REVIEW ARTICLE
Dan L. Longo, M.D., Editor
Medical Considerations before International Travel
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Travel Health and Safety
Travel-Related Medical Considerations.In 2015, international tourist arrivals in all countries exceeded 1.2 billion persons. In 2014, the total number of arrivals in countries with emerging markets nearly surpassed the number in developed countries (http://www.e-unwto.org/doi/book/10.18111/9789284416899). Depending on the destination, 22 to 64% of travelers report some illness; most of these illnesses are mild and self-limited, such as diarrhea, respiratory infections, and skin disorders.1-4 Some travelers return to their own countries with preventable life-threatening infections.5 Yet 20 to 80% of travelers do not seek pretravel health consultation.6 Data about the effect of pretravel advice are limited, although such advice has had a positive effect on the prevention of malaria.7 Travelers visiting friends and relatives in their country of origin constitute the group with the highest morbidity, especially from malaria and typhoid; this group requires special approaches to illness prevention and education.8,9Persons who are planning to travel to other countries often ask their health care providers for information about preventive interventions. Nonspecialists can provide information and care to healthy adults traveling to common destinations by following protocols such as those offered in this review. Advice from a specialist10 is of benefit for persons who are planning high-risk or adventure travel, those who are immunocompromised11-13 or have underlying chronic disease, those who are planning to live abroad for a long time, women who are pregnant14 or plan to become pregnant soon, young children, and travelers with complicated itineraries.STRUCTURED APPROACH TO THE PRETRAVEL CONSULTATION
During the medical appointment that precedes international travel, a structured and sequenced approach (Figure 1FIGURE 1Structured Approach to Medical Consultation before International Travel.) is the most efficient way for the physician and other clinicians to address the necessary preventive and educational interventions. An individualized risk assessment that takes into consideration the exact place-by-place itinerary and factors that are particular to the prospective traveler should be performed first. Immunizations, malaria considerations, and travelers’ diarrhea should be covered next. Since appropriate behavior by the traveler can substantially reduce the risk of many specific travel-related health and safety problems, the remainder of the consultation should consist of education about behavioral and self-treatment strategies (Table 1TABLE 1
Important Practices for Reducing Disease Risk during International Travel.). Protection against insects and strategies for ensuring the safety of food and water are the most important. It is advisable to provide printed instructions (in lay language) because many of these measures will be initiated much later, at the traveler’s destination, and time constraints may preclude detailed discussion in the office. Individual risk factors vary greatly, and not all travelers to a given country will receive the same pretravel recommendations.
VACCINATIONS
Table 2TABLE 2Vaccines That Should Be Available during Pretravel Consultation. provides data on dosing, route of administration, need for boosters, and possible accelerated regimens for vaccines administered before travel. The discussion below, which focuses on indications for each vaccine in the context of travel, should be used in conjunction with the information in theinteractive graphic (available with the full text of this article at NEJM.org), which shows the geographic distribution of major travel-related diseases.
Verification and Update of Routine Vaccines
Routine vaccines are those that need to be readministered at regular intervals or series that need to be completed in a healthy adult without plans for international travel who has no medical or behavioral risk factors (Figure 1). For many vaccine-preventable diseases, the risk of acquisition is increased in developing countries.Importations of measles and mumps have resulted in travel-related outbreaks.45 International travelers born in the United States after 1956 must either have received two documented doses of the measles–mumps–rubella (MMR) vaccine or have evidence of immunity. Many persons born in the United States before 1970 have never received the MMR vaccine, and many born in the 1970s have not had the second dose, a recommendation that was made in 1990. Adults who have never received the tetanus–diphtheria–acellular pertussis (Tdap) vaccine should be given a dose of Tdap, regardless of the time elapsed since the last tetanus–diphtheria vaccination. Widespread outbreaks of measles, mumps, and pertussis are currently ongoing in developed and in developing countries.46 Persons born in the United States after 1979 must either have received two documented doses of varicella vaccine or have evidence of immunity.Influenza is the most common vaccine-preventable disease among travelers,47 including passengers on cruise ships. Because of year-round circulation of influenza virus in tropical and subtropical regions and an influenza season that occurs in winter in temperate regions in the southern hemisphere (which is summer in the northern hemisphere), all travelers to the tropics at any time of year and to temperate destinations where it is currently winter should have received the most current influenza vaccine available in their home country before traveling.48 Healthy travelers who are 65 years of age or older should be up to date on pneumococcal vaccination.Routine Travel Vaccines
Hepatitis A vaccine is indicated for every nonimmune traveler because of foodborne transmission of the disease and an estimated incidence of 1 case per 5000 travelers per month. A single dose of hepatitis A vaccine given any time before travel, even on the way to the airport, provides more than 94% seroprotection. The current adult population in the United States generally has little to no immunity to hepatitis A virus.Since most adults who were born in the United States have not been immunized with the hepatitis B vaccine, vaccination should be considered for all travelers, although predicting exposure to blood or body fluids during travel is difficult. In the absence of the usual risk factors for hepatitis B virus infection, long stays and close contact with residents in local communities may lead to more opportunities for injuries, the need for medical or dental care, sexual contact, and tattooing or body piercing.49 The relative likelihood of future international travel warrants consideration of a vaccine that confers lifelong protection.50South Asia has the highest risk of typhoid and paratyphoid fevers (see the interactive graphic), particularly for travelers visiting friends or relatives.51 Vaccination against Salmonella entericaserovar Typhi, a foodborne bacterial pathogen with increasing rates of multidrug resistance globally, may be considered for persons traveling to other areas where typhoid and paratyphoid fevers are endemic and sanitary conditions are suboptimal. The efficacy of either available vaccine against S.Typhi is only 60 to 80%.52 Adherence to the oral vaccine regimen may be as low as 70%.Travel Vaccines for Certain Destinations
Some vaccines are indicated solely because of a specific regional itinerary (interactive graphic), regardless of whether the traveler has a specific risk behavior. Meningococcal and poliomyelitis vaccines are routine childhood vaccines that may require boosters in adult travelers with certain itineraries.Yellow fever vaccine is necessary for personal protection during travel to some tropical countries in South America and sub-Saharan Africa where the acquisition of yellow fever is a risk. Separately, under the 2005 International Health Regulations (IHR), yellow fever vaccination may also be required for travelers arriving in countries where there is no local transmission of yellow fever from countries where yellow fever is endemic. That way, competent vector mosquitoes in the receiving country will be protected from acquiring and transmitting the virus. A specialized travel medicine clinic or a medical facility designated by the Centers for Disease Control and Prevention (CDC) as a yellow fever vaccination center is best situated to interpret nuanced requirements and recommendations, and referral to such a facility is recommended (http://wwwnc.cdc.gov/travel/yellow-fever-vaccination-clinics/search). Neither yellow fever vaccine nor any other vaccine is currently required for readmission to the United States. First doses of yellow fever vaccine, but not booster doses, have been associated with rare but severe or fatal adverse events (overall rate, 1 event per 250,000 doses)40,53; the risk is highest among persons over the age of 60 years and increases with advancing age.Until recently, the yellow fever vaccine was uniformly considered to provide protection for 10 years.41,54 Currently, the CDC recommends that for healthy, nonpregnant adults, 10-year boosters should be given to travelers planning a long stay in any area where there is a risk of yellow fever transmission, to all travelers spending any amount of time in high-risk areas such as West Africa, and to all persons traveling to an area with a current outbreak. On the basis of an analysis by CDC experts showing that 92% of vaccine recipients have virus-neutralizing antibody at 10 years and 80% have the antibody at 20 years, the CDC has concluded that most healthy persons can be considered to have long-term immunity.42 For the purposes of the IHR, a single dose of yellow fever vaccine is sufficient for entry to any country. However, some countries may still consider the vaccine protective for only 10 years. Decisions about yellow fever vaccination must be based on the risk–benefit ratio for the individual traveler, with consideration of the itinerary and any specific country-entry requirements.Because the supplies of postexposure biologic agents are unreliable in low-resource countries, administering rabies vaccine before travel simplifies any postexposure management.55,56 A pre-exposure rabies series is indicated for travelers planning a long stay in areas of Latin America, Asia, or Africa where the rabies threat is constant. However, at least one study has shown little correlation between travel duration and the likelihood of a potential rabies exposure.57 For short-term travel, high-risk groups include joggers, adventure travelers, bikers, hikers, cave explorers, young children, and frequent travelers.Japanese encephalitis is endemic in rural Asia near rice paddies and pig farms and presents rare but unpredictable risks for travelers.26 Vaccination is recommended for the following travel plans: a long stay in a rural area where Japanese encephalitis is endemic, expatriation in any country where the disease is endemic, a short-term stay involving extensive unprotected outdoor exposure (e.g., adventure travel) during transmission season in a rural area where the disease is endemic, or a short-term stay in an area with a local epidemic of the disease.Because meningococcal epidemics occur frequently in the “meningitis belt” in sub-Saharan Africa (see the interactive graphic) during the dry season, updated vaccination with the quadrivalent ACYW-135 meningococcal vaccine is indicated. In view of the high risk of disease transmission, Saudi Arabia requires proof of vaccination within the previous 3 years for pilgrims undertaking the Hajj or Umrah pilgrimage.33 Meningococcal B vaccine is not indicated for travel.Efforts to eradicate poliomyelitis have been successful in most countries, and the disease remains endemic only in Pakistan and Afghanistan (http://www.polioeradication.org/Keycountries.aspx). Adults traveling to these two countries or to countries that have outbreaks of vaccine-derived poliomyelitis and who have previously completed a primary vaccine series should receive one booster dose in adulthood.58Cholera vaccine, approved in 2016 by the Food and Drug Administration (FDA) for licensure in the United States, is recommended for aid workers, refugee workers, and health care workers exposed to displaced populations in areas where cholera is endemic or epidemic (see the interactive graphic).43 Since the 2010 earthquake in Haiti, cholera has been endemic in that country as well as in the Dominican Republic and Cuba.Cell-culture–based vaccines are available in regions of Europe and Asia where tickborne encephalitis is endemic (see the interactive graphic) but are unavailable in the United States.44Travelers planning to live in or to pursue extensive outdoor activities (hiking and camping) in countries where tickborne encephalitis is highly endemic should consider obtaining vaccination at the destination, if time allows.Immunizations can and should be given at the same time and in any combination. If, for some reason, two live viral vaccines (Table 2) are not administered on the same day, the second vaccine should be administered 1 month after the first. Minimum intervals between vaccine doses in a series must be respected, although with the exception of rabies vaccine, an interval of 4 or fewer days before the next scheduled injection is acceptable. There is no maximum interval between doses of a primary vaccine series; an interrupted series can be resumed beginning with the dose that is overdue.MALARIA PREVENTION
An average of 1500 imported cases of malaria are reported annually in the United States (http://www.cdc.gov/malaria/references_resources/mmwr.html). A malaria vaccine designed for young children in Africa is not appropriate for use in nonimmune adult or pediatric travelers.Estimates of the risk of malaria among travelers not receiving chemoprophylaxis range from 3.4% per month of travel in West Africa to 0.34% per month of travel on the Indian subcontinent and 0.034% per month of travel in South America. Transmission, and in particular high transmission, is quite focal. The lifetime range of flight of an anopheles mosquito, which bites only from dusk to dawn, is 1 km. Daytime travel to a known focal area of disease transmission, with departure to a malaria-free area to sleep at night, confers a negligible risk. Nighttime exposure to mosquitoes for even a few hours in a high-transmission area may result in infection. Mosquito-bite prevention is a primary approach to protection from malaria (Table 1). The decision about whether to prescribe chemoprophylaxis should also take into account the distribution and type of malaria in the area of the planned itinerary and the possibility of deviation from that itinerary, as well as the traveler’s personal tolerance for what may be an epidemiologically insignificant level of risk for the trip.A general malaria-distribution map (see the interactive graphic), as well as resources for information on the current, country-specific microepidemiology of malaria, including the CDC Travelers’ Health website, should be immediately accessible to clinicians prescribing malaria prophylaxis (Table S1 in the Supplementary Appendix, available at NEJM.org). Dosing and the properties of antimalarial agents that affect the choice of drug are presented in Table 3TABLE 3Drug Regimens for Prophylaxis against Malaria., and in Table S2 in the Supplementary Appendix; other considerations have been reviewed previously.59 In practice, daily atovaquone–proguanil is preferable to doxycycline or mefloquine for short-term travel (<3 weeks) and is most widely prescribed.6 Atovaquone–proguanil is associated with mild side effects and may be stopped just 7 days after the traveler has departed from an area of possible exposure. Longer courses appear to be safe but are costly. In most areas with malaria, atovaquone–proguanil, doxycycline, and mefloquine are equally effective (>95%) in preventing malaria, but disadvantages (e.g., more reports of adverse events in persons taking doxycycline or mefloquine, as well as resistance to mefloquine) may hamper their use (Table S2 in the Supplementary Appendix).60 Chemoprophylaxis may be started well before departure (3 to 4 weeks for mefloquine) if there is concern about possible side effects of any drug. Weekly administration of mefloquine, if side effects are not an issue, is preferable for long-term travel because of lower cost and convenience. Chloroquine, an older drug that is also administered weekly, is highly effective in the few areas that are known to have exclusively chloroquine-sensitive parasites.
If parasites of a malaria species that transmits a relapsing form of malaria (Plasmodium vivax or P. ovale) have entered the liver as a result of exposure during travel, relapses may occur months or, in rare cases, up to a few years after the traveler has returned home, since the primary prophylactic drugs discussed above are ineffective against dormant forms (hypnozoites) in the liver. Primaquine can be used to prevent relapsing malaria after the traveler has left the area where P. vivax or P. ovale is endemic. A relapse can occur even if the traveler received primary chemoprophylaxis and did not have an initial clinical episode of malaria during or soon after the actual exposure. Prophylaxis against primary attacks of malaria with the use of primaquine instead of one of the drugs noted above can be considered when exposure is limited to areas where only P. vivax is endemic. This strategy has the advantage of simultaneously reducing the risk of relapses.For stays in areas with very low rates of malaria transmission, some authorities — notably, in Europe — advise that only a standby drug be carried for self-treatment, to be taken in the event that symptoms suggestive of malaria occur and there is no access to competent medical care or to a facility in which a competent assessment of a blood smear for malaria can be performed within 6 to 12 hours.61 This strategy is especially attractive for long-stay travelers. A full course of atovaquone–proguanil or artemether–lumefantrine is recommended. In the United States, the CDC recommends continuous prophylaxis, as noted above, for travelers at risk but also suggests that treatment doses of these drugs may be carried for the treatment of confirmed malaria in areas where appropriate drugs for treatment may be unavailable or where there is concern about substandard or counterfeit medication.Travelers should be instructed in writing to continue taking antimalarial drugs for the appropriate period after the last possible exposure, with the explanation that malaria can still occur despite chemoprophylaxis and that three blood smears or rapid diagnostic tests for malaria are mandatory for any febrile illness occurring within 3 months after travel. Travelers to areas where false positive tests for malaria are common in clinical practice (e.g., Africa) should be reminded to continue taking the prophylactic drug even if they receive a diagnosis of malaria. Prevention of malaria in travelers residing in malarious areas for 6 months or longer presents complex problems leading to reduced adherence to chemoprophylaxis.62OTHER ARTHROPOD-BORNE DISEASES
Some infections are preventable only by antiarthropod measures (Table 1). Dengue accounts for up to 2% of cases of illness in travelers who have returned from countries where dengue is endemic and is the most common systemic febrile illness; severe dengue is very rare in travelers.3,4,63 At least 10 dengue vaccine candidates are being evaluated in clinical trials; a vaccine recently licensed in several countries where dengue is endemic is unsuitable for use in travelers, and no antiviral drugs are available.64 Chikungunya65 and Zika virus infection66 are emerging illnesses that are characterized by a rash (see the interactive graphic); they are clinically similar to dengue and occur in many overlapping areas. Chikungunya may result in debilitating arthritis. Zika virus infection is considered to cause microcephaly and other neurologic malformations in newborns and the Guillain–Barré syndrome.66 Rickettsial diseases, transmitted by ticks, mites, and fleas, are emerging in travelers.67 Rickettsia africae has been documented as the second most common cause of fever in travelers returning from sub-Saharan Africa, after malaria.3TRAVELERS’ DIARRHEA
Travelers’ diarrhea, defined as three or more unformed stools plus at least one accompanying symptom in a 24-hour period during travel and for up to 7 days after travel, is most frequently bacterial.68 Protozoa account for less than 5% of cases, and in adults, detection of norovirus or rotavirus is increasing. The mean duration of travelers’ diarrhea, even if untreated, is 4 to 5 days. Despite pretravel advice (Table 1), travelers’ diarrhea affects 10 to 40% of travelers.68 Treatment with a proton-pump inhibitor may increase the risk of travelers’ diarrhea.69 Chronic postinfectious sequelae of travelers’ diarrhea have been reported in 3 to 17% of travelers in small studies.70Standard self-treatment for travelers’ diarrhea consists of oral hydration together with an antimotility medication (usually loperamide), an antisecretory medication, or both for symptomatic relief. The addition of a single dose of a self-administered quinolone (500 mg of ciprofloxacin or levofloxacin) or azithromycin (1 g) can be considered for more rapid cessation of severe diarrhea. Three days of therapy with a quinolone or azithromycin at a dose of 500 mg per day may also be used. Azithromycin is the only option for persons traveling to Southeast Asia, India, or Nepal, where several common enteric pathogens are resistant to quinolones. The benefit of either antibiotic class should be weighed against the known side effects and drug interactions. Antibiotic prophylaxis for travelers’ diarrhea is not recommended except in rare circumstances.Antibiotic use for travelers’ diarrhea has been associated with intestinal colonization with antibiotic-resistant bacteria in returning travelers,71-73 but the use of loperamide alone has not.74 In South Asia, studies have shown that 80% of travelers with travelers’ diarrhea who were treated with antimicrobial agents acquired extended-spectrum β-lactamase–producing Enterobacteriaceae,71-73and in one study, 10% of carriers were still excreting the organisms 3 months after their return.72The potential for spread is of concern, although the public health implications are still unclear. A balanced approach should be sought to enable travelers to treat themselves for an often debilitating, if not life-threatening, problem while abroad, especially in developing countries where available local medications and health care may be substandard. Beyond bloody diarrhea, diarrhea with fever, or dysentery, the definition of severe diarrhea is subjective. However, knowing that antibiotic use contributes to antibiotic-resistant infections may encourage travelers to adhere to preventive measures and recommendations for managing symptoms.ALTITUDE ILLNESS
Common high-altitude destinations for leisure travel include La Paz, Bolivia; Cuzco, Peru; Lake Titicaca, on the border of Bolivia and Peru; Quito, Ecuador; Lhasa, Tibet; and Mount Kilimanjaro, Tanzania. Whether the ascent is made by motor vehicle or airplane, acute mountain sickness occurs in at least 25% of people who ascend rapidly, instead of gradually over a period of several days, to an altitude of 2500 m or higher and occurs in most people who ascend rapidly to 2800 m or higher.75 Even with a gradual ascent, the risk of altitude illness is unpredictable for first-time travelers to high-altitude destinations. For prevention, acetazolamide is effective at a dose of 125 mg twice daily beginning 24 hours before an ascent to an altitude of 2800 m or higher and continuing through the day after the highest altitude is reached. Severe complications such as pulmonary or cerebral edema, which are uncommon at altitudes below 3500 m, are best treated with supplemental oxygen and an immediate descent. Persons traveling to destinations at an altitude of 3500 m or higher for a stay of more than a few hours should consult an expert.THROMBOSIS
A causal but modest link between lack of mobility during travel and deep venous thrombosis or pulmonary embolism in otherwise healthy persons has been established. The overall absolute incidence of symptomatic venous thromboembolism in the month after a flight lasting more than 4 hours is 1 in 4600 flights and increases by 18% for each additional 2 hours in flight.76 The risk of severe pulmonary embolism is negligible on flights lasting less than 6 hours.77 Passengers with known risk factors are at highest risk. Preventive measures include avoiding dehydration and performing leg exercises while in flight. Of the many recommendations for prevention, only the use of graduated compression stockings (15 to 30 mm Hg) for passengers at increased risk is supported by data from randomized clinical trials,76 though prophylaxis with subcutaneous administration of low-molecular-weight heparin just before departure and again 24 hours later for travelers with thrombophilia or previous thrombotic events is often used in practice. Aspirin is of no proven benefit for travelers.76 Aisle seating promotes mobilization; no intrinsic benefit of premium-class seating has been shown.76CONCLUSIONS
A summary of pretrip preparations for persons seeking medical consultation in the United States for travel to selected common overseas destinations is shown in Table 4TABLE 4Major Considerations during Medical Consultation before Leisure Travel to Common Destinations.. A body of knowledge in travel medicine has been published by the International Society of Travel Medicine (http://www.istm.org/bodyofknowledge). Available publications, especially those from GeoSentinel, which is the International Society of Travel Medicine–CDC database of travel-related illnesses,1-3 and online resources (Table S1 in the Supplementary Appendix) should be consulted frequently to stay up to date on constantly changing epidemiology. Preventive strategies and medical interventions need to be individualized. No traveler should leave the consultation without understanding the importance of seeking expert medical advice immediately if fever develops after the return home.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.SOURCE INFORMATION
From the William C. Gorgas Center for Geographic Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham (D.O.F.); the Division of Infectious Diseases, Mount Auburn Hospital, Cambridge, MA (L.H.C.); the Department of Medicine, Harvard Medical School, Boston (L.H.C.); and the Division of Infectious Diseases, Emory University, Atlanta (P.E.K.).Address reprint requests to Dr. Freedman at the William C. Gorgas Center for Geographic Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, 1720 2nd Ave. S., BBRB 203, Birmingham, AL 35294, or atfreedman@uab.edu.
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