Chapter 3Infectious Diseases Related To Travel
Susan L. Hills, Randall J. Nett, Marc Fischer
Japanese encephalitis virus (JEV) is a single-stranded RNA virus that belongs to the genus Flavivirus and is closely related to West Nile and Saint Louis encephalitis viruses.
MODE OF TRANSMISSION
JEV is transmitted to humans through the bite of an infected mosquito, primarily Culex species. The virus is maintained in an enzootic cycle between mosquitoes and amplifying vertebrate hosts, primarily pigs and wading birds. Humans are incidental or dead-end hosts, because they usually do not develop a level or duration of viremia sufficient to infect mosquitoes.
JEV is the most common vaccine-preventable cause of encephalitis in Asia, occurring throughout most of Asia and parts of the western Pacific (Map 3-08). Local transmission of JEV has not been detected in Africa, Europe, or the Americas. Transmission principally occurs in rural agricultural areas, often associated with rice cultivation and flooding irrigation. In some areas of Asia, these ecologic conditions may occur near, or occasionally within, urban centers. In temperate areas of Asia, transmission is seasonal, and human disease usually peaks in summer and fall. In the subtropics and tropics, seasonal transmission varies with monsoon rains and irrigation practices and may be extended or even occur year-round.
In endemic countries, Japanese encephalitis (JE) is primarily a disease of children. However, travel-associated JE can occur among people of any age. The risk for JE for most travelers to Asia is extremely low but varies based on destination, duration, season, and activities.
From 1973 through 2008, there were 55 published reports of travel-associated JE among travelers from nonendemic countries. Only 4 cases among people from the United States have been reported since 1992, when a JE vaccine was first licensed in the United States.
The overall incidence of JE among people from nonendemic countries traveling to Asia is estimated to be less than 1 case per 1 million travelers. However, expatriates and travelers who stay for prolonged periods in rural areas with active JEV transmission are likely at similar risk as the susceptible resident population (5–50 cases per 100,000 children per year). Travelers on even brief trips might be at increased risk if they have extensive outdoor or nighttime exposure in rural areas during periods of active transmission. Short-term (<1 month) travelers whose visits are restricted to major urban areas are at minimal risk for JE. In endemic areas there are few human cases among residents because of vaccination or natural immunity. JEV is often still maintained in an enzootic cycle between animal and mosquitoes. Therefore, susceptible visitors may be at risk for infection.
Most human infections with JEV are asymptomatic; <1% of people infected with JEV develop clinical disease. Acute encephalitis is the most commonly recognized clinical manifestation of JEV infection. Milder forms of disease, such as aseptic meningitis or undifferentiated febrile illness, can also occur. The incubation period is 5–15 days. Illness usually begins with sudden onset of fever, headache, and vomiting. Mental status changes, focal neurologic deficits, generalized weakness, and movement disorders may develop over the next few days.
- The classical description of JE includes a parkinsonian syndrome with masklike facies, tremor, cogwheel rigidity, and choreoathetoid movements.
- Acute flaccid paralysis, with clinical and pathological features similar to those of poliomyelitis, has also been associated with JEV infection.
- Seizures are common, especially among children.
- Clinical laboratory findings might include a moderate leukocytosis, mild anemia, and hyponatremia. Cerebrospinal fluid (CSF) typically has a mild to moderate pleocytosis with a lymphocytic predominance, slightly elevated protein, and normal ratio of CSF to plasma glucose.
The case-fatality ratio is approximately 20%–30%. Among survivors, 30%–50% have significant neurologic, cognitive, or psychiatric sequelae.
JE should be suspected in a patient with evidence of a neurologic infection (such as encephalitis, meningitis, or acute flaccid paralysis) who has recently traveled to or resided in an endemic country in Asia or the western Pacific. Laboratory diagnosis of JEV infection should be performed by using a JEV-specific IgM-capture ELISA on CSF or serum. JEV-specific IgM can be measured in the CSF of most patients by 4 days after onset of symptoms and in serum by 7 days after onset. A ≥4-fold rise in JEV-specific neutralizing antibodies between acute- and convalescent-phase serum specimens may be used to confirm the diagnosis. Vaccination history, date of onset of symptoms, and information regarding other flaviviruses known to circulate in the geographic area that may cross-react in serologic assays need to be considered when interpreting results.
Humans have low levels of transient viremia and usually have neutralizing antibodies by the time distinctive clinical symptoms are recognized. Virus isolation and nucleic-acid amplification tests are insensitive in detecting JEV or JE viral RNA in blood or CSF and should not be used for ruling out a diagnosis of JE. Clinicians should contact their state or local health department or CDC’s Division of Vector-Borne Diseases at 970-221-6400 for assistance with diagnostic testing.
There is no specific antiviral treatment for JE; therapy consists of supportive care and management of complications.
PREVENTIVE MEASURES FOR TRAVELERS
One JE vaccine is licensed and available in the United States—an inactivated Vero cell culture–derived vaccine (Ixiaro). Ixiaro, manufactured by Intercell and distributed by Novartis Vaccines, was approved in March 2009 for use in people aged ≥17 years. Pediatric clinical trials are being conducted to enable licensure of Ixiaro for use in children. Other inactivated and live attenuated JE vaccines are manufactured and used in Asia but are not licensed for use in the United States.
JE-Vax, an inactivated mouse brain–derived vaccine manufactured by Biken and distributed by Sanofi Pasteur, was licensed in the United States in 1992 for use in travelers aged ≥1 year. In 2006, production of JE-Vax was discontinued, and all remaining doses expired in May 2011.
Efficacy and immunogenicity
There are no efficacy data for Ixiaro. The vaccine was licensed in the United States on the basis of its ability to induce JEV neutralizing antibodies as a surrogate for protection, as well as safety evaluations in almost 5,000 adults. In the pivotal noninferiority immunogenicity study, 96% of adults developed protective neutralizing antibodies after receiving a primary immunization series of 2 doses administered 28 days apart.
Dosage and administration
The primary immunization schedule for Ixiaro is 2 doses administered intramuscularly on days 0 and 28. The dose is 0.5 mL for people aged ≥17 years, and the 2-dose series should be completed ≥1 week before travel.
The full duration of protection after primary immunization with Ixiaro is unknown. In one study, 83% of people who received two doses of Ixiaro maintained protective levels of antibodies at 12 months after the first vaccine dose, and in a second study, 58% and 48% of people had protective antibodies at 12 and 24 months, respectively.
If the primary series of Ixiaro was administered ≥1 year previously, a booster dose should be given prior to potential reexposure or if there is a continued risk for JEV infection. Data on the response to a booster dose administered ≥2 years after the primary series are not available. Data on the need for and timing of additional booster doses are also not available.
There are no data on the use of Ixiaro as a booster dose after a primary series with JE-Vax. People who have received JE-Vax previously and require further vaccination against JEV should receive a 2-dose primary series of Ixiaro.
Vaccine safety and adverse reactions
Pain and tenderness were the most commonly reported symptoms in a safety study with 1,993 participants who received 2 doses of Ixiaro. Systemic side effects, including headache, myalgia, fatigue, and an influenzalike illness, were each reported at a rate of >10%. Because Ixiaro was licensed after study in <5,000 recipients, the possibility of rare serious adverse events cannot be excluded. Postlicensure studies and surveillance are further evaluating the safety of Ixiaro in a larger population.
Indications for Use of JE Vaccine for Travelers
When making recommendations regarding the use of JE vaccine for travelers, clinicians must weigh the overall low risk of travel-associated JEV disease, the high rate of death and disability when JE occurs, the low probability of serious adverse events after immunization, and the cost of the vaccine. Evaluation of an individual traveler’s risk should take into account the planned itinerary, including travel location, duration, activities, and seasonal patterns of disease in the areas to be visited (see Table 3-08). The data in the table should be interpreted cautiously, because JEV transmission activity varies within countries and from year to year.
The Advisory Committee on Immunization Practices recommends JE vaccine for travelers who plan to spend ≥1 month in endemic areas during the JEV transmission season. This includes long-term travelers, recurrent travelers, or expatriates who will be based in urban areas but are likely to visit endemic rural or agricultural areas during a high-risk period of JEV transmission. Vaccine should also be considered for the following:
- Short-term (<1 month) travelers to endemic areas during the JEV transmission season, if they plan to travel outside an urban area and their activities will increase the risk of JEV exposure. Examples of higher-risk activities or itineraries include: 1) spending substantial time outdoors in rural or agricultural areas, especially during the evening or night; 2) participating in extensive outdoor activities (such as camping, hiking, trekking, biking, fishing, hunting, or farming); and 3) staying in accommodations without air conditioning, screens, or bed nets.
- Travelers to an area with an ongoing JE outbreak.
- Travelers to endemic areas who are uncertain of specific destinations, activities, or duration of travel.
JE vaccine is not recommended for short-term travelers whose visits will be restricted to urban areas or times outside a well-defined JEV transmission season.
Precautions and Contraindications
A severe allergic reaction after a previous dose of Ixiaro is a contraindication to administration of further doses. Ixiaro contains protamine sulfate, a compound known to cause hypersensitivity reactions in some people. The safety and effectiveness of Ixiaro among children aged ≤16 years have not yet been determined. Limited data on the use of Ixiaro in people aged ≥65 years suggest safety and immunogenicity are similar to that among younger people, but further data are needed. No studies of Ixiaro in pregnant women have been conducted. Therefore, administration of Ixiaro to pregnant women usually should be deferred. However, pregnant women who must travel to an area where risk for JEV infection is high should be vaccinated when the theoretical risk of immunization is outweighed by the risk of infection.
(Updated September 1, 2011)
Personal Protection Measures
The best way to prevent mosquitoborne diseases, including JE, is to avoid mosquito bites (see Chapter 2, Protection against Mosquitoes, Ticks, and Other Insects and Arthropods).
Table 3-08. Risk for Japanese encephalitis, by country
|COUNTRY||AFFECTED AREAS||TRANSMISSION SEASON||COMMENTS|
|Australia||Outer Torres Strait islands||December–May; all human cases reported February–April||1 human case reported from north Queensland mainland|
|Bangladesh||Little data, probably widespread||Unknown; most human cases reported May–October||1 outbreak of human disease reported from Tangail District in 1977; sentinel surveillance has recently identified human cases in Chittagong, Dhaka, Khulna, Rajshahi and Sylhet Divisons; highest incidence reported from Rajshahi Division|
|Bhutan||No data||No data|
|Brunei||No data; presumed to be endemic countrywide||Unknown; presumed year-round transmission|
|Burma (Myanmar)||Limited data; presumed to be endemic countrywide||Unknown; most human cases reported from May–October||Outbreaks of human disease documented in Shan State; antibodies documented in animals and humans in other areas|
|Cambodia||Presumed to be endemic countrywide||Year round with peaks reported May–October||Sentinel surveillance has identified human cases in at least 14 provinces, including Phnom Penh, Takeo, Kampong Cham, Battambang, Svay Rieng, and Siem Reap|
|China||Human cases reported from all provinces except Xizang (Tibet), Xinjiang, and Qinghai; not considered endemic in Hong Kong and Macau, but rare cases reported from the New Territories||Most human cases reported June–October||Highest rates reported from Chongqing, Guizhou, Shaanxi, Sichuan, and Yunnan provinces; vaccine not routinely recommended for travel limited to Beijing or other major cities|
|India||Human cases reported from all states except Dadra, Daman, Diu, Gujarat, Himachal Pradesh, Jammu, Kashmir, Lakshadweep, Meghalaya, Nagar Haveli, Punjab, Rajasthan, and Sikkim||Most human cases reported May–October, especially in northern India; the season may be extended or year-round in some areas, especially in southern India||Highest rates of human disease reported from the states of Andhra Pradesh, Assam, Bihar, Goa, Haryana, Karnataka, Kerala, Tamil Nadu, Uttar Pradesh, and West Bengal|
|Indonesia||Presumed to be endemic countrywide||Human cases reported year-round; peak season varies by island||Sentinel surveillance has identified human cases in Bali, Kalimantan, Java, Nusa Tenggara, Papua, and Sumatra|
|Japan2||Rare sporadic human cases on all islands except Hokkaido; enzootic activity ongoing||Most human cases reported July–October||Large number of human cases reported until JE vaccination program introduced in late 1960s; most recent small outbreak reported from Chugoku district in 2002; enzootic transmission without human cases observed on Hokkaido; vaccine not routinely recommended for travel limited to Tokyo or other major cities|
|Korea, North||No data||No data|
|Korea, South2||Rare sporadic cases countrywide; enzootic activity ongoing||Most human cases reported May–October||Large number of human cases reported until routine JE vaccination program introduced in mid-1980s; highest rates of disease were reported from the southern provinces; last major outbreak reported in 1982; vaccine not routinely recommended for travel limited to Seoul or other major cities|
|Laos||Limited data; presumed to be endemic countrywide||Year round, with peak June–September||Sentinel surveillance has identified human cases in north, central, and southern Laos|
|Malaysia||Endemic in Sarawak; sporadic cases reported from all other states; occasional outbreaks reported||Year-round transmission; peak October–December in Sarawak||Most human cases from reported from Sarawak; vaccine not routinely recommended for travel limited to Kuala Lumpur or other major cities|
|Mongolia||Not considered endemic|
|Nepal||Endemic in southern lowlands (Terai); cases also reported from hill and mountain districts, including the Kathmandu valley||Most human cases reported June–October||Highest rates of human disease reported from western Terai districts, including Banke, Bardiya, Dang, and Kailali; vaccine not routinely recommended for those trekking in high-altitude areas or spending short periods in Kathmandu or Pokhara en route to such trekking routes|
|Pakistan||Limted data; human cases reported from around Karachi||Unknown|
|Papua New Guinea||Limited data; probably widespread||Unknown||Sporadic human cases reported from Western Province; serologic evidence of disease from Gulf and Southen Highland Provinces; a case of JE was reported from near Port Moresby in 2004|
|Philippines||Limited data; presumed to be endemic on all islands||Unknown; probably year-round||Outbreaks reported in Nueva Ecija and Manila; sporadic human cases reported form other areas of Luzon and the Visayas|
|Russia||Rare human cases reported from the Far Eastern maritime areas south of Khabarovsk||Most human cases reported July–September|
|Singapore||Rare sporadic human cases reported||Year-round transmission||Vaccine not routinely recommended|
|Sri Lanka||Endemic countrywide except in mountainous areas||Year-round with variable peaks based on monsoon rains||Highest rates of human disease reported from Anuradhapura, Gampaha, Kurunegala, Polonnaruwa, and Puttalam districts|
|Taiwan2||Rare sporadic human cases islandwide||Most human cases reported May–October||Large number of human cases reported until routine JE vaccination introduced in 1968; vaccine not routinely recommended for travel limited to Taipei or other major cities|
|Thailand||Endemic countrywide; seasonal epidemics in the northern provinces||Year-round with seasonal peaks May–October, especially in the north||Highest rates of human disease reported from the Chiang Mai Valley; sporadic human cases reported from Bangkok suburbs|
|Timor-Leste||Limited data; sporadic human cases reported||No data|
|Vietnam||Endemic countrywide; seasonal epidemics in the northern provinces||Year-round with seasonal peaks May–October, especially in the north||Highest rates of disease in the northern provinces around Hanoi and northwestern and northeastern provinces bordering China|
|Western Pacific Islands||Outbreaks of human disease reported in Guam in 1947–1948 and Saipan in 1990||Unknown; most human cases reported October–March||Enzootic cycle might not be sustainable; outbreaks may follow introductions of virus|
1Data are based on published reports and personal correspondence. Risk assessments should be performed cautiously, because risk can vary within areas and from year to year, and surveillance data regarding human cases and JEV transmission are incomplete.
2In some endemic areas, human cases among residents are limited because of vaccination or natural immunity. However, because JEV is maintained in an enzootic cycle between animals and mosquitoes, susceptible visitors to these areas still may be at risk for infection.
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