Chapter 3Infectious Diseases Related To Travel
Susan L. Hills, Ingrid B. Weber, Marc Fischer
Japanese encephalitis (JE) virus is a single-stranded RNA virus that belongs to the genus Flavivirus and is closely related to West Nile and Saint Louis encephalitis viruses.
JE virus 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.
JE virus 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 JE virus has not been detected in Africa, Europe, or the Americas. Transmission principally occurs in rural agricultural areas, often associated with rice cultivation and flood 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 prolonged or even occur year-round.
In endemic countries, where adults have acquired immunity through natural infection, JE is primarily a disease of children. However, travel-associated JE can occur among people of any age. For most travelers to Asia, the risk for JE is extremely low but varies based on destination, duration, season, and activities.
From 1973 through 2011, there were 58 published reports of travel-associated JE among travelers from nonendemic countries. From the time of licensure of a JE vaccine in the United States in 1992 through 2011, only 7 JE cases among US travelers have been reported to CDC.
The overall incidence of JE among people from nonendemic countries traveling to Asia is estimated to be <1 case per 1 million travelers. However, expatriates and travelers who stay for prolonged periods in rural areas with active JE virus 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 some endemic areas there are few human cases among residents because of natural immunity among older people or vaccination; however, JE virus is usually still maintained in these areas in an enzootic cycle between animals and mosquitoes. Therefore, susceptible visitors may be at risk for infection.
Most human infections with JE virus are asymptomatic; <1% of people infected with JE virus develop clinical disease. Acute encephalitis is the most commonly recognized clinical manifestation of JE virus 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 JE virus infection.
- Seizures are common, especially among children.
- Common clinical laboratory findings include 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 serious 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 JE virus infection should be performed by using a JE virus–specific IgM-capture ELISA on CSF or serum. JE virus–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 JE virus–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 JE virus or 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 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.
Personal Protection Measures
The best way to prevent mosquitoborne diseases, including JE, is to avoid mosquito bites (see Chapter 2, Protection against Mosquitoes, Ticks, & Other Insects & Arthropods).
One JE vaccine is licensed and available in the United States—an inactivated Vero cell culture–derived vaccine, Ixiaro (Table 3-06). Ixiaro, manufactured by Intercell and distributed by Novartis Vaccines, was approved in March 2009 for use in people aged ≥17 years and in May 2013 for use in children aged 2 months through 16 years. Other inactivated and live attenuated JE vaccines are manufactured and used in other countries but are not licensed for use in the United States.
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 JE, 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 a 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 (Table 3-07). The data in the table should be interpreted cautiously, because JE virus 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 JE virus 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 JE virus transmission. Vaccine should also be considered for the following:
- Short-term (<1 month) travelers to endemic areas during the JE virus transmission season, if they plan to travel outside an urban area and their activities will increase the risk of JE virus 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 JE virus transmission season.
Vaccine 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 JE virus 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.
The primary immunization schedule for Ixiaro is 2 doses administered intramuscularly on days 0 and 28. 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 clinical trial assessing duration of protection, 83% of adults who received 2 doses of Ixiaro maintained protective levels of antibodies at 12 months after the first vaccine dose. In a second study, 58% and 48% of adults had protective antibodies at 12 and 24 months, respectively, and in a third, 69% of adults had protective antibodies at 15 months.
For adults, if the primary series of Ixiaro was administered ≥1 year previously, a booster dose should be given before potential reexposure or if there is a continued risk for JE virus 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, and on the need for a booster does in children, are also not available.
There are limited data on the use of Ixiaro as a booster dose after a primary series with the mouse brain–derived inactivated JE vaccine. Two studies have been conducted, one in US military personnel and the other at 2 travel clinics in Europe. Both studies demonstrated that in adults who had previously received at least a primary series of mouse brain–derived inactivated JE vaccine, a single dose of Ixiaro adequately boosted neutralizing antibody levels and provided at least short-term protection. Both studies measured antibody responses at 4–8 weeks after the booster dose; therefore, additional studies are needed to determine the duration of protection after a single dose of Ixiaro in prior recipients of a mouse brain–derived vaccine. Until those data are available, people who have received JE-Vax, the mouse brain–derived vaccine formerly used in the United States, and require further vaccination against JE virus, should receive a 2-dose primary series of Ixiaro.
Vaccine Safety and Adverse Reactions
Local symptoms of pain and tenderness were the most commonly reported symptoms in a safety study with 1,993 adult participants who received 2 doses of Ixiaro. Headache, myalgia, fatigue, and an influenzalike illness were each reported at a rate of >10%. In children, fever was the most commonly reported systemic reaction in studies. 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 ongoing to further evaluate the safety of Ixiaro in a larger population.
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. 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 JE virus infection is high should be vaccinated when the theoretical risk of immunization is outweighed by the risk of infection.
CDC website: www.cdc.gov/japaneseencephalitis/
(Updated September 18, 2013)
Table 3-06. Vaccine to prevent Japanese encephalitis (JE)
|VACCINE||TRADE NAME (MANU-
|JE vaccine, inactivated||Ixiaro (Intercell)||≥17 years||0.5 mL||IM||0, 28 days||≥1 year after primary series|
|3 years through 16 years||0.5 mL||IM||0, 28 days||Data not yet available|
|2 months through 2 years||0.25 mL||IM||0, 28 days||Data not yet available|
Abbreviation: IM, intramuscular.
1If potential for JE virus exposure continues.
(Updated September 18, 2013)
Table 3-07. Risk for Japanese encephalitis (JE), by country1
|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||Presumed widespread||Most human cases reported May–October||Sentinel surveillance has identified human cases in Chittagong, Dhaka, Khulna, Rajshahi, and Sylhet Divisions; highest incidence reported from Rajshahi Division; outbreak reported from Tangail District, Dhaka Division, in 1977|
|Bhutan||Very rare reports; probably endemic in nonmountainous areas||No data||Proximity to other endemic areas and presence of vectors suggests virus transmission is likely|
|Brunei||No data; presumed to be endemic countrywide||Unknown; presumed year-round transmission||Proximity to other endemic areas suggests virus transmission is likely|
|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 15 of 23 provinces, including Phnom Penh, Takeo, Kampong Cham, Battambang, Svay Rieng, and Siem Reap; case reported recently in a traveler who visited Phnom Penh and Angkor Wat/Siem Reap only|
|China||Human cases reported from all provinces except Xizang (Tibet), Xinjiang, and Qinghai.||Most human cases reported during June–October||Highest rates reported from Guizhou, Shaanxi, Sichuan, and Yunnan provinces, and Chongqing City. Vaccine not routinely recommended for travel limited to Beijing, Shanghai, Hong Kong City/Kowloon, Macau, or other major cities (Updated August 20, 2013)|
|India||Human cases reported from all states except Dadra, Daman, Diu, Gujarat, Himachal Pradesh, Jammu and 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||Limited data; presumed to be endemic countrywide||No data; proximity to South Korea suggests peak transmission is likely to occur May–October|
|Korea, South2||Rare sporadic human 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||Vaccine not recommended|
|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; probably year-round||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; sentinel surveillance has identified human cases in 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||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; several cases reported recently in travelers who visited resort or coastal areas of southern Thailand.|
|Timor-Leste||Sporadic human cases reported; presumed to be endemic countrywide||No data; cases reported year-round in neighboring West Timor|
|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; vaccine not recommended|
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 natural immunity among older people or vaccination. 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.
- Campbell GL, Hills SL, Fischer M, Jacobson JA, Hoke CH, Hombach JM, et al. Estimated global incidence of Japanese encephalitis: a systematic review. Bull World Health Organ. 2011 Oct 1;89(10):766–74, 74A–74E.
- CDC. Japanese encephalitis among three US travelers returning from Asia, 2003–2008. MMWR Morb Mortal Wkly Rep. 2009 Jul 17;58(27):737–40.
- CDC. Japanese encephalitis in two children—United States, 2010. MMWR Morb Mortal Wkly Rep. 2011 Mar 11;60(9):276–8.
- CDC. Recommendations for use of a booster dose of inactivated Vero cell culture–derived Japanese encephalitis vaccine: advisory committee on immunization practices, 2011. MMWR Morb Mortal Wkly Rep. 2011 May 27;60(20):661–3.
- Fischer M, Lindsey N, Staples JE, Hills S. Japanese encephalitis vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010 Mar 12;59(RR-1):1–27.
- Hills SL, Griggs AC, Fischer M. Japanese encephalitis in travelers from non-endemic countries, 1973–2008. Am J Trop Med Hyg. 2010 May;82(5):930–6.
- Jeurissen A, Strauven T. A case of aseptic meningitis due to Japanese encephalitis virus in a traveller returning from the Philippines. Acta Neurol Belg. 2011 Jun;111(2):143–5.
- Schuller E, Klingler A, Dubischar-Kastner K, Dewasthaly S, Muller Z. Safety profile of the Vero cell–derived Japanese encephalitis virus (JEV) vaccine IXIARO(®). Vaccine. 2011 Nov 3;29(47):8669–76.
- Shlim DR, Solomon T. Japanese encephalitis vaccine for travelers: exploring the limits of risk. Clin Infect Dis. 2002 Jul 15;35(2):183–8.
- Tauber E, Kollaritsch H, Korinek M, Rendi-Wagner P, Jilma B, Firbas C, et al. Safety and immunogenicity of a Vero-cell-derived, inactivated Japanese encephalitis vaccine: a non-inferiority, phase III, randomised controlled trial. Lancet. 2007 Dec 1;370(9602):1847–53.
- Tauber E, Kollaritsch H, von Sonnenburg F, Lademann M, Jilma B, Firbas C, et al. Randomized, double-blind, placebo-controlled phase 3 trial of the safety and tolerability of IC51, an inactivated Japanese encephalitis vaccine. J Infect Dis. 2008 Aug 15;198(4):493–9.
- Werlinrud AM, Christiansen CB, Koch A. Japanese encephalitis in a Danish short-term traveler to Cambodia. J Travel Med. 2011 Nov–Dec;18(6):411–3.
- Woolpert T, Staples JE, Faix DJ, Nett RJ, Kosoy OI, Biggerstaff BJ, et al. Immunogenicity of one dose of Vero cell culture–derived Japanese encephalitis (JE) vaccine in adults previously vaccinated with mouse brain–derived JE vaccine. Vaccine. 2012 Apr 26;30(20):3090–6.
- World Health Organization. Japanese encephalitis vaccines. Wkly Epidemiol Rec. 2006 Aug 25;81(34/35):331–40.
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