobulin that results from a defect in the gene encoding Bruton’s
tyrosine kinase (Btk) [1, 2]. Patients with this immunodeficiency
typically present during the first year of life with recurrent bacterial infections, most commonly with otitis media, pneumonia,
gastrointestinal infections, or pyoderma [3, 4]. Mono- or oligoarticular arthritis in patients with X-linked agammaglobuReprints or correspondence: Dr. James E. Crowe, Vanderbilt University Medical Center, Division of Pediatric Infectious Diseases, D-7235
Medical Center North, Nashville, TN 37232–2581 (james.crowe@mcmail
.vanderbilt.edu).
Clinical Infectious Diseases 2000; 31:1287–8
q 2000 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2000/3105-0031$03.00
1287
4. Dean AD, Dean JQ, Coulombier D, et al. Epi-Info. Version 6: a word processing, database and statistics program for epidemiology on microcomputers. Atlanta: Centers for Disease Control and Prevention, 1994.
5. Calisher CH. Medically important arboviruses of the United States and Canada. Clin Microbiol Rev 1994; 7:89–116.
6. Grimstad PR, Barrett RL, Humphrey RL, Sinsko MJ. Serologic evidence
for widespread infection with La Crosse and St. Louis encephalitis viruses
in the Indiana human population. Am J Epidemiol 1984; 119:913–30.
7. Kappus KD, Monath TP, Kaminski RM. Reported encephalitis associated
with California serogroup infections in the United States, 1963-1981. Prog
Clin Biol Res 1983; 123:31–41.
8. Beaty BJ, Casals J, Brown KL, et al. Indirect fluorescent-antibody technique
for serological diagnosis of La Crosse (California) virus infections. J Clin
Microbiol 1982; 15:429–34.
9. Calisher CH, Pretzman CI, Muth DJ, Parsons MA, Peterson ED. Serodiagnosis of La Crosse virus infections in humans by detection of immunoglobulin M class antibodies. J Clin Microbiol 1986; 23:667–71.
10. Szumlas DE, Apperson CS, Hartig PC, Francy DB, Karabatsos N. Seroepidemiology of La Crosse virus infection in humans in western North
Carolina. Am J Trop Med Hyg 1996; 54:332–7.
11. Thompson WH, Evans AS. California encephalitis virus studies in Wisconsin.
Am J Epidemiol 1965; 81:230–44.
12. Monath TP, Nuckolls JG, Berall J, Bauer H, Chappell WA, Coleman PH.
Studies on California encephalitis in Minnesota. Am J Epidemiol 1970;
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13. Parkin WE, Hammon WM, Sather GE. Review of current epidemiologic
literature on viruses of the California arbovirus group. Am J Trop Med
Hyg 1972; 21:964–78.
14. Thompson WH, Gundersen CB. La Crosse encephalitis: occurrence of disease
and control in a suburban area. Prog Clin Biol Res 1983; 123:225–36.
15. Rowley WA, Wong YW, Dorsey DC, Hausler WJ, Currier RW. California
serogroup viruses in Iowa. Prog Clin Biol Res 1983; 123:237–46.
linemia is usually aseptic [5] and is rarely the sole presenting
manifestation of this condition [3].
Streptococcus pneumoniae is an infrequent cause of septic
arthritis and seldom infects the joints of children older than 2
years. In one series of 22 children with pneumococcal arthritis,
the age of the oldest patient was 23 months [6]. We report a
case of recurrent pneumococcal septic arthritis as the presenting
manifestation of X-linked agammaglobulinemia in a schoolaged child.
A 5-year-old boy presented to the emergency department
with right knee pain of 12 hours’ duration, swelling, erythema,
and refusal to bear weight on his right leg. He had been well
until the previous evening, when he experienced right knee pain
after a trivial bump against a table. He was afebrile and had
no other symptoms.
The patient’s past medical history was notable for the presence
of septic arthritis of the right knee 2 years previously. At that
time, he experienced swelling and tenderness of the knee after
bumping into a swing set. Cultures of blood and synovial fluid
specimens grew S. pneumoniae. After undergoing incision and
drainage of the right knee, he received ceftriaxone and rifampin
for 21 days and had a complete recovery. The patient had no
other hospitalizations and showed no history of recurrent sin-