Japanese Encephalitis Among Three U.S. Travelers Returning from Asia, 2003--2008

Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, is a leading cause of encephalitis in Asia (1). The risk for Japanese encephalitis (JE) for most travelers is low, but varies by travel destination, duration, season, and activities (2). As part of routine surveillance and diagnostic testing, state health officials or clinicians send specimens from patients with unexplained encephalitis to CDC. To characterize the epidemiologic and clinical features of JE cases, CDC reviewed all laboratory-confirmed cases that occurred during 1992 (when a JE vaccine was first licensed in the United States) to 2008. Four cases were identified, including one previously reported (3). This report describes the three previously unpublished cases. All were Asian immigrants or family members who traveled to Asia to live or to visit friends or relatives and had not been vaccinated for JE. The three patients experienced fever with mental status changes, but JE was recognized early in the clinical course of only one patient. All recovered, but two patients had residual neurologic deficits. Travelers to Asia might be at increased risk for JE because of rural itineraries and lack of perceived risk (4). To protect against JE, travelers should seek medical advice on protective measures, including possible JE vaccination, well in advance of departure for Asia. While in Asia, travelers should use personal protective measures to reduce the risk for mosquito bites. Health-care providers should assess the risk for JE in travelers to Asia and provide appropriate preventive or supportive treatment measures.

Case Reports

Case 1. On August 21, 2003, a woman aged 30 years was hospitalized in Minnesota with neck pain, confusion, and slow speech. The patient was born in Korea, moved to the United States at age 3 years, and moved back to Korea at age 26 years. For 7 months before illness onset, she had lived on an island off the coast of southern Thailand. She reportedly had no record of receiving JE vaccine. On July 30, while in Thailand, a dog bit her on the ankle. On August 1 and 4, she received rabies postexposure prophylaxis with rabies vaccine. On August 7, she was hospitalized with a nonspecific febrile illness, treated empirically with intravenous antibiotics, discharged the next day, then rehospitalized during August 10--14 for additional symptomatic treatment. On August 20, she returned to the United States.

On admission to the Minnesota hospital, she was afebrile with normal vital signs. Routine laboratory studies and brain scans were unremarkable. Cerebrospinal fluid (CSF) showed lymphocytic pleocytosis (33 white blood cells [WBC]/mm3 [normal: 0--5 WBC/mm3] with 97% lymphocytes, 27 red blood cells (RBC) per mm3 [normal: 0 RBC/mm3]), slightly elevated protein (51 mg/dL [(normal: 15--45 mg/dL]), and normal glucose concentrations. Other tests were negative, including bacterial cultures, polymerase chain reaction assays for herpes simplex and rabies viruses, a stool culture for enteroviruses, and enzyme immunoassays for immunoglobulin M (IgM) antibodies to a standard panel of domestic arboviruses.*

The patient received rabies immune globulin and intravenous corticosteroids, and completed the rabies vaccination series. Her mental status improved over several days, and she was discharged on August 26 with a presumptive diagnosis of viral meningoencephalitis. Serum and CSF samples collected on August 21 (day 14 of illness) subsequently tested positive for JEV-specific IgM and neutralizing antibodies at CDC. The patient recovered fully.

Case 2. On July 26, 2005, on a return flight to California from the Philippines, a woman aged 68 years developed weakness and loss of appetite. The next day, she developed fever, chills, nausea, and dry cough and was hospitalized on July 28 to receive intravenous antibiotics. The patient, an immigrant to the United States who reportedly never received JE vaccine, had spent the previous 3 months visiting friends and relatives in Manila. On admission to the hospital, she had fever (103.5°F [39.7°C]) and a peripheral WBC count of 11,900/mm3 (85% neutrophils). Other routine laboratory tests, abdominal computed tomography (CT) scan and ultrasound, and a chest radiograph were unremarkable.

Within a few hours after admission, the patient developed agitation, disorientation, and hypotension requiring intravenous vasopressors and she was transferred to the intensive-care unit. The next day, she became obtunded with spastic limb movements and upper-body muscle tension. She was treated empirically with lorazepam, tetanus immune globulin, acyclovir, and fluconazole. CSF showed lymphocytic pleocytosis (75 WBC/mm3 with 71% lymphocytes and 29% neutrophils), elevated protein (133 mg/dL), and normal glucose concentrations. CT and magnetic resonance imaging (MRI) of the brain and electroencephalography were noncontributory. During the next 3 weeks, the patient was extubated, regained her ability to speak, and was able to walk with assistance. On August 24 (hospital day 28), she was discharged for further outpatient rehabilitation. Serum obtained on August 4 (day 9 of illness) subsequently tested positive for JEV-specific IgM and neutralizing antibodies at CDC.

Case 3. In mid-January, 2008, a previously healthy boy aged 9 years and his family flew from their home in Washington to Phnom Penh, Cambodia, where they stayed for 1 week. He subsequently visited family in rural southern Vietnam for nearly 3 weeks and stayed another 5 days in a hotel in Ho Chi Minh City. Three weeks before departure to Asia, the family had visited a travel medicine clinic but deferred JE vaccination because of insufficient time to complete a full primary series, which is typically administered over 30 days.

On February 17, while in Ho Chi Minh City, the patient developed fever, headache, weakness, loss of appetite, and vomiting. On February 18, the family returned to Phnom Penh, where the patient was hospitalized with decreased mental status, seizures, and progressive limb weakness. On February 22, he was transferred to a hospital in Bangkok where he had fever, intermittent seizures, bilateral papilledema, motor aphasia, involuntary limb movements, and somnolence requiring mechanical ventilation. CSF showed 5 WBC/mm3, 42 RBC/mm3, and normal protein and glucose concentrations. Head CT and MRI scans showed abnormalities of the thalami, basal ganglia, and right caudate nucleus. A battery of laboratory tests for potential encephalitis pathogens was negative,† except for anti-JEV IgM in serum and CSF.

While hospitalized, the patient received anticonvulsants, diuretics, corticosteroids, antibiotics, and influenza antivirals. He was extubated on February 27 and airlifted to a hospital in the United States on March 18. The patient was discharged home on March 26 with substantial residual cognitive deficits, aphasia, and motor dysfunction. Six months later, he was walking independently, eating solid food, and making gains in speech recovery. Serum collected on March 25 (5 weeks after illness onset) subsequently tested positive for JEV-specific IgM and neutralizing antibodies at CDC, confirming the diagnosis made in Thailand.

Reported by: J Bakken, MD, St. Luke's Infectious Disease Associates, Duluth; D Neitzel, MS, Minnesota Dept of Health. L Taylor, R Civen, MD, Los Angeles County Dept of Public Health, California. LL Plawner, MD, Seattle Children's; S McKiernan, JS Duchin, MD, Public Health--Seattle & King County; R Baer, MPH, N Marsden-Haug, MPH, Washington State Dept of Health. S Thamthitiwat, MD, HC Baggett, MD, Div of Emerging Infections and Surveillance Svcs, National Center for Preparedness, Detection, and Control of Infectious Diseases; GL Campbell, MD, A Griggs, MPH, AJ Panella, MPH, J Laven, O Kosoy, MS, RS Lanciotti, PhD, JE Staples, MD, M Fischer, MD, Arboviral Diseases Br, Div of Vector-Borne Infectious Diseases, National Center for Zoonotic, Vector-Borne, and Enteric Diseases; M Duffy, DVM, EIS Officer, CDC.

Editorial Note:

JE is predominately a disease of rural Asia and parts of the western Pacific, especially where rice culture and pig farming coexist (1). In JE-endemic countries, most adults have protective immunity, and JE is primarily a disease of children. However, travel-associated JE can occur in any age group. In temperate areas, JEV transmission occurs mainly in summer and fall; in tropical and subtropical areas, seasonal transmission varies with monsoons and irrigation practices, and might be extended or occur year-round.

The risk for JE for most travelers to Asia is low, but varies based on travel destination, duration, season, and activities. The overall incidence of JE among persons traveling to Asia from countries where JE is not endemic is estimated to be <1 case per 1 million travelers (3). The risk to short-term travelers whose visits are limited to urban areas is negligible (1,2). In contrast, expatriates and travelers with prolonged stays in rural areas where JE is endemic or epidemic are at greater risk, possibly similar to that of the resident, nonimmune population (2). Travelers on even brief trips to rural areas might have increased risk (5--7), especially if they are extensively exposed to mosquitoes (2).

From 1973 to 1992, 11 JE cases were reported among U.S. residents, including five among civilian travelers (8). Since December 1992, when a JE vaccine was first licensed in the United States, only four cases of JE have been reported among U.S. residents, the three travel-associated JE cases described in this report and the case reported previously in 2004 (3). All four JE cases were among civilian travelers or expatriates. Two of the travel-associated JE cases described in this report were Asian-native adults who had immigrated to the United States many years earlier, and the third was in a U.S.-native child whose parents were Asian immigrants. Immigrants who return to their native countries to visit friends or relatives might be less concerned about or less aware of disease risks associated with travel to those countries, and thus might be less inclined to seek pretravel medical advice (4).

Although <1% of JEV infections result in clinical disease, JE is a devastating illness that has a case-fatality ratio of approximately 30% and causes neurologic sequelae in approximately 50% of survivors (1). No specific treatment exists. Therefore, prevention is paramount.§ Travelers to JE-endemic countries should be advised of the risks for JE disease and the importance of personal protective measures to reduce the risk for mosquito bites (9). The use of bed nets, insect repellents, and protective clothing, and avoidance of outdoor activity, especially in the evening and at night, are important preventive measures for JE (2). JE vaccine can reduce further the risk for infection for travelers in high-risk settings, depending on season, location, duration, and activities. In March 2009, the Food and Drug Administration approved a new inactivated Vero cell culture-derived JE vaccine (IXIARO) for use in persons aged ≥17 years. An inactivated mouse brain--derived JE vaccine (JE-VAX) has been licensed in the United States since 1992 for use in persons aged ≥1 year. However, JE-VAX is no longer being produced, and limited supplies remain. Therefore, CDC recommends that JE-VAX only be used for children aged 1--16 years.

JE should be suspected in a patient with evidence of a neuroinvasive viral infection (e.g., encephalitis, aseptic meningitis, or acute flaccid paralysis) who recently returned from a JE-endemic country in Asia or the western Pacific. Health-care providers should contact their state or local health department or CDC's Division of Vector-Borne Infectious Diseases (telephone: 970-221-6400) for assistance with JEV diagnostic testing.

Acknowledgments

The findings in this report are based, in part, on contributions by D Dassey, MD, Los Angeles County Dept of Public Health, California; T Feely, Public Health--Seattle & King County, and A Marfin, MD, Washington State Dept of Health; N Marano, DVM, Div Global Migration and Quarantine, and JJ Sejvar, MD, and S Hills, MBBS, Div of Vector-Borne Infectious Diseases, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, CDC.

References

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7. Caramello P, Canta F, Balbiano R, et al. A case of imported JE acquired during short travel in Vietnam. Are current recommendations about vaccination broader? J Travel Med 2007;14:346--8.
8. Marfin AA, Barwick Eidex RS, Kozarsky PE, Cetron MS. Yellow fever and Japanese encephalitis vaccines: indications and complications. Infect Dis Clin North Am 2005;19:151--68.
9. CDC. Protection against mosquitoes, ticks, fleas and other insects and arthropods. In: Health information for international travel 2008. Atlanta, GA: US Department of Health and Human Services, CDC; 2007:37--43. Available at http://wwwn.cdc.gov/travel/yellowbook/ch2/insects-arthropods.aspx.

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Date last reviewed: 7/16/2009