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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 1285 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 1286 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 References 1. Tsai TF. Arboviral infections in the United States. Infect Dis Clin North Am 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; 92:40–50. 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-