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Japanese Encephalitis in Children
Abstract & Commentary
By Lin Chen, MD
Dr. Chen is Assistant Clinical Professor, Harvard Medical School; Director, Travel Medicine Center, Mt. Auburn Hospital, Cambridge MA
Dr. Chen reports no financial relationship to this field of study.
Synopsis: Travelers visiting friends and relatives in endemic countries are at increased risk for Japanese encephalitis; their trip plans should be reviewed carefully, and they should be targeted for prevention with personal protective measures and Japanese encephalitis vaccine.
Source: Centers for Disease Control and Prevention. Japanese encephalitis in two children United States, 2010. MMWR Morbid Mortal Wkly Rep 2011;60:276-278.
Two children were diagnosed with japanese encephalitis (JE) in the United States in July 2010. The first child, aged 11 years, had onset of fever, headache, nausea, vomiting, and neck pain 4 days after returning from a 21-day trip visiting relatives in the Philippines. She had traveled with her relatives, and spent most of the time in Metro Manila. They stayed with relatives in a screened house, took day trips to coastal and rural areas, and also stayed for 2 nights at an island resort that was screened and air-conditioned.
The patient was hospitalized 2 days after symptom onset in Nevada, and found to have leukocytosis and CSF pleocytosis. She deteriorated over the 2-3 days after admission with somnolence, focal motor seizures, pulmonary edema, bradycardia, and hypotension that led to placing her on mechanical ventilation. Her head CT showed cortical sulci effacement; her EEG showed little cerebral activity. She developed ventricular tachycardia and died 5 days after onset of illness.
The child's brain tissue obtained via autopsy showed meningoencephalitis, positive immunohistochemical staining for JE complex flavivirus antigens, and RT-PCR confirmed JE virus (JEV) RNA. CSF on admission was positive for JEV-specific IgM.
The second child, a refugee 6 years of age, was born in Thailand to Burmese parents. His symptoms included fever, somnolence, headache, vomiting, and refusal to walk, and started en route to the United States, 2 days before his presentation in Texas. He was found to have leukocytosis, CSF pleocytosis, and brain MRI showing a neurocysticercosis lesion in the left frontal lobe as well as an abnormal signal in the left thalamus. Subsequently an EEG showed generalized cerebral activity.
The second child's CSF on day 6 showed JEV-specific IgM and serum neutralizing antibodies rose fourfold between acute and convalescent serum samples. His cysticercosis serology was negative, but he was treated with a 21-day course of albendazole and corticosteroid for neurocysticercosis, and he recovered following a 24-day hospitalization.
Japanese encephalitis (JE) virus is a flavivirus transmitted by the bite of Culex mosquitoes, primarily Culex tritaeniorhynchus, and it is endemic in Asia and parts of the western Pacific. JEV is maintained in an enzootic cycle between mosquitoes and vertebrate hosts such as pigs and wading birds, and is particularly common in rural farming areas with rice paddies. Most infections are subclinical, but < 1% may present after 5-15 days of incubation with fever, headache, mental status change, vomiting, seizures, acute encephalitis or aseptic meningitis; among those with clinical infection, 20%-30% of cases may be fatal, and 30%-50% develop long-term neuropsychological sequelae.1 Most infections occurring in endemic regions occur in children < 15 years of age.
JE infection occurs rarely in travelers, and the disease risk depends on season of travel, destination visited, trip duration, and activities. There have been 55 cases in citizens from 17 non-endemic countries reported in literature from 1973 to 2008, and the risk of acquiring JE is estimated to be < 1 case per 1 million travelers.2 However, potentially severe consequences of infection underpin the recommendations for vaccination.
A new inactivated Vero cell-derived vaccine (IXIARO®, Intercell), a two-dose series, administered 28 days apart, became licensed in the United States, Europe, and Australia in 2009. In the United States, it is licensed for individuals aged ≥ 17 years and has been well tolerated. Recommendations from the Advisory Committee on Immunization Practices regarding JE vaccine include:3
Recommended: Travelers who plan to spend a month or longer in endemic areas during the JEV transmission season
Consider: Short-term travelers (< 1 month) to endemic areas during the transmission season if they have high-exposure activities
Travelers to an area with ongoing JE outbreak
Travelers to endemic areas who are uncertain of specific destinations, activities, or duration of travel
For persons younger than 17 years of age in the United States, the currently indicated vaccine is JE-VAX®, but obtaining the vaccine requires contacting the distributor for each traveler. Several clinical trials are in progress to assess the safety and efficacy of the new Vero cell-derived vaccine in persons younger than 17 years.4 A Phase II study on children ages 1-3 years in India was recently published and showed the vaccine to be safe and immunogenic.5 A Phase II trial in Filipino children 3-12 years old also has been completed and is presented at the 12th Conference of the International Society of Travel Medicine in Boston, MA, USA, in May 2011.6 Expanding the licensure for IXIARO for use in children would reduce barriers to vaccinate this vulnerable group of travelers.
The first case reported here illustrates some important issues regarding JE: 1) JE is under-reported in some countries; 2) travelers visiting friends and relatives (VFR) are at a significantly increased risk of exposure to JE; and 3) VFR travelers often lack pre-travel health advice. The report noted that the child was born in the United States, as were her parents who did not travel).7,8
The second case underscores the importance of considering the diagnosis of JE infection in febrile travelers with neurologic findings who have visited endemic areas, even when there is already a possible explanation. Travel medicine providers should be familiar with the common clinical presentations of JE: fever accompanied by headache, mental status change, seizure, vomiting, focal neurologic changes. Hemorrhagic lesions of the thalamus have been described.
Finally, recent clinical trials on the duration of immunity found that 15 months after primary vaccination with IXIARO, the proportion of vaccinees with protective levels of antibody titer (≥ 1:10) declined to 58%-83% of subjects. One month after a booster dose, 100% achieved PRNT50 of ≥ 1:10, and > 98% remained protected serologically 12 months later.9 The ACIP voted in February 2011 to recommend a booster dose of IXIARO at 12 months after the primary series for travelers who remain at risk for JE infection.