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Chapter 5Post-Travel Evaluation

Fever in Returned Travelers

Mary Elizabeth Wilson

INITIAL FOCUS

Fever commonly accompanies serious illness in returned travelers. Because it can signal a rapidly progressive infection such as malaria, the clinician must initiate early evaluation, especially in people who have visited areas with malaria in recent months (see Chapter 3, Malaria). The initial focus in evaluating a febrile returned traveler should be on identifying infections that are rapidly progressive, treatable, or transmissible. In some instances, public health officials must be alerted if the traveler may have been contagious en route or infected with a pathogen of public health importance (such as yellow fever) at the origin or destination.

USE OF HISTORY, LOCATION OF EXPOSURE, AND INCUBATION TO LIMIT DIFFERENTIAL DIAGNOSIS

Often the list of potential diagnoses is long, but multiple recent studies help to identify more common diagnoses. A large proportion of illnesses in returned travelers is caused by common, cosmopolitan infections (such as bacterial pneumonia or pyelonephritis), so these must be considered along with unusual infections. Because the geographic area of travel determines the relative likelihood of major causes of fever, it is essential to identify where the febrile patient has traveled and lived (Table 5-02). Details about activities (such as freshwater exposure in schistosomiasis-endemic areas, animal bites, sexual activities, or local medical care with injections) and accommodations in areas with malaria (bed nets, window screens, air conditioning) during travel may provide useful clues. Preparation before travel (such as hepatitis A vaccine or yellow fever vaccine) will markedly reduce the likelihood of some infections, so this is a relevant part of the history.

Because each infection has a characteristic incubation period (although the range is extremely wide with some infections), the time of exposures needs to be defined in different geographic areas (Table 5-03). This knowledge will allow the clinician to exclude some infections from the differential diagnosis. Most serious febrile infections manifest within the first month after return from tropical travel, yet infections related to travel exposures can occasionally occur months or even >1 year after return. In the United States, >90% of reported cases of Plasmodium falciparum malaria manifest within 30 days of return, but almost half of cases of P. vivax malaria manifest >30 days after return. A history of travel and residence should be an integral part of every medical history.

FINDINGS REQUIRING URGENT ATTENTION

Presence of associated signs, symptoms, or laboratory findings can focus attention on specific infections (Table 5-04). Findings that should prompt urgent attention include hemorrhage, neurologic impairment, and acute respiratory distress. Even if an initial physical examination is unremarkable, it is worth repeating the examination, as new findings may appear that will help in the diagnostic process (such as skin lesions or tender liver). Although most febrile illnesses in returned travelers are related to infections, the clinician should bear in mind that other problems, including pulmonary emboli and drug hypersensitivity reactions, can be associated with fever.

CDC’s Division of Global Migration and Quarantine is responsible for preventing the transmission of illnesses across US borders and, in particular, for preventing transmission of such illnesses into the United States. Fever accompanied by any of the following syndromes deserves further scrutiny, because it may indicate a disease of public health importance:

  • Skin rash
  • Difficulty breathing
  • Shortness of breath
  • Persistent cough
  • Decreased consciousness
  • Bruising or unusual bleeding (without previous injury)
  • Persistent diarrhea
  • Persistent vomiting (other than air or motion sickness)
  • Jaundice
  • Paralysis of recent onset

People who travel to visit friends and relatives (VFRs) often do not seek pre-travel medical advice. A review of GeoSentinel Surveillance Network data showed that a larger proportion of immigrant VFRs than tourist travelers presented with serious (requiring hospitalization), potentially preventable travel-related illnesses.

Table 5-02. Common causes of fever, by geographic area

GEOGRAPHIC AREA COMMON TROPICAL DISEASE CAUSING FEVER OTHER INFECTIONS CAUSING OUTBREAKS OR CLUSTERS IN TRAVELERS
Caribbean Dengue, malaria (Haiti) Acute histoplasmosis, leptospirosis
Central America Dengue, malaria (primarily Plasmodium vivax) Leptospirosis, histoplasmosis, coccidioidomycosis
South America Dengue, malaria (primarily P. vivax) Bartonellosis, leptospirosis, histoplasmosis
South-central Asia Dengue, enteric fever, malaria (primarily non-falciparum) Chikungunya virus infection
Southeast Asia Dengue, malaria (primarily non-falciparum) Chikungunya virus infection, leptospirosis
Sub-Saharan Africa Malaria (primarily P. falciparum), tickborne rickettsiae, acute schistosomiasis, filariasis African trypanosomiasis

Table 5-03. Common infections, by incubation period

DISEASE USUAL INCUBATION PERIOD (RANGE) DISTRIBUTION
Incubation <14 days
Chikungunya 2–4 days (1–14 days) Tropics, subtropics (Eastern Hemisphere)
Dengue 4–8 days (3–14 days) Topics, subtropics
Encephalitis, arboviral (Japanese encephalitis, tickborne encephalitis, West Nile virus, other) 3–14 days (1–20 days) Specific agents vary by region
Enteric fever 7–18 days (3–60 days) Especially in Indian subcontinent
Acute HIV 10–28 days (10 days to 6 weeks) Worldwide
Influenza 1–3 days Worldwide, can also be acquired en route
Legionellosis 5–6 days (2–10 days) Widespread
Leptospirosis 7–12 days (2–26 days) Widespread, most common in tropical areas
Malaria, Plasmodium falciparum 6–30 days (almost always within 3 months of travel; occasionally longer) Tropics, subtropics
Malaria, P. vivax 8 days to 12 months (occasionally longer) Widespread in tropics and subtropics
Spotted-fever rickettsiae Few days to 2–3 weeks Causative species vary by region
Incubation 14 Days to 6 Weeks
Encephalitis, arboviral; enteric fever; acute HIV; leptospirosis; malaria See above incubation periods for relevant diseases See above distribution for relevant diseases
Amebic liver abscess Weeks to months Most common in developing countries
Hepatitis A 28–30 days (15–50 days) Most common in developing countries
Hepatitis E 26–42 days (2–9 weeks) Widespread
Acute schistosomiasis (Katayama syndrome) 4–8 weeks Most common in sub-Saharan Africa
Incubation >6 weeks
Amebic liver abscess, hepatitis E, malaria, acute schistosomiasis See above incubation periods for relevant diseases See above distribution for relevant diseases
Hepatitis B 90 days (60–150 days) Widespread
Leishmaniasis, visceral 2–10 months (10 days to years) Asia, Africa, Latin America, southern Europe, and the Middle East
Tuberculosis Primary, weeks; reactivation, years Global distribution, rates and levels of resistance vary widely

Table 5-04. Common clinical findings and associated infections

COMMON CLINICAL FINDINGS INFECTIONS TO CONSIDER AFTER TROPICAL TRAVEL
Fever and rash Dengue, chikungunya, rickettsial infections, enteric fever (skin lesions may be sparse or absent), acute HIV infection, measles
Fever and abdominal pain Enteric fever, amebic liver abscess
Undifferentiated fever and normal or low white blood cell count Dengue, malaria, rickettsial infection, enteric fever, chikungunya
Fever and hemorrhage Viral hemorrhagic fevers (dengue and others), meningococcemia, leptospirosis, rickettsial infections
Fever and eosinophilia Acute schistosomiasis, drug hypersensitivity reaction, fascioliasis and other parasitic infections (rare)
Fever and pulmonary infiltrates Common bacterial and viral pathogens, legionellosis, acute schistosomiasis, Q fever, leptospirosis
Fever and altered mental status Cerebral malaria, viral or bacterial meningoencephalitis, African trypanosomiasis, scrub typhus
Mononucleosis syndrome Epstein–Barr virus, cytomegalovirus, toxoplasmosis, acute HIV
Fever persisting >2 weeks Malaria, enteric fever, Epstein-Barr virus, cytomegalovirus, toxoplasmosis, acute HIV, acute schistosomiasis, brucellosis, tuberculosis, Q fever, visceral leishmaniasis (rare)
Fever with onset >6 weeks after travel Plasmodium vivax or ovale malaria, acute hepatitis (B, C, or E), tuberculosis, amebic liver abscess

CHANGE OVER TIME

Clinicians have access to resources on the Internet that provide information about geographic-specific risks, disease activity, and other useful information, such as drug-susceptibility patterns for pathogens. Infectious diseases are dynamic, as is demonstrated by a review of adult returned travelers with fever and rash seen in 2006 and 2007 at a Paris hospital. The most common diagnosis was chikungunya fever, followed by dengue and African tick-bite fever. In contrast, because of the wide use of vaccine, hepatitis A infection is becoming less common in travelers.

Common infections in returned travelers may be seen at unexpected times of the year. Because influenza transmission can occur throughout the year in tropical areas, and the peak season in the Southern Hemisphere is May to August, clinicians in the Northern Hemisphere must be alert to the possibility of influenza outside the usual influenza season.

Travelers may acquire infections caused by common bacteria that are unusually resistant. Bacteria that produce the enzyme NDM-1 (New Delhi metallo-β-lactamase-1), which confers resistance to virtually all available antibiotics, have been found in infections acquired during travel, most often related to medical care (both elective and emergency). These bacteria have been most commonly reported after exposures in the Indian subcontinent. Enteric fever, the term used to describe either typhoid or paratyphoid fever, has also become increasingly resistant to fluoroquinolones (see Chapter 3, Typhoid & Paratyphoid Fever).

The tables in this section identify some common infections by presenting findings or other characteristics, by area of travel and by incubation periods. These highlight only the most common infections. The listed references and websites should be consulted for more detailed information. In most studies, a specific cause for fever is not identified in about 25% of returned travelers.

KEEP IN MIND

  • Initial symptoms of life-threatening and self-limited infections can be identical.
  • Fever in returned travelers is often caused by common, cosmopolitan infections, such as pneumonia and pyelonephritis, which should not be overlooked in the search for more exotic diagnoses.
  • Patients with malaria may be afebrile at the time of evaluation but typically give a history of chills.
  • Malaria is the most common cause of acute undifferentiated fever after travel to sub-Saharan Africa and to some other tropical areas.
  • Malaria, especially P. falciparum, can progress rapidly. Diagnostic studies should be done promptly and treatment instituted immediately if malaria is diagnosed (see Chapter 3, Malaria).
  • A history of taking malaria chemoprophylaxis does not exclude the possibility of malaria.
  • Patients with malaria can have prominent respiratory (including acute respiratory distress syndrome), gastrointestinal, or central nervous system findings.
  • Dengue is the most common cause of febrile illness among people who seek medical care after travel to Latin America or Asia.
  • Viral hemorrhagic fevers are important to identify but are rare in travelers; bacterial infections, such as leptospirosis, meningococcemia, and rickettsial infections, can also cause fever and hemorrhage and should be always be considered because of the need to institute prompt, specific treatment.
  • Sexually transmitted diseases, including acute HIV, can cause acute febrile infections.
  • Consider infection control, public health implications, and requirements for reportable diseases.

BIBLIOGRAPHY

  1. Bottieau E, Clerinx J, Schrooten W, Van den Enden E, Wouters R, Van Esbroeck M, et al. Etiology and outcome of fever after a stay in the tropics. Arch Intern Med. 2006 Aug 14–28;166(15):1642–8.
  2. Bottieau E, Clerinx J, Van den Enden E, Van Esbroeck M, Colebunders R, Van Gompel A, et al. Infectious mononucleosis-like syndromes in febrile travelers returning from the tropics. J Travel Med. 2006 Jul–Aug;13(4):191–7.
  3. Freedman DO, Weld LH, Kozarsky PE, Fisk T, Robins R, von Sonnenburg F, et al. Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med. 2006 Jan 12;354(2):119–30.
  4. Hochedez P, Canestri A, Guihot A, Brichler S, Bricaire F, Caumes E. Management of travelers with fever and exanthema, notably dengue and chikungunya infections. Am J Trop Med Hyg. 2008 May;78(5):710–3.
  5. Jensenius M, Davis X, von Sonnenburg F, Schwartz E, Keystone JS, Leder K, et al. Multicenter GeoSentinel analysis of rickettsial diseases in international travelers, 1996–2008. Emerg Infect Dis. 2009 Nov;15(11):1791–8.
  6. Jensenius M, Fournier PE, Raoult D. Rickettsioses and the international traveler. Clin Infect Dis. 2004 Nov 15;39(10):1493–9.
  7. Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis. 2010 Sep;10(9):597–602.
  8. Leder K, Tong S, Weld L, Kain KC, Wilder-Smith A, von Sonnenburg F, et al. Illness in travelers visiting friends and relatives: a review of the GeoSentinel Surveillance Network. Clin Infect Dis. 2006 Nov 1;43(9):1185–93.
  9. O’Brien D, Tobin S, Brown GV, Torresi J. Fever in returned travelers: review of hospital admissions for a 3-year period. Clin Infect Dis. 2001 Sep 1;33(5):603–9.
  10. Ryan ET, Wilson ME, Kain KC. Illness after international travel. N Engl J Med. 2002 Aug 15;347(7):505–16.
  11. Wilson ME, Freedman DO. Etiology of travel- related fever. Curr Opin Infect Dis. 2007 Oct;20(5):449–53.
  12. Wilson ME, Weld LH, Boggild A, Keystone JS, Kain KC, von Sonnenburg F, et al. Fever in returned travelers: results from the GeoSentinel Surveillance Network. Clin Infect Dis. 2007 Jun 15;44(12):1560–8.
 
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