Regional risks and seasonality in travel-associated campylobacteriosis

Backgound The epidemiology of travel-associated campylobacteriosis is still largely unclear, and various known risk factors could only explain limited proportions of the recorded cases. Methods Using data from 28,704 notifications of travel-associated campylobacteriosis in Sweden 1997 to 2003 and travel patterns of 16,255 Swedish residents with overnight travel abroad in the same years, we analysed risks for travel-associated campylobacteriosis in 19 regions of the world, and looked into the seasonality of the disease in each of these regions. Results The highest risk was seen in returning travellers from the Indian subcontinent (1,253/100,000 travellers), and the lowest in travellers from the other Nordic countries (3/100,000 travellers). In Africa, large differences in risk between regions were noted, with 502 /100,000 in travellers from East Africa, compared to 76/100,00 from West Africa and 50/100,000 from Central Africa. A distinct seasonal pattern was seen in all temperate regions with peaks in the summer, while no or less distinct seasonality was seen in tropical regions. In travellers to the tropics, the highest risk was seen in children below the age of six. Conclusions Data on infections in returning travellers together with good denominator data could provide comparable data on travel risks in various regions of the world.


Background
Campylobacter infection is a zoonotic disease, observed in most parts of the world. The disease is caused by Campylobacter jejuni, or less commonly Campylobacter coli. It is estimated to cause 5-14% of diarrhoea, worldwide [1]. The incubation period is usually 2 to 5 days (range 1 to 10 days), and persons not treated with antibiotics may excrete the organisms for as long as 7 weeks [2]. Also in the Western world Campylobacter infection has emerged to be most important bacterial cause of gastrointestinal infection. Animals (variety of fowl, swine, cattle, sheep, dogs, cats, and rodents) are the major reservoir for the bacteria. Campylobacter does not easily grow in food, but the critical infective dose is low [3].
Unlike salmonellosis with well-known routes of transmission, the epidemiology of campylobacteriosis is still largely unclear, and various known risk factors could only explain limited proportions of the recorded cases [4]. Known risk factors for the disease include ingestion of undercooked meat, contaminated food and water or raw milk, direct contact with pets, farm animals and small children, and swimming in lakes, but also travel abroad [3,[5][6][7]. Direct person-to-person transmission between adults appears to be uncommon. In temperate regions, campylobacteriosis has a distinct seasonal pattern, with the peak incidence in the summer months [4,6,8,9], but seasonal data on campylobacteriosis from tropical regions are scarce.
Approximately 80 million persons from industrialized countries travel every year to places in Africa, Asia, Pacific Islands, Latin America and remote areas of Eastern Europe, and between, 25 and 50 % of travellers to these areas experience travellers' diarrhoea [10][11][12]. About 80 % of all episodes of traveller's diarrhoea have a bacterial cause, and Campylobacter infection is a leading cause together with infections due to enterotoxigenic Escherichia coli (ETEC), salmonellosis, and shigellosis [11,13].
In this study we have used returning travellers to Sweden as sentinels to estimate the comparative risks for travelassociated campylobacteriosis in 19 regions of the world, and looked into the seasonality of the disease in each of these regions.

Notification data on campylobacteriosis
Campylobacteriosis is a notifiable disease according to the Swedish communicable disease act. Cases are notified in parallel to the Swedish Institute for Infectious Disease Control (SMI) by the clinician having seen the patient (clinical notification) and the laboratory having diagnosed the pathogen (laboratory notification). At the SMI the notifications from the two sources are merged into case records, using a unique personal identification number issued to all Swedes, and used in all health care contacts. The clinical notifications contain epidemiological information of relevance, including country of infection. For this study we retrieved notification information (age, sex, country of infection and month of infection) from the national surveillance database [14] on all cases of campylobacteriosis notified in the period 1997-2003, with country of infection outside Sweden. All information in the database is derived from the notifications, and the data (including "country of infection") are thus based on the best judgment of the notifying clinician based on the patient history and knowledge of the characteristics of the pathogen in question. Since we focused on travel-associated infections, refugees and newly arrived immigrants (with incomplete personal identification number) were sorted out before analysis.

Denominator data on travel patterns
Data on travel patterns were obtained from a commercial database, the Swedish Travel and Tourist Database (TDB) [15]. This database contains data from monthly telephone interviews with 2,000 randomly selected Swedish residents, with travel-related questions. Out of the total database, containing data from almost 170,000 interviews, we used 16,255 records of persons with recent overnight travel outside Sweden. Each record included information on principal geographical country/region of travel, age, sex, and month of travel, but no data on any illness. Data from the TDB are often given as regions rather than countries, to account for low numbers of respondents outside the most popular travel destinations.

Statistical methods
The age, sex and geographical distribution of the interviewees in the TDB, were standardised against the total population of Sweden to give an extrapolation of the actual number of travellers to each country during the seven years. We then estimated risks per 100,000 travellers (divided on the exposures sex, age and region of travel) using notifications on Campylobacter infection (cases) as numerator and extrapolated total numbers of travellers To adjust for possible confounding and test for interaction, we also calculated odds ratios (OR) with corre-sponding 95% CI for the same exposures with a logistic regression model.
In an initial crude analysis, odds ratios (ORs) for all exposures (age, sex, and travel destination) on the outcome campylobacteriosis were analysed, with the lowest incidence in each category used as reference. Confounding was then assessed using Mantel-Haenszel stratification. ORs for exposures with significant association with the

Results
Of 53,223 persons notified with campylobacteriosis in the period 1997 to 2003, 28,704 (54%) were travel-associated, corresponding to 42.3 cases per 100,000 travellers ( Table 1). The total number of infections from single countries both reflected the risk of disease in the various countries, but to a large extent also the travel pattern of Swedes. The five most commonly stated countries of infection were Thailand (n = 6,129), Spain (n = 5,646), Turkey (n = 1,812), Morocco (n = 1,501), and India (n = 1,086).
The 16,255 respondents with overnight travel outside Sweden in 1997-2003 from the TDB database corresponded to almost 68 million travel episodes; 78% leisure trips and 22% business trips (Table 2). Travel to several countries within one region was quite common, but overnight stay in more than one region was rare (less than 0.1% of travellers ). Also the association between age and campylobacteriosis was modified by travel destination, and in travellers from tropical destinations, especially from Africa and Asia/Oceania the highest risk was seen in the youngest children (Table 3).

Methodological issues
In this study we report the risks for travel-associated campylobacteriosis and seasonality of the risks in various parts of the world, based on more than 28,000 notified cases. The large number of cases gives more precise risk estimates for this disease than in previous studies, although the estimates are given for quite large regions in parts of the world with few Swedish travellers. The denominator data from the TDB has previously been used in studies on dengue fever [16] and rickettsiosis [17]. We have also tested the reliability of the TDB by comparing the TDB data with in-flight passenger data obtained from some countries with such requirements. For destinations with many travellers, the two sources of information were highly compatible, e.g. less than 5 % difference for travel to Thailand.
Map showing Campylobacter risk per 100 000 returning travellers to Sweden from different regions of the world Figure 1 Map showing Campylobacter risk per 100 000 returning travellers to Sweden from different regions of the world. In regions with a distinct seasonality, the month with the highest risk (OR) is given.
Notification data only reflects a small (but unknown) proportion of all travel-related Campylobacter infections. One should therefore be cautious in drawing conclusions from the magnitude of the figures, and rather focus on the relative risks between the various regions, as estimated by the odds ratios. Since the data are all from the same source, the risk figures from the various regions are directly comparable. However, there may be a tendency of investigating travellers from the tropics more vigorous than travellers from e.g. the other Nordic countries, thus underestimating the risks in nearby countries. However, such selection bias could likely not explain the huge differences between say West Africa and East Africa.
Since we have no comparable data on the length of stay among the cases in our study, we were not able to include length of stay in our logistic regression model. However, the TDB clearly shows a longer median stay among travellers in far-away destinations. For instance the median stay in Spain was 6 nights, while in Thailand it was 14 nights.
On the other hand, only cases detected after the return to Sweden are included in the analysis. The disease data therefore mainly reflect infections contracted during the last week of stay at the travel destination. Differences in length of travel are therefore to some extent evened out.
It has previously been suggested that the risk of travellers' diarrhoea is higher during the first two weeks in highly endemic areas [10,18]. The calculated risks in this study may therefore be underestimated in travel destinations with more prolonged stay. However, persons staying long periods abroad are also less likely to be telephone interviewed in Sweden, balancing the missed cases.

Regional risks
The differences in risk between various regions were considerable, not only between industrialized and developing countries, but also between different developing countries. The Indian Subcontinent, East Africa, East Asia, and North Africa stood out as special high-risk areas. In a recent Finnish study, the risk of travel associated Campylobacter jejuni infection was 10 per 100,000 travellers returning from Spain and Portugal, and 50, 60, and 80 per 100,000 returning travellers from China, Thailand and India, respectively [19]. The lower risks, and lesser differences between the countries may be explained by a much smaller number of cases (n = 205) to base the risk estimates on. East Africa and India have also previously been identified as high-risk areas for travel-associated diarrhoea of various aetiology [20,21], but the very large differences in the risk of campylobacteriosis between East Africa, and West, Central and Southern Africa have to our knowledge not previously been described.
Age, sex and season (month of travel/infection) were identified as possible confounders for the association between travel destination and risk for campylobacteriosis and were thus included in the logistic regression model. All three variables contributed significantly to the model, but the overall effect of these confounders did not alter the rank order between the regions in the logistic regression model compared to the crude analysis.

Age and gender
The highest risks were seen in young adults and small children, and especially in the tropics the highest risks were seen in the youngest. This is consistent with previous findings that in developed countries the disease most of hits children below the age of 5 years and young adults, while in developing countries it is most often seen in children below the age of 2 years, with an annual incidence of 40-60 % [1]. The data are also consistent with the results from other studies on traveller's diarrhoeas [11]. De Las Casas has suggested that the high risk in young adults is due to a more adventurous lifestyle when it comes to eating habits, and the elevated risk in the youngest is due to increased faecal/oral contamination and decreased immunity [22], explanations that seem plausible. An alternative explanation put forward is that young people with a greater appetite ingest more bacteria, and thereby increasing their risk of infection.
In travellers returning from Europe, male gender was an independent risk factor for Campylobacter infection. This pattern is also seen in domestically acquired Swedish campylobacteriosis cases, where 56% of the notified cases in 2003 were males, and in the US where campylobacteriosis is more common in males of all age groups [8,9]. The higher risk in males in the US has been attributed to sexspecific differences in food-handling practices and consumption practices as well as a higher susceptibility to gastro-intestinal infections in males [9]. For travel destinations to tropical or subtropical destinations, the risk was not influenced by gender, consistent with other studies on travel-associated diarrhoea [23].

Seasonality
In each of the 19 regions in the study, we looked closely at the seasonality of the disease. As has previously been shown [3,[6][7][8][9], there was a striking seasonal pattern in all temperate regions, with distinct peaks in the summer. Previously these summer peaks have been partly attributed to returning travellers [4], but obviously this could not explain the same peaks in our study. The magnitude of the summer peaks was also in the same order in domestic Swedish cases, as in the returning travellers from other temperate countries.
In the tropical regions, seasonal peaks of campylobacteriosis have not previously been recognized [8]. Also in this study the seasonal pattern was much less distinct in tropical than in temperate regions, and only in East Asia (peak incidence in December) and in the Caribbean (peak incidence in February) could a seasonal pattern be discerned. In a study on US medical students in Mexico, the peak incidence of Campylobacter infection was seen between November and April [18]. With only 15 cases and 8 TDB respondents, our study did not have the power to detect any seasonality in Central America.

Conclusions
Data on infections in returning travellers together with good denominator data could provide comparable data on travel risks in various regions of the world. This study has revealed large and unexplained regional incidence differences, e.g. between East and Central Africa. The very distinct seasonal pattern seen in all temperate regions could not be discerned in the tropics.