ORIGINAL ARTICLES

Risk Factors for Typhoid Fever in Travelers TomasJelinek, Hans-Dieter Nothduvjl, Frank von Sonnenbug, and Thomas Loschev

Background: The incidence of typhoid fever in the developing world remains high and has been estimated at 540 cases per 100,000 of the population per year. International travelers to such areas are at risk of infection, especially if they travel under low hygienic standards.

Methods: In order to identify the risk factors leading to infection in travelers and expatriates, travel histories, anamnes- tic and clinical features of 31 patients with typhoid fever, who presented to a German travel clinic, were investigated.

Results: Compared to the total patient population of the outpatient clinic during the period of investigation (n = 17,029 patients), patients who presented with typhoid fever were older (39 years versus 31 years, p < .001) and traveled longer (58 days versus 19 days, p < .001). While only 19.2% of the total patient population had traveled to the Indian subconti- nent prior to referral, 35.4% of the patients with typhoid fever had acquired the infection there (p c ,001). Similar results were obtained for South East Asia and Indonesia: twenty percent of the total patient population traveled there in contrast with 32.2% of patients with typhoid fever (p < .001). Latin America was visited by 16.3% of all patients, but only 6.4% of patients with typhoid (p < .001).

Conclusions: The risk of infection appears to be highest when making an extended journey to the Indian subconti- nent. Short-term visitors to Latin America and Africa are apparently at a markedly lower risk. Three travelers were infected despite oral vaccination against typhoid fever prior to departure. Risk factors as age of the traveler, time, dura- tion, and destination of the journey should be considered in pretravel counseling. It should, however, be made clear that vaccination does not provide complete protection against infection with typhoid fever.

Typhoid fever is now a rare disease in industrialized countries. In the U.S., the number of reported cases dropped from 35,994 in 1920 to an average of 500 cases per year in the 1990s.'>'The annual incidence oftyphoid fever in western Europe, Japan, and the United States is now estimated at 0.24-3.7 cases per 100,000 population per year.3 The impressive control of this once predom- inant disease has been achieved without special eradica- tion program^.^ Salmonella typhi is an organism that is transmitted by the fecal-oral route via contaminated

Tomas Jelinek, MD, Hans-Dieter Nothdutft, MD, Frank von Sonnenburg, MD, and Thomas Loscher, MD Department of Infectious Diseases and Tropical Medicine, University of Munich, Munich, Germany.

Reprint requests: Dr. Tomas Jelinek, Department of Infectious Diseases and Tropical Medicine, University of Munich, Leopoldstr. 5,80802 Munich, Germany

J Travel Med 1996;3:200-203.

water and food, Salmonella typhi can be successfully reduced by improvements in water supplies, sanitation, and food h ~ g i e n e . ~ However, the incidence of typhoid fever in the developing world remains high and has been estimated at 540 cases per 100,000 of the population per year.3 The disease is especially threatening in countries where large parts of the population lack effective sani- tation and hygiene control. Studies from Indonesia indi- cate that, in some areas of the country, the incidence of typhoid fever reaches 10 cases per 1000 population per year and that the disease is therefore among the five major causes of death.3 International travelers to such areas are at risk of infection, especially if they travel under low hygienic standards. In 1983-84,70% of infections with S. typhi in the United States were attributable to foreign travel.' This number is in sharp contrast to only 33% of cases during 1967-1 972.5 In air travelers from the United States, the risk of infection has been estimated to be high- est in India and Pakistan with over 400 cases per one mil- lion travelers.6 Comparable data are only scarcely available for European travelers. In Germany, 197 cases of typhoid fever were reported in 1993.' Data on the origin of the infection and specific risks for travelers have not been eval- uated. However, a good knowledge of endemic areas, risk groups, and risk behavior is warranted for the physician giving pretravel advice to travelers. In order to identify the risk factors leading to infection in travelers and expa- triates, we investigated travel histories, medical histories and clinical features of patients with typhoid fever who presented to our outpatient clinic.

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Patients and Methods

Patients From 1990 to 1994,31 patients presenting to our

outpatient clinic were diagnosed as having typhoid fever. AU patients were Germans or had been German residents for more than 10 years. Data regarding travel hstory, med- ical history, and therapy were investigated thoroughly in order to determine behavioral and travel-related risk factors, which had possibly contributed to the infection. Individual data points were stored in a computerized data base (Excel, Microsoft) and subsequently analyzed by Mantel-Haenszel-Test for statistical significance (Epi Info, World Health Organization).

Methods Blood samples were collected from all travelers with

clinical signs suggestive of typhoid fever and submitted for hematologic and serologic testing and blood cultures. Bone marrow aspirate cultures* were not obtained.Titers of agglutinating antibodies to 0 and H antigens were measured by the single serumWidal Stool samples of 27 out of 31 patients with typhoid fever were also inves- tigated. Diagnosis was confirmed either bacteriologi- cally, by detection of Snlmonella typhi in blood cultures or stool samples, or by proof of rising antibody-titers against 0 and H antigens of S. typhL3

Treatment All 31 patients were treated by administration of

antibiotics after establishment of diagnosis. Regular fol- low-up examinations were performed for at least 6 months.

Number '' 0 Asia 1 OAfrica I Of 10

cases 8

6

4

2

' Jan-March AprJune JulySept Oct-Dec

Month

Figure 2 Typhoid fever in travelers - periodicity of importation.

Results

Ten (32.2%) of the 31 investigated patients were female, 21 (67.8%) were male.The mean age was 39 years (median 34 years, range 9-69 years).The mean duration of travel was 58 days (median 30 days, range 7 to 365 days). Twenty-three patients (74.1%) acquired infection in Asia, 6 (19.5%) in Africa, and one (3.2% each) in Cen- tral and South America, respectively (Fig. 1) .The high- est proportion of infection (35.4%) was imported from the Indian subcontinent (six patients were infected in India, four in Nepal, and one in Pakistan) followed by Indonesia (25.8%). All eight patients, who had traveled to Indonesia prior to infection, visited Java; five contin- ued their journey to Bali, and two to Sulawesi. Kenya, Gambia, and Egypt contributed two infected patients each. One patient was infected in China,Turkey, Mex- ico, and Ecuador, respectively. A seasonal distribution was observed, with a steady increase of imported cases

Table 1 Typhoid Fever in Travelers-Symptoms and Clinical Signs on Presentation (n = 31, more than one symptom possible)

Symptom Number %

Fever >39OC 29 93.5 Headache 20 64.5 Diarrhea 17 54.8 Fatigue 8 25.8 Dizziness 7 22.6 Abdominal pain 6 19.4 Splenomegaly 6 19.4 Nausea 5 16.1 Cough 5 16.1 Itching exanthema 4 12.9

Hepatomegaly 2 6.5 Constipation 3 9.7

Rose spots 0 0 Figure 1 Typhoid fever in travelers - areas of infection.

2 0 2 Journa l o f Travel Medicine, Volume 3, Number 4

towards the last quarter of the year and sharp decline towards the first quarter (Fig. 2).Accordingly, the num- ber of patients infected in Asia increased from the first to the last quarter. Patients who acquired infection in Africa did not follow this profi1e:They were evenly dis- tributed throughout the last three quarters of the year.

AU but two patients presented with fever over 39OC (Table 1). Other common symptoms included headache, dizziness, abdominal pain, and fatigue. Rose spots, com- monly assumed as a highly typical sign of typhoid fever,3 were not apparent in a single patient.A surprisingly high proportion of the patients, 17 out of 31 (54.896), presented with diarrhea. In seven of these patients, diarrhea was the first clinical sign, usually followed by high fever. In two patients, symptoms consisted solely of diarrhea, nausea, general fatigue and dizziness, suggesting not typhoid fever, but rather another gastrointestinal infection. Six patients presented with splenomegaly, two with hepatomegaly. All other clinical findings were normal. Three out of 31 patients (9.7%) received an oral vacci- nation against typhoid fever prior to departure. None of these patients was on H, blockers or antacids when receiving the vaccination. Infection was proved by stool culture in two and by blood culture in one. Neither symp- toms on onset of the disease, nor the duration of symp- toms before establishment of diagnosis, differed from the patients without vaccination. Five out of 31 patients (1 6%) suspected malaria as the cause of their symptoms and treated themselves with therapeutic doses of anti- malarials (chloroquine, halofantrine, or mefloquine) prior to referral to our outpatient clinic. One patient was assumed to have acute amebiasis and took metronidazole; another suspected a dysenteric infection and took the only antibiotic he carried, tetracycline. None of these suspected infections could be confirmed retrospectively by sero- logic or parasitologic testing.

Full blood counts in all 31 patients revealed a mean leukocyte count of 6.1 X 10’ cells per liter (median 5.7 X lo9 cells per liter, range 3.8-1 1.4 X 10’ cells per liter) with a mean lymphocyte part of 28% (range 9-3996). Completely negative eosinophil counts were apparent in all patients. In 15 of 31 patients (48.4%), diagnosis was established by blood culture positive for S. typki; this method failed to produce positive results in the other 16 patients. S. typhi could also be detected in stool samples of 13 patients (41.9%). Only one of these patients had a positive blood culture result as well. Diagnosis was based solely on serologic findings in four patients. In these patients, titers of agglutinating antibodies to 0 and H anti- gens as measured by the single serum Widal test3 were clearly elevated (0 2 160, H 2 160), and clinical find- ings were suggestive of typhoid fever. The mean time elapsing between the onset of symptoms and establish- ment of diagnosis was 3.3 days (median 2 days, range 1-14

days). The microscopic examination of stool samples revealed concomitant infections in 5 patients. Three of these patients also had an infection attributable to Gia- rdia lamblia and Entamoeba histolytica and two to Ascaris lumbricoides.

Seventeen out of 31 patients (54.8%) were treated in our outpatient department with quinolones (ofloxacin or ciprofloxacin) over 14 days. One of these 17 patients (5.9%) presented 91 days later with a relapse.This patient was treated again with quinolones without experi- encing another relapse. Nine out of 31 patients (29%) were treated with co-trimoxazole over 14 days before presenting to our outpatient clinic. Four out of these nine patients experienced relapses after 20 to 57 days following treatment and were treated again with quinolones. Also before presenting to our outpatient clinic, one patient each was treated with thiamphenicol, tetracycline, and ampi- cillin, respectively, over 10 days. None of these patients presented with a relapse.

Discussion

Compared to our total patient population during the period of investigation (n = 17,029 patients), patients who presented with typhoid fever were older (39 years ver- sus 31 years, p < .001) and traveled longer (58 days ver- sus 19 days, p < ,001). While only 19.2% of our total patient population had traveled to the Indian subconti- nent prior to referral, 35.4% of the patients with typhoid fever had acquired the infection there (p < .001) (Fig. 1). Similar results were obtained for South East Asia and Indonesia. Twenty percent of our total patient popula- tion traveled there in contrast to 32.2% of patients with typhoid fever (p < ,001). Latin America was visited by 16.3% of all patients, but only 6.4% of patients with typhoid fever had been there (p < .001). Similarly,Africa had been visited by 31.9% of all patients and by 19.5% of patients with typhoid (p < ,001). Obviously, the risk of infection is highest when making an extended jour- ney to the Indian subcontinent. Short-term visitors to Latin America and Africa are apparently at markedly lower risk. These findings are comparable to previous investigations from various nonendemic countries. 1.3

Journeys to areas with a high endemicity in Asia seem to bear an increased risk during the second half of the year.This is reflected by the fact that 16 out of23 patients (69.6%) who acquired typhoid in Asia, presented during the time from July-December (Fig. 2).

Symptoms and clinical findings, especially high fever, do contribute to diagnosis in patients with typhoid fever, but typical signs like rose spots might frequently be missing and atypical signs like diarrhea might be pre- sented (Table l).Therefore, the infection should also be considered in patients with uncharacteristic findings.

J e l i n e k e t a l , T y p h o i d F e v e r i n T r a v e l e r s 203

It has frequently been stated that pretravel vaccina- tion against typhoid fever does not produce a sufficient immunity in all vaccinees.'Various studies found a level of protection between 72%-95%.3 It was therefore no sur- prise that three of 31 patients (9.7%) in our study had been vaccinated by an oral live vaccine containing the Ty 21a strain of S. typhi. Seven out of the 31 patients (22.6%) suspected another disease (malaria, amebic, and bacterial dysentery) as the cause of their symptoms and started treatment on their own.These patients took anti- malarials or antibiotics, respectively.These measures were not sufficient to treat their actual infection. It should there- fore be emphasized that professional help should be sought whenever possible in case of febrile illness dur- ing a j0urney.A medical examination should also be rec- ommended if emergency treatment is carried out by the traveler himself.

The absence of eosinophils in the white cell blood count, as observed in all our patients, seems to be a typ- ical, but, of course not, a pathognomonic sign of typhoid fever. Diagnosis was established by detection of S. typhi in blood or stool cultures in all but four patients.The sin- gle serum Widal test proved to be crucial in diagnosing the remaining four patients. However, previous oral vac- cination with the live vaccine strainTy 21a does produce positive results in the Widal test, as It is therefore important to determine whether the patient received a vaccination or not before interpreting the test results.

Risk factors such as age of the traveler, time, dura- tion, and destination of the journey should be considered

in pretravel counse1ing.A person with one or more risk factors for typhoid fever is more likely to benefit from a vaccination. It should, however, be made clear that vaccination does not provide complete protection against infection.

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