SECTION 6 International Medicine: Principles of International Health
Travel Medicine JANE N. ZUCKERMAN
KEY CONCEPTS • With more than a million international tourists traveling around the world in 2013, and with an increasingly interconnected world, the discipline of travel medicine has never been more important in the prevention of travel-related disease in individuals and populations.
itineraries, and newly licensed vaccines and preventive medications, specialized travel clinics are available in many countries which have healthcare professionals trained in travel medicine, and which are able to provide accurate preventive advice.6
• Accidents remain the most common cause of morbidity and mortality in travelers, with education the mainstay of prevention.
Immunizations can be divided into three categories: • recommended as part of routine health maintenance irrespective of international travel; • required for entry into a country under International Health Regulations (2005) or by an individual country; and • recommended because of the potential risk of exposure during travel. Travel-related immunizations are often the reason that an individual attends a travel clinic, although the risk of most vaccinepreventable illness is less than one case per 1000 journeys. Comprehensive travel health records should be kept: the type and dose of vaccine, date of administration, manufacturer and lot number, site of administration and administrator’s signature. Prior to administration of any vaccine, patients should undergo informed consent. The use of vaccine information sheets, often available from vaccine manufacturers, will help to explain to travelers the benefits and risks of each vaccine. Full manufacturer’s prescribing information should always be consulted before administration of a vaccine, as schedules, doses and products will often differ between countries.
• The potential risk of importing infectious disease is likely to rise as a consequence of travel amongst such mobile populations, increasingly recognized as a real threat to global public health.
IMMUNIZATIONS FOR ROUTINE HEALTH MAINTENANCE
• The travel health risk assessment is an essential component of identifying the health needs and protecting the health of the individual traveler. • The use of malaria chemoprophylaxis should be encouraged and prescribed for at risk travelers and in particular those visiting friends and relatives (VFRs). • Bite avoidance measures are an essential adjunct to the prevention of arthropod-borne disease. • Vaccines remain the most effective method of preventing infectious disease and influenza should be recognized as one of the most common vaccine-preventable illnesses during travel. • Environmental hazards are an increasingly important consideration with travel to altitude in particular, being a popular pursuit.
Travel medicine has become an established discipline, required to meet the health needs of ever increasing numbers of travelers to a variety of destinations. International arrivals are expected to reach nearly 1.6 billion by the year 2020, of which 1.2 billion will be intraregional and 378 million will be long-haul travelers.1 The travel health consultation for international travelers is an example of exclusively preventive medicine and the first step is to complete a travel health risk assessment and to establish the traveler’s health needs: determining the itinerary and duration of travel, the accommodation and planned activities, and the health status of the traveler.2 In order to determine destination-specific risks, the global epidemiology of infectious disease health risks should be understood and up-to-date information should be accessed from national public health authorities.3,4 The next step is to review the traveler’s health. Although at least 25% of individuals travel with chronic medical conditions, these generally do not prevent a person from traveling. Risks can be mitigated alongside consideration of planned activities; vaccines and/or prophylactic medications should be balanced against a traveler’s health requirements. Once a travel health risk assessment has been completed, the health professional should provide the traveler with the tools to manage this risk. These usually include the administration of vaccines, selftreatment and prophylactic medications, and preventive advice. Each traveler should also be informed how to access medical care during travel and on return as many travelers will need to seek medical care during and after their trip.5 To take account of the constantly changing epidemiology of disease and patterns of microbial resistance, the complexity of many travel
The pre-travel health consultation often provides the opportunity to update routinely recommended immunizations according to age and mostly includes tetanus, diphtheria, pertussis, measles, mumps and rubella, Haemophilus influenzae type b, polio and pneumococcal vaccines for infants, and influenza and pneumococcal vaccines for older adults. Consideration should be given to the differences that exist between national immunization recommendations worldwide.7,8 Issues of inadequate coverage and waning immunity also determine the recommendation of vaccines. Measles is no longer endemic to the USA and nearly all cases are imported or linked to imported infections. Although important gains have been made in global control of measles, particularly in Africa, ongoing measles outbreaks in both low- and high-income regions threaten efforts to control the disease.9,10 Waning immunity against pertussis has led to an increase in cases in older individuals and the introduction of adult formulations of pertussis vaccine combined with tetanus and diphtheria (Tdap).11 Where available, this vaccine should be used to boost levels of protection for those travelers who may be at risk of exposure or, importantly, to afford protection to susceptible people encountered during travel. Children should receive vaccines appropriate for travel and in line with the national childhood immunization program. Occasions may arise whereby the schedule of administration of a vaccine may be accelerated if a child is traveling before they would have received a scheduled vaccine and if the risk of the vaccine-preventable illness during their trip is assessed as being significant. In the case of measles, a single dose may be given from 6 to 11 months for travel to high-risk destinations, with the routine schedule still administered beginning at 12–15 months.
Older adults (those aged 65 years and over) make up an increasing proportion (as high as 15%) of international travelers. In addition, there are many travelers with chronic medical conditions such as HIV/ AIDS, diabetes or chronic pulmonary, renal, hepatic or cardiac disease and it is recommended that such travelers should be vaccinated with influenza and pneumococcal vaccines. The recognition that influenza is one of the most common vaccine-preventable illnesses during travel has led to the consideration of administering vaccine to healthy travelers going to areas of seasonal influenza (year round in tropical regions, December to March in the northern hemisphere, and April to September in the southern hemisphere).12 Outbreaks can occur out of season when persons from diverse regions of the world congregate in close quarters, such as on cruise ships or during mass gatherings, e.g. the Hajj. The practicalities of obtaining vaccine out of season or vaccine that is matched to influenza strains at the destination may be difficult. Seasonal influenza vaccine is not expected to provide protection against highly pathogenic avian influenza A (H5N1) and the role of antivirals used as self-treatment or prophylaxis has yet to be evaluated extensively.13
REQUIRED IMMUNIZATIONS Vaccination may be required under International Health Regulations (IHR 2005)14 or by an individual country as a condition of entry. The only vaccine that currently may be required under IHR (2005) is yellow fever (YF) vaccine. There is a risk of YF transmission in countries throughout the Amazon basin of South America, and in subSaharan Africa between 15° north and 10° south of the equator. YF is re-emerging and expanding into new regions, as has been seen in South America in 2008 with expansion of disease into new regions of Brazil, Argentina and Paraguay. Although YF disease risk maps are published by both the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) and national public health authorities, determining the actual risk of a traveler’s journey can be challenging.15 In general, travelers to rural regions in areas with a risk of YF transmission (either an endemic area where there are the appropriate mosquito vectors and nonhuman primate hosts for transmission, or infected areas where there are cases of YF reported) should receive vaccine. Other countries that are not at risk of YF transmission may require vaccination of travelers arriving from YF-risk countries. Country-specific requirements can be found in the CDC and WHO, National Travel Health Network and Centre (NaTHNaC) publications, and on their respective websites, amongst others.3,16,17 Health professionals must therefore decide if the vaccine is required for entry and/or recommended because of risk. YF vaccination must be recorded in the International Certificate of Vaccination or Prophylaxis.18 In addition to vaccine, travelers should protect themselves against the daytime-biting Aedes spp. mosquito through using bite avoidance measures. In 2001, newly recognized severe adverse events, viscerotropic and neurological, were reported following administration of YF vaccine to first-time vaccine recipients. Viscerotropic reactions are reported to occur within 2 weeks following vaccination (median of 4 days) and are characterized by the dissemination of vaccine virus associated with multiorgan failure, in which approximately 50% of cases are fatal. In these cases there are high titers of circulating vaccine virus, prolonged viremia and an unregulated inflammatory response.19,20 The neurological adverse events are characterized by a meningoencephalitis that begins up to 4 weeks following vaccination (median 14 days), with nearly all cases recovering.21 Acute disseminated encephalomyelitis and Guillain–Barré syndrome are also associated with neurological adverse events. The risk factors do not appear to be related to mutation of vaccine virus, but rather to an alteration in the host response. Older age, particularly 60 years and older, and the absence of a thymus (a contraindication to vaccination) carry an increased risk for both viscerotropic and neurological adverse reactions. Cholera vaccine is no longer required under IHR (2005) for international travel, and smallpox vaccine has not been required since 1982 following the global eradication of smallpox in 1977. Meningococcal
Chapter 107 Travel Medicine
vaccine is required for religious pilgrims to Saudi Arabia (see following section).
TRAVEL-RELATED IMMUNIZATIONS Vaccines discussed in this section are recommended because there may be a risk of exposure to infectious disease during travel. The risk of hepatitis A during travel has declined in many countries, particularly Latin America and East and South East Asia, with transition from high to lower endemicity.22,23 Nevertheless, vaccination can be considered for most travelers as hepatitis A vaccines are well tolerated, highly effective, give long-term (perhaps lifelong) protection and are being incorporated into routine immunization schedules.24 Hepatitis A vaccines are protective even if given shortly prior to departure and have superseded the use of immune serum globulin. Where appropriate, serological testing for previous exposure to hepatitis A can be performed in travelers with a high likelihood of previous hepatitis A infection, i.e. those born and raised in countries with high endemicity for hepatitis A and those with a history of jaundice. Protection against both hepatitis A and B may be achieved with the use of a combined antigen vaccine, administered frequently as an accelerated primary course over a period of 3 weeks, with a booster dose a year later. Typhoid and paratyphoid are imported diseases in most highincome countries. The highest risk of infection is in travelers to South Asia (India, Pakistan and Bangladesh); however, cases also originate from Latin America and Africa.25,26 Multidrug-resistant Salmonella enterica Typhi is common. There are two vaccines with similar efficacy (60–70%): an oral live-attenuated (Ty21a) vaccine and a polysaccharide (Vi antigen) injectable vaccine.27 The Ty21a vaccine is well-tolerated, effective in children older than 4 years and provides protection for 5 years; the Vi antigen vaccine is given in a single intramuscular dose and is effective for 2–3 years. Typhoid vaccines do not confer full protection against S. enterica Paratyphi, which may be more commonly imported in returning travelers than S. enterica Typhi.26 Cholera is endemic throughout Asia and Africa and parts of the Middle East; however, infection is rare in travelers. Vibrio cholerae 01 is endemic in all regions, whereas V. cholerae 0139 has circulated in Asia. More than 90% of cholera cases are reported from Africa, although some countries in Asia, such as Bangladesh where cholera is endemic, do not report cases to the WHO.28 There is currently one cholera vaccine licensed: an oral vaccine that combines killed V. cholerae with the binding (B) subunit of cholera toxin. This vaccine is well tolerated and confers rates of protection between 60% and 85% against cholera depending upon the age of the recipient and the time interval measured.29 Because of the very low risk of cholera in travelers, vaccine should be reserved for those who will be working in refugee settings or who will travel in cholera-endemic regions and will be remote from medical care. There has been interest in the use of this vaccine to protect against the syndrome of travelers’ diarrhea. While there is cross protection against Escherichia coli expressing the heat labile enterotoxin (LT), the protection is modest and the vaccine should not generally be used for this indication.29 Global efforts at polio eradication have been largely successful in several WHO regions of the world (the Americas, Western Pacific and European) and in 2014, only parts of three countries in the world, Nigeria, Pakistan and Afghanistan, remain endemic for the disease, the smallest geographic area in history. Outbreaks of polio in Asia, Africa and Middle East resulting from international travel are a cause of public health concern and travelers should have completed a primary course of a polio-containing vaccine and have a booster according to their national guidelines. Saudi Arabia requires polio vaccination in travelers age 15 years and younger coming from countries reporting wild-type polio. Other immunizations recommended because of potential exposure during travel include those against hepatitis B (administered as part of the routine childhood immunization program in more than 180 countries worldwide), Japanese B encephalitis, Neisseria meningitidis, rabies, tick-borne encephalitis and tuberculosis.
SECTION 6 International Medicine: Principles of International Health
Japanese B encephalitis is a virus transmitted by the Culex spp. mosquito found in Asia. Prolonged residence in endemic areas or engaging in high-risk activities such as camping, bicycling or field work are indications for vaccination. Rural Asia, particularly where rice and pigs are farmed, is the highest risk area; pigs act as a reservoir for the virus and the rice fields as a breeding ground for the Culex mosquito vector. Protection is afforded following administration of a Vero cellderived inactivated vaccine, which has replaced the mouse brainderived vaccine.30 Meningococcal vaccine is recommended for travelers to areas highly endemic for meningococcal disease such as the meningitis belt of sub-Saharan Africa (particularly during the months from December to June). Following the global spread of meningococcal W135 disease, which was traced to international travel of Hajj pilgrims in 2000, Saudi Arabia requires vaccination with a quadrivalent vaccine containing serogroups A, C, Y and W135 for religious pilgrims arriving for the Hajj or Umrah.31 All travelers should be counseled about avoiding exposure to rabies virus. In most low-income regions of the world, rabies is transmitted to humans by the bite of a dog (see Chapters 74 and 171) although other mammals (e.g. bats, cats, foxes) can also transmit the virus. In North America, bat-transmitted rabies is most common. Preexposure protection against rabies should be considered for those whose risk is increased by type of activity (e.g. running, cycling), occupation (e.g. veterinarians) and longer duration of stay.32 Children may be at increased risk as they are less likely to avoid contact with animals and to report a bite or lick. The intramuscular route of administration of the vaccine is preferred to ensure adequate development of immunity. In order to decrease risk of transmission, all bites should be thoroughly washed with soap and water; postexposure rabies treatment should then be obtained. A traveler who has received pre-exposure vaccine will not need rabies immune globulin (RIG, either human or equine), which is difficult to obtain or unavailable in many areas of the world. If vaccine has not been received before travel, both vaccine and RIG will need to be given.33 Regimens may differ, but if postexposure treatment is administered properly the traveler should be protected. Travelers who had an overseas rabies exposure and treatment should be evaluated upon return. They can have serology checked and postexposure treatment initiated while awaiting serologic evidence of protection (see Chapter 171). Tick-borne encephalitis is a viral meningoencephalitis spread by Ixodes spp. ticks throughout forested areas of Eastern and Central Europe, and Siberia in the spring and summer months. Unpasteurized dairy products in endemic areas may also transmit the virus.34 There are two inactivated vaccines which have limited availability outside of continental Europe and require three doses over a year to achieve full protection, which is not practical for most travelers. For rapid shortterm protection of children and adults, the second dose may be given 2 weeks after the first dose and so provides at least 90% protection. Travelers to risk areas should observe bite avoidance measures against ticks by the use of protective clothing, repellents and insecticides. These measures will help to prevent Lyme disease, which is also transmitted by the bite of Ixodes ticks. The risk of acquiring tuberculosis during travel is greatest in travelers to countries of high endemicity (e.g. incidence of >40 cases/100 000 population), those who will stay for a long period (>1–3 months) and those who will have close contact with potentially infectious persons (e.g. healthcare workers, and those visiting and staying with friends and relatives). The risk of infection has ranged from about 1 case/1000 persons/month in Peace Corps volunteers to 8 cases/1000 persons/ month in healthcare workers.35,36 Guidance on immunization against tuberculosis differs worldwide with countries immunizing only high risk groups or treating infection after two-step tuberculin testing. The UK has set guidelines for travelers that include children under the age of 16 and healthcare workers to high endemic regions who have not previously received BCG.37 Travelers who are not vaccinated should be offered pre- and post-travel tuberculin (purified protein derivative)
skin testing or interferon-gamma testing to check for conversion and, therefore, infection.38 The post-travel skin test should be administered 1 month or more after return.
IMMUNIZATION IN SPECIAL GROUPS Two important groups of travelers require special consideration before immunization – pregnant women and immunocompromised hosts (see also Chapter 87). For pregnant women, inactivated vaccines may be given but only if the risk is determined to be significant.3,7 Live vaccines such as measles, mumps and rubella and varicella vaccine should not be administered, although data have not demonstrated clearly adverse outcomes when women have received rubella vaccine. Yellow fever vaccine should be avoided unless there is high-risk travel; seroconversion to YF virus during pregnancy may be lower, necessitating revaccination after delivery.39 HIV-infected patients are another group to consider separately.3,40 All travelers should be asked about possible HIV risk factors before vaccination; the safety, immunogenicity and efficacy of the vaccine being considered, with the need being balanced against the risk of the disease. Vaccine immunogenicity decreases with advanced HIV disease; a CD4 lymphocyte count of <200–400 cells/mL or <15–25% by agespecific percentages correlates with decreased immunogenicity. Although it has not been studied clearly, this may also be a cut-off point for an increased risk of adverse consequences of live viral vaccines. If assurance of immunity is needed, then post-vaccination serology should be obtained for the appropriate antigens. In addition to vaccination, HIV-infected travelers should consider the health risks associated with travel to low- and middle-income regions. Many enteric infections, such as Salmonella, Cyclospora and Cryptosporidium, and systemic infections such as leishmaniasis and tuberculosis, are more prevalent and can be prolonged and difficult to treat in HIV-infected individuals.
Travelers’ Diarrhea Travelers’ diarrhea (TD) affects 30–60% of travelers and is the most common illness during visits to low-income regions of the world.41 Illness usually begins in the first week after arrival and is typically mild, characterized by three or more loose to watery stools accompanied by another symptom of nausea, abdominal cramping or malaise. Fever is usually less than 38°C and vomiting is uncommon. In most cases, illness is self-limiting over 3–5 days and dysentery with tenesmus and bloody stools occurs in less than 10% of patients. Although most individuals can continue with their activities, about 25% will need to alter plans. Enterotoxigenic Escherichia coli (ETEC) accounts for 20–30% of the known causes, and a newly described E. coli, enteroaggregative E. coli, causes another 15–20%.42,43 Shigella, Salmonella and Campylobacter spp. are the most common other bacteria (see Practice Point 11). Viruses (typically rotavirus and norovirus) cause 5–20% of cases and protozoa (Giardia, Cryptosporidium and, less commonly, Cyclospora) cause 5% or less and are usually associated with longer duration of travel. Although the overall incidence of TD does not decline with increasing time of residence in low- and middle-income areas, partial immunity will develop to ETEC diarrhea. A short course (1–3 days) of an antibiotic, such as ciprofloxacin, or where resistance to fluoroquinolones is known, azithromycin, will improve diarrhea within 20–36 hours. A full description of the prevention and treatment of TD can be found in Chapter 38 and Practice Point 11)
Malaria Prevention Malaria is one of the most important diseases to prevent as it can be fatal. The type of malaria and the risk of acquisition vary by destination and reason for travel, but worldwide there are approximately 7500 cases each year in returned travelers. Of the five recognized species of malaria in humans (Plasmodium falciparum, P. vivax, P. ovale, P. malariae and, rarely, P. knowlesi), P. falciparum is the most severe form and is also the most frequently imported species. Over 80% of P. falciparum cases are acquired by travelers on trips to Africa, and especially West
Africa, where transmission can occur in both urban and rural areas. Travelers with the highest risk for acquiring malaria are those who return to their country of birth to visit friends and relatives, termed VFR travelers; they are usually traveling to West Africa where they are most likely to acquire P. falciparum or to South Asia where they usually acquire P. vivax.
BITE AVOIDANCE MEASURES Malaria is transmitted by the female Anopheles mosquito, which is most active during the night-time hours from dusk to dawn. During this period travelers should wear loose-fitting cotton clothing that covers their arms and legs, apply repellents to exposed areas of skin and sleep in enclosed areas behind screens or under netting. The most effective repellents are those that contain DEET (N,N-diethyl-3methylbenzamide). A concentration of 50% will provide protection lasting from 6 to 12 hours. DEET-containing repellents are safe to use in children and pregnant women, but should be applied carefully to avoid systemic absorption: they should not be applied to mucous membranes or irritated skin and should be washed off when coming indoors. Sunscreen should be applied before insect repellent. Picaridinbased repellents are also effective. Bed nets should be treated with a residual insecticide (e.g. permethrin-containing compounds). This can also be applied to clothing and will kill insects rather than only repel them. Mosquito coils and sprays containing pyrethroids can be used in enclosed sleeping areas. Bite avoidance measures, such as described above, should be used as adjuncts to the use of malaria chemoprophylaxis unless traveling in very low-risk malaria areas where medical treatment should be sought urgently if any symptoms were to develop.
CHEMOPROPHYLAXIS Chemoprophylaxis should be taken on a regular basis during travel and for a period of time after return that depends on which medications are taken. Most cases of malaria in returned travelers occur because the traveler fails to take any chemoprophylaxis, takes incorrect prophylaxis or does not comply with their prophylaxis. The choice of a chemoprophylactic regimen should be based on risk of exposure, types of parasite prevalent in the travel destination and health conditions of the traveler. Up-to-date sources (including authoritative websites) should be consulted before prescribing any antimalarial.3,14,16 Chloroquine as a single agent is effective only in areas where P. falciparum remains sensitive or is not present: Mexico, Central America west and north of the Panama Canal, the Dominican Republic and Haiti, Egypt, most areas of the Middle East and parts of China. Travelers to all other risk areas in Africa, Asia and Latin America will need to take atovaquone–proguanil, doxycycline or mefloquine. Atovaquone–proguanil and doxycycline are effective in treatment and prophylaxis of all malaria species, although experience using atovaquone–proguanil with non-falciparum species is limited.44 Both drugs are started 1–2 days before exposure to malaria and then taken daily. Doxycycline is continued for 28 days after leaving the malarious area, but atovaquone–proguanil can be discontinued after 7 days because it has a causal prophylactic effect: it kills developing hepatic stage parasites, but not the dormant, hypnozoite forms of P. vivax or P. ovale. These may emerge from the liver many months after return from the place of exposure. Atovaquone–proguanil is ideally targeted for short-term travelers to areas of risk. Doxycycline cannot be given to children under the age of 8 in the USA (under 12 in the UK) or to pregnant women. It should be swallowed with water whilst in the upright position to prevent esophageal irritation. Doxycycline may predispose to vaginal yeast infection and can act as a photosensitizer. Mefloquine is highly effective in preventing malaria, including chloroquine-resistant P. falciparum. When it is taken in prophylactic doses, minor gastrointestinal (GI) and neuropsychiatric events occur in 5–30% of users.45 The neuropsychiatric side effects can include sleep disturbance, vivid dreams, mood changes, anxiety, headache and dizziness. Serious adverse events such as psychosis are rare with an occurrence of about one case per 6000–20 000 users. Travelers should be
Chapter 107 Travel Medicine
screened for contraindications to mefloquine before prescribing it: a known hypersensitivity to the drug, a history of seizures or psychiatric disorder, or an underlying cardiac conduction abnormality. Some travel health consultants prescribe mefloquine 2–3 weeks before departure to assess patient tolerance and allow a switch to other agents if there is a problem. Seventy percent of adverse reactions occur during the first three doses. Loading doses of the drug are not advocated. The combination of chloroquine plus proguanil has been recommended by practitioners in the UK for areas in which there are low levels of chloroquine-resistant P. falciparum malaria and only a small risk of acquisition, such as most areas of risk in India. In low-risk areas, some European experts do not recommend taking any chemoprophylaxis; rather they suggest being observant to febrile episodes and carrying stand-by self-treatment.46 US and UK authorities do not advocate this approach. Health practitioners should consult the appropriate expert recommendations for their country. Primaquine is an alternative chemoprophylactic in persons intolerant of other options and can be considered following specialist advice.47 It is a causal prophylactic and will prevent the establishment of liver hypnozoites of P. vivax and P. ovale. The drug is taken daily beginning 1–2 days before exposure and can be discontinued 7 days after leaving the risk area. It is a requirement that glucose-6-phosphate dehydrogenase (G6PD) deficiency is ruled out in all persons for whom primaquine is prescribed. Rural, forested areas of Thailand that border Burma and Cambodia, western Cambodia (including Siem Reap) and southern areas of Vietnam that border Cambodia have multidrug-resistant P. falciparum malaria. Travelers to these areas should take atovaquone–proguanil or doxycycline for prophylaxis. All travelers should understand that no antimalarial is 100% protective and that they can develop malaria in spite of being com pliant with prophylaxis. If they develop a fever or flu-like illness overseas that could be malaria, they should seek medical care. The evaluation needs to include a blood smear performed by a competent laboratory, because the sensitivity of symptoms or physical findings alone is low. The use of self-administered rapid diagnostic kits is not generally recommended as travelers have difficulty using and interpreting these tests; they are not currently licensed for this purpose. In circumstances where travelers cannot obtain prompt medical care, self-treatment can be considered. The self-treatment drug(s) should differ from what the traveler is taking for chemoprophylaxis. Options include atovaquone–proguanil, artemether–lumefantrine and quinine plus doxycycline. Pregnant women should not travel to malarious areas unless absolutely necessary, because of the added risk of complications of malaria during pregnancy. Chloroquine and proguanil (with added folate) are safe. Mefloquine can be taken after the first trimester, and may be acceptable in the first trimester if there are no alternatives. Doxycycline is contraindicated and there are insufficient safety data on atovaquone– proguanil during pregnancy. Primaquine should not be given because the G6PD status of the fetus cannot be determined.
Environmental Hazards Travel to the tropics is associated with increased heat and humidity; the effects that these changes can have on health should be taken into account. These range from a feeling of malaise and tiredness to increased loss of salt and water with resultant dehydration. Travelers should maintain hydration, limit exercise and sleep in a cool environment, particularly if they are elderly or have chronic medical problems. Excessive sun exposure should be avoided by wearing loose-fitting cotton clothing to cover exposed skin, wearing hats and using sunscreens with a sun protection factor of at least 15. If the patient is taking doxycycline for malaria prophylaxis, it is particularly important to limit sun exposure. Skin should be kept dry and clean to avoid cellulitis and dermatophyte infection. Travelers to altitudes above 2500–3500 meters (8200–11 500 feet) can experience acute mountain sickness (AMS) or the more severe and
SECTION 6 International Medicine: Principles of International Health
potentially fatal conditions of high-altitude pulmonary edema (HAPE) and high-altitude cerebral edema (HACE).48,49 AMS is characterized by headache, nausea, vomiting, insomnia and lassitude and may affect up to 50% of persons who rapidly ascend above 4000 m. The risk of illness can be lessened by acclimatization: spending a few days at intermediate altitudes of 1500–3000 m and gradually ascending, sleeping at elevations no more than 300–500 m higher each night. Acetazolamide, a carbonic anhydrase inhibitor, can be taken to assist acclimatization, particularly when persons must ascend quickly. It is given at a dose of 125–250 mg orally twice daily, starting 2 days before being at altitude and for several days at altitude.50 It has also been used to treat mild symptoms of AMS. Dexamethasone can be used to treat AMS but in severe illness the safest course is always to descend. Acetazolamide is contraindicated in persons with sulfonamide allergy. Jet lag is a common problem, particularly when more than five time zones are crossed. It is easier to travel west and lengthen the day than to travel east and shorten the day. In order to help with jet lag, several methods have been proposed: light exposure, short-acting hypnotics and melatonin.51 When traveling east, exposure to bright light in the late morning and early afternoon may aid in the adjustment. A shortto intermediate-acting benzodiazepine or benzodiazepine receptor agonist can facilitate and maintain sleep in the new time zone, decreasing the contribution of fatigue to the effects of time zone adjustment. Melatonin, which is secreted during the night hours, has been studied extensively. A dose of 3–8 mg taken 2–3 hours before bedtime for the first few nights in the new time zone may be helpful. However, the purity and effectiveness of over-the-counter preparations have not been documented. Deep venous thrombosis (DVT) and pulmonary embolism are recognized complications of long-haul travel. DVTs can occur in as many as 3% of persons flying for 10–15 hours and who have cardiovascular risk factors; oral contraceptive pills, pregnancy, recent surgery, certain coagulation disorders and malignancy also contribute to risk.52,53 Some long-haul travelers will develop a pulmonary embolism.54 In order to decrease risk, travelers should maintain their hydration and exercise their lower extremities at regular intervals. Fitted, below-the-knee support stockings will decrease the incidence of DVT and for highest risk passengers low molecular weight heparin can be considered. Aspirin is not recommended.
Behavioral Factors Although there is much focus on infectious illness, the most important contributors to severe morbidity and mortality, particularly in young adults, are accidents and injuries, with those related to road traffic accidents and drowning most common.55,56 Road safety can be improved by using safety belts in vehicles, avoiding excessive speed, not driving at night or after drinking alcohol, and not riding on motorcycles and mopeds. When swimming, travelers should be aware of undercurrents and never dive into unknown waters. To prevent assault and theft, travelers should not wear jewelry and clothing that draws attention, and they should travel in groups, avoiding high-risk urban areas, particularly at night. Travel advisories are posted routinely on governmental websites. Sexually transmitted diseases, including HIV and hepatitis B, gonorrhea, syphilis and chancroid, are prevalent in many destination countries in Africa, Asia and Latin America. Travelers should be counseled about safe sexual practices, and take condoms with them on their trip.57,58 Postexposure prophylaxis against HIV may be necessary (see Practice Point 30),59 and women may need emergency contraception. Tattooing, injections and dental instruments should be avoided to decrease the risk of acquiring blood-borne pathogens such as hepatitis B and C and, less likely, HIV.
Other Diseases and Considerations Dengue fever, a viral disease (see Chapter 133) transmitted by Aedes mosquitoes, has seen a resurgence, particularly in Asia, the Caribbean
and Latin America, and is a theoretical risk in the south-eastern USA. Dengue is characterized by the sudden onset of fever, headache, myalgias and arthralgias, abdominal discomfort, rash and mild liver abnormalities.60 Severe disease (dengue hemorrhagic fever and dengue shock syndrome) is characterized by thrombocytopenia and vascular leak, and usually occurs in children following a second infection with a different dengue serotype. There is no vaccine available for prevention, so travelers need to exercise precaution against this daytime-feeding mosquito. Complying with bite avoidance measures will help to prevent not only dengue but a clinically similar viral infection, chikungunya virus, that in recent years has been a problem on the islands of the Indian Ocean and in countries of South and South East Asia.61 Other less common insect-transmitted diseases such as leishmaniasis, trypanosomiasis, filariasis and rickettsial infection will also be prevented by observing insect bite avoidance measures. African trypanosomiasis has been documented in travelers to East African game parks, and African tick-bite fever caused by Rickettsia africae is a risk in southern Africa.62 Schistosoma spp. (see Chapter 118) can infect travelers who swim in fresh-water lakes and rivers, particularly in endemic areas of east and southern Africa.63 Travelers to risk areas should avoid fresh-water swimming unless it is in a chlorinated pool. Letting water stand for 48 hours or warming it to 122°F (50°C) for 5 minutes will render it safe from the Schistosoma parasites. Fresh-water swimming, particularly after periods of flooding, can be a risk for acquisition of leptospirosis. Although the viral hemorrhagic fevers, Ebola, Lassa and Marburg (see Chapter 132), garner a great deal of media attention, they are a rare risk for travelers. Current outbreaks of disease can be identified by reviewing up-to-date information on ProMED (www.promedmail .org) or by checking the disease outbreak sites of the WHO, CDC and NaTHNaC web pages. Any returning traveler who is suspected of having a viral hemorrhagic fever should be managed according to WHO guidelines.64 Travelers need to know how to access medical care during their trip. They should purchase a travel health insurance package that includes help in locating medical care, paying for the care upfront and, if necessary, providing for emergency evacuation. Embassies or consulates can assist in locating medical services, and mission hospitals can be a source of care. A small first-aid kit that contains analgesics, bandages, a thermometer and any frequently used over-the-counter medications is helpful as it can be difficult to find the simplest medicines overseas. All travelers should carry an extra supply of their prescription medications, and avoid putting them into checked luggage.
POST-TRAVEL ILLNESS Travelers should report illness upon return and health practitioners should be able to recognize common syndromes: fever, diarrhea, respiratory illness and rash.2,5,65 Although routine post-travel follow-up for short-term travelers is usually not necessary, anyone who experienced major illness overseas or new-onset illness after return should be evaluated. A differential diagnosis can be developed by considering geography (the locations visited), activities undertaken, incubation periods of disease, frequency of occurrence and preventive measures taken (e.g. immunizations, compliance with prophylaxis).66 A more detailed discussion of individual syndromes and diseases is provided in other relevant chapters. References available online at expertconsult.com.
Chapter 107 Travel Medicine
KEY REFERENCES Centers for Disease Control and Prevention: Health information for international travel 2014. Atlanta: US Department of Health and Human Services, Public Health Service; 2014. Available: http://wwwnc.cdc.gov/travel/ page/yellowbook-home-2014. Croft J.: Drugs for preventing malaria in travellers (Review). The Cochrane Library, Issue 1. Chichester, UK: John Wiley; 2010. Ericsson C.D.: Travellers’ diarrhea. In: Zuckerman J.N., ed. Principles and practice of travel medicine. 2nd ed. WileyBlackwell; 2013:197-209. Hill D.R.: Starting, organizing and marketing a travel clinic. In: Keystone J.S., Kozarsky P.E., Nothdurft H.D., et al., eds. Travel medicine. 3rd ed. St Louis: Mosby; 2012: 13-24. Immunization against infectious disease. Public Health England March 2014. Available: https://www.gov
.uk/government/collections/immunisation-against -infectious-disease-the-green-book. Imray C., Booth A., Wright A., et al.: Acute altitude illnesses – Clinical Review. BMJ 2011; 343:d4943. Kozarsky P.: The body of knowledge for the practice of travel medicine – 2006. J Travel Med 2006; 13(5): 251-254. MacPherson D.W., Gushulak B.D., Sandhu J.: Death and international travel – the Canadian experience: 1996 to 2004. J Travel Med 2007; 14:77-84. Monath T.P., Gershman M., Staples J.E., et al.: Yellow fever vaccine. In: Plotkin S.A., Orenstein W.A., Offit P.A., eds. Vaccines. 6th ed. Philadelphia: Saunders Elsevier; 2012:870-968. Memish Z.A., Goubeaud A., Bröker M., et al.: Invasive meningococcal disease and travel. J Infect Public Health 2010; 3(4):143-151.
Ryan E.T., Wilson M.E., Kain K.C.: Illness after international travel. N Engl J Med 2002; 347:505-516. Suh K.N., McCarthy A.E., Mileno M.D., et al.: Highrisk travelers. In: Zuckerman J.N., ed. Principles and practice of travel medicine. 2nd ed. Wiley-Blackwell; 2013: 515-531. Warrell M.J.: Current rabies vaccines and prophylaxis schedules: preventing rabies before and after exposure. Travel Med Inf Dis 2012; 10:1-15. Wilder-Smith A.: Dengue infections in travelers. Paediatr Int Child Health 2012; 32(s1):28-32. World Health Organization: International travel and health, 2014. Geneva: WHO; 2014. Available: http://www.who .int/ith/en/.
Chapter 107 Travel Medicine 953.e1
REFERENCES 1. The World Tourism Organization (UNWTO). Available: http://www2.unwto.org/. 2. Kozarsky P.: The body of knowledge for the practice of travel medicine – 2006. J Travel Med 2006; 13(5):251254. 3. Centers for Disease Control and Prevention: Health information for international travel 2014. Atlanta: US Department of Health and Human Services, Public Health Service; 2014. Available: http://wwwnc.cdc .gov/travel/page/yellowbook-home-2014. 4. World Health Organization: International travel and health, 2014. Geneva: WHO; 2014. Available: http:// www.who.int/ith/en/. 5. Freedman D.O., Weld L.H., Kozarsky P.E., et al.: Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med 2006; 354:119130. 6. Hill D.R.: Starting, organizing and marketing a travel clinic. In: Keystone J.S., Kozarsky P.E., Nothdurft H.D., et al., eds. Travel medicine. 3rd ed. St Louis: Mosby; 2012:13-24. 7. Kroger A.T., Atkinson W.L., Marcuse E.K., et al.: General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2011; 60:1-64. 8. Immunization against infectious disease. Public Health England March 2014. Available: https://www.gov .uk/government/collections/immunisation -against-infectious-disease-the-green-book. 9. European Centre for Disease Prevention and Control: Measles and rubella monitoring January-December 2013. Available: http://www.ecdc.europa.eu/en/ healthtopics/measles/epidemiological_data/pages/ annual_epidemiological_reports.aspx. 10. World Health Organization: Increased transmission and outbreaks of measles, European Region 2011. Wkly Epidemiol Rec 2011; 86(49):557-564. 11. Centers for Disease Control and Prevention: Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (tdap) in pregnant women and persons who have or anticipate having close contact with an infant Aged <12 Months: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2011. MMWR 2011; 60(41):1424-1426. 12. Masuet-Aumatell C., Toovey S., Zuckerman J.N.: Prevention of influenza among travellers attending at a UK travel clinic: beliefs and perceptions. A cross-sectional study. Influenza Other Respir Viruses 2013; 7(4):574583. 13. Fiore A.E., Fry A., Shay D., et al.; Centers for Disease Control and Prevention (CDC): Antiviral agents for the treatment and chemoprophylaxis of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2011; 60(RR01):1-24. 14. World Health Organization: International health regulations, 2005. Geneva: WHO; 2005:1-60. 15. Barnett E.D.: Yellow fever: epidemiology and prevention. Clin Infect Dis 2007; 44:850-856. 16. The National Travel Health Network and Centre. Yellow Fever. Available: http://www.nathnac.org/pro/ factsheets/yellow.htm. 17. World Health Organization: International travel and health, 2014. Yellow Fever. Geneva: WHO; 2014. Available: http://www.who.int/ith/vaccines/yf/en/. 18. Wilder-Smith A., Hill D.R., Freedman D.O.: The revised International Health Regulations (2005): impact on yellow fever vaccination in clinical practice. Am J Trop Med Hyg 2008; 78:359-560. 19. Monath T.P., Gershman M., Staples J.E., et al.: Yellow fever vaccine. In: Plotkin S.A., Orenstein W.A., Offit P.A., eds. Vaccines. 6th ed. Philadelphia: Saunders Elsevier; 2012:870-968. 20. Belsher J.L., Gay P., Brinton M., et al.: Fatal multiorgan failure due to yellow fever vaccine-associated viscerotropic disease. Vaccine 2007; 25:8480-8485.
21. McMahon A.W., Eidex R.B., Marfin A.A., et al.: Neurologic disease associated with 17D-204 yellow fever vaccination: a report of 15 cases. Vaccine 2007; 25:17271734. 22. Mütsch M., Spicher V.M., Gut C., et al.: Hepatitis A virus infections in travelers, 1988–2004. Clin Infect Dis 2006; 42:490-497. 23. Nothdurft H.D.: Hepatitis A vaccines. Expert Rev Vaccines 2008; 7:535-545. 24. Centers for Disease Control and Prevention: Update: Prevention of hepatitis A after exposure to hepatitis A virus and in international travelers. Updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2007; 56:1080-1084. 25. Connor B.A., Schwartz E.: Typhoid and paratyphoid fever in travelers. Lancet Infect Dis 2005; 5(10):623628. 26. Foreign travel-associated illness - a focus on travellers’ diarrhoea Version 2 11 January 2011 Health Protection Agency. 27. World Health Organization: Typhoid vaccines: WHO position paper. Wkly Epidemiol Rec 2008; 83:49-59. 28. World Health Organization: Cholera, 2007. Wkly Epidemiol Rec 2010; 13(85):117-128. 29. Hill D.R., Ford L., Lalloo D.G.: Oral cholera vaccines: use in clinical practice. Lancet Infect Dis 2006; 6:361373. 30. Tauber E., Kollaritsch H., Korinek M., et al.: Safety and immunogenicity of a Vero-cell-derived, inactivated Japanese encephalitis vaccine: a non-inferiority, phase III, randomised controlled trial. Lancet 2007; 370:18471853. 31. Memish Z.A., Goubeaud A., Bröker M., et al.: Invasive meningococcal disease and travel. J Infect Public Health 2010; 3(4):143-151. 32. Warrell M.J.: Current rabies vaccines and prophylaxis schedules: preventing rabies before and after exposure. Travel Med Inf Dis 2012; 10:1-15. 33. Uwanyiligira M., Landry P., Genton B., et al.: Rabies postexposure prophylaxis in routine practice in view of the new Centers for Disease Control and Prevention and World Health Organization recommendations. Clin Infect Dis 2012; 55:201-205. 34. Lindquist L., Vapalahti O.: Tick-borne encephalitis. Lancet 2008; 371(9627):1861-1871. 35. Johnston V.J., Grant A.: Tuberculosis in travelers. Travel Med Infect Dis 2003; 1(4):205-212. 36. Jung P., Banks R.H.: Tuberculosis risk in US Peace Corps Volunteers, 1996 to 2005. J Travel Med 2008; 15:87-94. 37. Immunisation against infectious diseases. Tuberculosis. Public Health England March 2014. Available: https:// www.gov.uk/government/publications/tuberculosis -the-green-book-chapter-32. 38. Diel R., Goletti G., Ferrara G., et al.: Interferon-γ release assays for the diagnosis of latent Mycobacterium tuberculosis infection: a systematic review and meta-analysis. Eur Respir J 2011; 37:88-99. 39. Suzano C.E., Amaral E., Sato H.K., et al.: The effects of yellow fever immunization (17DD) inadvertently used in early pregnancy during a mass campaign in Brazil. Vaccine 2006; 24:1421-1426. 40. Suh K.N., McCarthy A.E., Mileno M.D., et al.: High-risk travelers. In: Zuckerman J.N., ed. Principles & Practice of Travel Medicine. 2nd ed. Wiley-Blackwell; 2013:515531. 41. Ericsson C.D.: Travellers’ diarrhea. In: Zuckerman J.N., ed. Principles & Practice of Travel Medicine. 2nd ed. Wiley-Blackwell; 2013:197-209. 42. Shah N., DuPont H.L., Ramsey D.J.: Global etiology of travellers’ diarrhoea: systematic review from 1973 to the present. Am J T Med Hygiene 2009; 80:609-614. 43. Huang D.B., Okhuysen P.C., Jiang Z.D., et al.: Enteroaggregative Escherichia coli: an emerging enteric pathogen. Am J Gastroenterol 2004; 99:383-389.
44. Baird J.K.: Effectiveness of antimalarial drugs. N Engl J Med 2005; 352:1565-1577. 45. Croft J.: Drugs for preventing malaria in travellers (Review). The Cochrane Library, Issue 1. Chichester, UK: John Wiley; 2010. 46. Chen L.H., Wilson M.E., Schlagenhauf P.: Controversies and misconceptions in malaria chemoprophylaxis for travelers. JAMA 2007; 297:2251-2263. 47. Hill D.R., Baird J.K., Parise M.E., et al.: Primaquine: Report from CDC expert meeting on malaria chemoprophylaxis. Am J Trop Med Hyg 2006; 75:402-415. 48. Imray C., Booth A., Wright A., et al.: Acute altitude illnesses – Clinical Review. BMJ 2011; 343:d4943. 49. Hudson S., Luks A., Carter P., et al.: Expedition and extreme environmental medicine. In: Zuckerman J.N., ed. Principles & Practice of Travel Medicine. 2nd ed. Wiley-Blackwell; 2013:328-380. 50. Basnyat B., Gertsch J.H., Johnson E.W., et al.: Efficacy of low-dose acetazolamide (125mg BID) for the prophylaxis of acute mountain sickness: a prospective, double-blind, randomized, placebo-controlled trial. High Alt Med Biol 2003; 4:45-52. 51. Waterhouse J., Reilly T., Atkinson G., et al.: Jet lag: trends and coping strategies. Lancet 2007; 369:117129. 52. World Health Organization: WHO research into global hazards of travel (WRIGHT) project: final report of phase I. Geneva: WHO; 2007:1-24. 53. Guyatt G.H., Akl E.A., Crowther M.: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 14:48S-52S. 54. Sugerman H.J., Eklöf B.G., Toff W.D., et al.: Air travelrelated deep vein thrombosis and pulmonary embolism. JAMA 2012; 308(23):2531. 55. MacPherson D.W., Gushulak B.D., Sandhu J.: Death and international travel – the Canadian experience: 1996 to 2004. J Travel Med 2007; 14:77-84. 56. Tonellato D.J., Guse C.E., Hargarten S.W.: Injury deaths of U.S. citizens abroad: new data source, old travel problem. J Travel Med 2009; 16:304-310. 57. Matteelli A., Schlagenhauf P., Carvalho A.C., GeoSentinel Surveillance Network, et al.: Travel-associated sexually transmitted infections: an observational crosssectional study of the GeoSentinel surveillance database. Lancet Infect Dis 2013; 13(3):205-213. 58. Richens J.: Sexually transmitted infections and HIV among travellers: a review. Travel Med Infect Dis 2006; 4:184-195. 59. Smith D.K., Grohskopf L.A., Black R.J., et al.: Antiretroviral postexposure prophylaxis after sexual, injectiondrug use, or other nonoccupational exposure to HIV in the United States: recommendations from the U.S. Department of Health and Human Services. MMWR Recomm Rep 2005; 54(RR–2):1-20. 60. Wilder-Smith A.: Dengue infections in travelers. Paediatr Int Child Health 2012; 32(s1):28-32. 61. Hochedez P., Canestri A., Guihot A., et al.: Management of travelers with fever and exanthema, notably dengue and chikungunya infections. Am J Trop Med Hyg 2008; 78:710-713. 62. Jensenius M., Fournier P.E., Vene S., et al.: African tick bite fever in travelers to rural sub-Equatorial Africa. Clin Infect Dis 2003; 36:1411-1417. 63. Meltzer E., Artom G., Marva E., et al.: Schistosomiasis among travelers: new aspects of an old disease. Emerg Infect Dis 2006; 12:1696-1700. 64. Bossi P., Tegnell A., Baka A., et al.: Bichat guidelines for the clinical management of haemorrhagic fever viruses and bioterrorism-related haemorrhagic fever viruses. Euro Surveill 2004; 9:E11-E12. 65. Bottieau E., Clerinx J., Schrooten W., et al.: Etiology and outcome of fever after a stay in the tropics. Arch Intern Med 2006; 166:1642-1648. 66. Ryan E.T., Wilson M.E., Kain K.C.: Illness after international travel. N Engl J Med 2002; 347:505-516.