Pediatric Annals

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CME Article 

Evaluation of Fever After International Travel

Claudia S. Crowell, MD; Julie Kim Stamos, MD

Abstract

As more people travel internationally, there is an increase of the global spread of infectious diseases. Approximately 8% of travelers to developing countries seek medical attention while abroad or after returning home, and 22% to 64% self-report a health problem during travel.

Abstract

As more people travel internationally, there is an increase of the global spread of infectious diseases. Approximately 8% of travelers to developing countries seek medical attention while abroad or after returning home, and 22% to 64% self-report a health problem during travel.

Claudia S. Crowell, MD, is Fellow, Pediatric Infectious Diseases, Northwestern University Feinberg School of Medicine. Julie Kim Stamos, MD, is Assistant Professor, Pediatric Infectious Diseases, Northwestern University Feinberg School of Medicine.

Dr. Crowell and Dr. Stamos have disclosed no relevant financial relationships.

Address correspondence to: Claudia S. Crowell, MD, Northwestern University Feinberg School of Medicine, 2300 Children’s Plaza, Box 20, Chicago, IL 60614; fax: 773-880-8226; or e-mail: ccrowell@childrensmemorial.org.

As more people travel internationally, there is an increase of the global spread of infectious diseases. Approximately 8% of travelers to developing countries seek medical attention while abroad or after returning home, and 22% to 64% self-report a health problem during travel.1

Fever is a sign of a potentially serious infection in returned travelers but can be difficult to evaluate, especially in young patients. Disease risks and incubation periods for travel-related infections vary, and travelers can acquire common as well as uncommon diseases.2 It is important that pediatricians recognize the presentation of diseases, which are unique to other parts of the world, and are able to approach the returned traveler with fever systematically.

Evaluation of the Returned Young Traveler with a Fever

In addition to the standard history and physical exam, a systematic approach to a returned young traveler presenting with fever should include an evaluation of pretravel preparation and a thorough travel history.

Pretravel Preparation

The immunization and chemoprophylaxis status of febrile returned travelers is important. Vaccines against hepatitis A, hepatitis B, and yellow fever are at least 90% to 95% effective, whereas the efficacy of the typhoid fever vaccines is only 50% to 80%.3 The status of regular childhood vaccines, such as polio and measles, is also important, because these diseases still occur in developing countries.

If the young patient traveled to a malaria-endemic country, administration of effective antimalarial chemoprophylaxis and use of personal protective measures (eg, insect repellent, bed net) should also be determined, paying close attention to adherence to pre-, during, and posttravel antimalarial chemoprophylaxis.

Taken properly, antimalarial chemoprophylaxis medications are 80% to 90% effective in preventing infection but may alter the natural course of disease in those who acquire it by decreasing the severity of symptoms and prolonging the incubation period.4

Travel History

A good travel history is essential to the evaluation of a febrile young returned traveler and should focus on destination, exposures, duration of travel, and time of illness onset (see Sidebar). Once this information has been obtained, the practitioner should consult the destination-specific page on the Centers for Disease Control and Prevention (CDC) website ( www.cdc.gov), the World Health Organization website ( www.who.int), or the International Society for Travel Medicine’s GeoSentinel link ( www.istm.org) to inform herself/himself about the endemic diseases and current outbreaks.

Sidebar.

The pediatrician should attempt to find out the following:
  1. Areas visited, including type of accommodation and urban or rural location.

  2. Season of travel.

  3. Purpose of travel (eg, business, tourism, visiting friends and family).

  4. Duration of travel.

  5. Time of symptom onset in relation to travel (ie, during or posttravel) and sequence of symptoms.

  6. Exposure to ill persons, mosquitoes, ticks, animals, unpasteurized milk, raw or undercooked food, tap water, or ice.

  7. Recreational activities, such as swimming in lakes, camping, or hiking.

Exposure history can help narrow the differential diagnosis, because certain infectious diseases are associated with specific food or insect exposures (see Table 1). The pediatrician can sometimes estimate the incubation period of the illness based on time of symptom onset in relation to travel dates and exposure history. Determining the incubation period can narrow the differential even further, because certain illnesses are associated with longer incubation periods than others. Most infectious diseases have incubation periods of less than 30 days, with the exception of certain types of malaria (Plasmodium vivax), viral hepatitis, tuberculosis, acute human immunodeficiency virus and amebic liver abscess.5 One caveat is that P. falciparum malaria may manifest more than 21 days after return from travel in patients receiving antimalarial chemoprophylaxis.

Exposure and Travel-Related Infections5,7–9

Table 1. Exposure and Travel-Related Infections5,7–9

Physical Exam and Laboratory Evaluation

Every febrile returned traveler should have a thorough physical exam, paying special attention to fever patterns, rash, organomegaly, and lymphadenopathy. Table 2 (see page 41) lists physical exam findings associated with specific diseases that may be encountered in a returned traveler.

Clinical Findings Associated with Specific Diseases that May Be Encountered in a Returned Traveler4,5,7

Table 2. Clinical Findings Associated with Specific Diseases that May Be Encountered in a Returned Traveler4,5,7

It is important to remember, however, that diseases common in the nontraveler (eg, viral respiratory infection, mononucleosis) can also be seen in the returned traveler. Laboratory evaluation should be dictated by the history and physical (eg, chest radiograph for respiratory symptoms, stool culture for diarrhea). Basic laboratory workup should include a complete blood count with differential, chemistry profile with liver function tests, urinalysis, and blood and urine cultures. Thick and thin blood smears (a total of three obtained 12 to 24 hours apart) should be obtained if there was travel to a malaria-endemic area.

Malaria

Malaria is the most common diagnosis in returned travelers presenting with a systemic febrile illness.2 It affects approximately 270 million people worldwide and is the cause of 1 million to 2.5 million deaths yearly.11

The CDC website ( www.cdc.gov/malaria/about/distribution.html) shows the geographic distribution of the four common species of the malaria-causing parasite (P. falciparum, P. vivax, P. ovale, and P. malariae). Although malaria is transmitted in areas of Africa, Asia, the Middle East, Central America, South America, and Oceania, it occurs more frequently in travelers returning from sub-Saharan Africa.2 Malaria is transmitted by the bite of an infected female anopheline mosquito.

P. falciparum infection results in the most severe disease of the four species and, left untreated, it can lead to renal failure, pulmonary edema, coma, and death. It can be especially dangerous in children. P. vivax and P. ovale are associated with relapsing disease because they have a dormant liver stage. Patients infected with P. malariae may be asymptomatic carriers for years before the development of symptoms.

Most young patients with malaria present with fever; however, because fever in malaria is typically cyclical in nature, not all patients will be febrile at the time of evaluation. Fever tends to occur every other day (tertian) in cases of P. falciparum, P. vivax and P. ovale infections, and every third day (quartan) in cases of P. malariae infection. Fever marks the release of parasites from the red blood cells into the bloodstream and is usually accompanied by chills, headache, body ache, and fatigue, although fever and headache may be the only presenting symptoms in children.

On physical examination, the pediatrician may note anemia, jaundice, and hepatosplenomegaly. Nonimmune young individuals are at increased risk for developing complications of falciparum malaria. In children, the most common complication of falciparum malaria is cerebral malaria, which can manifest as altered consciousness and seizures.11 Other complications seen in children include severe anemia, more common in children younger than 2 years, hypoglycemia, and acute renal failure. Pulmonary edema is a late complication more common in adults.

Laboratory abnormalities in cases of malaria include anemia, thrombocytopenia, leukopenia, transaminitis, and hyperbilirubinemia. Hypoglycemia can occur in cases of falciparum malaria before or as a consequence of quinine treatment and indicates a poor prognosis.

Malaria is diagnosed by direct examination of thick and thin blood smears: thick smears are used to identify the presence of the parasite, and thin smears are used to determine the infecting Plasmodium species and the parasite load. Polymerase chain reaction (PCR) testing can also be performed in certain laboratories to differentiate among the four Plasmodium species.

Treatment of acute malaria depends on the infecting Plasmodium species, the severity of disease, and the pattern of drug resistance in the geographic region where infection occurred.7 Severe malaria requires admission to the intensive care unit, and exchange transfusion should be considered if there is more than 10% parasitemia or evidence of end organ damage.

Dengue Fever

Dengue fever is an acute febrile illness caused by arboviruses of the flavivirus family.12 There are four distinct serotypes, and severe hemorrhagic complications occur when a patient is infected for the second time with a different serotype. It is postulated that the immune response to the first serotype leads to an insufficient immune response in subsequent infections. In turn, this leads to hemorrhagic manifestations if a second infection occurs with one of the other three serotypes.

The dengue viruses are endemic in Asia, the Pacific islands, the Americas (mostly Central and South America), Africa, and the Caribbean.13 The typical incubation period is 4 to 7 days. Young patients with dengue fever present with fever, headache (classically retro-orbital), myalgia and/or bone pain, and a blanching macular rash.12

One to 2 days after defervescence, a second maculopapular rash may appear and last for 1 to 5 days. Fever may accompany this second rash, giving a biphasic temperature curve. Dengue hemorrhagic fever initially presents similar to dengue fever. However, on or about day 3 to day 7 of illness, increased vascular permeability occurs with a subsequent rise in the hematocrit secondary to hemoconcentration.14 Fever subsides around day 5 to day 7 of illness, and this period of defervescence is associated with the development of dengue shock syndrome.

Dengue serologic titers can be measured but are often negative early in the course of disease and should be repeated in the convalescent phase. Treatment of patients with dengue fever is supportive, with strict avoidance of aspirin and ibuprofen, which may interfere with platelet function. A complete blood count should be obtained, and if hemoconcentration or thrombocytopenia is present, the young patient should be admitted and observed for development of dengue hemorrhagic fever or dengue shock syndrome. Patients who go on to develop either of these conditions should be supported with fluid resuscitation.

Typhoid Fever

Typhoid fever is caused by Salmonella serotype Typhi and several other Salmonella serotypes. Salmonella serotype Typhi is only found in humans and is endemic in the developing world.15 Approximately 400 cases occur in the United States each year; 75% of these cases are acquired during international travel.15

The incubation period for typhoid fever is 7 to 14 days, and young patients typically present with fever, malaise, and gastrointestinal symptoms of either constipation or diarrhea.16 Other manifestations of typhoid fever include hepatosplenomegaly and rose spots. A classic finding described with typhoid fever is pulse-temperature dissociation, with the patient’s pulse normal despite being febrile; however, this phenomenon is rarely seen in children.

Young patients suspected of having typhoid fever should have a complete blood count with differential, blood culture, and stool culture. Ceftriaxone is the preferred initial therapy for typhoid fever and can be narrowed based on susceptibility results of the isolated organism. Therapy is continued for 10 to 14 days, and the route of therapy should be chosen based on severity of disease, host, site of infection, and clinical response.16

Leptospirosis

Leptospirosis is caused by the spirochete Leptospirosis interrogans.17 It is widespread in wild and domestic animals worldwide. Infected rats shed the organism in their urine for life, and other animals shed the organism for 6 to 12 months. Humans are incidental hosts and acquire the disease from either contact with the urine of infected animals or contact with contaminated water or soil. The typical incubation period is 5 to 14 days.18 There are two distinct manifestations of leptospirosis: the anicteric form and the icteric form (also known as Weil’s syndrome).19

Anicteric leptospirosis is characterized by two phases. The first phase is known as the septicemic phase and generally lasts for 3 to 7 days before spontaneously resolving. Patients present in this phase with myalgia, headache, abdominal pain, conjunctival suffusion, and fever.

Some young patients go on to develop the second phase, also known as the immune phase, characterized by low-grade or no fever, headache, myalgia, rash, conjunctival suffusion, hepatomegaly, aseptic meningitis, and interstitial nephritis.

If the second phase occurs, it can last up to 1 month. Approximately 10% of patients infected with Leptospirosis present with Weil’s syndrome, the more severe, icteric form of leptospirosis.17 Young patients with Weil’s syndrome initially present similar to the first phase of the anicteric form. However, 4 to 6 days into illness, the patient will develop jaundice, azotemia, and hemorrhage. This form of leptospirosis carries a mortality rate of 5% to 10%.19

If leptospirosis is suspected, a complete blood count with differential, chemistry profile, liver function tests, and urine analysis should be obtained. Although many laboratory values may be abnormal in patients with leptospirosis, none is specific for the disease.

If the pediatric patient has clinical signs of meningitis, a lumbar puncture should be performed. Cerebrospinal fluid may show pleocytosis with a polymorphonuclear predominance early in the disease course that subsequently develops into a mononuclear predominance. The protein may be elevated, but glucose is normal. Diagnosis is confirmed either by culture of the organism from the blood, cerebrospinal fluid, or urine and/or demonstration of a fourfold or greater increase in anti-leptospiral antibodies in acute and convalescent sera.

Most cases of leptospirosis resolve spontaneously before the diagnosis can be confirmed, and therefore are not treated. If the diagnosis is made and the patient is still symptomatic, then therapy with intravenous penicillin for 7 to 14 days is recommended. For less severe cases, oral doxycycline or amoxicillin may be used.17

Schistosomiasis

Schistosomiasis is a chronic parasitic infection that affects approximately 200 million individuals.20 Most cases are asymptomatic, but approximately 10% of infected patients have severe disease.

There are three main Schistosoma species that cause disease in humans, depending on geographic location: Schistosoma mansoni, S. japonicum, and S. haematobium. Schistosomiasis is endemic in tropical and subtropical countries; S. mansoni is found in Africa, South America, and the Caribbean; S. haematobium is found in Africa and the Middle East; and S. japonicum is endemic in Asia ( wwwnc.cdc.gov/travel/yellowbook/2010/chapter-5/schistosomiasis.aspx.).

Humans become infected when the water-residing, free-living forms, the cercariae, penetrate the skin during exposure to contaminated freshwater lakes or streams. The schistosomula then travel to the lungs via the venous system, enter the arterial system, and travel to the liver, where they mature. The mature parasite then travels via the portal venous system to the intestine (S. mansoni or S. japonicum) or bladder (S. haematobium). Because it can take several weeks for Schistosoma to reach the intestine or bladder, the incubation period varies from 4 to 10 weeks.21

Patients who develop symptomatic schistosomiasis present with an acute febrile illness known as Katayama fever, characterized by fever, malaise, cough, hepatosplenomegaly, diarrhea, lymphadenopathy, and eosinophilia.21 Patients who go on to develop chronic infection can either be asymptomatic or develop portal hypertension (S. mansoni or S. japonicum) or bladder fibrosis (S. haematobium), depending on the worm burden.

Pediatric patients suspected of having schistosomiasis should have a complete blood count, looking for eosinophilia, liver function tests if there is hepatosplenomegaly, and a urine analysis to check for hematuria and/or proteinuria. Diagnosis is made by identification of the Schistosoma ova in stool or urine specimens by microscopy. Serologic testing should also be obtained, because microscopy can yield false-negative results during acute illness or in a laboratory inexperienced in identifying Schistosoma ova. The treatment of choice for schistosomiasis is praziquantel for 1 day, which is generally effective for mild disease, but does little to treat chronic severe disease.

Conclusion

It can be a challenge to determine the cause of fever in the returned traveler, because the differential is often broad. It is important to remember that the most common causes of fever in this patient population are diseases with global distribution (ie, common viral infections). However, uncommon, destination-specific diseases can be life-threatening and need to be considered based on the destination of travel, exposure history, patient symptoms and physical exam. This review is not fully inclusive, and the practitioner seeing a returned traveler with fever should always refer to the appropriate travel medicine resources mentioned above to help guide the evaluation.

References

  1. Steffen R, deBernardis C, Baños A. Travel epidemiology--a global perspective. Int J Antimicrob Agents. 2003;21(2):89–95. doi:10.1016/S0924-8579(02)00293-5 [CrossRef]
  2. Wilson ME, Weld LH, Boggild A, Keystone JS, Kain KC, von Sonnenburg F, Schwartz EGeoSentinel Surveillance Network. Fever in returned travelers: results from the GeoSentinel Surveillance Network. Clin Infect Dis. 2007;44(12):1560–1568. doi:10.1086/518173 [CrossRef]
  3. American Academy of Pediatrics. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009.
  4. Speil C, Mushtaq A, Adamski A, Khardori N. Fever of unknown origin in the returning traveler. Infect Dis Clin North Am. 2007;21(4):1091–113, x. doi:10.1016/j.idc.2007.08.005 [CrossRef]
  5. Suh KN, Kozarsky PE, Keystone JS. Evaluation of fever in the returned traveler. Med Clin North Am. 1999;83(4):997–1017.
  6. House HR, Ehlers JP. Travel-related infections. Emerg Med Clin North Am. 2008;26(2):499–516, x. doi:10.1016/j.emc.2008.01.008 [CrossRef]
  7. Lo Re V 3rd, Gluckman SJ. Fever in the returned traveler. Am Fam Physician. 2003;68(7):1343–1350.
  8. Spira AM. Assessment of travellers who return home ill. Lancet. 2003;361(9367):1459–1469. doi:10.1016/S0140-6736(03)13141-8 [CrossRef]
  9. McLellan SL. Evaluation of fever in the returned traveler. Prim Care. 2002;29(4):947–969.
  10. Malaria. In: Feigin RD, Cherry JD, Demmler-Harrison GJ, Kaplan SL, eds. Feigin & Cherry’s Textbook of Pediatric Infectious Diseases. 6th ed. Philadephia, PA: Saunders Elsevier; 2009: 2899–2918.
  11. Centers for Disease Control. Guidelines for Treatment of Malaria in the United States, 2009.
  12. Dengue Virus. In: Feigin RD, Cherry JD, Demmler-Harrison GJ, Kaplan SL, eds. Feigin & Cherry’s Textbook of Pediatric Infectious Diseases. 6th ed. Philadephia, PA: Saunders Elsevier; 2009: 2347–2356.
  13. www.cdc.gov/dengue/epidemiology/index.html. Accessed Dec. 10, 2010.
  14. Flaviviruses. In: Long SS, Pickering LK, Prober CG, eds. Principles and Practice of Pediatric Infectious Diseases. 3rd ed. Churchill Livingston; 2008: 1082–1087.
  15. www.cdc.gov/nczved/divisions/dfbmd/diseases/typhoid_fever. Accessed Dec. 10, 2010.
  16. American Academy of Pediatrics. Salmonella Infections. In: Pickery LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009: 584–589.
  17. Leptospira Species (Leptospirosis). In: Long SS, Pickering LK, Prober CG, eds. Principles and Practice of Pediatric Infectious Diseases. 3rd ed. Churchill Livingston; 2008: 938–940.
  18. American Academy of Pediatrics. Leptospirosis. In: Pickery LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009: 427–428.
  19. Leptospirosis. In: Feigin RD, Cherry JD, Demmler-Harrison GJ, Kaplan SL, eds. Feigin & Cherry’s Textbook of Pediatric Infectious Diseases. 6th ed. Philadephia, PA: Saunders Elsevier; 2009: 1810–1825.
  20. Schistosomiasis. In: Feigin RD, Cherry JD, Demmler-Harrison GJ, Kaplan SL, eds. Feigin & Cherry’s Textbook of Pediatric Infectious Diseases. 6th ed. Philadephia, PA: Saunders Elsevier; 2009: 3022–3032.
  21. American Academy of Pediatrics. Schistosomiasis. In: Pickery LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009: 592–593.

Exposure and Travel-Related Infections5,7–9

Insects
MosquitoMalaria, dengue fever, yellow fever, arboviruses
TickRocky Mountain spotted fever, Lyme disease, relapsing fever, ehrlichiosis, Congo-Crimean hemorrhagic fever, Q fever, tularemia
Tsetse flyAfrican trypanosomiasis
Sand flyLeishmaniasis
Black flyOnchocerciasis
ReduviidAmerican trypanosomiasis
Food and Water
Raw or undercooked foodEnteric infections (Salmonella, Shigella, etc.), amebiasis
Unpasteurized dairy productsBrucella, tuberculosis
Untreated waterCholera, hepatitis, giardia
Fresh water skin contactLeptospirosis, schistosomiasis, acanthamoeba, Naegleria
AnimalsRabies, rat-bite fever, tularemia, anthrax, Q fever
Sick ContactsMeningococcal disease, viral hemorrhagic fever, tuberculosis

Clinical Findings Associated with Specific Diseases that May Be Encountered in a Returned Traveler4,5,7

Physical CharacteristicSymptomDisease
Vital signsPulse-temperature dissociationTyphoid fever
SkinMaculopapular rashDengue fever, viral hemorrhagic fevers, leptospirosis, schistosomiasis
Petechiae or purpuraMeningococcemia, dengue fever, leptospirosis, viral hemorrhagic fevers, Rocky Mountain spotted fever
Rose spotsTyphoid fever (evanescent pink macules)
EscharRickettsioses, anthrax
JaundiceHepatitis, yellow fever, viral hemorrhagic fevers, dengue fever, malaria, leptospirosis
EyesConjunctivitisLeptospirosis
AbdomenHepatomegalyVisceral leishmaniasis, East African trypanosomiasis, typhoid fever
SplenomegalyMalaria, dengue fever, leptospirosis, viral hemorrhagic fevers, visceral leishmaniasis, typhoid fever
Lymph nodesGeneralized enlargementDengue fever, visceral leishmaniasis, tuberculosis, leptospirosis, brucellosis
LocalizedTularemia, rickettsioses, tuberculosis (scrofula)
NeurologicAltered mental statusMeningococcal disease, malaria, tuberculosis, viral encephalitis

Sidebar.

The pediatrician should attempt to find out the following:
  1. Areas visited, including type of accommodation and urban or rural location.

  2. Season of travel.

  3. Purpose of travel (eg, business, tourism, visiting friends and family).

  4. Duration of travel.

  5. Time of symptom onset in relation to travel (ie, during or posttravel) and sequence of symptoms.

  6. Exposure to ill persons, mosquitoes, ticks, animals, unpasteurized milk, raw or undercooked food, tap water, or ice.

  7. Recreational activities, such as swimming in lakes, camping, or hiking.

CME Educational Objectives

  1. Develop a systematic approach to a returned traveler with fever.

  2. Recognize the importance of pretravel counseling in the prevention of infectious disease acquired during travel.

  3. Identify the clinical presentations of important travel-related infections.

Authors

Claudia S. Crowell, MD, is Fellow, Pediatric Infectious Diseases, Northwestern University Feinberg School of Medicine. Julie Kim Stamos, MD, is Assistant Professor, Pediatric Infectious Diseases, Northwestern University Feinberg School of Medicine.

Dr. Crowell and Dr. Stamos have disclosed no relevant financial relationships.

Address correspondence to: Claudia S. Crowell, MD, Northwestern University Feinberg School of Medicine, 2300 Children’s Plaza, Box 20, Chicago, IL 60614; fax: 773-880-8226; or e-mail: .ccrowell@childrensmemorial.org

10.3928/00904481-20101214-09

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