Fever in Returned Travelers: Results from the GeoSentinel Surveillance Network

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1 MAJOR ARTICLE Fever in Returned Travelers: Results from the GeoSentinel Surveillance Network Mary E. Wilson, 1,2 Leisa H. Weld, 3 Andrea Boggild, 4,5 Jay S. Keystone, 4,5 Kevin C. Kain, 4,5 Frank von Sonnenburg, 6 and Eli Schwartz, 7,8 for the GeoSentinel Surveillance Network a 1 Mount Auburn Hospital, Cambridge, and 2 Harvard Medical School and Harvard School of Public Health, Boston, Massachusetts; 3 Centers for Disease Control and Prevention, Atlanta, Georgia; 4 McLaughlin-Rotman Centre, Tropical Disease Unit, University Health Network Toronto General Hospital and 5 University of Toronto, Toronto, Canada; 6 Department of Infectious Diseases and Tropical Medicine, University of Munich, Munich, Germany; and 7 Center for Geographic Medicine, Chaim Sheba Medical Center, Tel Hashomer, and 8 Sakler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Background. Fever is a marker of potentially serious illness in returned travelers. Information about causes of fever, organized by geographic area and traveler characteristics, can facilitate timely, appropriate treatment and preventive measures. Methods. Using a large, multicenter database, we assessed how frequently fever is cited as a chief reason for seeking medical care among ill returned travelers. We defined the causes of fever by place of exposure and traveler characteristics. Results. Of 24,920 returned travelers seen at a GeoSentinel clinic from March 1997 through March 2006, 6957 (28%) cited fever as a chief reason for seeking care. Of patients with fever, 26% were hospitalized (compared with 3% who did not have fever); 35% had a febrile systemic illness, 15% had a febrile diarrheal disease, and 14% had fever and a respiratory illness. Malaria was the most common specific etiologic diagnosis, found in 21% of ill returned travelers with fever. Causes of fever varied by region visited and by time of presentation after travel. Ill travelers who returned from sub-saharan Africa, south-central Asia, and Latin America whose reason for travel was visiting friends and relatives were more likely to experience fever than any other group. More than 17% of travelers with fever had a vaccine-preventable infection or falciparum malaria, which is preventable with chemoprophylaxis. Malaria accounted for 33% of the 12 deaths among febrile travelers. Conclusions. Fever is common in ill returned travelers and often results in hospitalization. The time of presentation after travel provides important clues toward establishing a diagnosis. Preventing and promptly treating malaria, providing appropriate vaccines, and identifying ways to reach travelers whose purpose for travel is visiting friends and relatives in advance of travel can reduce the burden of travel-related illness. Fever is an important marker of potentially serious illness in returned travelers [1, 2]. Evaluation of fever in returned travelers is difficult, because disease risks vary by geographic regions visited, travelers often visit multiple areas, and incubation periods for travel-related Received 18 November 2006; accepted 21 February 2007; electronically published 7 May The findings and conclusions in this paper are those of the authors and do not necessarily represent the views of the funding agency Presented in part: 52nd Annual Meeting of the American Society of Tropical Medicine and Hygiene, Philadelphia, PA, December 2003 (abstract 774). a Members of the GeoSentinel Surveillance Network are listed at the end of the text. Reprints or correspondence: Dr. Mary E. Wilson, 1812 Kalorama Sq. NW, Washington, DC (mary_wilson@harvard.edu). Clinical Infectious Diseases 2007; 44: by the Infectious Diseases Society of America. All rights reserved /2007/ $15.00 DOI: / infections range from a few days to 11 year. Although returned travelers may have infections that are caused by common, globally distributed pathogens, such as influenza, they may acquire unusual infections that are unfamiliar to most clinicians. Knowledge of disease risk by geographic area is critical to the evaluation of the ill returned traveler. It helps guide decisions about diagnostic tests and treatment and public health interventions when transmissible diseases are detected [3, 4]. Travelers also serve as sentinels; recognizing and reporting their infections can prompt alerts to other health care providers and travelers [5]. Although the travel medicine literature includes many studies of fever-related illness, all have described patients who were evaluated in a single institution or region [6 14]. Many studies included only hospitalized patients [7 9,11, 13, 14]; others have focused on 1560 CID 2007:44 (15 June) Wilson et al.

2 Figure 1. Distribution of regions of the world visited by ill travelers. A total of 6957 patients experienced fever; information regarding region of travel was missing or travel was to multiple regions for 403 travelers. specific diseases [15], age groups [13, 14], or types of travelers, and many have included persons who have traveled for immigration purposes, as well as those who traveled for business or pleasure. Studies that were published 110 years ago may lack relevance today, because of changes in travelers destinations and activities, shifts in disease distribution, availability of new vaccines (e.g., against hepatitis A) and drugs that reduce the risk of some infections, and increased awareness about certain infections and improved diagnostic tests. We used the GeoSentinel database to provide a standardized aggregate, multinational description of ill travelers returning from diverse global destinations. We examined how frequently fever is reported as a chief reason for seeking care, as well as the causes of fever. We also sought to define these causes according to geographic areas visited, characteristics of returned travelers, and interval to presentation after returning. Our large database reduces the population-specific bias that is present in many smaller studies. METHODS The 31 GeoSentinel sites contributing to this analysis are specialized travel or tropical medicine clinics located on 6 continents and staffed by clinicians who are recruited on the basis of their knowledge and experience in travel and tropical medicine. They contribute anonymous, questionnaire-based information on all ill travelers examined, which is then entered in a structured query language (SQL) database (details are available at [3, 16]. To be included in the database, patients must have crossed an international border within 10 years of visiting a GeoSentinel clinic and must be seeking medical care for an illness presumed to be travel related. Data collected includes demographic information, travel history, reason for most recent travel, inpatient or outpatient status, history of a pretravel clinic visit, and clinical findings (including patient symptoms and the results of physical examination and laboratory studies). Reasons for travel included tourism, business, research or education, missionary or volunteer work, or visiting friends and relatives. Travel duration, a proxy for duration of exposure, was measured as the duration of the most recent travel. Countries were assigned to 1 of 10 regional classifications (figure 1). Place of exposure was defined by the clinician if he or she had confidence that the infection was acquired in that place given the duration of the incubation period and/or known endemicity patterns or if the region was the only one visited by the patient. Chief reasons for seeking medical care, as described by the patient, were coded into 14 categories, with multiple reported reasons possible. Fever recorded in the database included reported and documented fevers. Thus, fever may have been present during the posttravel visit or may have been historical. The treating clinician assigned a final diagnosis from a standardized list of 556 possible diagnoses that are also categorized under 21 broad syndromes [3]. Diagnoses that had a predominant localization to 1 organ system were included in that organ system syndrome category. Thus, infections, such as malaria and dengue, were categorized as systemic febrile illnesses, whereas influenza and pharyngitis were categorized as respiratory illnesses. The category of vaccine-preventable illness represented diseases that had a high likelihood of being prevented by vaccines if vaccination was administered prior to travel (e.g., hepatitis A and B, influenza, measles, pertussis, meningococcal meningitis, enteric fever due to Salmonella en- Fever in Returned Travelers CID 2007:44 (15 June) 1561

3 terica serovar Typhi infection, and varicella). Probable diagnoses were restricted to patients who had an indisputable physical finding (e.g., tick eschar), a response to a highly specific therapeutic agent, or a classic clinical presentation and exposure history with the laboratory exclusion of other possible etiologies. Patients without an etiologic diagnosis or whose only diagnoses were fever and viral syndrome or a sign or symptom were categorized as having a syndrome of unspecified febrile illness. Inclusion and exclusion criteria. We included all travelers whose cases were reported to GeoSentinel from March 1997 through March 2006 who were seeking care after travel and who had diagnoses that were confirmed or probable. We excluded travelers who had sought medical care during travel, those who were traveling for immigration purposes, foreign visitors who were already ill when they arrived from their home country, and patients who were found to have no pathological illness (figure 2). Statistical analysis. We compared the patients who reported fever as a reason for seeking care after travel with all other ill returned travelers using x 2 tests or Fischer s exact test, as appropriate. We used regional multiple logistic regressions with backwards elimination to evaluate factors potentially associated with the presentation of fever, compared with presentation without fever, because of confounding by region of travel to each of the 4 most frequently visited regions. Selection of reference groups and dichotomous variables for the regressions was guided by current knowledge in travel medicine. P values reported from logistic regressions were based on Wald x 2 statistics. A 2-sided P value of!.05 was considered to indicate statistical significance. Statistical analysis was performed using SAS software, version 9 (SAS). RESULTS Of 54,834 ill travelers whose cases were reported to GeoSentinel, 24,920 met the inclusion criteria. Of the latter, 6957 (28%) reported fever as a chief reason for seeking care (figure 2). They visited GeoSentinel clinics in Europe (53% of travelers), the United States and Canada (25%), Israel (9%), Australia and New Zealand (8%), Asia (5%), and other sites (1%). Table 1 shows the analyses of demographic and exposure variables comparing GeoSentinel patients presenting with fever after travel with those who presented without fever after travel, overall and for each of the 4 most frequently visited regions. Travelers with and without fever did not differ by age. Ill returned female travelers presented with fever less often than did male travelers. The longer the interval between return and presentation, the less likely ill patients were to present with fever. Ill returned travelers who had visited sub-saharan Africa, southcentral Asia, or Latin America for!1 month reported fever Figure 2. Reports to GeoSentinel included in analysis of fever in returned ill travelers. more often than did those who traveled for 1 month. Those who traveled to sub-saharan Africa or south-central Asia without visiting a clinic before traveling were more likely to present with fever after returning from travel than were those who underwent such an evaluation. Travelers who were visiting friends and relatives (VFRs) were more likely than other types of travelers to report experiencing fever after travel to sub- Saharan Africa, south-central Asia, and Latin America. Although the number of travelers to Oceania was too small to perform a multivariate logistic regression, the percentages of travelers who presented with fever at different intervals after return were 41% (patients who presented 1 week after return), 43% (those who presented 2 6 weeks after return), and 47% (those who presented 6 weeks after return). We compared diagnoses assigned to febrile returned travelers with those assigned to travelers who were seeking care for other reasons (table 2). Of those who had systemic febrile illnesses, malaria was the most common specific etiology (59%). Although 52% of ill returned travelers were male, 58% of those who experienced fever and 71% of those who had fever and malaria were male ( P!.01). Falciparum malaria, which is preventable with the receipt of chemoprophylaxis, was identified in 14% of ill returned travelers with fever. Of the 113 rickettsial infections, 74% were tick-borne rickettsioses and 26% were other rickettsioses. Mononucleosis syndromes (e.g., Epstein- Barr virus infection, cytomegalovirus infection, acute HIV infection, or toxoplasmosis) occurred in 1.4% of patients with 1562 CID 2007:44 (15 June) Wilson et al.

4 Table 1. Characteristics of returned ill travelers with and without fever (6957 patients with fever among 24,920 ill returned travelers). Characteristic No. (%) of ill returned travelers with fever No. of ill returned travelers without fever Regional multiple logistic regression models in which variable is included as a significant a predictor Age, years! (31) 962 NS b 6230 (28) 16, (24) 761 NS Sex Male b 3995 (32) 8682 Female 2891 (24) 8967 A, B, C, D Reason for travel Tourism b 3802 (26) 10,782 Business 1036 (29) 2477 Research/education 283 (27) 785 Missionary/volunteer 384 (18) 1734 B, C Visiting friends and relatives 1431 (40) 2109 A, C, D Duration of travel, days (31) 8994 A, C, D 31 b 2597 (23) 8572 Interval time from travel to presentation, weeks (37) 4750 A, B, C, D (30) 5762 A, B, C, D 16 b 1511 (18) 7012 Recorded pretravel encounter No b 2535 (30) 5857 Yes 3488 (27) 9577 A, D Unknown 840 (27) 2309 A, D Total 6957 (28) 17,963 NOTE. A, variable was significant in sub-saharan Africa regression; B, variable was significant in Southeast Asia regression; C, variable was significant in Latin American regression; D, variable was significant in south-central Asia regression; NS,variable was not significant in any multiple logistic regression. a Two-sided P!.05 determined using the Wald test is considered to be statistically significant. b Reference group in multivariate logistic regressions. systemic febrile illnesses. Uncommon systemic illnesses included leptospirosis ( n p 25), amebic liver abscess ( n p 23), viral meningitis ( n p 13), and relapsing fever ( n p 4). Among those who experienced respiratory illness and fever, 11% had bacterial pneumonia and had 8% influenza or influenza-like illness. Upper respiratory infections occurred in 58% of patients who had respiratory illness and fever. Twelve patients (0.2%) with fever died; the listed contributory causes of death were malaria ( n p 4), acute respiratory distress syndrome ( n p 2), pulmonary embolism ( n p 1), unspecified febrile illness ( n p 1), sepsis ( n p 1), angiostrongyliasis ( n p 1), acute HIV infection with autoimmune disorder ( n p 1), and Epstein-Barr virus infection ( n p 1). Vaccine-preventable infections were identified in 3% of ill returned travelers who presented with fever. The most common infections were typhoid fever (which is due to S. Typhi infection; n p 100), acute hepatitis A ( n p 41), and influenza A ( n p 29). Exposures in south-central and Southeast Asia ac- counted for 170% of cases of typhoid fever. Vaccination data were generally unavailable. VFRs were more likely than other travelers to receive a diagnosis of a vaccine-preventable illness (OR, 1.8; 95% CI, ; x 2, 18; P!.001). The odds of having a vaccine-preventable cause of fever as a VFR versus the odds of having a vaccinepreventable cause of fever as another type of traveler was greatest after travel to Southeast Asia (OR, 5.9; 95% CI, ), south-central Asia (OR, 3.2; 95% CI, ), and Latin America (OR, 2.7; 95% CI, ), but not to sub-saharan Fever in Returned Travelers CID 2007:44 (15 June) 1563

5 Table 2. Summary of diagnosis groups and selected specific diagnoses in febrile patients after travel (6957 patients with fever among 24,920 ill returned travelers). Diagnosis No. (%) of ill returned travelers with fever Percentage of patients hospitalized Systemic febrile illness a All 2451 (35) 46 Malaria 1454 (21) 52 Malaria due to Plasmodium falciparum 964 (14) 56 Malaria due to Plasmodium vivax 388 (6) 51 Malaria due to other species 129 (2) 27 Dengue 430 (6) 29 Salmonella enterica serovar Typhi or Paratyphi infection 141 (2) 57 Rickettsia 113 (2) 20 Acute diarrheal disease b All 1027 (15) 15 Acute travelers diarrhea 293 (4) 5 Presumptive bacterial diarrhea 178 (3) 12 Due to Campylobacter species infection 154 (2) 12 Gastroenteritis 145 (2) 36 Due to nontyphoidal Salmonella species infection 76 (1) 32 Due to Shigella species infection 66 (1) 17 Respiratory illness c All 978 (14) 24 Acute unspecified respiratory infection 354 (5) 8 Bronchitis 104 (1) 11 Bacterial pneumonia 103 (1) 60 Tonsillitis 83 (1) 10 Influenza and influenza-like illness 75 (1) 47 Acute sinusitis 57 (1) 5 Genitourinary diagnosis d All 277 (4) 29 Acute urinary tract infection 168 (2) 24 Dermatologic diagnosis e 263 (4) 21 Nondiarrheal GI diagnosis f All 266 (4) 45 Acute hepatitis 90 (1) 59 Unspecified febrile illness g 1504 (22) 10 Vaccine-preventable illness h 226 (3) 60 All other diagnoses i 692 (10) 20 Total 6957 (100) 26 NOTE. Columns do not add up to 100% because patients can have 11 diagnosis. GI, gastrointestinal tract. a Data are for 3107 patients. b Data are for 4939 patients. c Data are for 1859 patients. d Data are for 799 patients. e Data are for 3997 patients. f Data are for 1930 patients. g Data are for 2851 patients. h Data are for 390 patients. Vaccine-preventable illnesses are also included in the appropriate diagnosis groups. Represented illnesses include hepatitis A and B; influenza A and B; measles; meningitis due to meningococcus, pneumococcus, or Haemophilus influenzae infection; meningococcal sepsis; mumps; pertussis; rubella; typhoid fever due to S. Typhi infection; tick-borne encephalitis; and varicella. i Data are for 6777 patients. Africa (OR, 1.3; 95% CI, ). Thirty-four percent of febrile returned travelers from south-central Asia who had enteric fever were VFRs. VFRs with fever were also less likely than other travelers with fever to have sought pretravel advice (OR, 0.24; 95% CI, ). Table 2 shows the percentage of ill returned travelers who received a diagnosis and who had fever who were hospitalized. These percentages are underestimates, because some patients who were reported as outpatients were subsequently hospitalized. Among all GeoSentinel patients, 77% of those who were 1564 CID 2007:44 (15 June) Wilson et al.

6 hospitalized had fever, in contrast to 23% of those who were examined as outpatients. The interval between return from travel and medical evaluation at a GeoSentinel site varied widely by diagnosis (figures 3A and 3B). The majority of patients (66%) with dengue were seen within 1 week of their return; 65% of patients with falciparum malaria but only 27% of those with vivax malaria were seen within 2 weeks of their return. Fifty-four percent of patients with vivax malaria and 34% of patients with hepatitis (mostly hepatitis A and unspecified hepatitis) were seen 16 weeks after return. The proportion of febrile illness due to specific pathogens also shifted over time (figure 3B). The predominant disease syndromes varied widely by geographic region (table 3). Ill travelers from Oceania (predominantly Papua New Guinea) and sub-saharan Africa most often reported fever; among these travelers, malaria was the primary diagnosis received. Dengue was the most common cause of systemic febrile illness in those who had visited Southeast Asia, but it was rarely seen in travelers to sub-saharan Africa. In examining data for all 24,920 patients, fever was a chief reason for seeking care in 90% of those with malaria, 82% with dengue, 87% with influenza, 96% with leptospirosis, 87% with enteric fever (due to S. Typhi and S. enterica serovar Paratyphi), 100% with measles, and 72% with rickettsial infections. Only 55% of patients with acute hepatitis A and 18% of those with acute hepatitis B had fever recorded as a reason for seeking care. DISCUSSION Fever is common in ill returned travelers and frequently leads to hospitalization. Although our findings in ill returned travelers cannot indicate relative risks among all travelers, they do inform the evaluation of fever in returned travelers who seek medical care. Of all returned travelers with fever, 35% had a febrile systemic illness, 15% had a diarrheal disease, and 14% had a respiratory illness. Malaria was the most common specific diagnosis. Other studies of febrile returned travelers have identified malaria in 27% 48% of hospitalized patients; the wide variation reflects the different travel patterns and precautions taken by patients [6 9]. Plasmodium falciparum, which causes the most severe malaria, was identified in 66% of patients with malaria in our study. Malaria was overwhelmingly the most common diagnosis in febrile returned travelers who had visited Oceania or the Pacific Islands and sub-saharan Africa. In fact, falciparum malaria was listed as a contributory cause in 33% of deaths in our febrile travelers. In our database, 10% of patients with malaria did not report fever as a chief reason for seeking care; these patients may have experienced prominent gastrointestinal or respiratory symptoms or severe headaches that led clinicians to focus on other diagnoses. A Canadian study [17] found that the diagnosis of Figure 3. Interval from return from travel to clinic presentation for patients who had fever, by specific febrile illness. A, Frequency of systemic febrile illnesses based on the duration of the interval to presentation to a GeoSentinel site. The interval to presentation to a GeoSentinel site reflects a combination of factors (when exposure occurred during the trip; the acuity, severity, and duration of illness; access to care; and the incubation period of the infection). B, Proportion of systemic febrile illnesses based on the duration of the interval to presentation to a GeoSentinel site. malaria was initially missed in 59% of cases, and the average delay before receipt of treatment for patients with falciparum malaria was 7.6 days after presentation to a health care facility. After malaria, the most common specific infections causing systemic febrile illness were dengue, enteric fever, and rickettsioses. Although dengue was identified in 6% of returned travelers with fever, those recorded in our database may reflect only a portion of cases. Symptoms of dengue can be mild and nonspecific and, as such, may not prompt laboratory investigation. Also, because the incubation time of dengue is short (5 10 days), travelers may become ill with dengue during travel [18]. Indeed, a serosurvey performed among Israeli travelers who had spent at least 3 months in a tropical area found that the seroconversion rate was 6.7% [19]. Dutch travelers to Asia (median stay, 1 month) had a seroconversion rate of 2.9% [20]. Serological diagnosis of dengue, however, can be difficult and Fever in Returned Travelers CID 2007:44 (15 June) 1565

7 Table 3. Regional distribution of ill travelers with fever and major diagnosis groups, by region of likely exposure, for ill returned patients with fever (6957 patients with fever among 24,920 ill returned travelers). Percentage of travelers, by condition Region of travel No. of travelers who had fever Fever a Systemic febrile illness Malaria Dengue Undiagnosed febrile illness Respiratory illness Diarrheal illness Vaccinepreventable illness Oceania/Pacific Islands 155 b Sub-Saharan Africa Southeast Asia South-central Asia Northern Asia Eastern Europe Northern Africa Caribbean and Central and South America Western Asia United States, Canada, Western Europe, Australia, and New Zealand Missing travel data Multiple travel exposures Total a Percentage of travelers to the area who had fever. b Destination: Papua New Guinea, 61%; Vanuatu, 11%; and Solomon Islands, 10%. Origin of travelers: Australia, 40%; United States, 10%; Germany, 10%; New Zealand, 7%; and Israel, 7%. is complicated by cross-reactions with other flaviviruses, including false-positive IgG results for dengue in travelers who have received pretravel immunization with flavivirus vaccines, such as yellow fever and Japanese encephalitis [21]. Enteric fever (due to S. Typhi and S. Paratyphi) was most frequently identified in persons returning from south-central Asia. Typhoid fever was also the most common vaccine-preventable infection documented in our study. Twenty-eight percent of enteric fever cases in our study were caused by S. Paratyphi. Typhoid vaccines are only partially protective (efficacy, 70%) against S. Typhi; against S. Paratyphi, the live, attenuated vaccine provides limited protection, and the Vi polysaccharide vaccine provides none [22 24]. Most travelers with rickettsial infections had tickborne rickettsioses, primarily after exposure in southern Africa. Other recent studies have also documented the increasing importance of tickborne rickettsioses in travelers [25, 26]. Time of presentation after travel can provide clues toward establishing a diagnosis (figure 3A and 3B). The interval-to-presentation profiles for vivax malaria and falciparum malaria are different. Although most cases of falciparum malaria occur early after return, clinical presentation can be delayed by the administration of drugs that have antimalarial activity [27]. In the United States, 190% of reported cases of falciparum malaria manifest within 1 month of return [28]. Although most infections in travelers have incubation periods!30 days, several can first manifest 30 days after travel (e.g., malaria, hepatitis, or tuberculosis) [2, 8], the most common being vivax malaria. Vivax malaria can occur late because of the dormancy of hypnozoites in the liver, which are not affected by the chemoprophylactic agents commonly used [29]. Our results are consistent with US data that show that almost one-half of cases of vivax malaria had an onset of symptoms 130 days after patient return [28]. Time to presentation to a GeoSentinel site was not always a reflection of incubation period. Some patients were evaluated during convalescence, sometimes after referral from another clinician. The fact that many patients who received a diagnosis of dengue in this study had a prolonged interval to presentation (12 weeks) underscores that fever in this group was likely historical and that these individuals were observed during convalescence. Infections with a global distribution, such as respiratory and urinary tract infections, are also observed in ill returned travelers [30 35]. Thus, clinicians who are caring for ill returned travelers must maintain a broad differential diagnosis that encompasses common, globally distributed infections including HIV infection, CMV infection, and toxoplasmosis as well as exotic ones [34, 35]. A substantial proportion (22%) of returned travelers with fever had an unspecified febrile illness, which is similar to results observed in other studies. In studies of patients in a tertiary care hospital, unidentified febrile illnesses accounted for 21% of cases [9], no diagnosis accounted for 25% of cases among inpatients [6], and viral illness accounted for 34% of cases among pediatric patients [13]. Almost 26% of febrile patients and 46% of those with sys CID 2007:44 (15 June) Wilson et al.

8 temic febrile illness were hospitalized, suggesting that ill returned travelers consume substantial medical resources. Furthermore, the high rate of hospitalization (60%) for travelers experiencing vaccine-preventable causes of fever underscores the importance of pretravel vaccination. Although our database does not include duration of hospitalization, other studies have found a mean duration of hospitalization of days in febrile patients after international travel [9, 11]. Ill returned travelers who were male were more likely than female travelers to have fever as a reason for seeking care. Male travelers may be more susceptible to infection, follow riskier itineraries, or take fewer precautions, thus putting them at higher risk for febrile illnesses, such as malaria. Alternatively, women may have a lower threshold for seeking care and may be more likely to present to a health care facility for nonfebrile illnesses. VFRs who traveled sub-saharan Africa, south-central Asia, and Latin America were more likely to experience fever than were any other group. VFRs were also twice as likely as other travelers to receive a diagnosis of a vaccine-preventable cause of fever, especially typhoid fever, and were less likely than other travelers to have sought pretravel medical advice. Other studies have also observed travel-related health problems in VFRs [36, 37]. Of the cases of malaria among civilians reported in the United States in 2004, 53% involved VFRs [38]. A variable proportion of travelers who have infections that are typically associated with fever did not indicate fever as a chief reason for seeking medical care. This group may have been afebrile at the time of presentation or may have been seen during convalescence. This is a reminder that fever may be intermittent, unrecognized by patients, partially suppressed by antipyretics, or overshadowed by other acute symptoms, such as severe headache. Clinicians should inquire about a history of fever, as well as measure temperature when evaluating ill returned travelers. Our data do not represent a comprehensive study of all illnesses in all travelers. Our results reflect the types of illnesses that are severe enough to lead returned travelers to seek care at a GeoSentinel clinic sites known for their expertise in tropical medicine. Our analysis could not capture all febrile illness in travelers, because infections that have short incubation periods may manifest during travel. Because the GeoSentinel sites accounting for the observations of the majority of patient entries are located in academic medical centers, and because some sites are restricted to outpatients, our results may not be representative of all travelers. Returned travelers with mild or selflimited illness may frequently be seen in primary care practices. This analysis is unique for several reasons. The multicenter population is large and up-to-date, and reflects a heterogeneous group of travelers in origin, travel destination, age, sex, and purposes for travel. The study focuses on illness that manifests after travel, and includes both inpatients and outpatients. It provides the quantitative data that will enable clinicians to focus on specific diagnostic tests in ill returned travelers and to identify populations, destinations, and diseases that should be targets for preventive services. Profiles of infections by intervals to presentation can guide clinicians to more-likely diagnoses at different times after travel. Fever after travel to tropical locations may be caused by common, globally distributed infections. Fevers that occur early after return are most likely to be potentially fatal, because this is the time of manifestation of symptoms of falciparum malaria. All clinicians must make a travel history part of the initial evaluation, because febrile returned travelers often are given priority in an emergency department or primary care clinic. On the basis of high rates of hospitalization, our study suggests that febrile returned travelers consume considerable economic resources. Many infections in travelers are preventable with the use of vaccines or other specific interventions, such as malaria chemoprophylaxis, and specific treatment or supportive care can be lifesaving. These results can help clinicians reduce travel-related morbidity, mortality, and resource consumption. CONTRIBUTING MEMBERS OF THE GEOSENTINEL SURVEILLANCE NETWORK Elizabeth Barnett (Boston University, Boston, MA), Graham Brown and Joseph Torresi (Royal Melbourne Hospital, Melbourne, Australia), Giampiero Carosi and Francesco Castelli (University of Brescia, Brescia, Italy), Lin Chen and Mary Wilson (Harvard University, Cambridge, MA), Bradley Connor (Weill Medical College of Cornell University, New York City, NY), Jean Delmont and Philippe Parola (Hôpital Nord, Marseille, France), David Freedman (University of Alabama, Birmingham, AL), Alejandra Gurtman (Mount Sinai Medical Center, New York City, NY), Devon Hale and Stephanie Gelman (University of Utah, Salt Lake City, UT), Nancy Piper-Jenks (Hudson River Health Care, Peekskill, NY), Elaine Jong and Jean Haulman (University of Washington, Seattle), Jay Keystone and Kevin Kain (University of Toronto, Toronto, Ontario, Canada), Phyllis Kozarsky (Emory University, Atlanta, GA), Carmelo Licitra (Orlando Regional Health Center, Orlando, FL), Louis Loutan (University of Geneva, Geneva, Switzerland), Michael Lynch (Fresno International Travel Medical Center, Fresno, CA), Susan MacDonald (Beijing United Family Hospital and Clinics, Beijing, China), Susan McLellan (Tulane University, New Orleans, LA), Robert Müller (TCS Travel Medicine Centre, Johannesburg, South Africa), Thomas Nutman and Amy Klion (National Institutes of Health, Bethesda, MD), Prativa Pandey (CIWEC Clinic Travel Medicine Center, Kathmandu, Nepal), Cecilia Perret Perez (Centro de Enfermedades Tropicales y Salud del Viajero, Santiago, Chile), Hiroko Sagara Fever in Returned Travelers CID 2007:44 (15 June) 1567

9 (Yokohama Municipal Citizen s Hospital, Yokohama, Japan), Bradley Sack and Robin McKenzie (Johns Hopkins University, Baltimore, MD), Eli Schwartz (Sheba Medical Center, Tel Hashomer, Israel), Marc Shaw (Travellers Health and Vaccination Centre, Auckland, New Zealand), William Stauffer and Patricia Walker (Regions Hospital, St Paul, MN), Robert Steffen and Patricia Schlagenhauf (University of Zurich, Zurich, Switzerland), Frank von Sonnenburg (University of Munich, Munich, Germany), Annelies Wilder-Smith and Poh Lian Lim (Tan Tock Seng Hospital, Singapore, Singapore), and Murray Wittner (Albert Einstein School of Medicine, Bronx, NY). Acknowledgments Financial support. GeoSentinel: the Global Surveillance Network of the International Society of Travel Medicine is supported by Cooperative Agreement U50/CCU from the Centers for Disease Control and Prevention. Support also comes from Genome Canada and a Canadian Institutes of Health Research Team grant in Malaria (to K.C.K.). 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