Infection and global travel have been linked throughout history. Up to 10% of global travelers develop infections during travel.3 However, many of these infections could be avoided through proper vaccination and risk avoidance. Travelers themselves have served as conduits for spreading various infectious diseases across the globe. For example, travelers from China brought cases of severe acute respiratory syndrome (SARS) to North America in 2003.32
Travelers to sub-Saharan Africa, Southern Asia, Central and South America, and the Caribbean experience higher rates of infection than those traveling to other parts of the world.8 The major routes of infection in the developing world include: (1) food or waterborne pathogens spread via fecal-oral transmission, (2) insect vector-borne infections, (3) transcutaneous spread (eg, helminthic), (4) respiratory-spread, and (5) STIs.
Food and Water Borne Infections
Diarrheal Illness. Gastrointestinal ailments are common among travelers.1 Nausea, gas, changes in stool consistency and frequency can occur in even the most cautious global travelers. These changes can be brought on by changes in diet, stress, and alteration of gastrointestinal flora.33 Most diarrheal and gastroenteritis episodes are caused by consumption of infectious (fecal) contaminated food or water.4 The entity called traveler’s diarrhea is defined as three or more unformed stools per 24 hours plus at least one additional symptom (abdominal cramping, tenesmus, nausea, vomiting, fever, or fecal urgency).34 Traveler’s diarrhea, which can be caused by bacteria, viruses and protozoa, has an estimated incidence of 10% to 40% for 2-week global travels.34 The highest rates of infection occur in Asia, the Middle East, Africa, Central America, and South America.1 See Chapter 91 for additional discussion of traveler’s diarrhea.
Common bacterial causes of traveler’s diarrhea include: enterotoxigenic or enteroaggregative strains of Escherichia coli, Campylobacter, Salmonella (non-typhoidal), and Shigella. Common viral causes include: Rotavirus and Norovirus.1,33,34 The most common protozoal cause of traveler’s diarrhea is Giardia intestinalis. Less common protozoal causes include: amebiasis (Entamoeba histolytica), Cryptosporidiosis, and Cyclosporiasis. With the exception of Cyclosporiasis, protozoal disease onset usually takes longer because of a 1- to 2-week incubation period.1 Infections caused by these organisms and their treatment are discussed in Chapter 113.
A key feature of the pretravel consultation should include a discussion about safe eating and drinking practices. Risk avoidance is the best way to reduce the occurrence of traveler’s diarrhea, but it is difficult to avoid all risks. Even following the old adage “boil it, cook it, peel it, or forget it” may not always protect travelers.33,34 Use of probiotics and drinking non-ice containing alcoholic beverages when eating potentially infected food may reduce the occurrence of infection, but supportive data have not been consistent.34,35 Several water purification techniques and products are available. They include heat, filtration, ultraviolet light treatment, halogen treatment, and chlorine dioxide-based treatment.36 Each method has advantages and disadvantages that can be discussed with travel health experts. Heat is generally the most consistent method, but it has difficulty in masking bad tastes and odors.
Oral bismuth subsalicylate has been used to prevent traveler’s diarrhea. Bismuth subsalicylate is believed to exert some antisecretory and limited antimicrobial activity.33,37 Use of bismuth subsalicylate was 65% effective in preventing traveler’s diarrhea during a 3-week clinical trial in Mexico.37 Common side effects include darkening of the tongue and stool. The drug is contraindicated in patients who should not take salicylates (ie, hypersensitivity to salicylates, children). Bismuth subsalicylate also interferes with the absorption of doxycycline, which is often used in travel medicine.4
Although prophylactic antibiotic use can reduce the risk of traveler’s diarrhea, such use is generally not recommended, primarily because of the risk of developing drug resistance or Clostridium difficile infection.1 Travelers can bring antibiotics in their medical kit for self-directed initiation for symptomatic disease along with antimotility agents like loperamide.11,12,13 The recommended adult empiric antibiotic regimen is single-dose or short-course oral fluoroquinolones (eg, ciprofloxacin 500 mg daily for 1-3 days) or azithromycin (500 mg daily for 3 days or 1,000 mg once).34 Azithromycin may now be preferred in South or Southeastern Asia because of increased presence of fluoroquinolone-resistant Campylobacter. Dehydration is a serious side effect of pronounced diarrheal illness. Travelers to remote areas with high rates of traveler’s diarrhea should consider packing oral rehydration solution powder.4
Good hand hygiene is also important for limiting traveler’s diarrhea. Unfortunately, travelers may not always have access to soap and clean running water. This can be a concern for travelers in remote areas without water and “squat potty” restrooms. Alcohol hand sanitizers reduce the occurrence of traveler’s diarrhea, and thus should be used when soap and water are not available.38
Vaccine-Preventable Food and Water Borne Pathogens. Typhoid fever (caused by Salmonella enterica serotype Typhi) is a serious disease spread by contaminated food and water. Clinical presentation may include high fever, weakness, stomach pain, headache, loss of appetite, constipation, and rash. Internal bleeding and death can occur rarely.1 The U.S. ACIP recommends typhoid vaccine for travelers to certain countries (see http://wwwnc.cdc.gov/travel). Vaccination may be given by either injectable killed Vi capsular polysaccharide vaccine or by oral live-attenuated Ty21a vaccine.1,39 The injectable vaccine is recommended as a single IM injection for travelers elder than or equal to 2 years of age. A booster is recommended if needed for travel every 2 years.39 Immunization with the live oral capsule vaccine consists of one capsule taken every other day for four doses. A booster can be taking every 5 years if needed. The live vaccine is for travelers elder than or equal to 6 years of age. The capsules must be refrigerated and taken with cool water. The oral vaccine has been associated with more gastrointestinal side effects and rash. The live vaccine is contraindicated in immunocompromised travelers, and pregnancy is an additional caution.1,39
A cholera vaccine is available outside the United States, but given the low risk of infection in travelers, vaccination is no longer routinely recommended.4 Interestingly, Cholera vaccines may provide some protection against some strains of enterotoxigenic E. coli.3
Hepatitis A is a picornavirus shed in the feces of infected persons that can contaminate food and water. Vaccination is now widely available in the United States and other developed nations and has become a standard pediatric vaccine (see Chapter 40).10
Infections transmitted by arthropods (eg, insects) are common in the developing world. Vector-borne infections can range from asymptomatic to fatal. Figure e124-1 displays a WHO world map of vector-borne infection deaths. The majority of vector-borne infections are attributed to arboviruses, which is a term that means arthropod-borne virus.40 Most of these infections do not have reliable treatments.41 Therefore, prevention strategies are essential for limiting vector-borne infections. Such “risk avoidance” strategies should include avoiding infected habitats, wearing protective clothing, using protective bed netting, and applying insect repellent.42 If available, use of recommended vaccines and chemoprophylaxis when indicated is also essential. Travelers with flexible travel plans can reduce exposure by traveling during seasons with less insect activity (ie, the dry season). Travelers should also be educated about daily insect activity patterns. While insect bites can occur at any time of day or night, there are times of increased insect activity. For example, mosquitoes that transmit Dengue, YF, and chikungunya bite more frequently between dawn and dusk, whereas mosquitoes that transmit malaria and Japanese encephalitis primarily bite from dusk to dawn.1 Exposure to mosquitoes and other insects may occur indoors as well as outdoors. Exposure risk is reduced in air conditioned buildings or in areas that do not have direct exposure to the outdoors.43 Pyrethroid insecticide-treated bed netting provides a greater protective effect than untreated netting.44
World-wide deaths from vector-borne disease for 2002.
Wearing protective clothing that limits access to human skin in areas of high insect activity is highly advisable. This can be a challenge in very hot climates or when participating in outdoor activities. Application of EPA-registered insect repellant such as DEET (N,N-diethyl-3-methylbenzamide) or picaridin to skin can provide protection against vector-borne disease. Unfortunately, compliance with daily application can be suboptimal.45 For best effect and safety, DEET 20% to 50% concentration should be used.1 Travelers should be provided with written material about proper application to reduce the risk of repellant toxicity. In addition, it is advisable to purchase repellants in developed countries to ensure product quality. Clothing can also be sprayed with repellants to increase protection.45 Alternatively, clothing that has been pretreated with repellants and insecticide agents like permethrin can be purchased through specialty travel vendors.
When infected with arboviruses, humans experiencing periods of high viremia can serve as amplification sources of infection if they remain in areas with mosquito activity. These individuals should continue to be protected from mosquitoes to reduce further spread of infection.
Mosquito-Borne Infections. Malaria, which is caused by plasmodium protozoa and spread by Anopheles mosquitoes, is an important travel-related infection. Travelers to malaria-affected regions should discuss preventative strategies with an expert during pretravel consultation. The selection of prophylactic medications (if any) is based on potential efficacy, safety, and affordability. Antimalarial drugs should always be purchased before traveling overseas. In the developing world antimalarial drugs can be purchased, but they may be counterfeit, subject to resistance, or of substandard quality.1 Malaria is discussed in more detail in Chapter 115.
Dengue fever is caused by one of four related single-stranded RNA Flaviviruses, named Dengue Virus (DENV) 1, 2, 3, or 4.46 DENVs are endemic in over 100 countries throughout the tropics and subtropics, which includes parts of the Americas, the Caribbean, Africa, South Asia, and Oceania. Areas of recent Dengue fever activity can be seen on the Healthmap.org surveillance website (http://www.healthmap.org/dengue/index.php). Dengue is the most common vector-borne infection affecting travelers in tropical and subtropical countries, with estimates of 50 to 100 million Dengue cases per year.47 Dengue cases have surpassed malaria in all regions except for sub-Saharan Africa.8 Dengue is also more common in urban and suburban environments than malaria because of the type of mosquito vector.48 DENV transmission is facilitated by the daytime-biting Aedes aegypti or Aedes albopictus mosquitoes.
Most patients with Dengue fever experience either an asymptomatic (75%) or a self-limiting, febrile illness that can be quite pronounced.1,49 Classic symptoms include acute onset of high fever, severe headache, retro-orbital pain, fatigue, myalgias, arthralgias, and rash.49 As its former name “break-bone fever” suggests, bone and joint pain can be quite intense. About 5% of infected individuals go on to develop severe infection with shock, which typically involves plasma leakage (increased vascular permeability) with or without bleeding.46 Severe infections may include hepatitis, neurologic disorders, myocarditis, blood dyscrasias, shock, or severe bleeding. Overall, about 1% of patients develop hemorrhagic fever.41
The clinical course of Dengue in symptomatic cases occurs in three stages: (1) febrile stage, (2) critical stage, and (3) recovery. During the first stage, fever lasts from 2 to 7 days. Patients experience defervescence as they enter the critical phase, which is characterized by some degree of plasma leakage. Most patients improve during this phase, but others progress to more severe disease. As plasma leakage diminishes, the patient enters the recovery phase. After any DENV infection, patients usually have lifelong protection against that specific DENV serotype. Unfortunately, patients subsequently infected with a different serotype may develop an extremely severe secondary infection that is triggered by an immune response in the presence of cross-reactive non-neutralizing antibodies.46,49,50
Classic Dengue fever is rarely fatal among travelers, but they may require hospitalization and even medical evacuation to their home countries for care.49 Mortality rates up to 20% have been estimated in severe infection if left untreated, whereas patients receiving proper supportive care have only a 1% mortality rate.46 Acetaminophen is preferred over aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) for fever reduction because of the increased risk of bleeding with symptomatic disease.49 There are currently no vaccines, antiviral medication treatments or prophylactic agents for patients with Dengue fever. However, a new quadrivalent vaccine has been developed and is under regulatory review at the time of writing.51 Risk avoidance remains the best way to avoid Dengue.
Chikungunya virus (CHIKV) is a single-stranded RNA Togavirus. CHIKV transmission is facilitated by the daytime-biting A. aegypti or A. albopictus mosquitoes. CHIKV was initially endemic in rural parts of Africa but spread to Indian Ocean nations and Asia over the past 70 years.52 Prior to 2013, CHIKV was not active in the western hemisphere.53 Since that time, the virus has become endemic in Central and South America and the Caribbean. The number of suspected or confirmed cases of CHIKV has now reached 1.74 million in the Americas, with about 80% of CHIKV infections coming from six countries (Dominican Republic, Colombia, El Salvador, Guadeloupe, Honduras, and Martinique).54 Worldwide estimates of CHIKV activity are difficult to tabulate, but an autochthonous incidence rate of 118.7 cases/100,000 population has been reported for the Americas for 2014.55
From 3% to 28% of people infected with CHIKV remain asymptomatic.1 After an incubation period of about 2 to 4 days, symptomatic patients may abruptly manifest symptoms of high fever, headache, back pain, myalgia, and intense arthralgias.52 A variety of skin manifestations also accompanies infection in 40% to 50% of infected persons, with maculopapular rash predominating. Given similar symptoms, the same vector and overlapping endemic regions, it can be difficult to distinguish Chikungunya from Dengue. Incapacitating arthralgias (primarily of the hands and feet) are said to occur more with Chikungunya.53 Dengue patients experience more blood dyscrasias. As with Dengue, there are no vaccines, antiviral medication treatments or prophylactic agents for CHIKV. Risk avoidance is the best way to avoid Chikungunya infection. Supportive care and treatment is similar between Chikungunya and Dengue, except that NSAIDs can be used in the care of CHIKV infected patients because of the lack of thrombocytopenia or hemorrhagic complications in this condition.52 CHIKV infection are rarely fatal (<1%), although the elderly may have worse prognoses than younger individuals.53
Japanese Encephalitis Virus (JEV) is a single-stranded RNA flavivirus that is transmitted to humans by the Culex species mosquitoes. Pigs serve as a major reservoir for the virus, but wading birds can also serve as reservoirs.56,57 Endemic regions for JEV include East Asia, western Asia islands between the main continent and the northern tip of Australia, and the Indian subcontinent. The transmission risk is much lower than with Dengue or malaria, with an estimated incidence of less than 1 case per 1 million travelers.58 Rates are much higher if travelers stay longer in endemic areas or have significant rural exposure (ie, near pigs and rice paddies). In the more temperate regions of northeast Asia, JEV transmission is seasonal; epidemics are more likely to occur between April and October.57 In the subtropics and tropics, transmission can occur year round but may intensify during the rainy season.
Most humans develop asymptomatic JEV infection; less than 1% of infected patients develop symptoms.1 The most common manifestations include fever, flu-like symptoms, acute encephalitis, or aseptic meningitis. Humans infected with JEV do not experience very high viremia and are therefore less likely to amplify the spread of infection.57 JEV has been associated with severe illness and an estimated case-fatality rate of 20% to 30% with neurologic sequelae in about 30% to 50% of severe infection survivors.58 Fortunately, vaccines are available to prevent infection. The vaccine available in North America and Europe is an inactivated JEV SA14-14-2 strain prepared in Vero cells (trade name: Ixiaro). It is administered in a two-dose series given 28 days apart.59 The vaccine contains protamine sulfate, which may be associated with hypersensitivity reactions. Very rare but serious reactions including anaphylaxis could occur following vaccination.4,59,60
The JEV vaccine is recommended for travelers who plan to spend a month or longer in endemic areas during the JEV transmission season (season varies with latitude).57,58 This includes long-term travelers or expatriates who will be based in urban areas but are likely to visit endemic rural or agricultural areas during a high-risk period of JEV transmission. The JEV vaccine should be considered for short-term (<1 month) travelers to endemic areas during the JEV transmission season if they plan to travel outside of an urban area and have an increased risk for JEV exposure (eg, spending substantial time outdoors in rural or agricultural areas; participating in extensive outdoor activities; staying in accommodations without air conditioning, screens, or bed nets), and travelers to an area with an ongoing JEV outbreak or travelers to endemic areas who are uncertain of specific destinations, activities, or duration of travel. JEV vaccine is not recommended for short-term travelers whose visit will be restricted to urban areas or periods outside of a well-defined JEV transmission season. The vaccine is FDA approved for adults and children as young as 2 months of age.59
Yellow fever virus is a single-stranded RNA Flavivirus that is spread by Aedes or Haemagogus species of mosquitoes. The World Health Organization (WHO) estimates that 200,000 cases of YF and 30,000 deaths attributable to YF occur annually.61 The major areas of endemic YF activity are equatorial South America and sub-Saharan Africa (within 15 degree of the equator). YF virus has three transmission cycles: jungle (sylvatic), intermediate (savannah), and urban, each with different proportionate roles for nonhuman and human primates as a source of vector-facilitated transmission.62
Yellow fever infections cause asymptomatic or subclinical infections in the majority of infected persons.1 Symptomatic individuals can experience variable clinical presentations that can range from mild, undifferentiated febrile illness to severe disease with jaundice and hemorrhagic manifestations. Infected patients can experience an abrupt onset of a high fever (up to 104°F [40°C]), chills, severe headache, myalgias, back pain, anorexia, nausea, prostration, vomiting, and dizziness. Some infected patients develop a severe form of illness characterized by jaundice, hemorrhagic symptoms, shock, and multiorgan system failure, after a brief (hours to days) remission period.1 Case-fatality rates are 20% to 50% in severe cases.63
While there are no effective antiviral medications to treat YF, vaccines can prevent infection. At least four live-attenuated vaccines are approved by the WHO.1 The formulation available in North America is a 17D-204 strain (trade name: YF-Vax).64 The vaccine is recommended as a single-dose immunization for adults and children at least 9 months of age. Immunity usually develops by the 10th postvaccination day. Reimmunization was recommended every 10 years for those at continuing risk of exposure, but most experts do not recommend a “booster” dose because the vaccine provides immune protection for many decades.1,61
Adverse reactions to the YF vaccine include local site reactions, mild headaches, myalgia, and low-grade fevers, which can last for 5 to 10 days.62 The product labeling carries precautionary warning about three serious adverse reactions. The first is immediate hypersensitivity reactions including anaphylaxis. These reactions have mainly been seen in patients with egg allergies. The vaccine is contraindicated in anyone with a history of acute hypersensitivity reaction to any components of the vaccine (including gelatin) or a history of acute hypersensitivity to eggs or egg products. The second serious reaction is vaccine-associated neurotropic disease (referred to as YEL-AND), previously described as postvaccination encephalitis. YEL-AND also includes acute disseminated encephalomyelitis, Guillain-Barre syndrome, bulbar palsy, and Bell’s palsy.41 Lastly, vaccine-associated viscerotropic disease (YEL-AVD), previously described as multiple organ system failure, is another rare serious adverse event associated with vaccination. The relationship between YF vaccination and these subsequent illnesses is not well understood. The incidence of YEL-AND and YEL-AVD has been estimated at 0.8 cases/100,000 doses administered and 0.4 cases/100,000 doses administered, respectively.41 However, the incidence of each appears to increase with advancing age.
Because it is a live vaccine it is contraindicated in immunocompromised patients, including symptomatic HIV-infected patients or those with CD4+ cells less than 200/mm3 (<0.2 × 109/L), patients with malignant neoplasms, patients on immunosuppressant therapy, and children less than 6 months of age. A history of thymic dysfunction is now also regarded as a contraindication due to an apparent association with YEL-AVD.62 The vaccine should be used with caution in children 6 to 8 months of age, patients 60 years of age and older, asymptomatic HIV-infected patients with CD4+ cells between 200 and 499/mm3 (0.2 × 109 and 0.499 × 109/L), pregnancy, and during breastfeeding. An additional precaution is use in patients with latex allergies because the vial stopper is made of latex.64
According to International Health Regulations, YF vaccine must only be administered at certified YF vaccination centers.1,62 Within the United States, state and territorial health departments have the authority to designate nonfederal vaccination centers. Most other countries use governmental-affiliated clinics to provide official YF vaccinations. Under International Health Regulations, any country may require proof of YF vaccination from travelers coming from countries with YF activity, even if travelers stop in a country to connect flights. A few countries (mostly in Africa) require proof of vaccination from all arriving travelers. Travelers must allow a minimum of 10 days from vaccination to country entry. Proof of vaccination must be in the form of a signed and stamped International Certificate of Vaccination or Prophylaxis.1 The same form can be used as a waiver to document that a patient has a contraindication to receiving YF vaccination. Each country may have its own entry requirements. For example, some countries may require a YF vaccine booster at 10 years. Global travelers should check health-related entry requirements for each country they plan to visit. This information can be obtained from travel medicine consultants, foreign embassies, or governmental websites. An informed traveler is less likely to experience quarantine, refusal of entry, or vaccination in country.1
Tick-Borne Infections. Ticks are small blood-sucking acarines that can introduce parasites, bacteria, or viruses into vertebrates.65 After mosquitoes, ticks are the next most common vector for transmitting human infectious diseases world-wide. In North America and Eurasia, they are actually the most common vectors.66 Some of the most common tick-borne infections that travelers may encounter outside of the Unitede States are: Borrelia burgdorferi (Lyme borreliosis), Borrelia Spp. (Tick-borne relapsing fever), Rickettsia africae (African tick bite fever), tick-borne encephalitis virus (TBEV; European encephalitis), Rickettsia conorii (Mediterranean spotted fever), Francicella tularensis (tularemia), and Babesia Spp. (babesiosis).65 While antimicrobial therapies are available to treat most of the bacterial and protozoal pathogens, prevention is the best strategy to protect travelers from unwanted infections and complications.1,65
Travelers spending time in outdoor environments with tick activity should wear protective clothing, and apply DEET to unprotected skin.65 Clothing can also be sprayed with the acaricide permethrin. Daily self-inspection is important to identify ticks early. Proper tweezer removal should be performed if ticks are found to be attached to skin.
There are no effective treatments for TBEV, but vaccines are available outside the United States. These vaccine are often recommended for campers, hikers, or occupational workers who are likely to be exposed to ticks in the TBEV regions of Europe and Asia.1,65
Rabies. Rabies, a noninsect vector-borne infection, is an important life-threatening infection, which causes more than 60,000 deaths annually.67 Certain wild mammals are referred to as high-risk “rabies vector species” such as raccoons, foxes, skunks, bats, and groundhogs. However, humans traveling in the developing world are more likely to contract the infection from domestic-appearing vectors, like dogs.4,68 In these parts of the world it is not uncommon to see dogs, cats, and monkeys on the streets or in tourist areas. Postexposure bite management is identical with wild and domestic exposures. The affected site should be cleaned immediately with soap and water, and then victims should be assessed for post-exposure prophylaxis.1 Unfortunately, access to quality rabies vaccine and immune globulin may be a challenge for global travelers, especially in remote areas.4 In some countries, pharmaceutical quality standards may not be as high as in developed countries. In addition, supplies of available rabies products at local medical facilities may be counterfeit or poorly stored (subject to temperature variations).1 With such a high mortality risk, exposed individuals, especially in small towns and villages, may require medical evacuation to reliable hospitals with adequate supplies of quality vaccine and immune globulin. Rabies is discussed in more detail in Chapter 125.
Tuberculosis is one of the most common infectious diseases in the developing world. Travelers to developing countries can be easily exposed to infected persons with contagious “active” forms of the disease.30 The CDC advises travelers to “avoid exposure to TB patients in crowded environments (such as hospitals, prisons, or homeless shelters).”1 Travelers providing care to such patients should consider the use of personal protective devices, such as N-95 masks. TB infection is discussed in Chapter 112.
Influenza is another important global infection concern. There are concerns about pandemic avian influenza epidemics occurring in the future.4 Fortunately, human-to-human cases are unlikely. Global travelers should avoid markets and farms where live poultry are sold or raised and avoid contact with dead poultry, chicken blood, or undercooked chicken in avian influenza-affected areas.1 Influenza is discussed in Chapter 109.
Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is responsible for a severe illness that was first reported in Saudi Arabia in 2012 and has since spread to several other regions, including North America.69 Common symptoms include severe acute respiratory illness including fever, cough, and shortness of breath. Mortality rates have been estimated at 30% to 40% among patients with laboratory-confirmed infection.70 All reported cases have been linked to countries in and near the Arabian Peninsula. Currently, there are no antiviral medications to treat MERS-Co-V, nor are there vaccines to prevent MERS-CoV infection at present time. Risk avoidance strategies in endemic areas include good hand hygiene, avoiding contact with sick people, and avoiding contact with camels and raw or uncooked camel milk or meat.1,69
Two vaccine-preventable infections that should be assessed as part of pretravel consultation are measles and meningococcal infections. Most travelers have immunity against measles, but an assessment of vaccine history with consideration of measuring titers should be part of a pretravel consultation. Widespread vaccination against Neisseria meningitidis is less likely than measles. Persons traveling to high risk areas like the “meningitis belt” of sub-Saharan Africa should also be assessed for immunity.1 These vaccine-preventable illnesses are discussed in greater detail in Chapter 125.
Neglected Tropical Diseases
Neglected tropical disease are infectious diseases that are found in some of the poorest tropical regions of the world and have not been considered a priority by funding agencies, pharmaceutical companies, or global policymakers.71 These diseases rarely cause infection among global travelers from more developed countries unless they spend significant time in high-risk areas. Some of the more common diseases in this category are leishmaniasis, trypanosomiasis (Chagas and African), schistosomiasis, ascariasis, lymphatic filariasis, hookworm infection, and dracunculiasis (Guinea worm). Interested readers can learn more about these in the CDC Yellow book1 or in Chapter 115.
Global travel has long been linked with STIs.72 Global travelers may alter their behavior patterns as they leave their “normal environment.” Travelers may give into hedonistic tendencies, especially if they use alcohol and illicit drugs. Travelers may behave with increased promiscuity when in exotic places, including sexual activity with commercial sex workers.72,73 Global travelers taking part in risky (unprotected) sexual activity put themselves at risk for infections such as syphilis, gonorrhea, chlamydia, HIV, and hepatitis B (see Chapters 117 and 126).
Miscellaneous Travel Infections
Ebola virus belongs to the family of filoviruses and causes a viral hemorrhagic fever. Ebola can be spread through direct contact with blood or body fluids of an infected person through broken skin or mucous membranes in the eyes, nose, mouth, or other areas.74 Ebola has long been feared because of its ability to spread with an insidious incubation period of up to 21 days. There have been at least 20 recognized outbreaks of Ebola, all occurred in Africa. Estimated fatality rates have been between 25% and 90%.75 The largest Ebola outbreak in West Africa in 2014 attracted worldwide attention. Healthcare workers from around the globe went to the region to assist, and many of them contracted the virus and died.74
Altitude sickness or high altitude illnesses (HAI) result when the partial pressure of oxygen (PO2) in the inspired air is lower than that to which the patient is accustomed. There are three main syndromes that can develop from high altitude exposure: (1) acute mountain sickness (AMS), (2) high altitude cerebral edema (HACE), and (3) high altitude pulmonary edema (HAPE). These different manifestations depend upon a few factors: the terminal altitude, the rate of ascent, the time spent at maximum altitude and the altitude when sleeping. The reduction in oxygen inspired over short periods leads to physiologic changes that place stress on the body and may lead to severe illness and even death.76,77,78,79,80 Patients who are exposed to reduced oxygen concentrations gradually are able to compensate. This process is called acclimatization. However, when individuals ascend too rapidly they will experience a characteristic set of symptoms.81
An individual who experiences rapid ascent will begin to hyperventilate, become tachycardic and could experience erythropoiesis upregulation to increase available red blood cells to carry oxygen. Characteristic symptoms of AMS includes headache combined with one of the following symptoms: anorexia, nausea or vomiting, fatigue, headache, insomnia, or dizziness.81 If the appropriate steps are not taken to treat or abate the progression of AMS, the individual could deteriorate further and develop HACE. This deterioration can occur in as little as 12 hours and could subsequently lead to death from vasogenic edema and decreased cerebral perfusion. The signs and symptoms of HACE are ataxia, seizures, slurred speech, neurologic deficits (rare), altered mentation, and decreased consciousness. Decreased consciousness and cerebellar ataxia are the most useful signs in identifying HACE.81 Although patients may present with pulmonary edema in addition to central nervous system effects, patients may also present only with pulmonary edema. HAPE presents as increased breathlessness upon exertion and progresses to increased breathlessness during rest with weakness and cough. HAPE is due to a noncardiogenic, hydrostatic pulmonary edema.82 Individuals who ascend to high altitude will experience some degree of hypoxic pulmonary vasoconstriction that leads to pulmonary hypertension and increased capillary pressure in patients who are susceptible to HAPE. HAPE has the potential to be more rapidly fatal than any of the other HAIs.76,78,79,81,82,83,84,85
The mainstay of therapy in all altitude-related illnesses is descent to a lower altitude (typically at least a 300-meter reduction in altitude). The administration of oxygen is an appropriate adjunct in severe cases and potentially is an option in mild cases. Due to the lack of availability in the field and the repercussions of mismanagement of deteriorating cases, oxygen therapy is not a likely option for treatment until the patient is able to descend to a base station with supplies.
Several medications have shown benefit in treating or preventing HAI and could be used as adjunctive therapy to decent and oxygen therapy.78,82,83,86 Acetazolamide has been used for many years for the treatment and prevention of AMS and HACE. Acetazolamide is a carbonic anhydrase inhibitor that reduces hydrogen ion secretion in the proximal renal tubules and increases renal excretion of sodium, potassium, bicarbonate, and water leading to metabolic acidosis. This metabolic acidosis leads to a compensatory hyperventilation and increased oxygenation of the blood. This mechanism facilitates the acclimatization process and quickly improves AMS and HACE. Due to its sulfonamide chemical structure, individuals with documented allergies to sulfonamides should avoid acetazolamide.76,78,84,87
Phosphodiesterase-5 (PDE-5) inhibitors do not have proven efficacy as monotherapy for the treatment of HAPE. Several case reports exist that are contradictory regarding efficacy and true benefit as a sole agent. The majority of clinicians utilize PDE-5 inhibitors as prophylaxis but the question remains regarding treatment benefit.
Dexamethasone is a corticosteroid that has been used as an alternative to acetazolamide in the treatment and prevention of AMS, HACE, and even HAPE. Once initiated, dexamethasone should not be discontinued at altitude prior to acclimatization due to the possibility of rebound cerebral and pulmonary edema. The mechanism by which dexamethasone provides benefit in patients with AMS, HACE, and HAPE has not been well established but is thought to act through its anti-inflammatory properties and antagonism of vascular endothelial growth factor.78,82,83
Nifedipine is a calcium channel antagonist that has proven efficacy for treatment of HAPE. Nifedipine causes pulmonary arterial vasodilation, which improves alveolar fluid clearance and oxygenation of the blood. Reduced pulmonary artery pressure and pulmonary vascular resistance contribute to the positive effects of nifedipine on HAPE.80,81,83
Phosphodiesterase-5 inhibitors (evidence exists for sildenafil and tadalafil) are effective in preventing HAPE, but there is a paucity of studies regarding their use as monotherapy for treatment of HAPE. Although evidence for the treatment of HAI does not currently exist for vardenafil, it is likely that it would have the same beneficial effect as prophylaxis given its mechanism of action. The theoretical concern that these agents have risk for systemic hypotension is present; however, the clinical relevance of this risk in healthy populations without medication interactions is questionable.76,81,82,88
Opioid analgesics should be avoided in individuals who will be ascending to high altitude (or even in individuals ascending to a higher relative altitude prior to acclimatization) due to their ability to reduce the hypoxic ventilator response (HVR).81
Jet lag is a syndrome that develops when travelers cross one or more time zones and are unaccustomed to the new time zone. This syndrome can be characterized by fatigue, malaise, and a disorganized sleep-wake cycle that can lead to poor performance and gastrointestinal distress. The syndrome is created by misaligning an individual’s normal activity schedule with their circadian rhythm. The main treatment for jet lag is to realign the circadian rhythm with the new schedule.89 Use of natural methods for adjusting circadian rhythms, such as sunlight exposure, phototherapy, or pretravel sleep schedule modification, are typically inexpensive, easy to administer and provide good outcomes.89 Adjustment of a sleep schedule prior to travel may be difficult depending upon the individual’s normal habits and the destination of their travel. As the number of time zones increases the difficulty of adjustment of sleep schedule also increases. This is also true regarding the severity of jet lag experienced. Other treatment modalities, such as supplemental melatonin, may provide a more flexible treatment method.89,90,91
In the majority of double-blind, placebo-controlled trials, melatonin was beneficial for treatment of jet lag.92 Melatonin is produced endogenously by the pineal gland and is essential in the regulation of circadian rhythms. Positive effects on quality of sleep were seen when patients were given melatonin prior to sleep. The dosing range varies among studies but doses from 0.5 mg to 8 mg appear to have equal efficacy.93 Melatonin also has some hypnotic effects and can aid in initiation of sleep. Melatonin’s status as a dietary supplement lends to it being readily available and the known side effects of melatonin are relatively mild (eg, dizziness, enuresis, headache, and nausea). There is also no definitive evidence of toxicity associated with high dosages of melatonin.89,94,95,96,97
Sedative hypnotics, such as benzodiazepines and other medications that agonize the benzodiazepine receptors, are also effective at initiation of sleep and maintenance of sleep, but have inherent drawbacks to their use. Although safe to use in most patients, cognition and alertness can be impaired after benzodiazepine-induced sleep. They are also potentially habit forming and should be reserved for severe cases that are not effectively managed with light therapy and melatonin.89,90
Stimulants, such as modafinil or amphetamines, can be used to increase alertness and performance during the adjustment period after travel if the patient’s daily life or performance at work is impaired. Side effect profiles, drug-drug interactions, and abuse potential also limit their utility for regular use.89
Traveler’s thrombosis, also referred to as travel associated venous thromboembolism (TAVTE), can occur in otherwise healthy individuals who are not known to be hypercoagulable. Individuals traveling for multiple hours in confined spaces that limit ambulation are at particular risk for thrombosis. Other risk factors for traveler’s thrombosis include personal height less than 63 inches (160 cm) and height over 75 inches (190 cm) in individuals traveling by air.98 Those who are less than 63 inches (160 cm) will likely be unable to place their feet firmly on the floor during the flight and may experience increased pressure on the popliteal vein. This pressure contributes to development of venous stasis, which is one of Virchow’s classic triad of risk factors for VTE. Individuals over 75 inches (190 cm) in height are more likely to be restricted from movement when in a standard seat. This restriction could limit blood flow and also cause venous stasis. Other factors that have been shown to increase the risk of TAVTE are genetic predispositions to clotting (Factor V Leiden), obesity, and oral contraceptive use.98,99,100,101
Although increased fluid intake has been purported to be helpful for preventing TAVTE, scientific evidence does not support this theory.102 However, this should not dissuade passengers from staying well hydrated. While hydration may have no direct beneficial effect on prevention of traveler’s thrombosis, the need to urinate may prompt the individual to ambulate to the restroom. Average healthy urine production ranges from 40 to 80 mL/h and the adult bladder capacity ranges from 300 to 400 mL. The urge to void usually occurs when the bladder is one quarter full. This would mean that assuming normal hydration the average healthy traveler would be prompted to urinate every 1 to 2 hours. Ambulation and the use of lower extremity muscles, by isometric exercises performed during long haul travel, is the best known way to prevent VTE and traveler’s thrombosis. Compressions stockings have been shown to reduce asymptomatic clots when appropriately fitted.103 Compression stockings that have not been custom fitted or appropriately sized do not add any additional protection and in some cases could cause more issues. Pharmacologic prophylaxis is not warranted in most situations and should be avoided due to an increased risk of major bleeding. Patients who have previously been diagnosed with VTE, undergone recent major surgery, or have known malignancy are at high risk of VTE without the added impact of confined travel and therefore should be considered on an individual basis for pharmacologic prophylaxis.24 The use of aspirin for prevention of traveler’s thrombosis is not supported by the literature and should not be recommended for prophylaxis in travelers.99,100,101,104
Chemical prophylaxis for traveler’s thrombosis in patients who are at high risk for clotting is currently not recommended by the CHEST guidelines while other guidelines suggest to consider a low-molecular weight heparin when certain risk factors are present. There have been no studies designed to identify risk of clotting when traveling with no chemical prophylaxis in patients with significant risk.
Travel, whether short or long, exposes the traveler to both physical and mental stress. Traveling into regions with disrupted personal routines and unfamiliar environmental and cultural elements can make assimilation difficult. This process of exposure and reaction to a different culture has been referred to as acculturation or “culture shock.”105,106 Controlled psychiatric illnesses and undiscovered predispositions to mental illness may be induced by exposure to these stressful situations. Pretravel screening and education are essential for travelers who are going to be abroad for a substantial amount of time. Patients with a history of mental illness should be counseled on the need for an adequate medication supply and impeccable adherence while abroad.
The most common psychiatric reason for evacuation from an international trip is depression.107 Patients who have previously been diagnosed with depression should continue their prescribed medications and minimize alcohol consumption while traveling. Nearly all psychiatric illnesses that are experienced while traveling require treatment with medication.107 Proper preparation for the trip will reduce the difficulties associated with acquiring appropriate medications and medical care. Given the propensity for exacerbations of mental illness while travelling internationally and the possibility of suicide due to untreated or unrecognized depression, it is prudent to purchase travel insurance that includes medical evacuation coverage and coverage for repatriation of remains. The costs associated with medical evacuation can be high, and travel insurance is typically quite affordable in comparison.105,106,107
Global Health Organizations and Non-Governmental Organizations
Global health organizations provide many services to developing and developed countries along with information and education resources. Guidance to travelers regarding issues they may encounter while in country is one of these services. From travel advisories to health emergencies, organizations like the WHO provide timely information and guidance for the prevention of illnesses that could lead to significant morbidity or mortality. Many countries have organizations similar to the WHO that serve the country in which they are based. These organizations also provide guidelines and statistical information regarding travel and disease in their specific impoverished areas.108
Non-governmental organizations (NGO) are non-profit, voluntary citizens’ groups that organized on a local, national, or international level.109 They provide substantial quantities of quality medical care to patients throughout developing countries.109 Due to NGO’s contributions to the impoverished population’s care, they have established themselves as a major contributor to improving the health of individuals who would normally not have access to quality healthcare. These contributions improve quality and quantity of life in developing countries.109
Medications and Supplies for Medical Missions and Outreach
Providing medical services in other countries require supplies similar to those used in the country of origin. There is a varied approach to regulation of medications in different parts of the world. There are concerns with acquisition and use of medications in these countries that must be considered. Many countries do not have a regulatory body that regulates the standards for the purity and the quality of the products that are distributed. Consequently, medications acquired abroad could be impure or contain varied amounts of the active medication.110 Due to this variability, it is advisable to obtain medications in the origin country or from a company that has a good reputation for standardization and quality. Medication costs also differ among countries, and the cost could be lower or higher depending on site-specific factors. Medications that undergo quality and safety checks are typically more expensive due to the time required to validate the methods and verify product quality. In many parts of the developing world, medication acquisition is as simple as walking into a pharmacy and requesting the medication with or without a prescription.14
The transport of medications into a country may require significant documentation regarding origin of the medication, visual inspection of the product, and potential taxation. Legal regulations of medications also vary significantly. Seizure of supplies by customs agents could lead to fines and cancellation of the planned provision of medical care. Researching custom law of the destination country is vital to facilitate entrance and exit of the country. Many organizations have paid employees that deal with this aspect of the trips to ensure there are no issues. However, this may be a role for pharmacists given their product knowledge and versatility.14