Peter F. Weller MD, FACP1
1Professor of Medicine, Harvard Medical School, Co-Chief, Infectious Diseases Division, and Chief, Allergy and Inflammation Division, Beth Israel Deaconess Medical Center
The author has received grant or research support from and is an advisor to GlaxoSmithKline.
The provision of health advice and the administration of prophylactic measures can help reduce the morbid and, at times, mortal risks of infectious illnesses that may be acquired during international travel. The Centers for Disease Control and Prevention (CDC) publishes Health Information for International Travel, which provides information on required and recommended vaccinations and malaria prophylaxis, as well as general advice.1 Health Information for International Travel 2003–2004 is available for purchase on the Internet, athttp://www.bookstore.phf.org/cat24.htm, or by phone, at 1-877-252-1200. Other information regarding international travel is readily available on the CDC Web site (http://www.cdc.gov), such as the Green Sheet, which provides reports of cruise-ship sanitation inspections; detailed guidelines on the need for yellow fever immunizations; guidelines on international health issues for travelers by country; recently recognized disease outbreaks; and general guidelines on immunizations and other medical issues for travelers. Information may also be obtained from state public health departments, local physicians or clinics catering to travelers, the embassies of individual countries, and Internet-based advisory services. Even the most up-to-date information sources, however, may not be able to provide precise information on specific diseases prevalent in specific locales, because mechanisms for recognizing and reporting diseases are often lacking in developing areas.
Pretravel Evaluation and Immunizations
Medical consultation should be obtained at least 1 month before international travel to allow time for immunizations [see Table 1]. A general patient medical history should be obtained to define pertinent underlying medical conditions. For instance, splenectomy predisposes a person to more severe malaria, babesiosis, and infections with encapsulated bacteria, including meningococcal infections. A history of allergies to antimicrobial agents or to other components of vaccines should be determined. Knowledge of the duration and purpose of a trip, as well as of the countries and locales to be visited, can help in estimating the risks of exposure to endemic diseases. In addition, specific groups of travelers—including pregnant women; persons with HIV; persons with chronic diseases such as chronic obstructive pulmonary disease, diabetes mellitus, hypercoagulable states, and cardiovascular disease; and health care workers—may require more time before travel to address their potentially altered needs for immunization and prophylaxis.
Table 1 Guidelines for Immunizations for Travelers
The only immunization legally required for entrance into specific countries is that for yellow fever.
Yellow fever is a mosquito-transmitted viral infection, whose severity may range from an influenzalike illness to potentially fatal hepatitis and hemorrhagic fever. Yellow fever occurs only in equatorial Africa and in areas of tropical South America [see Figures 1a and 1b].1Persons older than 6 months visiting countries where yellow fever is known to exist should be immunized. In addition, those traveling outside of urban areas in countries that are in the yellow fever endemic zones but are not officially reporting the infection should be immunized because the disease may be underrecognized. Some countries, especially in Asia, may require yellow fever immunizations for entry, especially for persons who have traveled in potentially endemic countries.1 Yellow fever vaccine, a live virus vaccine grown in chick embryos, is effective.
Figure 1a. Yellow Fever in Africa
Yellow fever (gray areas) is endemic in parts of Africa (shown here) and South America (Figure 1b). Several countries consider these zones infected areas and require an International Certificate of Vaccination against yellow fever from travelers from these zones.
Figure 1b. Yellow Fever in South America
Yellow fever (gray areas) is endemic in parts of Africa (Figure 1a) and South America (shown here). Several countries consider these zones infected areas and require an International Certificate of Vaccination against yellow fever from travelers from these zones.
Although generally safe, yellow fever vaccines are uncommonly associated with encephalitis (referred to as yellow fever vaccine-associated neurotropic disease [YEL-AND]) and a potentially fatal multiorgan system failure (referred to as yellow fever vaccine-associated viscerotropic disease [YEL-AVD]). In the United States, estimated rates of these two complications are four to six cases per million doses for encephalitis and three to five cases per million doses for multiorgan failure.1 However, the risks of illness and death due to yellow fever in an unvaccinated traveler are greater, estimated to be one per 1,000 and one per 5,000 a month, respectively.1 Thus, for those entering yellow fever endemic areas, yellow fever vaccination is indicated; however, vaccine use should be limited to those who are truly at risk. This is especially true for travelers older than 60 years, because they appear to be at greater risk for developing YEL-AVD.2 For these travelers, vaccine may be indicated only if the risk of potential exposure is high (e.g., when travel in endemic areas outside urban centers is anticipated). A history of thymus disorders appears to be a contraindication for vaccine. In an analysis of 23 vaccinated persons who developed YEL-AVD, four (17%) had a history of thymus disease.2 Travelers with a history of thymus disorders or dysfunction, including myasthenia gravis, thymoma, thymectomy, or DiGeorge syndrome, should not receive yellow fever vaccine. If travel to yellow fever-endemic regions cannot be deferred, persons with thymus disorders should be advised to use N,N-diethyl-m-toluamide (DEET) and permethrin to reduce mosquito bites [see Insect Repellents and Avoidance, below].2
Initially, a single subcutaneous dose of 0.5 ml is given. A booster dose is required every 10 years. Immunizations, which are recorded on the International Certificate of Vaccination, are available only from designated physicians and centers, an updated listing of which can be found on the Internet at http://www.2.ncid.cdc.gov/travel/yellowfever. Yellow fever vaccine, which contains both egg proteins and gelatin, rarely causes anaphylaxis.3 For those persons allergic to egg proteins or gelatin, skin testing with yellow fever vaccine (per directions included on the package insert) may help determine whether vaccine can be given safely.
Because yellow fever vaccine is a live virus vaccine, cautions and potential contraindications to its use apply to those who are pregnant, lactating, or immunocompromised. In these persons, if the sole indication for administration of yellow fever vaccine is to satisfy legal requirements for entry, a physician's letter documenting the contraindications to vaccination can be provided to the traveler; in addition, advice should be sought from the embassy or consulate of the country or countries to be visited.
Travelers are at increased risk for influenza infection.1 Influenza, like hepatitis A, has become one of the more common infections in travelers that are preventable by vaccine. In temperate countries, influenza is prevalent in the winter months; whereas in the tropics, influenza transmission occurs year-round. For travelers to the Northern Hemisphere, the risk is greatest during December through February; and for travelers to the Southern Hemisphere, the risk is greatest from April through September. Summertime outbreaks of influenza have occurred on cruise ships in the Northern and Southern hemispheres. For travelers to tropical countries, the risk of influenza exists throughout the year.1
Persons at high risk for influenza, including those older than 50 years, should receive influenza vaccine (1) if influenza vaccine was not received during the preceding fall or winter, (2) if travel is planned to the tropics, (3) if travel is planned with large groups of tourists (e.g., on cruise ships), or (4) if travel is planned during seasons in which influenza is prevalent.1,4 In North America, travel-related influenza vaccination should be administered in the spring, if possible, because vaccine may be unavailable in the summer.
Cholera is caused by toxigenic Vibrio cholerae groups 01 and 0139. Although the number of cases of cholera seen in the United States has increased in recent years, many of the cases have been the result of the illness being imported into the United States by travelers from other countries; tourists from the United States visiting other countries have only rarely been infected. Cholera is acquired by ingestion of contaminated water, ice, or food, including raw or undercooked fish and shellfish. Travelers in endemic regions should be advised of the precautions to be followed to minimize risks of acquiring cholera and other enteric infections [see Travel-Related Illness, below] and of the importance of rehydration in the treatment of cholera. Dietary precautions include consuming only boiled or treated water, eating thoroughly cooked food, avoiding all fruit not peeled by onself, and avoiding undercooked or raw fish or shellfish, including seviche.
Routine immunization is not recommended for travelers.1 In the unlikely event that a locale requires immunization for cholera, immunization would need to be obtained outside the United States in countries in which current cholera vaccine is available. Currently, no country requires proof of cholera immunization as a condition for entry, and the World Health Organization recommends against such a requirement. Some local authorities, however, may require immunization (to determine local requirements, travelers may consult the embassies of the countries to which they will be traveling). The only cholera vaccine licensed for use in the United States is no longer manufactured. In other countries, two cholera vaccines (Dukoral, from Biotec AB, and Mutacol, from Berna) have been licensed for use, but neither of these vaccines is indicated for most travelers.1 Travelers who are at risk for cholera and who expect to travel to areas remote from medical care should take with them packets of oral rehydration salts. Antimicrobial agents often employed for therapy for traveler's diarrhea, such as ciprofloxacin, are usually very effective in helping terminate cholera infections.5
Travelers to countries in which polio is endemic or in which there is a current epidemic are at risk for the disease and should be immunized. Countries considered to be free of wild poliovirus are all countries in the Western Hemisphere, the Western Pacific Region (which includes China), and the European region.1 Polio transmission continues in some developing countries, including Afghanistan, India, Pakistan, Nigeria, and Niger, although efforts to achieve global eradication of polio are ongoing.
Travelers who were immunized previously should receive one booster dose of polio vaccine. Oral live virus vaccine is no longer recommended for immunizations in the United States.4 The inactivated vaccine is preferred to avoid the small risk of paralytic disease from the oral vaccine. Patients with an altered immune status should receive inactivated vaccine. Children who have not been immunized should receive a full series of immunizations with inactivated polio vaccine. Adults who have not been immunized should receive a series of three doses of enhanced-potency inactivated vaccine.1 If there is insufficient time before travel for at least three doses of inactivated vaccine to be given at intervals of 1 to 2 months, the following alternatives are recommended1: if less than 1 month is available before travel, a single dose of inactivated vaccine is given; if between 1 and 2 months is available before travel, two doses of inactivated vaccine are administered 4 weeks apart. Travelers who were incompletely immunized previously should receive the remaining required doses of vaccine.
Tetanus and Diphtheria
A tetanus-diphtheria booster should be administered every 10 years [see 7:V Anaerobic Infections].1 Older persons and women are more likely to lack the tetanus and diphtheria antibodies and thus are more likely to require boosters.7,8
There are no data on the risk to travelers of acquiring pneumococcal infections; however, those at risk, including those older than 65 years [see 7:I Infections Due to Gram-Positive Cocci], are recommended as candidates to receive pneumococcal vaccinations.
Because of the declining prevalence of measles in the United States, disease imported by immigrants and by returning residents accounts for an increasing proportion of cases in this country. Measles may be acquired during travel in developed countries, including those in Europe and Asia, as well as in less developed countries.1 Most persons who were born before 1957 are immune because of natural exposure and do not require vaccination. Persons who were born after 1956 who either have not been immunized or were immunized before 1980 and who have neither serologic evidence of infection nor a history of physician-diagnosed measles should be immunized with a single subcutaneous dose of measles vaccine before travel. Measles vaccine is contraindicated for both pregnant and immunodeficient patients. HIV-infected patients, unless they are severely immunocompromised, should be immunized before travel because measles can be severe and even fatal in persons with HIV infection.1,9
Salmonella typhi infection is prevalent in many areas of Asia, Africa, and Latin America. Typhoid is acquired from contaminated food or water. Although the overall risk of acquiring typhoid during travel remains low (2.3 million cases per million travelers),10 foreign travel accounted for 74% of 1,393 cases of typhoid reported to the CDC between 1994 and 1999.11 The risk was greatest for those traveling to the Indian subcontinent (India, Pakistan, and Bangladesh) and Haiti. Of note, even those traveling for no more than a couple of weeks were at risk of acquiring typhoid. Given the safety of current typhoid vaccines, typhoid vaccination should be considered for short-term travel in high-risk areas, as well as for any travel to areas off the usual tourist itinerary.11
Two typhoid vaccines are available for use in the United States. One typhoid vaccine is an oral vaccine (Vivotif Berna, from Berna) that uses the attenuated Ty21a strain of S. typhi; this vaccine does not cause the local and systemic side effects frequently produced by the older, parenteral vaccine. The oral vaccine is supplied as a packet of four enteric-coated capsules that must be refrigerated. Patients need explicit guidance on refrigerating the vaccine because failure to do so might compromise its efficacy.12 At least 2 weeks before departure, the traveler takes one capsule every other day until all four capsules have been taken. Because mefloquine and antibiotics inhibit the growth in vitro of S. typhi strains, including Ty21a, it is prudent to separate the oral administrations of mefloquine and antibiotics and of Ty21a vaccine by 24 hours.1 It is recommended that a booster dose of Ty21a vaccine, consisting of four capsules taken on alternate days, be given every 5 years to persons who continue to be at risk for exposure to typhoid. The safety of the oral vaccine has not been established for patients with deficient humoral or cell-mediated immunity, and thus, patients with congenital or acquired immunodeficiencies should not receive it. It may be given to children 6 years of age or older.
The second typhoid vaccine is a capsular polysaccharide vaccine for parenteral use (Typhim Vi, from Aventis Pasteur). Primary vaccination consists of one I.M. dose of 0.5 ml; the same dose is administered as a booster every 2 years. The vaccine is well tolerated but, like the oral vaccine, protects only 50% to 80% of recipients.1,13 This vaccine is safe for immunocompromised persons, including HIV-infected patients.1 The only contraindication to its use is a history of serious reactions to the vaccine. It may be given to children 2 years of age and older.
Rabies vaccine—either human diploid cell rabies vaccine (HDCV), purified chick embryo cell vaccine (PCEC), or rabies vaccine adsorbed (RVA)—is an inactivated viral preparation. Immunizations with either of the three vaccine preparations consists of three I.M. doses, 1 ml each, administered on days 0, 7, and 21 or 28.1 Preexposure immunization with rabies vaccine is not indicated for most travelers but should be strongly considered for persons who anticipate contact with wild animals or who are living for a month or more where rabies is endemic. Dog rabies is present in most countries of Asia, Africa, and Central and South America and is prevalent in parts of Brazil, Bolivia, Mexico, El Salvador, Guatemala, Colombia, Ecuador, Peru, India, Nepal, the Philippines, Sri Lanka, Thailand, and Vietnam.1 Preexposure immunization does not eliminate the need for postexposure immunization but abbreviates its course and eliminates the need to administer rabies immune globulin. If left untreated, rabies is fatal, and postexposure rabies immune globulin and postexposure vaccine are frequently unavailable in many areas of the world.
Plague vaccine is no longer commercially available. Vaccination against plague is not indicated for most travelers.1 However, prophylaxis should be considered for travelers to areas in which plague is epidemic or actively epizootic. For adults, tetracycline or doxycycline is appropriate prophylactic therapy; for children younger than 8 years, trimethoprim-sulfamethoxazole is recommended.1
Hepatitis A is prevalent in many less-developed countries [see Figure 2] and is the most common infection acquired by travelers that is preventable by vaccine. In visitors to developing countries, even those staying in luxury hotels, the incidence of hepatitis A in unprotected travelers is about 3 per 1,000 travelers per month of stay, and this rate rises to 20 per 1,000 travelers per month for those eating or drinking under poor hygienic conditions.14
Figure 2. Prevalence of Hepatitis A
The prevalence of hepatitis A is high in those countries shaded blue, intermediate in those shaded gray, and low in the white areas of the map.
Immunization for hepatitis A is recommended for persons who will be traveling or working in countries with intermediate or high endemicity for hepatitis A infection.1 Although hepatitis A previously was prevented solely by the administration of immune globulin, two monovalent inactivated hepatitis A vaccines and a combined hepatitis A and hepatitis B vaccine are now available. The monovalent vaccines, HAVRIX (GlaxoSmithKline) and VAQTA (Merck), have proved safe and highly effective.15 For adults, two I.M. 1.0 ml doses should be administered in the deltoid muscle at 0 and 6 to 12 months. For persons between 2 and 18 years of age, two doses, 0.5 ml each, should be administered at 0 and 6 to 12 months. VAQTA contains no preservative, whereas HAVRIX contains 2-phenoxyethanol. The bivalent hepatitis A and hepatitis B vaccine, TWINRIX (GlaxoSmithKline), is likewise safe and effective and is administered to those 18 years of age or older in three I.M. 1.0 ml doses at 0, 1, and 6 months. TWINRIX contains 2-phenoxyethanol.
With the monovalent vaccines, many persons who have been vaccinated will have detectable antibody responses within 2 weeks after the first dose; 94% to 100% of persons treated will have protective levels of antibody by 1 month after the first dose. The second dose of vaccine provides longer-term protection. If the immunization schedule is unduly interrupted, it is not necessary to restart the full regimen; the second dose may simply be administered. A vaccination series started with one brand of vaccine may be completed with the same or the other brand of hepatitis A vaccine. Travelers who receive vaccine less than 2 weeks before travel are at risk for acquiring hepatitis and should also receive immune globulin, given at an injection site different from the one for vaccine.
For travelers who are allergic to vaccine components or who opt not to receive the vaccine, immune globulin should be administered. Administration of immune globulin should begin shortly before departure in a dose of 2.0 ml I.M. for adults (1.0 ml for patients, including children, weighing 23 to 45 kg; 0.5 ml for those weighing less than 23 kg). If the stay is to be longer than 3 months, the adult dose is 5.0 ml (2.5 ml for patients weighing 23 to 45 kg; 1.0 ml for those weighing less than 23 kg). If the duration of stay is prolonged, the latter dosage schedule should be repeated every 4 to 6 months. Immune globulin should be given at least 2 weeks after measles, mumps, or rubella live virus vaccines. Conversely, these vaccines should be given at least 3 months after immune globulin. Immune globulin does not interfere with the immune response to killed virus vaccines or to yellow fever or polio vaccines.
Because immune globulin has been in limited supply and because the hepatitis A vaccines have proved to be highly effective against hepatitis A infection, which is frequent in travelers, immunization with hepatitis A vaccine has become the principal approach for preventing hepatitis A infection in travelers. The hepatitis A vaccines are safe in pregnancy and immunosuppression.
The risk to travelers of acquiring hepatitis B is generally low, compared with the risk of acquiring hepatitis A. The risk increases, however, in regions where hepatitis B is highly prevalent [see Figure 3], if there is contact with blood or bodily secretions, if sexual contact with infected persons occurs, or if travel is prolonged.1 Immunization for hepatitis B, which is recommended for all persons who work in health care fields with potential exposure to human blood, is especially important for medical workers traveling in countries with high or intermediate hepatitis B endemicity. Hepatitis B immunization should be considered for persons residing for more than 6 months in regions where hepatitis B is endemic and for persons with potential contact with blood (including those receiving tattoos or body piercing), potential sexual contact, or potential need for medical or dental procedures.
Figure 3. Prevalence of Hepatitis B
Hepatitis B is highly endemic in those countries shaded blue (prevalence > 8%). Those regions shaded gray, where the prevalence is 2% to 7%, are considered to be of intermediate endemicity. The prevalence of hepatitis is less than 2% in the white areas of the map.
Two monovalent hepatitis B vaccines are available, both of which include recombinant HBsAg (hepatitis B surface antigen) protein produced in yeast. Except for rare hypersensitivity reactions to vaccine components, including yeast proteins, the two recombinant vaccines are safe and efficacious; there are no other medical contraindications, including pregnancy and immunosuppression, for administration of these vaccines. The two vaccines, Recombivax HB (Merck) and Engerix-B (GlaxoSmithKline), are administered in three I.M. doses: at 0, 1, and 6 months. Engerix-B may also be given in four doses: at 0, 1, 2, and 12 months. Immunization should start 6 months before travel, but if this schedule is not feasible, some protection is afforded by one or two doses administered before travel. Full protection will be achieved in most cases by completion of the three-dose or four-dose schedule.1 For travelers who will depart before the recommended series can be completed, an accelerated regimen, involving doses given on days 0, 7, and 14, can be administered; the accelerated regimen is not approved by the Food and Drug Administration. Travelers receiving the accelerated course should receive a booster at least 6 months later to provide long-term immunity.1
An additional vaccine for hepatitis B is TWINRIX, a combined hepatitis A and hepatitis B vaccine. Primary immunization with TWINRIX consists of three doses administered at 0, 1, and 6 months. The bivalent vaccine can be used to complete immunization series started with monovalent hepatitis A and B vaccines.
Although acquisition of meningococcal disease is uncommon in travelers from the United States, immunization should be considered for travelers to areas with recognized epidemics or to regions where such disease is hyperendemic, especially if prolonged contact with the local populace is anticipated. Epidemics of meningococcal disease are frequent in the area of sub-Saharan Africa extending from Guinea in the west to Ethiopia in the east [see Figure 4]. Vaccination against meningococcal disease is legally required only for pilgrims who make the Hajj pilgrimage to Mecca, Saudi Arabia. Routine immunization is also indicated for persons who have either deficiencies of terminal complement components or functional or anatomic asplenia. The currently available quadrivalent vaccine is composed of meningococcal polysaccharides from Neisseria meningitidis serogroups A, C, Y, and W-135. A single 0.5 ml subcutaneous dose of vaccine is administered to both adults and children and will induce an antibody response in 10 to 14 days.1 Duration of immunity is at least 3 years.
Figure 4. Distribution of Meningococcal Disease in Africa
Epidemics of meningococcal disease are frequent in the area of sub-Saharan Africa that extends from Guinea in the west to Ethiopia in the east.
Japanese encephalitis, an arboviral infection transmitted by mosquitoes, may occur in epidemics during the late summer and autumn in northern tropical areas and temperate regions of some countries. The risk of acquiring Japanese encephalitis infection varies by season and geographic area [see Table 2].1 The disease rarely occurs in Hong Kong or Japan. Persons at highest risk are those who live for extended periods in endemic or epidemic areas. The risk for short-term travelers to urban centers is low, and in temperate countries, the risk for travelers to either an urban or a rural area is negligible during the winter.
Table 2 Risk of Japanese Encephalitis by Country, Region, and Season
Although Japanese encephalitis is highly uncommon, prevention is important for those traveling specifically to epidemic or endemic areas [see Table 2], because the risk of serious neurologic sequelae is high. Exposure to mosquitoes should be minimized by the use of insect repellents, protective clothing, and mosquito screens. Also, vaccination should be considered for persons traveling during summer monsoon months, for those visiting rural areas, and for those planning to stay more than 1 month in urban or rural areas.
Vaccination is not usually recommended for travelers to Singapore or Hong Kong, urban Japan or China, or high-altitude regions in Nepal. An effective formalin-inactivated, mouse-derived vaccine (JE-Vax, Aventis Pasteur) has been licensed by the FDA. Primary immunization for persons older than 3 years consists of three doses, 1 ml each, administered subcutaneously on days 0, 7, and 30. An abbreviated schedule of 0, 7, and 14 days can be used if there is insufficient time before travel to administer the standard immunization. A booster dose of 1 ml may be administered after 2 years. About 20% of recipients of JE-Vax vaccine experience local reactions and mild systemic side effects (e.g., fever, headache, myalgias, and malaise).1
Allergic reactions, including generalized urticaria, angioedema, respiratory distress, and anaphylaxis, have developed in about six per 1,000 recipients; at times, the onset of allergic reaction is delayed for hours or even a week after vaccine administration. Those with a history of urticaria and allergies (including hay fever and reactions to hymenoptera venom) appear to have a greater risk of developing allergic reactions to the vaccine. Reactions have been responsive to epinephrine, antihistamines, steroids, or a combination of these agents.1,16Because of late-developing allergic reactions, immunizations should be completed 10 days before travel; vaccine recipients need to be advised to remain accessible to emergency medical care.
Tick-borne encephalitis is a viral infection of the central nervous system that is transmitted by ticks. The disease occurs in Scandinavia, western and central Europe, and countries of the former Soviet Union. The disease is transmitted principally from April through August, when the tick vector, Ixodes ricinus, is most active. Infections may also be acquired by consumption of unpasteurized dairy products from infected cows, goats, or sheep. Effective vaccines are available in Europe and in many travel clinics in Canada; vaccines are not available in the United States. Vaccination should be considered for travelers who anticipate extensive outdoor exposure (e.g., camping or related activities) in the endemic regions during the spring and summer months.1
Vaccines that contain live attenuated viruses (i.e., oral polio, measles, mumps, rubella, and yellow fever vaccines) should not be given to pregnant women or to persons who have known or potential immunodeficiencies (e.g., leukemia, lymphoma, or a generalized malignant disorder) or who are receiving cortico steroids, alkylating agents, antimetabolites, or irradiation. Oral polio vaccine, which is no longer recommended in the United States, should not be given to a patient if an immunodeficient person resides in the same household. If a pregnant woman cannot defer travel to areas of high risk for yellow fever, yellow fever vaccine may be given.1 For travelers infected with HIV, immunization with live oral polio and attenuated oral typhoid vaccines should be avoided in favor of killed parenteral vaccines. The risks of live yellow fever vaccine have not been defined for HIV-infected persons, but persons with asymptomatic HIV infection who cannot avoid exposure in areas endemic for yellow fever should be offered the choice of immunization.1 Because measles can be severe in patients with HIV, measles immunization should be provided, unless the patient is severely immunocompromised (i.e., total CD4+ T cell count < 200 µl).9
Contraindications to vaccination also include hypersensitivity to components of the vaccine. Neomycin and gelatin are present in some vaccines. Persons who have immediate hypersensitivity reactions to neomycin, gelatin, or preservative agents should avoid vaccines containing these substances. Yellow fever vaccine, which contains egg proteins and gelatin, may be contraindicated in patients who have allergic reactions to these proteins. In general, there is a poor correlation between a history of egg sensitivity and skin-test reactivity to egg antigen. The most reliable predictor of reactions to egg-containing vaccines is skin testing with the vaccine itself.1 If travel plans cannot be changed, persons who have positive skin tests or known egg hypersensitivity (i.e., urticaria, oropharyngeal swelling, bronchospasm, or hypotension) should be given a letter documenting the contraindication to immunization and obtain a waiver before travel from the embassy of any country requiring yellow fever immunization.
INSECT REPELLENTS AND AVOIDANCE
To reduce the risk of all mosquito-borne infections (e.g., malaria, yellow fever, and dengue fever), travelers should be instructed about the importance of minimizing the potential for insect bites. The most effective insect repellents contain DEET.17,18 DEET is available in many products in concentrations ranging from 25% to more than 75% and repels mosquitoes, ticks, fleas, and biting flies. Protection lasts for several hours but is shortened by losses from swimming, washing, rainfall, sweating, and wiping. A long-acting formulation, which contains polymer to limit the losses of DEET that result from dermal absorption and evaporation, has been developed by the military and is available in the United States as Ultrathon (3M).
The absorption of DEET through the skin can cause such adverse reactions as dermatitis, allergic reactions, and neurotoxicity. Potential toxicity can be avoided by using solutions of 30% to 35% DEET and following instructions for its use. The repellent should be applied sparingly to clothing and exposed skin only. The product should be applied carefully to avoid introducing it into the eyes, to avoid contact with wounds and sensitive skin, and to prevent inhalation or ingestion. Clothing and bed netting can also be treated with permethrin for protection against mosquitoes and ticks.19 Treated clothing will effectively repel mosquitoes for more than 1 week even with washing and field use. Permethrin is available, often in outdoor supply stores, as a nonstaining aerosol clothing spray (e.g., Permanone Tick Repellent).
The provision of appropriate malaria chemoprophylaxis is the most important preventive measure for travelers to malarious areas. Several hundred United States civilians contract malaria each year,1 and infections from Plasmodium falciparum are potentially lethal and do cause deaths in travelers [see 7:XXXIV Protozoan Infections].20 Morbidity and mortality are largely avoidable with chemoprophylaxis. Malaria is prevalent in parts of Mexico, Haiti, Central and South America, Africa, the Middle East, Turkey, the Indian subcontinent, Southeast Asia, China, the Malay archipelago, and Oceania. Chloroquine-resistant P. falciparum (CRPF) malaria occurs in most areas [see Figure 5]. Details on the prevalence by country and regions within countries of both malaria and CRPF malaria are reported annually by the CDC and may be accessed online (http://www.cdc.gov/travel/yb/index.htm).1 Because even brief exposures to infected mosquitoes can transmit malaria infections, travel in malarious regions, no matter how brief, mandates the use of chemoprophylaxis. When uncertainty exists over the need for chemoprophylaxis, it should be initiated. If a traveler can ascertain that malaria is not a risk after arriving in an area, prophylaxis can be terminated as long as further travel into malarious areas is not planned.
Figure 5. Distribution of Chloroquine-resistant Malaria
This map displays the distribution of the chloroquine-resistant malaria (gray areas) and chloroquine-sensitive malaria (blue areas) in the Americas and in Asia, Europe, and Africa.
Travelers should be advised that it is possible to acquire malaria despite prophylaxis and regardless of the prophylactic regimen used. Symptoms can begin as early as 8 days after infection or as late as several months after departure from a malarious area. Travelers should be cautioned to seek medical attention promptly for any febrile illness and to inform the physician of their prior itinerary. The wisdom of general protective measures against mosquito bites should also be stressed for all travelers to malarious areas. Because the vector mosquitoes usually feed at night, it is advisable to diminish exposure between dusk and dawn by remaining in screened areas; using mosquito netting, ideally treated with permethrin; covering exposed skin with clothing; and using insect repellent.
The choice of appropriate chemoprophylactic agents against malaria depends on the geographic areas to be visited and, importantly, whether these areas are endemic for CRPF [see Figure 5]. If travel is not to include areas where CRPF has been reported (e.g., Central America and the Caribbean), chloroquine remains the chemoprophylactic agent of choice. For most of the world, however, alternatives to chloroquine are required. Mainline alternatives to chloroquine include mefloquine and atovaquone-proguanil (Malarone).
For those limited geographic regions not yet experiencing CRPF [see Figure 5], the chemoprophylactic agent of choice is chloroquine, given as either chloroquine phosphate (Aralen) or hydroxychloroquine sulfate (Plaquenil).1 Chloroquine phosphate, 500 mg (300 mg of chloroquine base), or hydroxychloroquine sulfate, 400 mg (310 mg of hydroxychloroquine base), should be taken once weekly beginning 1 to 2 weeks before travel and continuing during the stay and for 4 weeks after departure from malarious areas. Minor side effects, including gastrointestinal disturbances, dizziness, blurred vision, and headache, may be alleviated by taking the drug after meals. Serious side effects are rare. Specifically, retinal injury, which can occur when high doses of chloroquine are used to treat rheumatoid arthritis, does not occur with the weekly dosages used for malaria prevention, even when such a regimen is continued for 5 years. However, deaths from malaria have occurred among tourists from the United States who avoided chloroquine prophylaxis out of a misguided concern for ocular toxicity.
Mefloquine (Lariam) is active against CRPF and against P. falciparum that is resistant to sulfadoxine with pyrimethamine (Fansidar). With the now-widespread geographic prevalence of CRPF [see Figure 5], either mefloquine or atovaquone-proguanil is for many travelers the mainstay of malarial chemoprophylaxis. Strains of P. falciparum that are resistant to mefloquine, however, have been recognized in Africa and along the border between Thailand and Cambodia. Mefloquine, 250 mg, is taken once a week, beginning 1 to 2 weeks before travel and continuing during the stay and for 4 weeks after departure from a malarious area.1 (This schedule is similar to that for chloroquine.) For travelers who will be immediately arriving in malarious areas, a loading dose of mefloquine (250 mg daily for the first 3 days) is advisable.
Despite the benefits of mefloquine to travelers in regions with CRPF malaria, mefloquine has acquired an unsalutary reputation. Mefloquine causes side effects, including nausea, dizziness, vertigo, light-headedness (described as an inability to concentrate), bad dreams, seizures, and psychosis. These reactions occur principally when the drug is given at therapeutic doses, which are higher than those given for prophylaxis. The incidence of psychosis or seizures has been about one per 10,000 travelers treated with chemoprophylactic mefloquine, which is comparable to the incidence associated with chloroquine use.21 Other controlled trials have demonstrated that mefloquine is reasonably well tolerated in groups receiving this agent.22,23,24 Thus, the uncommon and self-limited, but bothersome, side effects of mefloquine are to be weighed against the very real risks of serious and fatal malaria in many nonimmune travelers.
Mefloquine use has also been associated with sinus bradycardia and prolongation of the QT interval. Therefore, mefloquine probably should not be used by persons with cardiac conduction abnormalities but may be used by patients without arrhythmias who are taking beta blockers.1 Other contraindications to mefloquine include a history of serious neuropsychiatric disorders or seizures. Mefloquine appears to be safe and effective for young children.25 Studies indicate that use of mefloquine in pregnancy during the second and third trimesters is not associated with adverse fetal or pregnancy outcomes; more limited data suggest that mefloquine is probably safe during the first trimester.26,27,28 Mefloquine has no deleterious effects on fine motor skills, such as those required by airplane pilots.29
Atovaquone-proguanil (Malarone) is available in many countries, including the United States, for the chemoprophylaxis of malaria. Atovaquone-proguanil is formulated as a fixed-dose tablet in adult strength (250 mg atovaquone/100 mg proguanil) and in pediatric strength (62.5 mg atovaquone/25 mg proguanil). For prophylaxis, one tablet is taken daily, beginning 1 to 2 days before travel and continuing for the duration of travel and for 1 week after departure from malarious areas. One, two, or three pediatric-strength tablets are taken by children weighing 11 to 20 kg, 21 to 30 kg, or 31 to 40 kg, respectively.
Atovaquone-proguanil is well tolerated; side effects, which are uncommon, are abdominal pain, nausea, vomiting, head ache, and rash. Atovaquone-proguanil is safe and efficacious for prophylaxis of P. vivax and P. falciparum malaria, including CRPF. For P. vivax and P. ovalemalaria, atovaquone-proguanil, like mefloquine and chloroquine, does not prevent development of hepatic hypnozoite stages, so treatment with primaquine (so-called terminal prophylaxis) may be necessary to prevent relapses with these species [see Primaquine, below]. Atovaquone-proguanil, therefore, is an alternative to mefloquine for malaria chemoprophylaxis1 in regions of Thailand, Myanmar (Burma), and Cambodia where mefloquine-resistant P. falciparum malaria is present.
Doxycycline, taken alone, is an alternative chemoprophylactic agent.1 It should be taken in a dosage of 100 mg daily, beginning 1 to 2 days before travel and continuing for 4 weeks after departure from malarious areas. The use of doxycycline is appropriate for persons who are intolerant of sulfonamides, pyrimethamine, chloroquine, or mefloquine and for persons who are planning short-term visits in forested areas of Thailand, Myanmar (Burma), or Cambodia, where strains of malaria that are resistant to chloroquine, mefloquine, and sulfadoxine with pyrimethamine (Fansidar) are present.1 Doxycycline may cause photosensitivity skin reactions and is contraindicated in pregnant women and in children younger than 8 years.
Proguanil (Paludrine) is not available in the United States but is available in Canada, Europe, and much of Africa. This agent, like pyrimethamine, is a dehydrofolate reductase inhibitor, and some strains of malaria are resistant to it. Proguanil (200 mg) is taken daily in combination with a weekly dose of chloroquine. The combination of proguanil and chloroquine, however, is much less effective than mefloquine or atovaquone-proguanil against chloroquine-resistant P. falciparum malaria and hence is not recommended.1,30
Primaquine may be used either as a single agent taken daily for chemoprophylaxis against all species of malaria or as an agent to eradicate residual intrahepatic stages of P. vivax and P. ovale. For the latter purpose, primaquine is administered during the last weeks of or just after a course of prophylaxis with either chloroquine or mefloquine. When intended as terminal prophylaxis, primaquine may be administered as 30 mg of the base daily for 14 days. Such terminal prophylaxis is generally reserved for persons who have had more than a casual potential exposure to P. vivax or P. ovale; other persons may be followed clinically and evaluated if they become symptomatic. For use as a primary chemoprophylactic agent, 30 mg of primaquine base is taken daily starting 1 day before travels and continuing for 2 days after departure from a malarious area.31
Because primaquine can cause severe hemolysis in patients who have glucose-6-phosphate dehydrogenase (G6PD) deficiency, this disorder must be excluded before the drug is administered. As a chemoprophylactic agent, primaquine is reserved for the rare individual who is unable to take other recommended chemoprophylactic regimens. CDC suggests primaquine be used only after consultation with malaria experts, including those at the CDC Malaria Hotline (1-770-488-7788).1
Sulfadoxine with Pyrimethamine
For chemoprophylaxis in areas where CRPF malaria occurs, it was formerly recommended that a single tablet of Fansidar, which contains 500 mg of long-acting sulfadoxine and 25 mg of pyrimethamine, be taken once a week along with chloroquine beginning 1 to 2 weeks before arrival in an endemic area and continuing for 4 weeks after departure from such an area. However, severe mucocutaneous reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have developed after the use of two or more doses of Fansidar. These reactions produced fatalities with an incidence of about one per 11,000 to 20,000 travelers from the United States. Moreover, P. falciparum malaria is increasingly resistant to antifolate agents. Consequently, Fansidar is not recommended for chemoprophylactic use.
PROPHYLAXIS DURING PREGNANCY
Malaria infections represent a major health hazard to the mother and fetus.32,33 Infections are potentially more serious during pregnancy and increase the risks of stillbirths, abortions, and other adverse pregnancy outcomes. For pregnant women who cannot defer travel or residence in malarious areas, chloroquine, which is without established teratogenicity, may be used.1 Mefloquine appears to be safe in pregnancy.26,27,28 For the pregnant traveler in regions with CRPF malaria, the benefits of effective mefloquine chemoprophylaxis need to be balanced with any potential, but as yet not recognized, adverse effects of mefloquine in pregnancy. Sulfadoxine should be avoided before delivery because of the risk of neonatal jaundice. Pyrimethamine, which is teratogenic in animals because it interferes with folate metabolism, is generally avoided but probably could be used. Doxycycline should not be used during pregnancy because of the effects of tetracyclines on the fetus, which include dental discoloration and dysplasia and inhibition of bone growth. To avoid the risk of inducing hemolytic anemia in utero in a G6PD-deficient fetus, primaquine should not be taken during pregnancy. The safety of malarone in pregnancy has not been established.
In a study of more than 10,000 Swiss who had traveled in developing countries for less than 3 months, 15% experienced health problems, and 3% were unable to work for an average of 15 days.34 Infections with the greatest incidence per month abroad included giardiasis (seven cases per 1,000 months abroad), amebiasis (four cases per 1,000), hepatitis (four cases per 1,000), and gonorrhea (three cases per 1,000). Malaria, syphilis, and helminthic infections occurred at a lower incidence (fewer than one case per 1,000). No cases of typhoid fever or cholera were reported. The most common modes of acquisition of infection were enteral and sexual. Travelers should be cautioned about sexual contacts, especially in areas where hepatitis B or HIV is prevalent, and be advised to use condoms and barrier protection during sexual encounters.
Because of the global prevalence of HIV, postexposure antiretroviral prophylaxis may be germane for travelers who may have occupational exposures (e.g., health care workers) and for students and workers who are traveling and may be at risk for HIV exposure. The availability of local postexposure prophylactic medications should be ascertained at overseas work or study sites. Options for two- or three-drug regimens of postexposure antiretroviral therapy are discussed elsewhere [see 7:XXXIII HIV and AIDS]. If selected antiretroviral therapy is not assuredly available at work or study sites, sufficient medication should be carried by the traveler to ensure that a 28-day course of antiretroviral therapy is available.
Stays at major resorts and first-class hotels are associated with less risk than stays in less frequented locales or rural dwellings or encampments. In areas where sanitation and personal hygiene may be poor, it is prudent to be careful of food and water, although such care does not necessarily diminish the risk of diarrheal disease. Fruit that is peeled by the traveler is safe, whereas vegetables may be contaminated with fecally passed organisms in the soil and should not be consumed raw. Unpasteurized dairy products should be avoided, as should inadequately cooked fish or meat. If water is of uncertain quality, travelers should avoid drinking it or using ice made from it. Boiling will render water safe. Chlorination will kill most bacterial and viral pathogens, but protozoal cysts of Giardia lamblia and Entamoeba histolytica may survive. Carbonated beverages, beer, wine, and drinks made from boiled water are safe.
In areas where schistosomiasis is prevalent, swimming in freshwater should be avoided, although swimming in chlorinated or saltwater is safe. Even short exposures to infested water during rafting or swimming have caused the onset of acute schistosomiasis.
Most infections acquired during travels will present within weeks of travel, but some may not manifest themselves until much later; hence, knowledge of a patient's travel history is important.
Altitude illnesses may develop in travelers who arrive at heights between 6,000 and 8,000 ft (1,829 and 2,438 m) above sea level.1Travelers may arrive at these altitudes rapidly by flying into an airport at these elevations or more slowly by driving or climbing. Altitude illness includes three syndromes: acute mountain sickness (AMS), high-altitude pulmonary edema (HAPE), and high-altitude cerebral edema (HACE). AMS, the most common form of altitude illness, may occur at altitudes between 4,000 and 6,000 ft. Symptoms include headache, fatigue, loss of appetite, nausea, and, sometimes, vomiting. AMS usually develops 6 to 12 hours after arrival at the higher altitude. HACE is a progression of AMS characterized by extreme lethargy, confusion, and an ataxic gait during a tandem gait test.
HAPE may develop alone or in conjunction with HACE. Symptoms include increasing breathlessness. HAPE is more likely than HACE to be fatal. Travelers who develop HACE or HAPE must immediately descend to lower altitudes. Travelers to elevated altitudes need to be cautioned about the symptoms of these syndromes [see 14:X Pulmonary Edema], advised about the gravity of HACE and HAPE, and admonished not to delay descent to lower altitudes if these potentially lethal syndromes develop.
Three medications can be used to prevent and treat altitude illnesses. Acetazolamide can prevent AMS if taken before ascent; it also can hasten recovery. Dosing is 125 mg every 12 hours beginning the day of ascent. Dexamethasone (4 mg every 6 hours) can be used to prevent and treat AMS and HACE. Some investigators recommend relying on acetazolamide for prophylaxis and reserving dexamethasone for treatment of symptoms.1 Persons who have experienced HAPE are at increased risk of its recurrence. If travel to high altitudes is unavoidable, nifedipine (10 to 20 mg every 8 hours) can prevent and ameliorate HAPE in those prone to experience this syndrome.
Diarrhea is the most common illness of travelers.35 Infectious agents, primarily bacterial but also viral and parasitic pathogens, are responsible for traveler's diarrhea. Over 75% of cases of traveler's diarrhea are caused by bacteria, with enterotoxigenic Escherichia colibeing the most frequent cause. Other common bacterial causes of traveler's diarrhea include Shigella species, Campylobacter jejuni, Aeromonas species, Plesiomonas shigelloides, Salmonella species, and noncholera Vibrio species.35 Rotavirus and Norwalk agent are the most common viral causes; Giardia, Cryptosporidium, Cyclospora, and, less commonly, Dientamoeba fragilis, Isospora belli, Balantidium coli, Strongyloides stercoralis, and E. histolytica are parasitic causes.
In addition to exercising caution about food and water,36 travelers may take either of two approaches: chemoprophylaxis and postonset treatment.
The benefits of chemoprophylaxis may be offset by the risks of taking chemoprophylactic agents. Side effects of short-term prophylactic doses of bismuth subsalicylate may include tinnitus, blackening of the stool and tongue, and impaired absorption of doxycycline, which is important if doxycycline is used as daily antimalarial chemoprophylaxis. Side effects of antibiotics may include skin rashes and vaginal candidiasis, photosensitivity skin eruptions (especially with doxycycline), and, in rare instances, potentially life-threatening bone marrow suppression, mucocutaneous reactions, or anaphylaxis. Although these potential side effects temper the routine use of chemoprophylaxis, specific needs or wishes of travelers may dictate its use. Patients with underlying medical conditions that may be aggravated by a serious diarrheal illness, including active inflammatory bowel disease, type 1 (insulin-dependent) diabetes mellitus, and heart disease in the elderly, as well as patients whose activities during travel cannot tolerate interruption by an episode of diarrheal illness, should consider chemoprophylaxis. Several regimens are available [see Table 3]. Bismuth subsalicylate, which should not be taken by persons with peptic ulcer disease, coagulopathies, or allergies to salicylates, is not as completely effective as quinolone antibiotics but has fewer side effects and enables the use of quinolone antibiotics, if they are needed for therapy. Resistance among bacterial causes of traveler's diarrhea is not common at present for the quinolone antibiotics (except for quinolone-resistant Campylobacter infection prevalent in Thailand) but is quite common for trimethoprim-sulfamethoxazole and doxycycline, limiting their efficacy. Chemoprophylactic medications should be started on the first day of arrival and continued for 1 to 2 days after returning home but not for more than 3 weeks.
Table 3 Chemoprophylaxis and Treatment of Traveler's Diarrhea
A generally preferable alternative to chemoprophylaxis is early therapy for traveler's diarrhea [see Table 3]. Because of the likelihood of bacterial resistance, trimethoprim-sulfamethoxazole is less effective than regimens employing quinolone antibiotics. Antibiotics will shorten the duration of traveler's diarrhea to a range of 16 to 30 hours, compared with a range of 59 to 93 hours in those not receiving antibiotics. The use of loperamide, which diminishes intestinal motility and fluid and electrolyte losses, together with antibiotics can further abbreviate symptoms. In a study of patients with dysentery caused by Shigella or enteroinvasive E. coli, the use of loperamide with ciprofloxacin, in comparison with ciprofloxacin alone, led to briefer (median, 19 hours versus 42 hours) and milder (median, two stools versus 6.5 stools) diarrheal illness, without untoward effects.37 Loperamide has not been studied in children, and adults with prolonged fever or bloody stools should be advised to cease loperamide use and seek medical attention. Azithromycin is an alternative to quinolone antibiotics that can be used by pregnant patients; it is the agent of choice where quinolone-resistant Campylobacter infection is prevalent. Rifaximin (Xifaxan, from Salix), a nonabsorbable agent, is approved by the FDA for traveler's diarrhea caused by noninvasive strains of Escherichia coli.38 Rifaximin should not be used if dysentery is suspected (i.e., if symptoms include fever and bloody stools) or if other causes of diarrhea (e.g.,Campylobacter, Shigella, or invasive E. coli) are possible or isolated.
For any diarrheal illness, maintenance of hydration is of cardinal importance and can often be achieved by oral replacement of lost fluid and electrolytes. Convenient and inexpensive packets of oral rehydration salts formulated according to World Health Organization recommendations (i.e., 3.5 g of sodium chloride, 1.5 g of potassium chloride, 20 g of glucose, and 2.9 g of trisodium citrate in each packet) are available in both developed and developing countries. Each packet of oral rehydration salts is added to a liter of boiled or treated water and should be consumed or discarded within 12 hours if kept at ambient temperature or within 24 hours if kept refrigerated.
MEDICAL ISSUES DURING TRANSIT
Cruise ships that dock at ports in the United States are inspected for sanitation by officials from the CDC. Inspections are aimed at minimizing the potential for outbreaks of gastrointestinal disease on board. Travelers may obtain information on whether specific cruise ships meet sanitation standards from travel agents, state health departments, or the CDC.1 Outbreaks of influenza have occurred aboard cruise ships in the past 10 years in various regions, including Alaska and the Yukon Territory. Travelers older than 50 years should consider influenza vaccination.
Because jet aircraft are not pressurized to sea level, passengers will be exposed to high-altitude environments. The atmospheric pressure maintained within the cabin of an airplane flying at 27,000 to 42,000 ft is equivalent to the pressure at an altitude of 3,000 to 8,000 ft, so that at a cruising altitude of 35,000 ft, the cabin pressure is about 600 mm Hg. Because of the decreased pressure, the arterial oxygen tension (PaO2) of normal persons will fall to about 68 mm Hg. In patients with chronic obstructive lung disease, the PaO2 will fall even lower. However, despite a fall in PaO2, patients may not show symptoms of hypoxia. Although hypoxia occurs in pregnant women, jet air travel has no deleterious effects on them or their fetuses. It is difficult to establish precise criteria for the use of supplemental oxygen for air travelers. Caution is indicated, however, for patients with impaired cardiopulmonary function: supplemental oxygen may be administered during flights at altitudes higher than 22,500 ft.
Scuba divers should wait 12 to 48 hours, depending on the length of their diving exposures, before boarding a commercial aircraft. This measure is important for avoiding the occurrence of aeroembolism, commonly known as the bends, which could develop in an underpressurized cabin if nitrogen gas dissolved in the person's fat cells is mobilized.
In patients with upper respiratory tract infections, differential air pressures between blocked eustachian tubes or sinuses and the cabin may develop on ascent or descent and impair hearing or cause pain in the ears or sinuses; symptoms can be relieved by the use of decongestants. Persons prone to motion sickness should take a prophylactic medication. Prolonged immobilization during flight may cause venous thrombosis in persons with preexisting thrombotic or venous disease [see 1:XVIII Venous Thromboembolism]. The exact risks and rates for developing venous thromboembolism during air travel are not yet defined.39 Leg exercise and walking during the flight and use of below-the-knee stockings have been suggested to be beneficial, but evidence is lacking.
Figures 1a, 1b, 2, 3, 4, 5 Tom Moore.
Editors: Dale, David C.; Federman, Daniel D.