Fever in Travelers After Visiting Malaria-endemic Areas
Abstract & Commentary
By Lin H. Chen, MD, Assistant Clinical Professor, Harvard Medical School; Director, Travel Medicine Center, Mt. Auburn Hospital, Cambridge, MA. Dr. Chen has received research grants from the Centers for Disease Control and Prevention and Xcellerex.
This article originally appeared in the January 2012 issue of Infectious Disease Alert. It was edited by Stan Deresinski, MD, FACP, FIDSA, and peer reviewed by Timothy Jenkins, MD. Dr. Deresinski is Clinical Professor of Medicine, Stanford University, and Dr. Jenkins is Assistant Professor of Medicine, University of Colorado, Denver Health Medical Center. Dr. Deresinski does research for the National Institutes of Health, and is an advisory board member and consultant for Merck, and Dr. Jenkins reports no financial relationships relevant to this field of study.
Synopsis: Common specific causes of fever in Finnish returned travelers were Campylobacter, malaria, bacteremia, HIV, and influenza; they included a significant proportion of potentially life-threatening infections, and more than one diagnosis. Evaluation of such fevers should be systematic and thorough.
Source: Siikamaki HM, Kivela PS, Sipila PN, et al. Fever in travelers returning from malaria-endemic areas: Don't look for malaria only. J Travel Med 2011;18:239-244.
Authors from the Helsinki University Central Hospital, a tertiary hospital in Finland, retrospectively reviewed patient records from 2005 to 2009 to define the causes of fever in returned travelers and to evaluate the diagnostic approach. The 462 records were selected through requests for malaria smears in the emergency department.
The most common categories of diagnoses were acute diarrhea (27%), systemic febrile illness (21%), and respiratory illness (15%). Campylobacteriosis was the most common specific diagnosis (9%), while malaria was diagnosed in 4%. Bacteremia was identified in 5% of patients tested (21/428), and influenza was diagnosed in 8 patients. HIV antibodies were performed in 174 patients (38%) and 3% were positive. Non-infectious etiologies caused fever in 3%, and in 25% of the cases the etiology remained unknown.
Potentially life-threatening illnesses were diagnosed in 26% of the patients, and were associated with elevated C-reactive protein (CRP) ≥ 100 (odds ratio [OR], 3.6; 95% confidence interval [CI], 2.0-6.4) and thrombocytopenia (OR, 3.8; 95% CI, 2.0-7.3). One patient died of septicemia. Forty-five patients (10%) had more than one diagnosis.
A number of serious, life-threatening infections can cause fever in a returned traveler, and the evaluation may be challenging for clinicians unfamiliar with the epidemiology at the destination countries. Data from studies on travelers are welcome to further strengthen work-ups for particular diagnoses.
A well-established network of specialized travel and tropical medicine clinics, GeoSentinel, analyzed fever in 24,920 returned travelers seen from March 1997 through March 2006 and found fever to be the main cause for seeking medical evaluation in 6,957 (28%).1 In that analysis, 15% of the fever cases were due to diarrheal disease, 14% due to respiratory illness, and 35% had a febrile systemic illness. Malaria, found in 21% of febrile returned travelers, was the most common specific cause identified.1 Etiologies for fever varied by region visited and by time of presentation after travel, and the most significant risk factors were travelers who visited sub-Saharan Africa, south-central Asia, and Latin America and whose reason for travel was visiting friends and relatives (VFR). Malaria caused 33% of the 12 deaths among febrile travelers.1
A number of centers have studied fever in their returned travelers. A prospective observational study from January 1997 to December 2001 on fever in returning travelers (n = 147) admitted to a university teaching hospital in Milan, Italy, found that malaria accounted for nearly half of admissions (47.6%), followed by presumed self-limiting viral infections (12%).2 The most useful investigations at this center were blood smears and PCR for malaria, which were positive in 65% of cases for which they were performed. Serology was useful to identify hepatitis A and dengue virus infections.2
Investigators in Marseilles, France, also conducted a 5-year prospective observational study on the etiologies of fever in travelers returning from the tropics admitted to a university teaching hospital (n = 613).3 Malaria was the most common diagnosis (75.2%), with most cases (62%) acquired by VFR travelers from the Comoros Islands; 8.2% of the patients remained unexplained.3
Bottieau et al from University Hospital Antwerp, Belgium, also analyzed the etiology of fever and diagnostic predictors from April 2000 to December 2005 in nearly 2,000 returned travelers.4,5 Exposures occurred commonly in sub-Saharan Africa and Southeast Asia-Pacific (68% and 12%, respectively).4 Tropical diseases accounted for 39% of the cases, cosmopolitan infections for 34%, and 24% remained unknown. Approximately one-quarter required hospitalization.
The travel destinations were major determinants of tropical infections, with malaria and rickettsial infections as the leading diagnoses after a stay in Africa (35% and 4%, respectively); dengue, malaria, and enteric fever after travel to Asia (12%, 9%, and 4%, respectively); and dengue and malaria on return from Latin America (8% and 4%, respectively).4
Although malaria accounted for only 4% of the diagnoses in the study by Siikamaki et al, other European studies found malaria to be a more significant cause of morbidity,1-5 and also a major cause of mortality.1,4 Therefore, malaria remains one of the most important diagnoses to exclude when a returned traveler presents with fever. Some findings associated with malaria from these studies include splenomegaly, thrombocytopenia, lack of localizing symptoms, and hyperbilirubinemia.5 Other key predictors of fever etiology include: skin rash and skin ulcer for rickettsial infection (mainly African tick bite fever); skin rash, thrombocytopenia, and leukopenia for dengue; eosinophilia for acute schistosomiasis; and splenomegaly and elevated serum alanine aminotransferase level for enteric fever.5
Siikamaki and colleagues reaffirm that a significant proportion of febrile returning travelers had a potentially life-threatening illness (about one-quarter). Bacteremia was as common as malaria. Also, the significant finding of several HIV cases warrants routine HIV testing. Both blood cultures and HIV tests should be considered in febrile travelers. Importantly, the high proportion of patients (10%) with more than one diagnosis highlights the need for careful systematic work-up. A hospital-based study of the causes of fever in adults on the Thai-Myanmar border found that dual diagnoses were common, especially malaria (25% of the diagnoses) and leptospirosis (17%).6
In summary, fever is common in ill returned travelers and often results in hospitalization. The time of presentation and geographic region of exposure provide key information to generate the differential diagnoses. Particular symptoms and findings suggest some specific diagnoses. Travel medicine specialists who evaluate febrile returned travelers should evaluate the patient systematically, and include studies for malaria, blood cultures, and HIV tests especially in cases where localizing symptoms are lacking.
1. Wilson ME, Weld LH, Boggild A, et al; GeoSentinel Surveillance Network. Fever in returned travelers: Results from the GeoSentinel Surveillance Network. Clin Infect Dis 2007;44:1560-1568.
2. Antinori S, Galimberti L, Gianelli E, et al. Prospective observational study of fever in hospitalized returning travelers and migrants from tropical areas, 1997-2001. J Travel Med 2004;11:135-142.
3. Parola P, Soula G, Gazin P, et al. Fever in travelers returning from tropical areas: Prospective observational study of 613 cases hospitalised in Marseilles, France, 1999-2003. Travel Med Infect Dis 2006;4:61-70.
4. Bottieau E, Clerinx J, Van den Enden E, et al. Fever after a stay in the tropics: Diagnostic predictors of the leading tropical conditions. Medicine (Baltimore) 2007;86:18-25.
5. Bottieau E, Clerinx J, Schrooten W, et al. Etiology and outcome of fever after a stay in the tropics. Arch Intern Med 2006;166:1642-1648.
6. Ellis RD, Fukuda MM, McDaniel P, et al. Causes of fever in adults on the Thai-Myanmar border. Am J Trop Med Hyg 2006;74:108-113.