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During recent decades, typhoid fever has largely disappeared from industrialized countries but

remains a serious public health problem in many Asian regions, Africa, and South America. Accord-ing to the World Health Organization (WHO) es-timates, 21 million cases occur each year, including 200,000 deaths. 1 Obtaining reliable data on disease burden in developing countries is diffi cult since many hospitals lack facilities for blood culture and most of the patients are treated as outpatients. 2

In industrialized countries, typhoid fever occurs mainly in returned travelers. First, to determine the need for preventive strategies, eg, for vaccination, continuous monitoring is needed to assess where

the risk for travelers is highest. Thus, we calculated travel-associated risk for different regions. In a sec-ond step, we compared these rates to those of previ-ous decades to detect changes with time to suggest adjustments to the current typhoid vaccine recom-mendations for travelers.

Methods

We analyzed the 1993 to 2004 database on Salmo-nella typhi infections reported to the Swiss Federal Offi ce of Public Health (SFOPH). This authority requests an initial report from the laboratory; a questionnaire is completed thereafter by the at-tending physician. Only confi rmed cases according to the Centers for Disease Control defi nition were evaluated. 3

Travelers ’ statistics collected by the Swiss Federal Offi ce of Statistics (SFOS) for 1993 to 2002 were used as denominator to calculate the risk. 4 Information sources of the SFOS included

Imported Typhoid Fever in Switzerland, 1993 to 2004

Andreas Keller , MD , * Markus Frey , MD , * Hans Schmid , PhD , † Robert Steffen , MD , * Thomas Walker , MD , * and Patricia Schlagenhauf , PhD * * Division of Epidemiology and Prevention of Communicable Diseases, WHO Collaborating Centre for Travellers ’ Health, Institute of Social and Preventive Medicine, University of Zurich Travel Clinic, CH-8001 Zurich, Switzerland ; † Swiss Federal Offi ce of Public Health, Division of Epidemiology and Infectious Diseases, CH-3003 Bern, Switzerland

DOI: 10.1111/j.1708-8305.2008.00216.x

Background . In industrialized countries, typhoid fever occurs mainly in returned travelers. To determine the need for preventive strategies, eg, for vaccination, continuous monitoring is needed to assess where the risk for travelers is highest. Methods . To investigate where the risk for travelers to acquire typhoid fever is highest, 208 patients with typhoid fever and recent travel were matched with travelers ’ statistics collected by the Swiss Federal Offi ce of Statistics. Results . At the beginning of the study period, up to 30 infections with Salmonella typhi were recorded per year in Swit-zerland. Since 2001, less than 15 confi rmed cases per year occurred. A majority of the 208 (88.5%) typhoid cases were as-sociated with recent travel. Countries with highest risk were Pakistan (24 per 100,000), Cambodia (20 per 100,000), Nepal (14 per 100,000), India (12 per 100,000), and Sri Lanka (9 per 100,000). Conclusions . We found that over a 12-year period (1993 – 2004), the travel-associated risk of typhoid fever is highest for destinations in the Indian subcontinent. All other regions showed a decline, most markedly in southern Europe. Our re-sults suggest that typhoid fever vaccination should be recommended for all travelers to countries in South Asia. Other-wise, vaccination of tourists to frequently visited low- and intermediate-risk areas is not necessary, unless there are behavioral risk factors.

Corresponding Author: Andreas Keller, MD, Univer-sity of Zurich Travel Clinic/ISPM, Hirschengraben 84, CH-8001 Zurich, Switzerland. E-mail: andreas.keller@access.uzh.ch

Guest Editor: Herbert L. DuPont

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national tourist offi ces, national offi ces of statis-tics, embassies, and the World Tourism Organi-zation to collect data of arrivals of Swiss residents to various countries or regions worldwide (more than 1 d of stay). For 2003 and 2004, denominator data were collated from the national tourist of-fi ces and the travel industry publication “ Travel Inside ” because the SFOS no longer provides trav-elers ’ statistics. 5 Travel regions were coded as described by the United Nations Economic and Social Development Agency. 6

Results

During the 12-year study period, there were 235 confi rmed typhoid cases reported. A majority of 208 (88.5%) typhoid cases were associated with re-cent travel; 18 (7.7%) denied international travel 3 months before onset of symptoms. For the remain-ing 9 (3.8%), no travel information was available.

The ratio of male to female patients was 1.42. Most patients affected were teenagers and young adults; 95 (40.4%) and 69 (29.4%) cases were re-ported in those aged 15 to 29 and 30 to 44 years, respectively. Seventy-seven patients with typhoid fever (32.8%) were foreign nationals; almost all of them had recently traveled to their country of ori-gin. None of the patients died, but 180 (76.6%) needed hospitalization.

At the beginning of the study period, up to 30 in-fections with S typhi were recorded per year and this number decreased, and since 2001, less than 15 con-fi rmed cases per year occurred, which leads to an annual incidence of less than 0.2 cases of typhoid fever per 100,000 residents ( Figure 1 ).

Based on 94 confi rmed imported cases in the pe-riod 1999 to 2004, the highest risk of typhoid fever was noted when the destination was in South Asia. The rate for this region exceeded 7 per 100,000 travelers. If the Maldives islands, a frequently vis-ited tourist destination without a single case of im-ported typhoid in the past, was excluded, the rate even reached 11 per 100,000 trips. Countries with highest risk were Pakistan (24 per 100,000), Cambodia (20 per 100,000), Nepal (14 per 100,000), India (12 per 100,000), and Sri Lanka (9 per 100,000). In the intermediate-risk group with rates from 1 to 5 per 100,000 trips were the Philippines and Indonesia (4 per 100,000 each), Malaysia, Morocco, and Dominican Republic and Mexico (1 per 100,000 each). All other countries and regions had a risk below 1 per 100,000, including frequently visited Kenya, Tanzania, Thailand, and all coun-tries in South America.

As shown in Table 1 , a continued decrease of the typhoid fever risk over several decades has been re-corded mainly among travelers to southern Europe and Turkey and also to a lesser extent in those to Africa and South America. Only little improve-ment could be detected in South and Southeast Asia.

Discussion

Our analysis suggests that the highest risk of ty-phoid fever remains in South Asian destinations. This is concordant with older Swiss data and also a recent Swedish survey that rated India and its neighboring countries as high-risk areas with a rate for the 1997 to 2003 period of 42 per 100,000. 7 – 9 A study of Israeli travelers from 1995 to 2003 demon-strated a rate of 23.7 per 100,000 for the Indian subcontinent. 10 In a US survey among resident travelers visiting India, 11 to 41 per 100,000 were diagnosed with typhoid, and a 1-year review in 1997 of all travel-related cases in the United States showed that 65% traveled to India, Pakistan, Bangladesh, or Haiti. 11,12 Travel-associated risk in southern Europe and Turkey has decreased; this possibly may be due to improvements in sanitary conditions.

Double notifi cation as practiced in Switzerland should assure adequate recording of diagnosed ty-phoid cases. Nevertheless, the presented data are likely to underestimate the risk of typhoid fever because an unknown number of infected patients may have been successfully treated by appropriate antimicrobials without proper diagnosis. An addi-tional group may have been diagnosed while still traveling abroad, and such cases would not be communicated to the Swiss notifi cation system. Travelers ’ statistics do not indicate if the travelers were vaccinated against typhoid fever. Despite the limited effi cacy of the vaccine, unvaccinated

Figure 1 Typhoid fever in travelers from Switzerland (1993 – 2004).

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travelers would have a higher risk. The SFOS and the Swiss travel industry defi ne their data as arrivals of Swiss residents in foreign countries. 4,5 However, these can be only estimations because some coun-tries record nationality rather than country of resi-dence at immigration. Another weakness is that travelers ’ statistics do not contain information about age and gender of travelers; thus, the two databases are not fully comparable.

Our results suggest to recommend typhoid fever vaccination for all travelers to countries in South Asia. In contrast, we suggest that vaccination of tourists to frequently visited low- and intermediate-risk areas (such as Kenya and South Africa with risk rates below 0.4 per 100,000 travelers) is not neces-sary, unless there are behavioral risk factors. While WHO estimates of typhoid fever burden in the local population rank these same countries and regions among intermediate and high risk, with incidences of 10 up to more than 100 per 100,000

per year, the degree of endemicity in native resi-dents is less relevant to risk assessments for travel-ers, who rarely consume food and beverages in crowded high-risk slum areas. 1 Additional data are needed for areas less frequently visited, such as countries in the Near and Middle East and Central and West Africa. As future steps, the collection of control data and the elaboration of a logistic regres-sion model would help to elucidate if our prelimi-nary results are conclusive.

Acknowledgments

We thank the SFOPH for providing the necessary data and for most valuable advice. We are grateful to the physicians who completed and submitted the questionnaires of their typhoid fever patients. This study was performed without external funding at the Institute of Social and Preventive Medicine, University of Zurich, Switzerland.

Table 1 1974 to 2004 evolution of typhoid fever risk among travelers from Switzerland

Typhoid fever patients per 100,000 travelers (95% CI)

1974 – 1981 * 1984 – 1987 † 1993 – 1998 ‡ 1999 – 2004 ‡

Asia East Asia 0.67 0.27 (0.00 – 0.64) 0.35 (0.00 – 0.84) South Asia 21.82 10.79 (7.67 – 13.91) 7.55 (5.15 – 9.95) India 3.33 § 43.11 12.07 (7.14 – 17.00) 11.88 (6.92 – 16.84) Southeast Asia 3.50 1.48 (0.85 – 2.11) 1.28 (0.69 – 1.86) Indonesia 3.69 6.19 (2.83 – 9.56) 3.57 (0.92 – 6.21) West Asia 4.00 0.00 0.09 (0.00 – 0.26) 0.07 (0.00 – 0.21) Africa North Africa 4.00 4.68 1.41 (0.72 – 2.10) 0.70 (0.28 – 1.11) Egypt N/A 5.80 3.50 (1.67 – 5.34) 0.49 (0.00 – 1.04) Morocco N/A 8.00 0.56 (0.00 – 1.66) 1.21 (0.00 – 2.58) Sub-Saharan Africa 6.67 5.00 1.46 (0.67 – 2.25) 0.20 (0.00 – 0.48) Southern Africa N/A 0.00 0.52 (0.00 – 1.54) 0.00 (0.00 – 0.75) America North America 0.00 0.00 0.00 (0.00 – 0.00) 0.00 (0.00 – 0.00) Central America N/A 4.71 0.30 (0.00 – 0.89) 0.97 (0.02 – 1.93) Caribbean 1.00 0.00 0.23 (0.00 – 0.67) 0.34 (0.00 – 0.80) South America 1.67 1.31 2.08 (0.99 – 3.17) 0.35 (0.00 – 0.75) Europe Northern Europe 0.02 0.00 0.02 (0.00 – 0.06) 0.00 (0.00 – 0.00) Western Europe N/A 0.01 0.00 (0.00 – 0.00) 0.00 (0.00 – 0.00) Southern Europe N/A 0.14 0.08 (0.04 – 0.13) 0.04 (0.01 – 0.06) Italy 0.83 0.15 0.05 (0.00 – 0.10) 0.02 (0.00 – 0.06) Spain 0.67 0.14 0.00 (0.00 – 0.00) 0.01 (0.00 – 0.04) Turkey 6.67 1.97 0.70 (0.00 – 1.49) 0.12 (0.00 – 0.35) Eastern Europe N/A 0.00 0.00 (0.00 – 0.00) 0.00 (0.00 – 0.00) Australia N/A 0.00 0.58 (0.00 – 1.39) 0.00 (0.00 – 0.00)

N/A = not available; CI = confi dence interval. * Data from Steffen. 7 † Data from Schottenhaml. 8 ‡ Typhoid fever case numbers were provided by the Swiss Federal Offi ce of Public Health; traveler numbers were provided by the Swiss Federal Offi ce of Statistics 4 and the journal Travel Inside . 5 § Rate was calculated for East-, South-, and Southeast Asia together.

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Declaration of Interests

P. S. has received speakers ’ honoraria and travel expenses from Roche and GlaxoSmithKline. She acted as a consultant to Roche in a drug safety data-base evaluation. R. S. has accepted fee for speaking, organizing and chairing education, consulting, and/or serving on advisory boards, also reimbursement for attending meetings and funds for research from Astral, Baxter, Berna Biotech/Crucell, Glaxo-SmithKline, Novartis Vaccine, Optimer, Roche, Salix, Sanofi Pasteur MSD, and/or SBL Vaccine. All other authors state that they have no confl icts of interest.

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