Chapter 52: Travel Medicine

In 2012 the United Nations World Tourism Organization reported that the international arrivals across boundaries surpassed the 1 billion mark for the first time in history, up from 996 million in 2011. This represents over a 71% increase in 15 years growing at a rate of 3–4% every year. There were 59 million international departures from the United States in 2011. Travelers may be business travelers to large cities where there are special dangers related to urban travel, but increasingly travelers are seeking out exotic locations as tourist destinations. Pretravel advice is often an afterthought for these travelers. Unfortunately, travel can also lead to health problems that range from unpleasant to life-threatening illnesses.

It is estimated that fewer than half of travelers seek any kind of pretravel advice. Many people ask their family physicians for recommendations, and at times the advice that they receive is either uninformed or outdated. Individuals returning to their country of origin are even less likely to consult a physician before travel, and preventable systemic illness is seen more commonly in this group than other tourists. It is important for all primary care physicians to be prepared to give accurate advice to travelers about both pretravel preparation and how to deal with illnesses contracted abroad. Sometimes there is not enough time to obtain the required immunizations, and priorities must be established. The goal of this chapter is to enable the family physician to provide guidance to patients wishing to be prepared for illnesses and emergencies related to travel.

Case 1

A 28-year-old man in good health is planning a 2-month trip to Kenya. He will be working in Nairobi but also plans to visit game parks and participate in outdoor activities.

• What history must be obtained?

• What specific advice should the patient be given, especially regarding hygiene, safety, and food preparation?

• What immunizations are needed?

• What malaria prophylaxis is recommended?

• Where can the physician find the answers to these questions?

The first step is to obtain a thorough history—including any preexisting medical conditions and use of medications that may have side effects or may interact with other drugs that will be prescribed—and to perform a thorough physical examination. What is the patient’s exact itinerary, what countries will he visit en route, and in what order? What accommodations will he have? Will he remain in urban areas or visit some rural regions? What is his immunization history? This information will help determine necessary immunizations and prophylaxis. The physician can also help the traveler ensure that he has potentially essential items, such as insect repellent. If the patient has a chronic illness, he should be given pertinent portions of his medical record and a list of medications and allergies to take along in case he must seek medical care abroad.

Several websites provide helpful information about travel and health requirements (see listing at the end of this chapter). After reviewing these requirements, the physician would find that this patient faces several risks that should be discussed:

• Malaria, especially at lower elevations such as in game parks.

• Diarrhea, caused by parasites or bacteria such as Escherichia coli or Shigella.

• Typhoid fever and other salmonelloses.

• Hepatitis A, B, C, and E.

• Schistosomiasis, especially if swimming or wading in local bodies of water.

• Violence and petty thievery, especially in urban areas such as Nairobi.

• HIV/AIDS and other sexually transmitted diseases.

• Poor infrastructure for dealing with serious emergencies, such as motor vehicle accidents, especially outside of urban areas.

In the United States, as 78 million baby boomers approach retirement age, increasing numbers of older adults will plan for international travel. They will require the same steps pretravel, but since they are more likely to have chronic conditions and special needs, they may need some additional preparation.

Travelers’ Medical Kit

Every traveler should carry a medical kit that addresses basic care for common illnesses and injuries. The essential components of such a kit are listed in Table 52-1, but they must be adjusted, depending on individual needs. If a patient uses a medication that is taken regularly, s/he should be advised to carry along enough to last for the entire trip and probably 1 or 2 weeks’ extra. This will allow for unexpected changes in travel plans. A small supply should be kept in the carry-on bags, in case luggage is lost or delayed. All applicable airline regulations regarding carry-on baggage must be observed to ensure that the medication is not confiscated. Travelers should carry a letter from their physician if they plan to take along any controlled substance. This letter will help answer questions from immigration officials and other authorities in case questions are raised. Travelers should not forget to bring spare eyeglasses or contact lenses, contact lens solution, and their ophthalmologic prescription, in case of loss or breakage.

If the traveler is planning a long stay, the physician may be asked to supply prescribed medications on a regular basis from the United States, particularly if the drug in question is not available at the international destination. Increasingly, however, medications prescribed in the United States are available abroad (often much more cheaply) and can be obtained without difficulty by a knowledgeable traveler. Travelers should be cautioned to carefully examine any medications bought overseas, because ingredients may differ from those used in the US products, and some ingredients may not be considered safe by the US standards.

Insurance

Travelers should check their health insurance policies to determine whether they include coverage for medical expenses incurred abroad. If coverage is provided, they should bring a blank insurance form in case it is needed or it becomes necessary to contact the insurance company. Term travel health insurance policies are also available. Evacuation insurance is essential in the event of a serious accident or medical problem. Some policies will return travelers to their home cities; others will evacuate them to the nearest location where they can receive medical care comparable to that available in their home country. Among the better-known companies offering evacuation insurance and emergency travel insurance are CSA Travel Protection (http://www.csatravelprotection.com), International SOS (http://www.internationalsos.com), MEDEX Insurance (http://www.medexassist.com), MedjetAssist (http://www.medjetassistance.com), and Multi-National—HCC Medical Insurance Services, LLC (http://www.hccmis.com/legal/). Policies can also be obtained through travel agencies. Finally, the traveler may wish to purchase trip insurance. This type of insurance ensures reimbursement in case a trip must be canceled for medical or other reasons beyond the traveler’s control. (It should be noted that most trip insurance policies do not cover cancellation for personal reasons, such as a change in plans.) This insurance is especially attractive for older travelers, who are more likely to have a medical emergency that prevents them from traveling. The US Department of State answers questions about medical coverage on their website (http://travel.state.gov/travel/cis_pa_tw/cis/cis_1470.html; accessed 3/10/13).

Air Travel Concerns

Some medical conditions require special attention during air travel. These conditions include many severe, common illnesses, including anemia, clotting disorders, disfiguring dermatoses, dyspnea at rest, incontinence, otitis media, pulmonary or acute upper respiratory infections, and sickle cell hemoglobinopathies. Medical contraindications to air travel are listed in Table 52-2. Any traveler with an acute infectious disease should be cleared by a physician before traveling. If there is any question about the diagnosis, the individual should not travel until the risk is known. Exposure to tuberculosis and other serious infections can occur during flight, and an individual with a serious infectious disease should not travel on a commercial flight. Ill or handicapped travelers must notify the airline 72 hours before departure to ensure that the plane is properly equipped. Services such as a wheelchair, oxygen, stretcher, and other necessary equipment can usually be provided with advance notice.

A. Use of Respiratory Assistive Devices on Aircraft

Patients with sleep apnea or requiring oxygen should carry their portable machines with them especially during long travels. In May 2009, the US Department of Transportation (DOT) issued a final ruling that all air carriers conducting passenger service (on aircraft originally designed for a passenger capacity of ≥19 seats) must permit someone with a disability to use a ventilator, respirator, continuous positive airway pressure (CPAP) machine, or an FAA-approved portable oxygen concentrator (POC), unless the device fails to meet applicable FAA requirements for medical portable electronic devices (M-PEDs) and does not display a manufacturer’s label indicating that the device meets those FAA requirements. Currently, all FAA-approved POCs meet FAA requirements for M-PEDs.

Travel Health at Sea or on Cruise Ships

The sea has drawn adventurers, explorers, and settlers, as well as recreational travelers, to its shores and beyond for centuries. In 2008, the North American cruise industry, which makes up most of the global cruise market, comprised 161 ships carrying more than 13 million passengers to destinations worldwide. Nearly 9 million cruise passengers departed from US ports.

Exposure to dry, recirculated air, unfamiliar viral and bacterial pathogens, and new environmental allergens make respiratory illness the most common diagnosis in a ship’s infirmary. Most cases are self-limited and should be treated symptomatically. Isolated cases of gastrointestinal illness aboard cruise ships are common, representing 5—10% of sickbay visits. Many of these cases are precipitated by changes in diet, overindulgence, and food and water ingested off the ship in developing countries. Fortunately, outbreaks of food- and waterborne illness are rare. As with shoreside outbreaks, more than half are due to the Norwalk (or related) viruses or undetermined agents. The rest are due to various bacterial agents, most notably enterotoxigenic Escherichia coli, salmonella, shigella, Staphylococcus aureus, Clostridium perfringens, and campylobacter. The Vessel Sanitation Program (VSP), developed and administered by the CDC, has been instrumental in the steady decline of gastrointestinal outbreaks aboard cruise ships.

Food and Water Sanitation

Many infectious diseases can be prevented by attention to food and water sanitation and good hygiene. These diseases include intestinal viral, bacterial, and parasitic infections. Travelers should be advised to avoid eating food that has not been cooked adequately or peeled by them. Cooking must be thorough, not just warming, and a clean knife must be used for peeling. If fish are eaten, they should be fresh, not dried or old-looking. Cans should be inspected for bulging or gas formation. Only dairy products that have been pasteurized should be consumed, and products that have been ultrapasteurized by the ultraheat treatment (UHT) method are preferred. Avoid raw vegetables and unpeeled fruits. Fruits and vegetables should be peeled by the traveler before consumption. Hands must be kept clean and fingernails trimmed. Clean silverware and plates should be used; these can be rinsed in boiling water or bleach rinse to sterilize them.

Travelers should be advised that bottled or canned drinks are safe as long as the seal is intact. Iced and lukewarm drinks should not be trusted, but hot drinks such as coffee or tea are generally safe if prepared recently and still hot when served. Tap water can be purified by either boiling it, treating it with iodine or chlorine, or filtering it with a reliable ultrafilter water purification system, as described below:

• Bring water to a rolling boil for 1 minute. Although the actual temperature reached will be slightly lower at higher elevation, this does not seem to have clinical relevance.

• Treat the water with iodine (10 drops of tincture per liter) and let stand for 30 minutes, or treat it with chlorine (1–2 drops of 5% chlorine bleach per liter of water) and let stand for 30 minutes. Although chlorine may not kill all parasitic cysts or viruses, water treated with chlorine has a better taste than iodized water; furthermore, chlorine does not affect thyroid function over long periods of use.

• Reliable water filtration systems are available through various sources [eg, Campmor (http://www.campmor.com) includes information on several systems]. A pore size of 0.2 μm is needed to filter out all enteric bacteria and parasites. If the water is cloudy or especially dirty-looking, some gross filtration or sedimentation must be done first before using a small-pore filter. Adding iodine resins to the filter will kill viruses if contact is sufficient.

Injury Prevention & Personal Security

The leading cause of mortality in travelers is motor vehicle accidents. Drivers should be aware of local motor vehicle laws and never mix alcohol with driving or any activity that requires mental alertness. Other common accidents that occur during travel include drowning, carbon monoxide poisoning, electric shock, and drug reactions. Travelers should be aware that jet lag and other causes of drowsiness while traveling (eg, medications to alleviate motion sickness) may heighten the risk of injury. If a traumatic injury occurs, travelers should be cautioned not to agree to blood transfusions unless absolutely necessary.

Although the risks to personal security in many parts of the world may be similar to those encountered in many urban areas of the United States, travelers may be at greater risk in areas where they are obviously foreigners or tourists. Most commonly, the risks to personal security are related to theft of personal belongings and the occasional violent methods used, especially in the urban areas of Africa and Latin America.

Another rarely discussed but important area of personal security is that of sexual activity while traveling. The freedom from a daily schedule and uniqueness of the situation may cause travelers to let down their normal guard. The incidence of sexually transmitted diseases, especially HIV, is quite high in many popular tourist destinations, including much of Africa, the Caribbean, Thailand, and some parts of Latin America. Travelers should be cautioned to use good judgment (especially in situations involving alcohol use), barrier protection such as condoms, and caution with oral-genital contact.

Obtaining Medical Care Abroad

Obtaining reliable medical care abroad can be difficult. Frequent travelers may wish to become members of the International Association for Medical Assistance to Travelers (IAMAT), which provides up-to-date advice on where to seek competent medical care for virtually any area of the world. [Contact information: 1623 Military Rd., No. 279, Niagara Falls, NY 14304-1745; (716) 754-4883; www.iamat.org.] The International Society of Travel Medicine (www.istm.org) and the American Society of Tropical Medicine and Hygiene (www.astmh.org) are also excellent resources for those seeking to find travel clinics anywhere in the world.

Immunizations

No vaccines are currently required for travel, with the exception of yellow fever vaccine if travel is planned through an endemic area. However, travelers from the United States should be up-to-date on all routine immunizations, including diphtheria, pertussis, tetanus, measles, mumps, varicella-zoster, rubella, influenza, pneumonia, and for children Haemophilus influenzae type b (see Chapter 7). For previously immunized adults, a single dose of polio vaccine is recommended for travel to an area with a risk of polio. Europe, Australia and the Western Pacific, and the Western Hemisphere have been certified polio-free.

Yellow fever vaccine is recommended for travelers to certain areas of Africa and Latin America. If there is a definite risk, the vaccine is recommended for all travelers at least 9 months of age. In some areas it is not generally recommended unless the person is at high risk (prolonged travel, heavy exposure to mosquitoes or inability to avoid mosquito bites). In areas without transmission, the vaccine is not recommended.

Typhoid and hepatitis A vaccines are recommended for travelers to most areas of the world. Two typhoid vaccines are currently available in the United States: Ty21a and Vi. Efficacy of both vaccines is 50–80%. Ty21a is a live oral vaccine that conveys protection for 5 years. It is taken as a series of four tablets, one every other day. The tablets must be refrigerated until ingested. Vi is a parenteral vaccine that provides protection for 2 years. Persons receiving this vaccine have a higher incidence of systemic reactions such as fever or malaise for the first 2–3 days after administration than those who receive the oral vaccine, and they may also develop injection site soreness.

Meningococcal vaccine is indicated for travelers to areas of sub-Saharan Africa and any area where meningococcal disease is endemic or epidemic. Saudi Arabia now requires that Hajj and Umrah visitors be vaccinated with a tetravalent vaccine before entering the country. Meningococcal conjugate vaccine group 4 (MCV4) is preferred among persons aged 11–55 years, and meningococcal polysaccharide vaccine group 4 (MPSV4) is the recommended vaccine among children aged 2–10 years and adults >55 years. Duration of immunity lasts at least 5 years, and adverse reactions are generally mild. Japanese encephalitis (JE) vaccine is recommended for travelers to endemic areas of rural Asia during periods of transmission, especially if the traveler plans to live there or stay for >30 days.

Cholera vaccine is no longer available in the United States; however, an oral vaccine, Vibrio cholerae whole-cell/B subunit vaccine (Dukoral), is available abroad. This vaccine also provides limited protection against infection with enterotoxic E. coli. No country now requires cholera vaccination; however, some local authorities may ask for this documentation. A single dose of the oral vaccine is sufficient; or a medical waiver written on physician letterhead will satisfy this request.

Rabies vaccine is recommended for travelers to high-risk developing countries and countries where rabies immune globulin is not available. Long-term travelers or those who may have extensive outdoor or nighttime exposure and those whose occupations place them at risk should consider this vaccine. Postexposure vaccination is still required.

Hepatitis B vaccine is recommended for travelers to high-risk areas, especially long-term travelers, and those engaging in high-risk sexual behaviors. Medical workers must be vaccinated, as should the future adoptive parents of children from a developing country.

All travelers are at a risk of pertussis, and all adults aged >19 years who have not received a prior Tdap or are in close contact with infants should receive a single dose of Tdap even if a Td booster has been administered recently.

Table 52-3 summarizes information for these and other vaccines. Up-to-date immunization information can be obtained from the Centers for Disease Control and Prevention (CDC; www.cdc.gov/travel).

Travelers’ Diarrhea

General Considerations

Travelers’ diarrhea occurs in a significant number of people who travel to foreign countries, and approximately 30–50% of travelers to high-risk areas (Mexico, Latin America, Africa, Asia, and the Middle East) will develop diarrhea during a 1–2 week stay. It is caused by fecal-oral contamination of food or water by bacteria, parasites, and viruses. The condition is more common in young adults, and the best chance for prevention involves strict attention to hygiene, sanitation, and food preparation, as outlined earlier. Food from restaurants and street vendors are common sites for exposure, and thus eating in a private home may be safer. It is extremely difficult to avoid all dangers in food and drink, and multiple studies have shown no correlation between personal hygiene measures and travelers’ diarrhea. Nevertheless, it is prudent to follow basic hygiene measures while abroad.

In contrast to the developed world, where viruses are the most common cause of diarrhea, enterotoxigenic E. coli and other bacteria such as Shigella, Salmonella, Vibrio, and Campylobacter species, are the most common causes of diarrhea in most parts of the developing world. There are significant regional differences.

Clinical Findings

Travelers’ diarrhea is characterized by the abrupt onset of at least a twofold increase in loose stools, usually four to five stools per day. Most episodes begin 4–14 days after arrival but can occur sooner if the concentration of bacteria ingested is sufficiently high. Common signs and symptoms include loose or watery stool, abdominal cramping, bloating, urgency, malaise, and nausea. Vomiting occurs in ≤15% of those affected. Symptoms usually resolve in 3–4 days if not treated but can last longer. Depending on the cause, fever, bloody stool, and painful defecation may occur, but these symptoms are not common. Physical findings include a benign abdomen with diffuse tenderness but no rigidity and increased bowel sounds. Patients may appear dehydrated depending on the severity of the diarrhea. Although travelers’ diarrhea rarely is life-threatening, it can result in significant morbidity; one in five travelers with diarrhea is bedridden for a day, and >33.3% have to alter their activities. Stool examination and culture may yield a causative agent, but in 40–70% of cases no pathogen is identified. It is very difficult to differentiate enterotoxic and nonpathogenic E. coli. Examination for C. parvum,C. microsporidium, or other less common organisms should be initiated only when diarrhea has persisted for >10–14 days.

Treatment

Treatment for travelers’ diarrhea includes fluid replacement and usually includes fluoroquinolone antibiotics (or in children, azithromycin) (Table 52-4). Trimethoprim-sulfamethoxazole and doxycycline are no longer generally recommended because of the development of widespread resistance. Rifaximin can also be used to treat noninvasive E. coli–induced travelers’ diarrhea. It is very useful in Latin America and Mexico, but is less useful when Campylobacter is the causative pathogen. In some countries, particularly Thailand and Nepal, Campylobacter infections may be resistant to fluoroquinolones; thus azithromycin or other antibiotics may be needed. Although a 3–5-day course on antibiotics is usually recommended, there is evidence that 1–2 days of treatment may be sufficient.

Bismuth subsalicylate can be used by chewing two tablets (or taking 1 oz of liquid) every 30 minutes in up to eight doses. The potential for salicylate toxicity should be considered in patients taking aspirin, pregnant women, or children. Loperamide or diphenoxylate may be used for adults but never in the presence of high fever or bloody stool. Generally, it is best to combine these agents with antibiotics, especially if diarrhea is moderate or severe.

Fluid replacement using World Health Organization ORS salts are available in most countries. In the United States the salts can be obtained through Cera Products (www.ceraproductsinc.com). A simple rehydration solution can be prepared at home using ½ teaspoon of table salt, ½ teaspoon of baking soda, and 4 tablespoons of sugar in 1 L of water; orange juice can be added to provide potassium. Adults should drink 8 oz after every diarrheal stool. Children aged <2 years should be given 2–4 oz and those aged 2–10 years, 4–7 oz. Acetorphan (Racecadotril), available in Europe but not in the United States, may be an effective adjunct to oral rehydration solutions. Women who are breastfeeding an infant with diarrhea should continue to do so. Patients can also be instructed to eat boiled rice, which often leads to faster resolution of the diarrhea.

Prevention

Although, as mentioned earlier, the effectiveness of dietary precautions have not been conclusively proven to prevent travelers’ diarrhea, it is important for travelers to observe good hygiene and sanitation and pay strict attention to food preparation and avoid high-risk food and adventuresome eating behavior.

The CDC does not recommend antibiotic prophylaxis for most travelers; however, it may be indicated in patients with active inflammatory bowel disease, brittle diabetes mellitus type 1, AIDS and other immunosuppressive disorders, unstable heart disease, and those on proton pump inhibitors. Travelers planning an exceptionally critical short trip, where even 1 day of illness could impact the purpose of the trip, may wish to use a prophylactic medication.

Fluoroquinolones have been found to provide ~90% protection. Ciprofloxacin 500 mg daily, levofloxacin 500 mg daily, norfloxacin 400 mg daily, or ofloxacin 300 mg daily, have all been used. Rifaximin has also been found to be safe and effective and provides 72% protection against travelers’ diarrhea. Bismuth subsalicylate (Pepto-Bismol two tablets 4 times a day) provides ~ 60% protection against travelers’ diarrhea. Probiotics have also been studied, but results are not conclusive. They seem to reduce the risk of travelers’ diarrhea by ~8%. There is no antibiotic with proven efficacy for prophylaxis against Campylobacter species, which are a more common cause of travelers’ diarrhea in South and Southeast Asia

Malaria

General Considerations

Malaria is a major international public health problem, responsible for considerable morbidity and mortality around the world each year. At least 40% of the world’s population live in areas in which malaria is endemic, and ~5% are infected at any one time. It causes an estimated 1 million deaths per year. Although 90% of cases occur in sub-Saharan Africa, the disease is found throughout the tropics. In most countries the distribution is spotty. Few Americans know much about the disease because it was eradicated in the United States in the 1940s. In the United States about 1500 cases of malaria acquired abroad are reported annually to the CDC.

Malaria is caused by infection with Plasmodium falciparum, P. vivax, P. malariae, P. ovale (two subspecies: P. ovale curtisi and P. ovale wallikeri) or P. knowlesi. The first two species account for the majority of infections, and most cases of severe infection and death are due to P. falciparum. The vector for transmission to humans is the female Anopheles mosquito. With the exception of Central America and parts of the Middle East, most P. falciparum infections are resistant to chloroquine, and some strains of P. vivax are also resistant. Travelers to the tropics should receive prophylaxis based on the latest CDC recommendations.

Incubation periods differ among the Plasmodium species (Table 52-5), and at times they may be much longer than those usually reported. P. falciparum, P. malariae and P. knowlesi do not form hypnozoites and do not produce chronic liver infection. Thus, infected patients should not relapse if treatment is adequate. This is not the case with P. vivax and P. ovale. Reactivation of dormant hypnozoites in the liver can occur with these species leading to relapse—sometimes decades after the original infection.

Clinical Findings and Diagnosis

A. Symptoms and Signs

Classical symptoms of malaria in a nonimmune person are fever, chills and sweats, headache, and muscle and joint pains. Nausea, vomiting, abdominal pain, and diarrhea can also occur. Symptoms usually begin 10 days to 4 weeks after infection; however, malaria symptoms might start as early as 7 days or as late as 1 year, depending on the species, after the traveler returns from a malarial area. Physical findings include fever, tachycardia, and flushed skin; mental confusion and jaundice may be present. The spleen and liver are often palpable, especially in persons who have had repeated infections. Symptoms may be much milder in a semi-immune person and may be only a headache or general body aches.

Severe malarial infection, usually due to P. falciparum, causes a multitude of complications, including cerebral malaria (with seizures, coma, or death), renal failure, hemoglobinuria (also called “black water fever”), hemolytic anemia, acute respiratory failure, shock, and hypoglycemia. Long-term complications include hypersplenism, nephrotic syndrome, and a seizure disorder.

B. Laboratory Findings

The gold standard for diagnosis remains detection of parasites by Giemsa-stained thick and thin blood smears. Thick films are more sensitive for picking up infections and for measuring parasite density, and thin films are more accurate for identification of species. The films must be fixed and stained properly, and experience is required to interpret the findings. Reputable laboratories can be difficult to identify by a traveler abroad. Also, where malaria is no longer endemic (ie, the United States), healthcare providers may not be familiar with the disease. Clinicians seeing a febrile patient may not consider malaria among the potential diagnoses and thus would not order the needed diagnostic tests. Laboratory workers may lack experience with malaria and fail to detect parasites when examining blood smears.

Data have now emerged to support routine use of rapid diagnostic tests (RDT) for diagnosis of malaria in endemic areas as the standard of care. Thus far only one RDT has been approved by the US FDA: the BinaxNOW malaria test kit. It tests for the histidine-rich protein II (HRP2) antigen specific for P. falciparum plus a panmalarial antigen specific for all human plasmodia. Sensitivity and specificity to P. falciparum is 95% and 94%, respectively. P. vivax sensitivity and specificity are 69% and 100%, respectively.

Limitations of the BinaxNOW® malaria test kit include: samples containing P. falciparum are needed as a positive control, negative results require confirmation by thick and thin smears, and both viable and nonviable organisms are detected, including gametocytes are sequestered P. falciparum parasites. Therefore, this test may not be used for monitoring response to therapy since antigen persists after elimination of the parasite. HRP2-based techniques may also be limited by mutations of the HRP2 gene or antibody interference at high levels of HRP2.

Some representative websites with information on rapid diagnostic tests for malaria include http://www.alere.com/us/en.html, http://www.rapidtest.com, and http://www.premiermedcorp.com. Complete information about these diagnostic tests is also available from the WHO web site at http://www.wpro.who.int/malaria/sites/rdt/.

C. Differential Diagnosis

The differential diagnosis of malaria includes most febrile tropical illnesses prevalent in the area that the traveler has visited (see the section on fever in a returning traveler, later in this chapter). The illnesses most often confused with malaria include influenza and viral infections, dengue fever, babesiosis, relapsing fever, yellow fever, hepatitis, typhoid fever, kala-azar, urinary tract infections, tuberculosis, endocarditis, and meningitis (especially in patients with cerebral symptoms).

Treatment

The medications used for the treatment of malaria vary and are frequently used in combinations. Ideally, determination of the correct treatment involves identification of the species of malaria, knowledge of where the traveler has been, and the medical history of the patient. No one drug acts on all stages of the disease, and different species of parasites show different responses. Full discussion of the treatment of malaria is beyond the scope of this chapter and may be found at www.cdc.gov/malaria/diagnosis_treatment/treatment.html.

A traveler who plans to visit a remote area without adequate medical facilities may wish to take along a reliable supply of medication for a full course of presumptive treatment if symptoms of malaria develop. Presumptive self-treatment should never take the place of being evaluated at a medical facility; however, it could be lifesaving if there is no nearby help. Table 52-6 includes two suggestions for presumptive self treatment: atovaquone-proguanil (Malarone) or artemether-lumefantrine (Coartem). Malarone should not be used if the patient is taking this as prophylaxis, and Coartem should not be used in patients taking mefloquine prophylaxis.

Artemisinin derivatives such as artemether and artesunate are well tolerated and are given in combination with another drug such as amodiaquine, sulfadoxine-pyrimethamine, mefloquine, or lumefantrine. Artemether-lumefantrine is the only artemisinin-based combination therapy (ACT) currently available in the United States, but others are available abroad. There have been a few reports of resistance to artemisinin. Combination therapy has the advantages of slowing the development of resistance, reducing the length of the required treatment course, and more effectiveness.

For more information about malaria in general, visit the Roll Back Malaria website at http://www.rbm.who.int. CDC clinicians are also on-call 24 hours to provide advice to clinicians on the diagnosis and treatment of malaria and can be reached through the Malaria Hotline 770-488-7788 (or toll-free at 855-856-4713).

Prevention

A common approach to malaria prevention is to follow the “A, B, C, D” rule. (awareness of risk, bite avoidance, compliance with chemoprohylaxis, and prompt diagnosis in case of fever).

A. General Measures

Travelers to endemic areas should be advised about basic measures to prevent mosquito bites, including wearing long sleeves, long pants, and light-colored clothing at dusk; avoiding perfumes that might attract mosquitoes; and treating bed nets with permethrin. A mosquito repellent containing 30–50% DEET (N,N-diethyl-meta-toluamide) is recommended. In Europe, 20% of picaridin and 35% of DEET have shown comparable efficacy for protection against malaria vectors for ≤8 hours after application.

B. Malaria Prophylaxis

Chemoprophylaxis is a strategy that uses medications before, during, and after the exposure period to prevent the disease caused by malaria parasites. The aim of prophylaxis is to prevent or suppress symptoms caused by blood-stage parasites. In addition, presumptive antirelapse therapy (also known as terminal prophylaxis) uses a medication (primaquine) toward the end of the exposure period (or immediately thereafter) to prevent relapses or delayed-onset clinical presentations of malaria caused by dormant liver stages of P. vivax or P. ovale.

In choosing an appropriate chemoprophylactic regimen, the traveler and the healthcare provider should consider several factors. The travel itinerary should be reviewed in detail to determine whether the traveler is actually at risk for acquiring malaria. The next step is to determine whether significant antimalarial drug resistance has been reported in that location. Resistance to antimalarial drugs has developed in many regions of the world. Healthcare providers should consult the latest information on resistance patterns before prescribing prophylaxis for their patients.

Five medications are currently available and approved in the United States for malaria prophylaxis: chloroquine (or hydroxychloroquine), mefloquine, doxycycline, atovaquone/proguanil and primaquine. See Table 52-6 for prophylactic dosages in adults and children.

1. Chloroquine (or hydroxychloroquine)

This drug is still effective for prophylaxis in Central America above the Panama Canal and in some areas of the Middle East. It should not be used for prophylaxis in other areas. Most strains of P/ falciparum and some strains of P. vivax have developed resistance to chloroquine. Some of its side effects are pruritus, headache, blurred vision, myalgia, alopecia, and spotty depigmentation. It can cause exacerbations of psoriasis, eczema, and dermatitis, and caution should be used if it is prescribed to people with these disorders. Retinal injury may occur with lifetime doses of >100 g. Chloroquine is safe in pregnancy and breastfeeding. Prophylaxis should begin 1–2 weeks before the traveler’s planned arrival in a malaria-endemic area and should continue for 4 weeks after return.

2. Mefloquine

This agent is effective for prophylaxis in most of the world except the border areas between Thailand, Myanmar, Cambodia, and Vietnam. P. falciparum shows a patchy, but increasing, resistance to the drug in some areas. It is considered safe to use in pregnancy and breastfeeding, although small amounts of drug are passed in breast milk. The most serious side effects are neuropsychiatric, such as bad dreams, paresthesias, hallucinations, and even psychotic reactions. Other side effects include vertigo, seizures, hepatotoxicity, headache, confusion, gastrointestinal upset, pruritus, and depression. It is contraindicated with serious psychiatric disorders or seizures. Caution is advised in patients with cardiac conduction abnormalities. Prophylaxis should begin at least 2 weeks before arrival in a malaria-endemic area and continue for 4 weeks after return.

3. Atovaquone/proguanil

This drug is effective and safe for children, but there is insufficient evidence to recommend it for use in pregnant women, children weighing <5 kg, or women breastfeeding infants weighing <5 kg. It is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min). Side effects are generally mild and include abdominal pain, vomiting, and headache. Prophylaxis should begin 1–2 days before arrival in a malaria-endemic area and continue for 7 days after return.

4. Doxycycline

This agent is efficacious, safe, and the least expensive choice for prophylaxis. Its use is contraindicated in pregnancy, breastfeeding, and in children aged <8 years. Side effects include gastrointestinal upset, esophagitis, vaginal yeast infection, phototoxicity, hepatic toxicity, pseudomembranous colitis, and increased intracranial pressure. Prophylaxis should begin 1 day before arrival in a malaria-endemic area and continue for 4 weeks after return.

5. Primaquine

Primaquine may be used as primary prophylaxis in areas with primarily P. vivax. It is taken 1–2 days before travel to a malarial area and daily for 7 days after return. Terminal prophylaxis is not needed if primaquine is used as primary prophylaxis. When used as terminal prophylaxis, it is taken daily for 14 days after leaving the malarial area. Adverse effects include gastrointestinal upset. In patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, it can cause hemolysis, which can be severe and even fatal. It should be used only in those with documented evidence of a normal (G6PD) level.

Despite the best preparations, many travelers become sick while abroad or are ill on their return home. Of the 50 million travelers to the developing world each year, >50% will have a travel-related health impairment and 10–20% will consult a physician, either while abroad or after returning home, due to a travel related illness. This section describes three common problems faced by the family physician—fever, diarrhea, and eosinophilia—with the goal of assisting the physician make a final diagnosis and provide appropriate treatment to the returning traveler. The differential diagnosis depends on the traveler’s itinerary and other factors, and all possibilities cannot be covered here. Fever and eosinophilia, in particular, may occur as symptoms in a wide range of infectious and inflammatory conditions.

Fever in a Returning Traveler

Fever in a returning traveler requires a thorough history (including immunizations and any use of prophylactic medications, illness in companions, sexual activities, and any nonprescribed drug use) and physical examination. Often localized symptoms or signs (eg, respiratory symptoms, jaundice) help narrow the diagnosis. See Table 52-7 for the physical findings in various disorders. If the diagnosis is not immediately obvious, diseases that are endemic in the area(s) visited should be considered. Stable patients may be safely observed for a few days, and most fevers will resolve spontaneously. No definite cause is found in ≥25% of returning travelers with a fever; however, in a 2007 report from the GeoSentinel Network, 21% of patients were found to have malaria, 6% to have dengue fever, and 17% to have a disease preventable by a vaccine or chemoprophylaxis. Fever usually has an infectious cause, but occult malignancies and rheumatologic conditions should be considered in the differential diagnosis.

If illness persists or the patient is unstable or seriously ill, laboratory investigation becomes the key to the diagnosis. Laboratory studies that may be appropriate include a complete blood count; malaria smear, and smears for Borrelia, Babesia, and Filaria; typhoid culture or antigen test, including urine for Salmonella and Legionella antigens; urinalysis; liver function tests; cultures of blood, urine, and possibly cerebrospinal fluid; stool examination; biopsy of skin lesions, lymph nodes, or other masses, bone marrow aspirate; hepatitis serology; and other serologies depending on the patient’s possible exposures. Acute and convalescent sera can be helpful in making a final diagnosis.

A chest radiograph should generally be done in febrile patients, especially if tuberculosis is suspected, and purified protein derivative (PPD) testing for tuberculosis should be performed. Seriously ill patients must be hospitalized, and any patient suspected of having a highly contagious condition must be isolated. This is especially true of travelers returning from Africa with hemorrhagic fever. Any case of suspected viral hemorrhagic fever must be reported to the local health department and to the CDC.

It is important to remember that “the common is still common,” and, in fact, the most common causes of fever in returned travelers are routine illnesses such as upper and lower respiratory tract infections, sinusitis, urinary tract infections, and influenza. A more extensive differential diagnosis of fever is listed in Table 52-8, but these diseases should be considered only if a more common cause is not readily apparent.

Malaria is one of the more common and worrisome causes of fever in a returning traveler. Most cases of serious fever requiring hospitalization in travelers are due to malaria. Infections, particularly with P. falciparum, frequently occur within 2 weeks of the mosquito bite, but may occur up to 5 years after exposure, especially if caused by P. vivax or P. ovale. In a seriously ill febrile traveler to a malarial area, for whom no cause can be found, it may be wise to include empiric treatment for malaria, even if the results of the blood smears are initially negative.

Diarrhea in a Returning Traveler

As discussed earlier, travelers’ diarrhea is an acute condition that usually resolves within 2 weeks. Most acute bacterial infections can be treated successfully with ciprofloxacin or other antibiotics. Some travelers, however, develop persistent diarrhea or other gastrointestinal (GI) symptoms that can be difficult to diagnose and treat. In fact, a recent study showed diarrhea and other GI symptoms constitute 35% of all problems in travelers presenting to their family physicians. Some travelers develop a transient lactase deficiency after any bacterial, viral, or parasitic infection. This problem usually responds to lactose restriction for 7–10 days. Some travelers, especially those not careful with their diet, may develop a small bowel bacterial overgrowth, which may require antibiotic treatment. In some travelers, just a change from their usual diet or the consumption of treated or boiled water or unpasteurized milk can cause a lingering diarrhea termed Brainerd diarrhea.

Some causes of persistent diarrhea in a returning traveler are listed in Table 52-9. If a patient’s response to antibiotic treatment is inadequate or the diarrhea persists for >7 days, a stool examination should be performed. Preferably three stools should be examined. In addition to checking for ova and parasites, an evaluation for Giardia antigen and bacterial cultures should also be performed. If symptoms of rectal disease are present, anoscopic and sigmoidoscopic examination should be done with biopsies as needed. If the results of these tests are negative, the physician should consider an empiric trial of metronidazole for the treatment of a possible Giardia or other protozoan infection. Irritable bowel syndrome (IBS) and, less commonly, inflammatory bowel disease may develop after travel in those who experience a bout of bacterial or viral diarrhea. In fact, one study showed that 63% of a group of 97 healthy student travelers to Mexico, who returned a questionnaire, developed diarrhea compatible with travelers’ diarrhea. Six months later, 18% still reported loose stools, 18% reported abdominal pain, and 9% had fecal urgency. Of the 60 patients who had acquired diarrhea in Mexico, 7 (11.7%) met the criteria for IBS 6 months later. Finally, sometimes underlying GI pathology, such as celiac sprue and other malabsorption disorders and even gastrointestinal malignancy, can be unmasked after a bout of diarrhea in a traveler.

Eosinophilia in a Returned Traveler

A high level of eosinophilia (>450 eosinophils/μL), which almost always indicates a parasitic infection, is characteristically found in helminthic infections, especially for those helminthes that have an extraintestinal migration phase and produce tissue infection. Strongyloides and lymphatic and tissue filariasis cause some of the highest levels, and infection in humans can persist for many years if not treated. Protozoans, such as Giardia and Plasmodium species, rarely cause eosinophilia, with the exceptions noted in Table 52-10. Schistosomiasis has become a serious problem for people swimming or rafting in freshwater in Africa. Allergic disorders, such as allergic rhinitis or asthma, can also cause eosinophilia. In one study from Israel, 82 of 995 travelers (8.2%) were found to have significant eosinophilia. Of these, 44 (53.7%) were found to have schistosomiasis mostly acquired in sub-Saharan Africa. Of the remaining 38 cases, a definitive parasitological diagnosis could be made in only 9 (23.7%) travelers. This is compatible with other studies. A therapeutic trial of albendazole was given to most of the cases without a specific diagnosis, and ~90% reported a favorable response with resolution of symptoms and a significant decrease in the eosinophil count after 2 months.

The workup for a traveler with eosinophilia must include multiple stool examinations, including stool concentration if schistosomiasis is suspected. Biopsy specimens of skin lesions (onchocerciasis) or swollen lymph nodes (filariasis) can be examined for definitive diagnosis. Several serologic tests are available from the CDC and other specialized laboratories. These include tests for toxocariasis, strongyloidiasis, filariasis, trichinosis, schistosomiasis, cysticercosis, and paragonimiasis. A therapeutic trial of albendazole is probably warranted as above if no diagnosis is found.