Am. J. Trop. Med. Hyg., 68(6), 2003, pp. 704-706
Copyright © 2003 by The American Society of Tropical Medicine and Hygiene
ACUTE UNDIFFERENTIATED FEVER CAUSED BY INFECTION WITH JAPANESE ENCEPHALITIS VIRUS
GEORGE WATT AND
KRISADA JONGSAKUL
Department of Retrovirology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand
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ABSTRACT
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To determine the proportion of acute undifferentiated fevers without neurologic deficits related to infection with Japanese encephalitis (JE) virus, flavivirus serology (dengue and JE) was performed in a cohort of 156 adults presenting to a hospital in Chiangrai, Thailand. Recent flavivirus infection was diagnosed for any individual with an IgM result > 40 units. A ratio of dengue virus IgM to JE virus IgM < 0.91 defined a JE virus infection. Diagnostic criteria for Japanese encephalitis were met in 22 individuals (14%), and were unequivocal in 8 patients. The admission findings in these eight subjects were similar to those described for other flavivirus infections. Thrombocytopenia was the most striking laboratory abnormality (median platelet count = 119,000/mm3, range = 44,000–236,000/mm3). Headache (75%), nausea (50%), myalgia (38%), rash (38%), and diarrhea (25%) were the most frequently encountered signs and symptoms. Infection with Japanese encephalitis virus is an underappreciated cause of acute undifferentiated fever in Asia.
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INTRODUCTION
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Most infections with Japanese encephalitis (JE) virus are subclinical,1 with the ratio of symptomatic to asymptomatic infections estimated to be 1:25 to 1:1000.2,3 When symptomatic, infections with tropical flaviviruses associated with encephalitis, such as JE virus, generally present as fever, fever with aseptic meningitis, or fever with encephalitis. Japanese encephalitis is said to rarely be mild and presents more often as frank encephalitis than do infections with other tropical flaviviruses.1 Neurologic disease is the most prominent clinical feature of the systemic infection.4 The neurologic picture and sequelae of JE have been described in detail,5,6 but descriptions of symptomatic infections without encephalitis are limited. We performed flavivirus serology during an investigation of acute febrile illness of unclear origin in Chiangrai in northern Thailand and were able to identify cases of JE virus infection. This gave us the opportunity to describe the clinical and laboratory findings of a group of Thai adults with non-neurologic JE virus infection.
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MATERIALS AND METHODS
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Patients.
Consecutive patients presenting to the adult outpatient department of Chiangrai Regional Hospital in northern Thailand during the rainy season months of June–December 1991 were screened. Individuals with an oral temperature 
37.5°C, a history of fever lasting 
2 weeks, no known chronic medical problems, and no known current infectious disease were examined further. Patients without focal or general neurologic deficits and with an unaltered level of consciousness were tested for flavivirus infection. A standardized code sheet was filled out in all cases and routine complete blood counts were performed. This minimum risk study was reviewed and approved by the Ethical Review Committee of the Chiangrai Provincial Ministry of Public Health (Chiangrai, Thailand). Written informed consent was obtained from all study volunteers.
Diagnosis of infection with JE virus.
An IgM capture enzyme-linked immunosorbent assay (ELISA) detects flavivirus-specific IgM that is usually present at the time the patient presents to hospital with JE virus infection.7 A positive IgM capture ELISA result can be obtained on a single specimen, and indicates a recent infection, usually within the past six weeks.1 Recent flavivirus infection was diagnosed for any individual with an IgM result > 40 units.8 This method has a sensitivity of 78% in admission sera and a specificity of 100%. A ratio of dengue IgM to JE IgM < 0.91 defined an infection with JE virus.9
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RESULTS
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Patients.
Dengue was diagnosed in 35 (22%) and JE virus infection was diagnosed in 22 (14%) of 156 adults with acute, undifferentiated fever (Table 1
). There were eight cases where the diagnosis of JE virus infection appeared to be unequivocal: cases 3, 4, 5, 6, 8, 20, 21, and 22 (Table 1). The admission signs and symptoms of these eight individuals were analyzed in more detail (Table 2). The median duration of fever prior to coming to hospital was seven days (range = 2–14 days). The condition of seven of these eight JE patients improved in hospital and they were able to be discharged.
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TABLE 1 Antibody capture enzyme immunoassay (EIA) results using Japanese encephalitis (JE) virus and dengue (DEN) virus*
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The only fatal case concerned a 26-year-old woman (ethnic minority, rice farmer, case 21, Table 1
). She had been febrile for 12 days prior to admission and developed severe shortness of breath one day before coming to hospital. On admission she was jaundiced and severely dyspneic. Abnormal findings on a physical examination included bleeding gums, conjunctival hemorrhage, and hepato-splenomegaly. Bloody diarrhea was also noted. The patient’s blood pressure was undetectable and she died in profound shock four hours after admission. Her hematocrit was 23%, and there were 3,950 leukocytes/mm3, with 84% polymorphonuclear cells and 16% lymphocytes. Her platelet count was 44,000/mm3. Bilateral alveolar infiltrates were observed on a chest radiograph, and serology for human immunodeficiency virus was non-reactive. The dengue IgM to JE IgM ratio was 0.48.
The median admission hematocrit and white blood cell counts for the eight clear-cut JE virus-infected patients were within normal limits (Table 2). Platelet counts were reduced (median = 119,000/mm3, range = 44,000–236,000/mm3). Headache (75%), nausea (50%), and myalgia (38%) were the most common symptoms. Twenty-five percent of the patients had diarrhea. A faint, generalized, macular rash predominating on the trunk was seen in three patients.
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DISCUSSION
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There is good evidence to support the use of the ratio of anti-dengue virus IgM to anti-Japanese encephalitis virus IgM for discriminating between the infecting virus species where the two viruses are sympatric.8,9 However, since we did not attempt to isolate JE virus, the possibility that cross-reactive antibodies to flavivirus, and not antibodies to JE virus, were detected in some patients cannot be entirely dismissed. It is possible, although unlikely, that some patients in this series actually had infections with dengue virus rather than infections with JE virus. Our sera were tested in the Department of Virology at the Armed Forces Research Institute of Medical Sciences in Bangkok, Thailand. This department has never found a case of virologically proven infection with dengue virus in which the IgM titer for JE virus was higher than the IgM titer for dengue virus (Nisaluk A, unpublished data). For the most recent 32 cases from whom dengue virus was isolated, the median ratio of dengue virus IgM to JE virus IgM was 3.5 (range = 14.4–1.1; Nisaluk A, unpublished data). Nevertheless, it would be inappropriate to place too much emphasis on serologic results from a single time point.
Fever, headache, myalgia, vomiting, thrombocytopenia, and rash were the predominant features of JE in our cases. These features are similar to those described for the tick-borne encephalitis complex, another flavivirus infection.10 Rash occurs with a number of flavivirus infections, including those by Spondewi virus11 and West Nile virus.12
Infection with JE virus was the apparent cause of 14% of acute febrile illness of unclear origin with non-neurologic symptoms in this series of cases from Chiangrai in northern Thailand. It is likely that JE virus is also an under-recognized cause of fever in other parts of Asia where infection with JE virus is endemic. Our patients were adults and had probably been previously exposed to JE virus; by age 30, nearly all Thai adults in nearby Chiangmai had been infected.13 It has been suggested that previous infection with JE virus protects against disease to a greater extent than it protects against reinfection.13 If so, perhaps pre-existing immunity offered these study subjects some protection against the more severe meningoencephalitic form of JE virus infection. In JE-endemic areas, JE virus infection should be considered in the differential diagnosis of acute fever with or without neurologic signs.
Received October 14, 2002.
Accepted for publication April 2, 2003.
Acknowledgments: We thank Dr. Mike Benenson for his careful review of the manuscript and suggestions for improvement, and Dr. Ananda Nisaluk for sharing her insights and diagnostic information about flavivirus infections in Thailand.
Authors’ address: George Watt and Krisada Jongsakul, Department of Retrovirology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand, APO AP 96546, USA, Telephone: 66-2-644-6735, Fax: 66-2-246-8908, E-mail: wattgh{at}thai.amedd.army.mil
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