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Evaluation of the febrile traveler should include careful documentation of the associated symptoms and signs, since these can help guide the clinician toward the correct diagnosis. The mode of onset of the illness (acute versus gradual) and the precise sequence of symptoms should also be ascertained.
A thorough physical examination must also be performed to elicit additional clues.

Vitals Signs
Although rarely diagnostic, determination of a fever pattern may be helpful. Several fever patterns have been identified. However, it is logistically difficult to obtain accurately recorded temperatures, and the administration of antipyretics interferes with this task. In particular, although fevers every 48 to 72 hours are typical of malaria, these characteristic cyclical fevers are rarely seen in travelers, since they are much more likely to occur in a relapse of malaria rather than an initial infection. A pulse rate that is slow for the degree of fever (pulse-temperature dissociation) may suggest typhoid fever or rickettsial infections.

Skin
Many febrile patients have a rash that can assist in the diagnosis. A maculopapular rash may be seen with many travel-related infections, notably dengue fever, leptospirosis, and typhus, as well as with acute human immunodeficiency virus and acute hepatitis B. A drug eruption should also be considered in the differential diagnosis of a maculopapular rash. Rose spots, crops of pink macules (2 to 3 mm in diameter) on the chest or abdomen, suggest typhoid fever. An eschar, a black necrotic ulcer with erythematous margins, may be found with many rickettsial diseases. Dengue fever, meningococcemia, Rocky Mountain spotted fever, and viral hemorrhagic fevers may present with petechiae, ecchymoses, or hemorrhagic lesions.

Eyes
The eyes should be examined for evidence of conjunctivitis (consider leptospirosis) or retinal hemorrhages (consider subacute bacterial endocarditis).

Sinuses, Ears, and Teeth
These are common sites of occult infection, and attention to these areas can help to avoid unnecessary testing for other causes of infections.

Heart and Lungs
Auscultation of the lungs should focus on the detection of inspiratory crackles and wheezes, and auscultation of the heart is performed to evaluate for the presence of a murmur, since subacute bacterial endocarditis is always a major consideration.

Abdomen
The presence of splenomegaly should be determined, since this is associated with a number of diseases, notably mononucleosis, malaria, visceral leishmaniasis, typhoid fever, and brucellosis.

Lymphadenopathy
Localized lymphadenopathy may be seen in many infections, and its presence is often less helpful than other signs. Generalized lymphadenopathy, however, has a more limited differential diagnosis, and this finding may be more useful.
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Pre-travel immunizations and chemoprophylaxis taken during travel must be determined, since these will influence the probability of acquiring infections. These interventions vary in efficacy. The proper administration of vaccines against hepatitis A, hepatitis B, and yellow fever effectively rules out each of these infections as a cause of a patient’s illness. However, vaccines against typhoid fever or use of immunoglobulin for the prevention of hepatitis A is only 70% to 80% effective, so these infections should still be considered among patients who have been immunized. Childhood immunizations against diseases such as polio, diphtheria, and measles may not provide adequate protection in adults unless a booster has been administered or natural disease reported. Immigrants from developing countries may not have received routine immunizations.
For travelers to malaria-endemic areas, the use of personal protective measures (insect repellents, bed nets) and chemoprophylaxis must be assessed. Note that no antimalarial chemoprophylactic regimen is completely protective. Furthermore, poor compliance with antimalarials among travelers is a well-documented cause of failure.
The health of the patient prior to travel is also of importance. The presence of underlying medical conditions (cardiopulmonary diseases, immunosuppression, asplenia) may increase susceptibility to various infections. Knowledge of the medications taken for treatment of a patient’s illness prior to and during travel is also essential, since these may alter the presentation of certain diseases.
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Doxycycline
Doxycycline (Vibramycin, Pfizer), a tetracycline, continues to be the preferred agent for persons unable to tolerate mefloquine or for those traveling to areas where mefloquine resistance is present. The drug is taken in a dose of 100 mg daily during exposure and continued for 4 weeks after the traveler returns home. No loading dose is required. Doxycycline has been shown to have comparable prophylactic efficacy to mefloquine, but the need for daily dosing may reduce adherence and, therefore, the drug’s effectiveness. Side effects of doxycycline include gastrointestinal upset, esophagitis, and vaginal candidiasis. Furthermore, since the drug can be photosensitizing, its use requires adequate sunscreen protection. Doxycycline is contraindicated in pregnant or lactating women and in children younger than 8 years of age. Long-term administration of tetracyclines has generally been well tolerated.

Atovaquone/Proguanil
The U.S. Food and Drug Administration recently approved a fixed combination tablet of atovaquone and proguanil (Malarone, Glaxo Wellcome) for the chemoprophylaxis of malaria. Travelers need only take the medication during periods of exposure and for 1 week after departure. This is an advantage over mefloquine and doxycycline, which need to be taken for 4 weeks following exposure. Atovaquone/proguanil has been found to be useful against strains of malaria that are resistant to other agents. The adult dosing regimen for prophylaxis consists of one tablet (250 mg atovaquone/100 g proguanil) daily starting 2 days before travel, one tablet per day during travel, and one tablet daily for 7 days after leaving an endemic area. The most common adverse effects are abdominal pain, nausea, and headaches. Since insufficient data exist on its safety in pregnancy, it should not be taken by pregnant or lactating women. Atovaquone/proguanil is also contraindicated in those with severe renal impairment. Overall, this combination is well tolerated and efficacious in the prevention of P. falciparum. More data are needed to confirm its efficacy against the other malaria species.

Primaquine
Primaquine (base, Sanofi-Synthelabo) has activity against both the blood and liver stages of malaria parasites. In patients who have been infected with P. vivax or P. ovale, relapses can occur far after chemoprophylaxis is discontinued because the standard drugs fail to eliminate the liver hypnozoites. To prevent relapses, a course of primaquine may be given as terminal prophylaxis (to eliminate latent intrahepatic stages) at the conclusion of the standard post-travel chemoprophylaxis regimen. One 26.3 mg tablet is administered daily for 14 days after the trip. Terminal prophylaxis is generally indicated only for people who have a prolonged exposure in malaria endemic areas or who have visited areas of intense P. vivax transmission. Primaquine causes acute intravascular hemolysis in those with an inborn deficiency of glucose-6-phosphate-dehydrogenase (G6PD). The drug should not be prescribed without confirming a normal G6PD level. Primaquine should not be used in pregnant patients.

Future Options
Since primaquine is effective against the hypnozoites developing in the liver, it has recently been reconsidered for causal prophylaxis (to interfere with the early intrahepatic development) of malaria, particularly if the exposure is short. Travelers would need to take primaquine only during exposure and for 1 week after. Randomized controlled trials of the use of primaquine as a chemoprophylactic agent (30 mg base/day) have demonstrated protective efficacy against both P. falciparum and P. vivax infections, but at this time primaquine is not licensed for this indication. Tafenoquine is a long-acting primaquine analogue with the same mechanism of action, but this drug is not yet licensed in the United States. Like primaquine, it can be used for causal prophylaxis. It has a long elimination half-life (14-28 days for tafenoquine versus 4-6 hours for primaquine) that allows for infrequent dosing regimens. Preliminary reports indicate that a once-weekly dose is effective against P. falciparum, and a 3-day loading dose alone provides protection for several weeks. Tafenoquine remains only a future option for the prevention of malaria, but it may improve medication compliance with malaria chemoprophylaxis.
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