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The n e w e ng l a n d j o u r na l of m e dic i n e

Review Article

DanL. Longo, M.D., Editor

Medical Considerations before International


Travel
DavidO. Freedman, M.D., LinH. Chen, M.D., and PhyllisE. Kozarsky, M.D.

I
n 2015, international tourist arrivals in all countries exceeded From the William C. Gorgas Center for
1.2 billion persons. In 2014, the total number of arrivals in countries with Geographic Medicine, Division of Infec-
tious Diseases, University of Alabama at
emerging markets nearly surpassed the number in developed countries (www Birmingham, Birmingham (D.O.F.); the
.e-unwto.org/doi/book/10.18111/9789284416899). Depending on the destination, Division of Infectious Diseases, Mount
22 to 64% of travelers report some illness; most of these illnesses are mild and Auburn Hospital, Cambridge, MA (L.H.C.);
the Department of Medicine, Harvard
self-limited, such as diarrhea, respiratory infections, and skin disorders.1-4 Some Medical School, Boston (L.H.C.); and the
travelers return to their own countries with preventable life-threatening infec- Division of Infectious Diseases, Emory
tions.5 Yet 20 to 80% of travelers do not seek pretravel health consultation.6 Data University, Atlanta (P.E.K.). Address re-
print requests to Dr. Freedman at the
about the effect of pretravel advice are limited, although such advice has had a William C. Gorgas Center for Geographic
positive effect on the prevention of malaria.7 Travelers visiting friends and relatives Medicine, Division of Infectious Diseases,
in their country of origin constitute the group with the highest morbidity, espe- University of Alabama at Birmingham,
1720 2nd Ave. S., BBRB 203, Birmingham,
cially from malaria and typhoid; this group requires special approaches to illness AL 35294, or at freedman@uab.edu.
prevention and education.8,9
N Engl J Med 2016;375:247-60.
Persons who are planning to travel to other countries often ask their health care DOI: 10.1056/NEJMra1508815
providers for information about preventive interventions. Nonspecialists can pro- Copyright 2016 Massachusetts Medical Society.

vide 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 A Quick Take
planning to live abroad for a long time, women who are pregnant14 or plan to is available at
become pregnant soon, young children, and travelers with complicated itineraries. NEJM.org

S t ruc t ur ed A pproach t o the Pr e t r av el C onsultat ion


During the medical appointment that precedes international travel, a structured
and sequenced approach (Fig.1) 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 substan-
tially 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 (Table1). 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 travelers 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 recommenda-
tions.

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The n e w e ng l a n d j o u r na l of m e dic i n e

Vac cinat ions their home country before traveling.48 Healthy


travelers who are 65 years of age or older should
Table2 provides data on dosing, route of admin- be up to date on pneumococcal vaccination.
istration, need for boosters, and possible accel-
erated regimens for vaccines administered be- Routine Travel Vaccines
fore travel. The discussion below, which focuses Hepatitis A vaccine is indicated for every non-
on indications for each vaccine in the context of immune traveler because of foodborne transmis-
travel, should be used in conjunction with the sion of the disease and an estimated incidence
information in the interactive graphic (available of 1 case per 5000 travelers per month. A single
with the full text of this article at NEJM.org), dose of hepatitis A vaccine given any time before
which shows the geographic distribution of ma- travel, even on the way to the airport, provides
jor travel-related diseases. more than 94% seroprotection. The current adult
population in the United States generally has
Verification and Update of Routine Vaccines little to no immunity to hepatitis A virus.
Routine vaccines are those that need to be read- Since most adults who were born in the
ministered at regular intervals or series that United States have not been immunized with the
need to be completed in a healthy adult without hepatitis B vaccine, vaccination should be con-
plans for international travel who has no medi- sidered for all travelers, although predicting ex-
cal or behavioral risk factors (Fig.1). For many posure to blood or body fluids during travel is
vaccine-preventable diseases, the risk of acquisi- difficult. In the absence of the usual risk factors
tion is increased in developing countries. for hepatitis B virus infection, long stays and
Importations of measles and mumps have close contact with residents in local communi-
resulted in travel-related outbreaks.45 Interna- ties may lead to more opportunities for injuries,
tional travelers born in the United States after the need for medical or dental care, sexual con-
1956 must either have received two documented tact, and tattooing or body piercing.49 The rela-
doses of the measlesmumpsrubella (MMR) tive likelihood of future international travel
vaccine or have evidence of immunity. Many warrants consideration of a vaccine that confers
persons born in the United States before 1970 lifelong protection.50
have never received the MMR vaccine, and many South Asia has the highest risk of typhoid
born in the 1970s have not had the second dose, and paratyphoid fevers (see the interactive graph-
a recommendation that was made in 1990. ic), particularly for travelers visiting friends or
Adults who have never received the tetanus relatives.51 Vaccination against Salmonella enterica
diphtheriaacellular pertussis (Tdap) vaccine serovar Typhi, a foodborne bacterial pathogen
should be given a dose of Tdap, regardless of the with increasing rates of multidrug resistance
time elapsed since the last tetanusdiphtheria globally, may be considered for persons traveling
vaccination. Widespread outbreaks of measles, to other areas where typhoid and paratyphoid
mumps, and pertussis are currently ongoing in fevers are endemic and sanitary conditions are
developed and in developing countries.46 Persons suboptimal. The efficacy of either available vac-
born in the United States after 1979 must either cine against S. Typhi is only 60 to 80%.52 Adher-
have received two documented doses of varicella ence to the oral vaccine regimen may be as low
vaccine or have evidence of immunity. as 70%.
Influenza is the most common vaccine-pre-
ventable disease among travelers,47 including Travel Vaccines for Certain Destinations
passengers on cruise ships. Because of year- Some vaccines are indicated solely because of a
round circulation of influenza virus in tropical specific regional itinerary (interactive graphic),
and subtropical regions and an influenza season regardless of whether the traveler has a specific
that occurs in winter in temperate regions in the risk behavior. Meningococcal and poliomyelitis
southern hemisphere (which is summer in the vaccines are routine childhood vaccines that may
northern hemisphere), all travelers to the tropics require boosters in adult travelers with certain
at any time of year and to temperate destinations itineraries.
where it is currently winter should have received Yellow fever vaccine is necessary for personal
the most current influenza vaccine available in protection during travel to some tropical coun-

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Medical Consider ations before International Tr avel

Risk Assessment Standard In-Office Interventions Focused Education before the Trip

Medical history, including medications, Administration of immunizations Vectorborne diseases (if risk)
disabilities, immune status, immuniza- Updating of routine vaccines Personal protection measures for malaria,
tions, surgeries, allergies, and pregnancy MMR, Tdap, pneumococcal, varicella, dengue, chikungunya, Zika virus
or breast-feeding influenza infection, leishmaniasis, rickettsial
Prior travel experience Routine travel vaccines disease, sleeping sickness
hepatitis A, typhoid, hepatitis B Other travel-related illnesses (as applicable)
Specific itinerary, including regions, Special travel vaccines
season, and dates Altitude illness
yellow fever, rabies, polio, Travelers thrombosis
Activities (e.g., adventure travel and events meningococcal, Japanese encephalitis, Motor vehicle injury
involving mass gatherings) cholera, tickborne encephalitis Bloodborne and sexually transmitted
Type of accommodations Malaria chemoprophylaxis (if risk) infections
Individualize to itinerary and patient Swimming, water exposure,
Travelers risk tolerance
Travelers diarrhea and marine hazards
Financial challenges Transportation-associated illnesses
Food and water precautions
Oral rehydration and use of loperamide Respiratory infection and tuberculosis
and bismuth Rabies and animal-associated illness
Antibiotic self-treatment options for Skin conditions and wounds
severe diarrhea Medical kit and medical care abroad
Prophylaxis with bismuth or antibiotic Personal health kit
(only if high risk) Available medical facilities
Evacuation insurance; supplemental
health insurance

Figure 1. Structured Approach to Medical Consultation before International Travel.


The consultation, conducted 4 to 6 weeks before departure, consists of an assessment of risk, interventions per-
formed in the office (Tables 2 and 3), and education for the trip. MMR denotes measlesmumpsrubella, and
Tdap tetanusdiphtheriaacellular pertussis.

tries in South America and sub-Saharan Africa for healthy, nonpregnant adults, 10-year boost-
where the acquisition of yellow fever is a risk. ers should be given to travelers planning a long
Separately, under the 2005 International Health stay in any area where there is a risk of yellow
Regulations (IHR), yellow fever vaccination may fever transmission, to all travelers spending any
also be required for travelers arriving in coun- amount of time in high-risk areas such as West
tries where there is no local transmission of Africa, and to all persons traveling to an area
yellow fever from countries where yellow fever is with a current outbreak. On the basis of an
endemic. That way, competent vector mosquitoes analysis by CDC experts showing that 92% of
in the receiving country will be protected from vaccine recipients have virus-neutralizing anti-
acquiring and transmitting the virus. A special- body at 10 years and 80% have the antibody at
ized travel medicine clinic or a medical facility 20 years, the CDC has concluded that most
designated by the Centers for Disease Control healthy persons can be considered to have long-
and Prevention (CDC) as a yellow fever vaccina- term immunity.42 For the purposes of the IHR, a
tion center is best situated to interpret nuanced single dose of yellow fever vaccine is sufficient
requirements and recommendations, and refer- for entry to any country. However, some coun-
ral to such a facility is recommended (wwwnc tries may still consider the vaccine protective for
.cdc.gov/t ravel/yellow-fever-vaccination-clinics/ only 10 years. Decisions about yellow fever vac-
search). Neither yellow fever vaccine nor any cination must be based on the riskbenefit ratio
other vaccine is currently required for re for the individual traveler, with consideration of
admission to the United States. First doses of the itinerary and any specific country-entry re-
yellow fever vaccine, but not booster doses, have quirements.
been associated with rare but severe or fatal Because the supplies of postexposure biologic
adverse events (overall rate, 1 event per 250,000 agents are unreliable in low-resource countries,
doses)40,53; the risk is highest among persons administering rabies vaccine before travel sim-
over the age of 60 years and increases with ad- plifies any postexposure management.55,56 A pre-
vancing age. exposure rabies series is indicated for travelers
Until recently, the yellow fever vaccine was planning a long stay in areas of Latin America,
uniformly considered to provide protection for Asia, or Africa where the rabies threat is con-
10 years.41,54 Currently, the CDC recommends that stant. However, at least one study has shown

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The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Important Practices for Reducing Disease Risk during International Travel.

Arthropod-borne illnesses (malaria, dengue, Travelers diarrhea Transportation-associated illnesses


chikungunya, Zika virus infection, Eat well-cooked, hot foods. To prevent barotrauma, chew or swallow dur-
Japanese encephalitis, leishmaniasis, Always wash hands before eating and after ing ascents and descents; feed young
rickettsial disease) using the toilet. children or provide them with a pacifier
Wear clothing that exposes as little skin as Avoid eating food from market stalls and during ascents and descents.
possible. street vendors. To prevent motion sickness, move to the
Apply a repellent containing N,N-diethyl-3- Avoid tap water and drinks or ice made from center of the vehicle; fix your gaze on
meta-toluamide (DEET; concentration, tap water, unless advised of their safety still, distant objects; and increase air-
3035%) or picaridin* (concentration, by a reliable source. flow across your face.
20% for tropical destinations).15,16 Avoid buffets where food covers or fly con- Treatment with scopolamine patches or tab-
Treat clothing with permethrin (or another trols are not used and where food has lets or with meclizine, initiated before
pyrethroid) when traveling in an area been sitting out for many hours. departure, may minimize symptoms of
of very high risk for malaria or other Avoid high-risk food such as shellfish, raw motion sickness during a cruise or
mosquito-borne or tickborne diseases. or undercooked foods, unpasteurized travel on rough roads. Ondansetron
Apply repellant according to the time of day dairy products, mayonnaise, cold sauc- has not been shown to prevent nausea
and type of insects to be avoided. es or salsas, fruits you havent peeled due to motion sickness.
Mosquitoes that transmit malaria yourself, and salads. If you are traveling east across more than three
(anopheles mosquitoes) are generally Swimming, water exposure, and marine hazards time zones, you can expose yourself to
night biters. Heed posted warnings and avoid beaches light early in the day, advancing the body
Mosquitoes that transmit organisms that are not patrolled. clock so that it will be synchronized with
causing dengue, chikungunya, Zika, Do not swim alone or after dark and do not the new time zone. Conversely, if you are
and yellow fever (aedes mosquitoes) walk on any beach after dark. traveling west, you can expose yourself to
are generally day biters with peak bit- Avoid use of alcohol or mind-altering drugs light at dusk and in the early part of the
ing times in the early morning and late while engaging in water sports. evening, delaying the body clock so that
afternoon. Avoid water where there is sewage contami- it will be synchronized with the new time
Mosquitoes that transmit West Nile virus nation or algae are present. zone. Crossing more than eight times
and Japanese encephalitis (culex mos- Avoid any exposure (e.g., rafting, swimming, zones in either direction reverses the
quitoes) are most active at dusk and or wading) to water known to be infect- time for morning or evening light.
again at dawn. ed with schistosomiasis (bilharzia).17 Zolpidem and possibly melatonin offer some
Sleep under a permethrin-impregnated bed SCUBA dive only with personnel certified by benefit in adapting to local sleeping
net, if you are not sleeping in a sealed, the Professional Association of Diving cycles.
air-conditioned room, in areas where Instructors (PADI) or the National Medical kit and medical care abroad
there is a high risk of malaria or Association of Underwater Instructors Carry a compact medical kit that includes the
Japanese encephalitis. (NAUI) and use equipment only following:
Perform a full body check at least once a day in from PADI- or NAUI-certified dive Simple first-aid supplies, such as bandages,
areas where tickborne disease is a risk. operators. gauze, hemostatic gauze, antiseptic,
Wear light-colored (not blue), heavyweight Follow established timetables for air travel antibiotic ointment, butterfly bandages,
clothing in areas where African try- after diving. skin glue, and splinter forceps.
panosomiasis is a risk; DEET is gener- In tropical waters, watch for jellyfish, sea ur- A thermometer and antipyretic agents.
ally ineffective. chins, and corals. Antifungal creams, cough and cold reme-
Respiratory infection and tuberculosis Decline water transportation in vessels with- dies, antacids, hydrocortisone cream,
Practice hand hygiene diligently. out personal flotation devices or life and blister pads.
As much as possible, avoid crowded public jackets. Condoms.
transportation and crowded public Wear appropriate footwear when walking, Sunscreen and insect repellent.
places that are poorly ventilated. wading, or swimming to avoid injury Adequate medical and evacuation insurance
Move away from anyone with a persistent and exposure to parasites and poison- should be arranged, even for short trips.
or intense cough. ous plants and animals. Contact information for hometown medical
Screen domestic workers for tuberculosis. Hikers, bikers, and adventure travelers with providers, health insurance carriers,
If you are planning a long stay, have a tuber- exposure to water or wet environments and a medical assistance company
culosis skin test before departure, may consider prophylaxis with 200 mg should be accessible at all times.
once per year thereafter, and on re- of doxycycline once per week (or 100 If you are planning a long stay, integrate into
turning home. mg daily if used for concomitant malar- the local expatriate medical infrastruc-
Avoid excessive outdoor activity in areas of ia prophylaxis) in developing countries ture (i.e., become familiar with the doc-
heavy air pollution during hot or hu- where there is a substantial risk of lep- tors, hospitals, pharmacies, and ambu-
mid times of the day. tospirosis.18 lance services that cater to foreigners)
Rabies and animal-associated illness Since sand may be contaminated in areas immediately after arrival so that you
Never assume that an animal is free of rabies. frequented by animals, sit on a towel, can seek competent care for any illness
Do not handle or feed pets or unknown ani- blanket, or piece of clothing if a chair early in its course.
mals (especially dogs and monkeys). or hammock is not available. Shake out If you have cardiac disease, carry a copy of a re-
If bitten, scratched, or licked on broken skin, all fabrics thoroughly after use. cent electrocardiogram on a portable USB
clean the wound immediately with Eating predatory reef fish (barracuda, jackfish, drive or make sure the electrocardiogram
soapy water and seek postexposure grouper, or snapper), even if well cooked, can be accessed on the Internet.
treatment for rabies (even if rabies may cause ciguatera poisoning. Carry all medicines in labeled prescription
vaccination was completed before ex- Eating mackerel, tuna, bonito, mahi-mahi, bottles.
posure) or herpes B virus (transmitted or amberjack may cause scombroid Carry a list of medical conditions, allergies,
by monkey bites). poisoning. and medications with dosages.
Consider minimizing going running or bicy-
cling in high-risk rabies areas.

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Medical Consider ations before International Tr avel

Table 1. (Continued.)

Bloodborne and sexually transmitted Skin conditions and wounds Prevention of motor vehicle and other
infections Broken skin may become infected and lead injuries
Use condoms in all sexual encounters; un- to serious problems. Any bite, cut, or Avoid overcrowded transportation.
protected casual sex, whether with lo- broken skin should be cleaned with Do not drink and drive.
cal residents or fellow travelers, always safe water. Apply an antiseptic solution Keep automobile doors locked and windows
poses a high risk. or spray. closed at all times, if possible.
Avoid sexual relations with commercial sex Increasing pain, redness, or discharge from a Seek vehicles with seat belts, which may re-
workers. cut suggests a spreading infection and sult in extra expense; decline vehicles
Understand that inhibitions are diminished may require antibiotic treatment. Seek without seat belts unless no other
when traveling away from the social medical help if this occurs. choice is available.
constraints of home; excessive use of In Africa, all clothes dried outdoors should Decline transportation in vehicles with worn
alcohol and recreational drugs can in- be ironed to avoid cutaneous myiasis tires, worn brakes, or inoperative
fluence behavior and encourage un due to the tumbu fly. lights.
intentional risk exposure. Hats and sunscreen are mandatory in the Avoid driving at night or alone, and never
Avoid skin-perforating procedures (acupunc- tropics. Sunscreen should always be drive outside urban areas after dark.
ture, piercing, or tattooing). applied to skin before an application Never drive a motorcycle or scooter abroad;
Unless you are in a life-threatening situation, of DEET. wear a helmet if you are a passenger.
avoid invasive medical or dental pro Use a helmet when bicycling, skiing, or skating.
cedures in unaccredited medical If you are planning a long stay, arrange for a
facilities; request proof of accreditation locally purchased mobile phone to be
by Joint Commission International or in the vehicle, if possible.
other international bodies.
Consider carrying disposable needles, syringes,
and sutures for remote travel.

* Picaridin products available in the United States with 20% concentration include Natrapel (Tender Corporation) and Picaridin Insect Repellent
(Sawyer). Picaridin is also known as icaridin in some countries. Picaridin, unlike DEET, has a pleasant smell and does not dissolve plastic materials.
The time from the end of the dive until the boarding of an aircraft is generally between 12 and 24 hours, depending on the type of dive.

little correlation between travel duration and the Efforts to eradicate poliomyelitis have been
likelihood of a potential rabies exposure.57 For successful in most countries, and the disease re-
short-term travel, high-risk groups include jog- mains endemic only in Pakistan and Afghanistan
gers, adventure travelers, bikers, hikers, cave ex- (www.polioeradication.org/Keycountries.aspx).
plorers, young children, and frequent travelers. Adults traveling to these two countries or to
Japanese encephalitis is endemic in rural Asia countries that have outbreaks of vaccine-derived
near rice paddies and pig farms and presents poliomyelitis and who have previously completed
rare but unpredictable risks for travelers.26 Vac- a primary vaccine series should receive one
cination is recommended for the following travel booster dose in adulthood.58
plans: a long stay in a rural area where Japanese Cholera vaccine, approved in 2016 by the
encephalitis is endemic, expatriation in any Food and Drug Administration (FDA) for licen-
country where the disease is endemic, a short- sure in the United States, is recommended for
term stay involving extensive unprotected out- aid workers, refugee workers, and health care
door exposure (e.g., adventure travel) during workers exposed to displaced populations in
transmission season in a rural area where the areas where cholera is endemic or epidemic (see
disease is endemic, or a short-term stay in an the interactive graphic).43 Since the 2010 earth-
area with a local epidemic of the disease. quake in Haiti, cholera has been endemic in that
Because meningococcal epidemics occur fre- country as well as in the Dominican Republic
quently in the meningitis belt in sub-Saharan and Cuba.
Africa (see the interactive graphic) during the Cell-culturebased vaccines are available in
dry season, updated vaccination with the quad- regions of Europe and Asia where tickborne en-
rivalent ACYW-135 meningococcal vaccine is in- cephalitis is endemic (see the interactive graphic)
dicated. In view of the high risk of disease but are unavailable in the United States.44 Travel-
transmission, Saudi Arabia requires proof of ers planning to live in or to pursue extensive
vaccination within the previous 3 years for pil- outdoor activities (hiking and camping) in coun-
grims undertaking the Hajj or Umrah pilgrim- tries where tickborne encephalitis is highly en-
age.33 Meningococcal B vaccine is not indicated demic should consider obtaining vaccination at
for travel. the destination, if time allows.

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252
Table 2. Vaccines That Should Be Available during Pretravel Consultation.*

Disease and Vaccine Route of Accelerated Schedule


Type Adult Dose Administration Standard Schedule for Series Estimated Duration of Protection References
Available in the United
States
Cholera: live attenuated 1 sachet Oral Single dose NA 36 mo Jackson and Chen19
bacteria
Hepatitis A: inactivated 1 ml Intramuscular 2 doses: day 0 and at Available in combined >20 yr (seropositivity); >40 yr ACIP,20 Theeten et al.21
virus 612 mo hepatitis A and B (antibody modeling)
formulation: days 0,
7, and 21 and at 12
mo
The

Hepatitis B: recombinant 1 ml Intramuscular 3 doses: day 0 and at Available in combined 30 yr Mast et al.,22 FitzSimons
hepatitis B sur- 1 mo and 6 mo hepatitis A and B et al.23
face antigen formulation: days
0, 7, and 21 and
at 12 mo
Combined hepatitis A and 1 ml Intramuscular 3 doses: day 0 and at 4 doses: days 0, 7, and >15 yr (data on monovalent vac- Van Damme et al.24
B: inactivated vi- 1 mo and 6 mo 21 and at 12 mo cines support long-term protec-
rus and recombi- tion from anamnestic response)
nant viral antigen
Influenza Grohskopf et al.25
Inactivated virus or 0.5 ml (0.1 ml for Intramuscular (intra- 1 dose NA 1 yr
recombinant, tri- intradermal admin- dermal formula-
n e w e ng l a n d j o u r na l

valent or quadri- istration) tion for age 18

The New England Journal of Medicine


of

valent 64 yr)
Live attenuated virus, 0.1 ml in each Intranasal spray 1 dose NA 1 yr
quadrivalent nostril

n engl j med 375;3nejm.org July 21, 2016


Japanese encephalitis: 0.5 ml Intramuscular 2 doses: days 0 and 28 2 doses: days 0 and 7 12 yr after initial dose; >6 yr if Fischer et al.,26 CDC,27
inactivated virus, boosted at 12 yr Jelinek et al.,28 EMA,29

Copyright 2016 Massachusetts Medical Society. All rights reserved.


m e dic i n e

derived from cell Paulke-Korinek et al.,30


culture Rabe et al.31
Measlesmumpsrubella: 0.5 ml Subcutaneous 2 doses: day 0 and at Lifelong, after 2 doses total at any McLean et al.32
live attenuated 4 wk time in life
virus
Meningococcal disease 0.5 ml Intramuscular 1 dose (off-label for NA 35 yr Cohn et al.,33 Baxter et al.34
quadrivalent those >55 yr old)

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ACYW-135: bacte-
rial polysaccha-
ride, conjugated

Poliomyelitis: inactivated 0.5 ml Subcutaneous Single dose in those NA Lifelong, after primary series plus Wallace et al.35
virus who received prima- a booster in adulthood (age
ry childhood series 18 yr)
Disease and Vaccine Route of Accelerated Schedule
Type Adult Dose Administration Standard Schedule for Series Estimated Duration of Protection References
Rabies: inactivated virus, 1 ml Intramuscular (0.1 ml 3 doses before expo- NA Patient should be informed that Manning et al,36 Wieten
derived from cell intradermally may sure: days 0, 7, 2 additional doses are required et al.37
culture be considered for and 2128 on days 0 and 3 after each pos-
use off-label) sible rabies exposure; no boost-
ers are otherwise indicated
Tetanusdiphtheria 0.5 ml Intramuscular 1 dose in those who NA 10 yr; 5 yr for travelers at high risk for CDC38
acellular pertussis received primary wounds (e.g., adventure travel-
(Tdap) or tetanus childhood series ers, those engaging in activities
diphtheria (Td): that may result in injuries, and
toxoid, protein travelers to places where medical
antigen care is substandard)
Typhoid Jackson et al.39
Bacterial cell-wall 0.5 ml Intramuscular 1 dose NA 23 yr
polysaccharide
Live attenuated 4 capsules Oral 4-capsule series, one 5 yr
bacteria every other day
Yellow fever: live attenu- 0.5 ml Subcutaneous 1 dose NA 10 yr for high-risk patients (in some Gershman and Staples,40
ated virus countries, protection is consid- WHO,41 Staples et al.42
ered to be long-term)
Not currently available in
the United States
Cholera: inactivated 1 sachet Oral 2 doses, 1 wk apart NA 2 yr WHO43
whole-cell bacteria
combined with
recombinant B
subunit of cholera
toxin

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The New England Journal of Medicine


Tickborne encephalitis: 0.5 ml Intramuscular 3 doses: day 0, at 3 doses: days 0, 7, and 3 yr WHO44
inactivated virus 13 mo, and 21 (protective 7 days
derived from cell at 512 mo after dose 3)
culture
Medical Consider ations before International Tr avel

Copyright 2016 Massachusetts Medical Society. All rights reserved.


* Consideration may be given to stocking human papillomavirus and herpes zoster vaccines, as well as other vaccines (e.g., pneumococcal vaccines) for travelers with chronic illnesses,
since the travel consultation is an excellent opportunity to update routine immunizations. CDC denotes Centers for Disease Control and Prevention, EMA European Medicines Agency,
FDA Food and Drug Administration, NA not applicable, and WHO World Health Organization.
The Advisory Committee on Immunization Practices (ACIP) recommends that the first dose of hepatitis A vaccine and IgG be administered in travelers older than 40 years of age who
are departing in less than 14 days for a destination where hepatitis A is endemic; however, this is rarely done in practice and is not included in any non-U.S. national guideline.
The initial accelerated schedule, with doses on days 0, 7, and 21, provides protection for up to 1 year; the additional dose at 12 months provides long-term protection similar to that
with the standard schedule.
The ACIP recommends use of the conjugate vaccine in persons 55 years of age or older who need repeated meningococcal vaccination, including travelers who may need another dose
in 5 years or more.

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253
The n e w e ng l a n d j o u r na l of m e dic i n e

Immunizations can and should be given at pendix, available at NEJM.org). Dosing and the
the same time and in any combination. If, for properties of antimalarial agents that affect the
some reason, two live viral vaccines (Table2) are choice of drug are presented in Table3, and in
not administered on the same day, the second Table S2 in the Supplementary Appendix; other
vaccine should be administered 1 month after considerations have been reviewed previously.59
the first. Minimum intervals between vaccine In practice, daily atovaquoneproguanil is prefer-
doses in a series must be respected, although able to doxycycline or mefloquine for short-term
with the exception of rabies vaccine, an interval travel (<3 weeks) and is most widely prescribed.6
of 4 or fewer days before the next scheduled in- Atovaquoneproguanil is associated with mild
jection is acceptable. There is no maximum inter- side effects and may be stopped just 7 days after
val between doses of a primary vaccine series; an the traveler has departed from an area of possi-
interrupted series can be resumed beginning ble exposure. Longer courses appear to be safe
with the dose that is overdue. but are costly. In most areas with malaria, atova
quoneproguanil, doxycycline, and mefloquine
are equally effective (>95%) in preventing malaria,
M a l a r i a Pr e v en t ion
but disadvantages (e.g., more reports of adverse
An average of 1500 imported cases of malaria events in persons taking doxycycline or meflo-
are reported annually in the United States quine, as well as resistance to mefloquine) may
(www.cdc.gov/malaria/references_resources/mmwr hamper their use (Table S2 in the Supplementary
.html). A malaria vaccine designed for young Appendix).60 Chemoprophylaxis may be started
children in Africa is not appropriate for use in well before departure (3 to 4 weeks for meflo-
nonimmune adult or pediatric travelers. quine) if there is concern about possible side
Estimates of the risk of malaria among travel- effects of any drug. Weekly administration of
ers not receiving chemoprophylaxis range from mefloquine, if side effects are not an issue, is
3.4% per month of travel in West Africa to 0.34% preferable for long-term travel because of lower
per month of travel on the Indian subcontinent cost and convenience. Chloroquine, an older drug
and 0.034% per month of travel in South Amer- that is also administered weekly, is highly effec-
ica. Transmission, and in particular high trans- tive in the few areas that are known to have ex-
mission, is quite focal. The lifetime range of clusively chloroquine-sensitive parasites.
flight of an anopheles mosquito, which bites If parasites of a malaria species that trans-
only from dusk to dawn, is 1 km. Daytime mits a relapsing form of malaria (Plasmodium
travel to a known focal area of disease transmis- vivax or P. ovale) have entered the liver as a result
sion, with departure to a malaria-free area to of exposure during travel, relapses may occur
sleep at night, confers a negligible risk. Night- months or, in rare cases, up to a few years after
time exposure to mosquitoes for even a few the traveler has returned home, since the pri-
hours in a high-transmission area may result in mary prophylactic drugs discussed above are
infection. Mosquito-bite prevention is a primary ineffective against dormant forms (hypnozoites)
approach to protection from malaria (Table1). in the liver. Primaquine can be used to prevent
The decision about whether to prescribe chemo- relapsing malaria after the traveler has left the
prophylaxis should also take into account the area where P. vivax or P. ovale is endemic. A re-
distribution and type of malaria in the area of lapse can occur even if the traveler received pri-
the planned itinerary and the possibility of devia- mary chemoprophylaxis and did not have an
tion from that itinerary, as well as the travelers initial clinical episode of malaria during or soon
personal tolerance for what may be an epidemio- after the actual exposure. Prophylaxis against
logically insignificant level of risk for the trip. primary attacks of malaria with the use of pri-
A general malaria-distribution map (see the maquine instead of one of the drugs noted above
interactive graphic), as well as resources for in- can be considered when exposure is limited to
formation on the current, country-specific micro- areas where only P. vivax is endemic. This strategy
epidemiology of malaria, including the CDC has the advantage of simultaneously reducing
Travelers Health website, should be immedi- the risk of relapses.
ately accessible to clinicians prescribing malaria For stays in areas with very low rates of ma-
prophylaxis (Table S1 in the Supplementary Ap- laria transmission, some authorities notably,

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Medical Consider ations before International Tr avel

in Europe advise that only a standby drug be gue and occur in many overlapping areas. Chi-
carried for self-treatment, to be taken in the kungunya may result in debilitating arthritis.
event that symptoms suggestive of malaria occur Zika virus infection is considered to cause micro-
and there is no access to competent medical care cephaly and other neurologic malformations in
or to a facility in which a competent assessment newborns and the GuillainBarr syndrome.66
of a blood smear for malaria can be performed Rickettsial diseases, transmitted by ticks, mites,
within 6 to 12 hours.61 This strategy is espe- and fleas, are emerging in travelers.67 Rickettsia
cially attractive for long-stay travelers. A full africae has been documented as the second most
course of atovaquoneproguanil or artemether common cause of fever in travelers returning
lumefantrine is recommended. In the United from sub-Saharan Africa, after malaria.3
States, the CDC recommends continuous pro-
phylaxis, as noted above, for travelers at risk but T r av el er s Di a r r he a
also suggests that treatment doses of these
drugs may be carried for the treatment of con- Travelers diarrhea, defined as three or more
firmed malaria in areas where appropriate drugs unformed stools plus at least one accompanying
for treatment may be unavailable or where there symptom in a 24-hour period during travel and
is concern about substandard or counterfeit for up to 7 days after travel, is most frequently
medication. bacterial.68 Protozoa account for less than 5% of
Travelers should be instructed in writing to cases, and in adults, detection of norovirus or ro-
continue taking antimalarial drugs for the ap- tavirus is increasing. The mean duration of travel-
propriate period after the last possible exposure, ers diarrhea, even if untreated, is 4 to 5 days.
with the explanation that malaria can still occur Despite pretravel advice (Table1), travelers diar-
despite chemoprophylaxis and that three blood rhea affects 10 to 40% of travelers.68 Treatment
smears or rapid diagnostic tests for malaria are with a proton-pump inhibitor may increase the
mandatory for any febrile illness occurring within risk of travelers diarrhea.69 Chronic postinfectious
3 months after travel. Travelers to areas where sequelae of travelers diarrhea have been report-
false positive tests for malaria are common in ed in 3 to 17% of travelers in small studies.70
clinical practice (e.g., Africa) should be remind- Standard self-treatment for travelers diarrhea
ed to continue taking the prophylactic drug even consists of oral hydration together with an anti-
if they receive a diagnosis of malaria. Prevention motility medication (usually loperamide), an
of malaria in travelers residing in malarious antisecretory medication, or both for symptom-
areas for 6 months or longer presents complex atic relief. The addition of a single dose of a
problems leading to reduced adherence to chemo- self-administered quinolone (500 mg of cipro-
prophylaxis.62 floxacin or levofloxacin) or azithromycin (1 g)
can be considered for more rapid cessation of
severe diarrhea. Three days of therapy with a
O ther A r throp od -Bor ne
Dise a se s quinolone or azithromycin at a dose of 500 mg
per day may also be used. Azithromycin is the
Some infections are preventable only by anti only option for persons traveling to Southeast
arthropod measures (Table1). Dengue accounts Asia, India, or Nepal, where several common
for up to 2% of cases of illness in travelers who enteric pathogens are resistant to quinolones.
have returned from countries where dengue is The benefit of either antibiotic class should be
endemic and is the most common systemic fe- weighed against the known side effects and
brile illness; severe dengue is very rare in travel- drug interactions. Antibiotic prophylaxis for
ers.3,4,63 At least 10 dengue vaccine candidates are travelers diarrhea is not recommended except in
being evaluated in clinical trials; a vaccine re- rare circumstances.
cently licensed in several countries where dengue Antibiotic use for travelers diarrhea has been
is endemic is unsuitable for use in travelers, and associated with intestinal colonization with anti-
no antiviral drugs are available.64 Chikungunya65 biotic-resistant bacteria in returning travelers,71-73
and Zika virus infection66 are emerging illnesses but the use of loperamide alone has not.74 In
that are characterized by a rash (see the interac- South Asia, studies have shown that 80% of
tive graphic); they are clinically similar to den- travelers with travelers diarrhea who were treat-

n engl j med 375;3nejm.org July 21, 2016 255


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The n e w e ng l a n d j o u r na l of m e dic i n e

Travel-Related Medical Considerations.


destinations. For prevention, acetazolamide is
effective at a dose of 125 mg twice daily begin-
ning 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 oxy-
gen and an immediate descent. Persons travel-
ing to destinations at an altitude of 3500 m or
higher for a stay of more than a few hours
The image shows the geographic distribution of should consult an expert.
malaria, with darker purple indicating greater
An interactive concentration of disease.
graphic is For further information on the geographic Thrombosis
available at distribution of diseases and behavioral strategies
NEJM.org that can reduce the risk of disease when traveling, A causal but modest link between lack of mobil-
see the interactive graphic, available at NEJM.org. ity during travel and deep venous thrombosis or
pulmonary embolism in otherwise healthy per-
ed with antimicrobial agents acquired extended- sons has been established. The overall absolute
spectrum -lactamaseproducing Enterobacteri- incidence of symptomatic venous thromboembo-
aceae,71-73 and in one study, 10% of carriers were lism in the month after a flight lasting more
still excreting the organisms 3 months after than 4 hours is 1 in 4600 flights and increases
their return.72 The potential for spread is of con- by 18% for each additional 2 hours in flight.76
cern, although the public health implications are The risk of severe pulmonary embolism is negli-
still unclear. A balanced approach should be gible on flights lasting less than 6 hours.77 Pas-
sought to enable travelers to treat themselves for sengers with known risk factors are at highest
an often debilitating, if not life-threatening, risk. Preventive measures include avoiding dehy-
problem while abroad, especially in developing dration and performing leg exercises while in
countries where available local medications and flight. Of the many recommendations for pre-
health care may be substandard. Beyond bloody vention, only the use of graduated compression
diarrhea, diarrhea with fever, or dysentery, the stockings (15 to 30 mm Hg) for passengers at
definition of severe diarrhea is subjective. How- increased risk is supported by data from ran-
ever, knowing that antibiotic use contributes to domized clinical trials,76 though prophylaxis
antibiotic-resistant infections may encourage with subcutaneous administration of low-molec-
travelers to adhere to preventive measures and ular-weight heparin just before departure and
recommendations for managing symptoms. again 24 hours later for travelers with thrombo-
philia or previous thrombotic events is often
used in practice. Aspirin is of no proven benefit
A lt i t ude Il l ne ss
for travelers.76 Aisle seating promotes mobiliza-
Common high-altitude destinations for leisure tion; no intrinsic benefit of premium-class seat-
travel include La Paz, Bolivia; Cuzco, Peru; Lake ing has been shown.76
Titicaca, on the border of Bolivia and Peru;
Quito, Ecuador; Lhasa, Tibet; and Mount Kili- C onclusions
manjaro, Tanzania. Whether the ascent is made
by motor vehicle or airplane, acute mountain A summary of pretrip preparations for persons
sickness occurs in at least 25% of people who seeking medical consultation in the United States
ascend rapidly, instead of gradually over a period for travel to selected common overseas destina-
of several days, to an altitude of 2500 m or tions is shown in Table4. A body of knowledge
higher and occurs in most people who ascend in travel medicine has been published by the
rapidly to 2800 m or higher.75 Even with a grad- International Society of Travel Medicine (www
ual ascent, the risk of altitude illness is unpre- .istm.org/bodyofknowledge). Available publica-
dictable for first-time travelers to high-altitude tions, especially those from GeoSentinel, which

256 n engl j med 375;3nejm.org July 21, 2016

The New England Journal of Medicine


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Copyright 2016 Massachusetts Medical Society. All rights reserved.
Table 3. Drug Regimens for Prophylaxis against Malaria.*

Drug (trade name) Tablet Size Adult Dose Use in Children Use in Pregnancy Initiation Discontinuation
Primary drug for all malaria spe-
cies in all areas
Atovaquoneproguanil (Malarone Adults: 250 mg of atova- 250 mg and 100 mg Yes; FDA-approved for No (insufficient data; 12 days 7 days
and generics) quone and 100 mg of once daily body weight 11 kg not recommended
proguanil; children: (for weight of 5 to by CDC)
62.5 mg of atovaquone <11 kg, recommend-
and 25.0 mg of proguanil ed off-label by CDC)
Alternative drugs for all malaria
species
Mefloquine hydrochloride (gener- 250 mg (228-mg mefloquine 250 mg once weekly Yes, all ages Yes 3 wk preferable; 12 4 wk
ics only in U.S.) base) wk acceptable
Doxycycline hyclate (Vibramycin, Hyclate: 20 mg, 50 mg, 100 mg once daily Contraindicated for age No (teratogenic) 12 days 4 wk
Vibra-Tabs, other brand 100 mg; monohydrate: <8 yr because of
names, and generics); doxycy- 100 mg staining of dental
cline monohydrate (Monodox, enamel
Adoxa, and generics)
Alternative drug for areas with ex-
clusively chloroquine-sensi-
tive malaria
Chloroquine phosphate (generics 500 mg (300-mg chloroquine 500 mg once weekly Yes, all ages Yes 1 wk 4 wk
only in U.S.) base); some generics
available in 250-mg
tablets (150-mg base)

n engl j med 375;3nejm.org July 21, 2016


Alternative drug for areas with

The New England Journal of Medicine


exclusively Plasmodium vivax
malaria
Primaquine phosphate for prima- 26.3 mg (15-mg primaquine 30-mg base once daily Yes, all ages No (potential toxic effects 1 day 7 days
ry prophylaxis (off-label use) base) for fetal erythrocytes)
Medical Consider ations before International Tr avel

Primary drug for relapse preven-

Copyright 2016 Massachusetts Medical Society. All rights reserved.


tion (P. vivax or P. ovale only)
Primaquine phosphate for relapse 26.3 mg (15-mg primaquine 30-mg base once daily Yes, all ages No As soon as possible 14 days total
prevention base) after exposure,
for which another
agent taken for
primary prophy-
laxis

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* Initiation is defined as the time before the first exposure to malaria, and discontinuation as the time after the last exposure (with the exception of primaquine phosphate for relapse pre-
vention, for which discontinuation is 14 days after the start of primaquine). AV denotes atrioventricular, G6PD glucose-6-phosphate dehydrogenase, and RCT randomized clinical trial.
See http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/malaria#4661 for dosing information for children.
In some countries, 250-mg Lariam tablets contain 250 mg of mefloquine base, equivalent to 274 mg of mefloquine hydrochloride.
Intensive-exposure areas warranting postexposure primaquine treatment after any trip duration include but are not limited to Papua New Guinea, Timor-Leste, and certain areas of
Indonesia. In other areas with P. vivax or P. ovale, persons who have had prolonged exposure (>6 months) or intensive exposure should consider postexposure primaquine treatment.

257
258
Table 4. Major Considerations during Medical Consultation before Leisure Travel to Common Destinations.*

Destination or Itinerary Vaccines Malaria Prevention Key Risk-Prevention Strategies Other Common Disease Risks
Peru: Machu Picchu and Hepatitis A and typhoid for all desti- Chemoprophylaxis for Amazon or jun- Take altitude precautions for Cuzco and Dengue, chikungunya, and Zika virus
Cuzco with Amazon or nations, yellow fever for gle; chloroquine effective in Madre Machu Picchu infection; cutaneous leishmania-
jungle extension Amazon or jungle de Dios region but not sis in jungle areas
in other jungle areas
India Hepatitis A and typhoid for all desti- Chemoprophylaxis for most destina- Take precautions against mosquitoes, es- Dengue, chikungunya, tuberculosis,
nations, Japanese encephalitis tions except those at an altitude of pecially in rural farming areas because typhoid, paratyphoid, hepatitis E,
for long stays or exposure to in- >2000 m in north and some short- of Japanese encephalitis risk; avoid an- and enteric bacterial disease
tensive rural farming during stay urban destinations; consult de- imal contact; take strict food and water
shorter stays, rabies for at-risk tailed maps precautions and precautions against
travelers and long stays motor vehicle injury
Kenya or Tanzania (East Hepatitis A for all destinations, ty- Chemoprophylaxis for all game Take tick and tsetse precautions; avoid Tick-bite fever (Rickettsia africae) in
Africa), South Africa, phoid for adventure travel, yel- parks except certain parks in South Kenya if medical contraindications to southern Africa; schistosomiasis
Zambia, or Botswana low fever for Kenya Africa; consult detailed maps yellow fever vaccine in all rivers, lakes, streams, and
(southern Africa) ponds; African trypanosomiasis
short-stay safari tours in Kenya, Tanzania, and Zambia
The

Mexico and Caribbean Hepatitis A and typhoid for rural Caribbean: chemoprophylaxis for Haiti, Take precautions regarding sun, swim- Dengue, chikungunya, and Zika virus
countries destinations, adventure travel, all resorts in the Dominican ming, water exposure, and marine haz- infection; complications from
tourist resorts and long stays Republic, and no other Caribbean ards and against sexually transmitted medical tourism
destination; Mexico: no chemopro- infections
phylaxis for any typical tourist desti-
nation; limited risk in some remote
areas; chloroquine effective
throughout risk areas in Caribbean
and Mexico
China usual urban tour- Hepatitis A and typhoid for all desti- Chemoprophylaxis not needed; risk of Avoid animal contact; avoid markets with Air pollution (poses substantial risk
ist destinations and nations, Japanese encephalitis malaria in a few remote areas infre- live poultry and do not eat under- for persons with cardiopulmo-
major river cruises for long stays or exposure to in- quently visited cooked poultry nary disease), schistosomiasis,
tensive rural farming during influenza, acute respiratory ill-
n e w e ng l a n d j o u r na l

shorter stays; rabies for at-risk ness, and avian influenza

The New England Journal of Medicine


of

travelers and long stays


Vietnam, Cambodia, Hepatitis A and typhoid for all desti- Chemoprophylaxis not needed for itiner- Avoid animal contact; avoid markets with Dengue, chikungunya, leptospirosis,
Thailand, and Laos nations, Japanese encephalitis aries if all overnight stays live poultry and do not eat under- scrub typhus, and murine typhus

n engl j med 375;3nejm.org July 21, 2016


urban and suburban for long stays or exposure to in- are in Ho Chi Minh City, Hanoi, cooked poultry; take precautions
tourist destinations, in- tensive rural farming during coastal cities of Vietnam, Mekong against mosquitoes (especially in rural
cluding major beach re- shorter stays or Mekong River River cruise boats, Siem Reap, farming areas because of Japanese en-

Copyright 2016 Massachusetts Medical Society. All rights reserved.


m e dic i n e

sorts and islands in cruises during farming season; Luang Prabang, Phnom Penh, cephalitis risk), chiggers, and fleas and
Thailand rabies for at-risk travelers and Bangkok, Chiang Mai, and major against sexually transmitted infections
long stays beach resorts and islands in
Thailand

* For all the considerations, the assumption is that all travelers are up to date with routine vaccines (i.e., MMR [measlesmumpsrubella], Tdap [tetanusdiphtheriaacellular pertussis], pneu-
mococcal, varicella, and influenza vaccines). Hepatitis B vaccine should be considered for all travelers, with a lower priority for short-stay travelers without specific risk behaviors. All persons
traveling to tropical destinations at any time of the year and all those traveling to destinations with temperate climates during influenza season should have received the most recent influen-

Downloaded from nejm.org by Jesus Patio on July 21, 2016. For personal use only. No other uses without permission.
za vaccine available in their home country. Complications from medical tourism (i.e., travel outside the home country for medical treatment) have been reported from all countries listed.
Some countries listed that do not have a local risk of yellow fever may have a requirement for proof of yellow fever vaccination for travelers arriving from areas where there is a risk.
Sources of information are provided in Table 1 in the Supplementary Appendix.
Medical Consider ations before International Tr avel

is the International Society of Travel Medicine need to be individualized. No traveler should


CDC database of travel-related illnesses,1-3 and leave the consultation without understanding the
online resources (Table S1 in the Supplementary importance of seeking expert medical advice im-
Appendix) should be consulted frequently to stay mediately if fever develops after the return home.
up to date on constantly changing epidemiology. Disclosure forms provided by the authors are available with
Preventive strategies and medical interventions the full text of this article at NEJM.org.

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