Irritable Bowel Syndrome Among a Cohort of European Travelers to Resource-Limited Destinations

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1 250 Irritable Bowel Syndrome Among a Cohort of European Travelers to Resource-Limited Destinations Raffaela Pitzurra, PhD, Michael Fried, MD, Gerhard Rogler, MD, Christina Rammert, MD, Alois Tschopp, PhD, Christoph Hatz, MD, Robert Steffen, MD, and Margot Mutsch, PhD Division of Epidemiology and Prevention of Communicable Diseases and World Health Organization Collaborating Centre for Travellers Health, Institute of Social and Preventive Medicine, University of Zurich, Zurich, Switzerland; Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland; Biostatistics Division, Institute for Social and Preventive Medicine, University of Zurich, Zurich, Switzerland DOI: /j x Background. Travelers diarrhea (TD) remains a frequent travel-associated infection. Between 4 and 32% of enteric infections were followed by a postinfectious irritable bowel syndrome (pibs) with long-term sequelae in various settings. Travel-related IBS incidence rates are based on small studies and IBS predictors have not been sufficiently evaluated. Methods. Adult travelers to resource-limited destinations participated in a prospective questionnaire-based cohort study. Demographics, travel characteristics, and medical history were assessed and those with functional or organic gastrointestinal disorders were excluded. Immediately after return from abroad, the volunteers completed a second questionnaire on TD, other health impairments, and on nutritional hygiene. Six-months post-travel, a follow-up questionnaire assessed IBS based on Rome III criteria. Risk factors were analyzed by multiple logistic regression. Results. Among a total of 2,476 subjects analyzed (participation rate 72.4%), 38 (1.5%) developed new IBS, and the 6-month incidence rate for pibs was 3.0% (95% CI ) following TD. Significant risk factors were TD during the surveyed journey (OR 3.7; 95% ), an adverse life event experienced within 12 months pre-travel (OR 3.1; ), and a diarrheal episode experienced within 4 months pre-travel (OR 2.7; 95% CI ). Following multiple diarrheal episodes, the risk of acquiring IBS increased by six times. Conclusions. In a large population of European travelers IBS had a lower incidence rate as compared to previous studies. Particular risk groups were identified; those may need to be protected. Irritable bowel syndrome (IBS) is characterized by relapsing and fluctuating gastrointestinal symptoms, including abdominal pain, discomfort, and changed bowel habits. 1 The diagnosis is based on the exclusion of other functional or organic disorders and the Rome I, II, and at last III criteria. 2 The pathogenesis of IBS is multifaceted and not fully understood. In patients Presented in part at the 11th Conference of the International Society of Travel Medicine, Budapest, May 24 to 28, 2009 (abstract FC 03.01). Corresponding Author: Robert Steffen, MD, Division of Epidemiology and Prevention of Communicable Diseases and World Health Organization Collaborating Centre for Travellers Health, Institute of Social and Preventive Medicine, University of Zurich, Hirschengraben 84, CH-8001 Zurich, Switzerland. roste@ifspm.uzh.ch. Guest Editor: Herbert L. DuPont with IBS, low-grade inflammatory processes increased epithelial barrier permeability, alterations in the intestinal flora which may activate the immune system, and evidence for neuroimmune interactions were found. 3,4 Known risk factors for IBS include genetic, 5 epigenetic, 6 environmental, and behavioral factors, including infectious diarrhea, 7 central nervous system, and psychological characteristics. 8,9 A worldwide prevalence of 10% to 15% 10,11 and an annual incidence of 0.2% to 7% 12,13 have been reported. Various studies indicated that an episode of acute gastroenteritis, such as travelers diarrhea (TD), was an important risk factor for developing postinfectious IBS (pibs). 14 In two meta-analyses and 8 studies, 16 respectively, were included. The pibs incidence rates ranged from 4% to 32%; the pooled ORs for developing pibs 6 months post-diarrhea were 5.2 (95% CI ) 15 and 7.3 (95% CI ), 16 respectively. TD is a very common infection usually self-limited among those visiting resource-limited destinations International Society of Travel Medicine, Journal of Travel Medicine 2011; Volume 18 (Issue 4):

2 IBS Among Travelers 251 Considering 80 million persons travel to high risk destinations and a mean 2-week incidence rate of TD of 25%, 17 some 20 million people would be affected per year. Previous studies of travelers reported IBS incidence rates between 4 and 14%, but those were limited by a sample size of less than 500, a low response rate, and/or by limited control for confounding factors. They were unable to generate data on age groups and travel destinations. Therefore, we aimed to establish incidence rates of IBS among a larger cohort of mainly European residents traveling to various resource-limited countries and to identify risk groups among those generally healthy travelers. The Ethical Commission of the Canton of Zurich, Switzerland, approved the study. Methods We designed a prospective questionnaire-based cohort study with a follow-up at 6 months post-travel. To achieve a precision of +/ 2% with a 4% pibs incidence rate and a confidence of 1 α = 95%, a sample size of n = 369 was needed. On the basis of an estimated TD incidence rate of 20% to 40% and, at the same time, assuming withdrawal rates of 30% to 50% an oversampling by a factor of 4 to 10 (at maximum) had to be applied. That resulted in at least 1,600 study subjects to be included. Participants Adults seeking pre-travel medical health advice at the Centre for Travel Health at the University of Zurich between July 2006 and January 2008 were invited to participate in the study voluntarily. Upon having signed a written informed consent the following inclusion criteria were verified: The subjects had to be German-speaking Swiss residents, had to stay in a resource-limited destination with a high risk of TD 21 between 1 and 8 weeks, but in total no longer than 12 weeks abroad when the 6 months following the index travel were included. Pregnant women, those who planned to use antibiotics for prophylaxis abroad, including doxycycline to prevent malaria, and those with severe chronic illness [anemia, cancer, human immunodeficiency virus (HIV), other diseases related to immunosuppression or immunosuppressive medication] were excluded. Additionally, persons with a history of previous gastrointestinal surgery, functional gastrointestinal disorders (FGID), organic gastrointestinal disorders, unresolved diarrhea, or diarrhea lasting over 14 days within the 4-month pre-travel period, and lastly, those with undiagnosed IBS fulfilling Rome III criteria prior to travel were also excluded. Following the recruitment all subjects received standard pretravel health advice including information on basic preventive measures and on treatment options against diarrhea. Definitions IBS assessment was performed according to the Rome III criteria 2 ; if IBS was associated with TD on the index trip it was defined as pibs, 22 while other new IBS cases were labeled unselected IBS. 23 TD and pre-travel diarrhea were defined as three or more unformed stools within 24 hours with or without accompanying symptoms. 24 A new TD episode had to be separated by a symptom-free interval of at least 72 hours. Continents and subcontinents were grouped according to the United Nations World Migrant Stock. 25 The country of origin was the one in which the subject spent the first 5 years of life. Newcomers were visiting any resource-limited travel region for the first time. The main categories of the International Classification of Diseases (ICD ) were used for co-medication and concomitant diseases. Allergies, including allergic asthma, allergic rhinitis, atopic dermatitis, and hymenoptera allergy, formed a separate disease entity. These were self-reported by the study subjects, but a diagnosis by a medical doctor was requested. Occurrence of major adverse life events 14 included death or a major illness of a close family member or friend, loss of job or business failure, marital separation or divorce, major personal illness, or injury experienced in the 12 months pre-travel. Study Procedure Three questionnaires were distributed: Pre-travel Q1 consisting of 30 items was collected at enrollment and aimed at determining travel characteristics (duration of stay, destination, purpose, newcomer), medical and socio-demographic predictors [including gender, age, education, comorbidity and medication, level of stress (four-scale rating), major adverse life events, height and body weight, allergies, and country of origin]. Data on pre-travel diarrhea, self-perceived susceptibility to TD, and family history of IBS were also collected. Questions regarding alcohol consumption and smoking were categorized according to the Swiss Health Surveys of the Swiss Federal Statistical Office. 26 Q2 had to be kept as a diary abroad and to be completed immediately after return. It verified travel characteristics and investigated details of TD. 17 Three months after the initiation of the study, additional questions on other health impairments abroad and on preventive practices to avoid TD (catering, adherence to the adage cook it, boil it, peel it or forget it, tap water consumption, self-perceived susceptibility towards diarrhea in general) wereaddedtoq2.q3consistedof15itemsandwassent to subjects either electronically or by postal mail at study end point, 6 months after they returned from index travel. These items evaluated IBS criteria, diarrhea, and other gastrointestinal symptoms within the past 6 months, as well as any gastrointestinal drugs used and additional travel to resource-limited destinations. Nonresponders were contacted twice by and twice by postal mail or telephone and invited to respond to Q2 and Q3. Q2-nonresponders were

3 252 Pitzurra et al. invited to report at least whether they had experienced diarrhea abroad. Missing Q3s were evaluated with respect to their diarrhea rates assessed in Q1 and Q2. Stool samples were not evaluated. Patients with IBS and those with similar symptoms were offered a free consultation at the Gastroenterology Outpatient Clinic at the Zurich University Hospital. On the basis of a separate protocol a detailed personal and family history were taken and physical examination was performed. All patients were recommended to have additional examinations to be paid by their insurance: hematology, serology (among others including assessment for thyroid disoders, HIV, IgA, sprue), a lactose breath test, sonography, colonoscopy with tissue biopsies. A single stool sample was examined for bacteriology, including Clostridium difficile toxin and culture and also pancreatic elastase; three samples were checked for leukocytes and parasites. Statistics Stata version 10.1 was used for descriptive, univariate, and multivariate analyses. Differences between groups on categorical variables were tested by Fisher s exact or chi-square test. Differences between groups on continuous variables were tested by the Wilcoxon rank sum test for independent samples with the α significance level set at The 2-week incidence rate and 95% confidence intervals (95% CI) were calculated based on Newcombe and Altman. 27 A multiple logistic regression model with IBS as outcome was used to establish predictors of IBS. Initially, all variables were included. ORs were determined by stepwise backward elimination of variables with p > For each half of the study subjects, we evaluated independent risk factors of developing IBS to analyze sensitivity. Also, we used an alternative time-schedule, assessing IBS for a 3-month period additionally to the follow-up of 6 months post-travel. Results Study Population A total of 3,420 subjects were recruited and 2,476 responded to all three questionnaires, thus the participation rate was 72.4%. Those who had to be excluded reported mostly preexisting FGID or undiagnosed IBS (Q1), or they had changed their travel plans (Q2) (Figure 1). Questionnaires Q2 and Q3 were returned within a median of 10 days after the first reminder. Gender was homogeneously distributed among the study population and the median age was 36 years (Table 1). The majority, 2,320 (95.0%) subjects originated from Europe, while 65 (2.7%), including 11 visiting friends or relatives (VFR), were from a resource-limited country. The educational level was high with 1,244 (51.3%) being university graduates. Popular tourist destinations were Southeast Asia, South Asia, and East Africa and the median duration of stay was 3 weeks (range 1 12). Overall, 181 (7.4%) subjects were newcomers who traveled to any resource-limited Figure 1 Patient recruitment flow chart.

4 IBS Among Travelers 253 Table 1 Selected socio-demographic, travel and health-related data of all travelers and of those with new onset of IBS (IBS+) Variable All n = 2,476 n (%) IBS+ n = 38 n (%) p Female gender 1,258 (50.8) 18 (47.4) Age, median (range), years 36 (18 82) 30 (19 70) Destination (continent) Africa 808 (32.6) 14 (36.8) Asia 1,105 (44.6) 18 (47.4) Latin America 557 (22.5) 6 (15.8) Duration of trip, median (range), weeks 3 (1 12) 3 (1-8) Purpose of travel Tourism 2,092 (84.5) 30 (78.9) Visiting friends and relatives 130 (5.3) 1 (2.6) Business 163 (6.6) 5 (13.2) TD 852 (34.4) 26 (68.4) < TD episodes 226 (9.2) 12 (31.6) Severe TD symptoms: Dysentery 146 (5.9) 8 (21.0) < Vomiting and cramps 66 (2.7) 2 (5.3) TD duration, median (range), days 2 (1 90) 3 (1 20) Allergies, self-reported but diagnosed by MD 550 (22.2) 11 (28.9) Hay fever 378 (15.3) 9 (23.7) Allergic asthma 92 (3.7) 4 (10.5) Diarrhea 4-mo pre-travel, resolved predeparture 305 (12.3) 12 (31.6) < Duration of diarrhea pre-travel, median (range), days 2 (1 10) 2 (1 5) Adverse life event 12-mo pre-travel 230 (9.4) 9 (23.7) Close family member with IBS 58 (7.5) 2 (11.1) IBS = irritable bowel syndrome; MD = medical doctors; TD = travelers diarrhea. Chi-square or Wilcoxon rank sum test, respectively. destination for the first time. Business travelers were predominantly male (p = ). Age did not correlate with the type of travel. Among the 550 (22.2%) subjects reporting confirmed allergies, hay fever (378, 69.0%) and allergic asthma (92, 16.9%) were reported most frequently. A total of 852 (34.4%) subjects suffered from TD abroad, but of those, only 33 (3.9%) belonged to the 921 subjects (921/1,470, 62.7%) who rated themselves as being intermediately to highly susceptible to diarrhea. The TD incidence rate was not influenced by gender, but it occurred significantly more often in subjects below 25 years of age (p = ). Females reported more pre-travel major adverse life events (p = 0.008). Among the 313 Q2 and Q3 nonresponders, all of whom had available diarrhea data, 18.4% (95% CI ) had experienced TD and 14.5% (95% CI ) pre-travel diarrhea. IBS Incidence Rates and Risk Factors According to Q3 data, 38 (1.5% of the study population) developed IBS, 26 (3.0% of the TD patients) of them were travel-related pibs (Table 2). Considering the unselected IBS incidence rate of 0.7% attributable risk difference in TD incidence was 2.3%. The overall IBS incidence rate for a 2-week stay was 1.0% (95% CI ), and for the subgroup of travelrelated pibs 2.8% (95% CI ). In the multiple logistic regression analysis, TD was the strongest independent risk factor for developing IBS, and also Table 2 Incidence rates of irritable bowel syndrome (N = 2,476) Six-months incidence rate (%) 95% CI IBS overall 1.5 (38/2476) Postinfectious IBS (TD+) 3.0 (26/852) Unselected IBS (no TD) 0.7 (12/1624) Travel-duration-related 6-mo incidence for a 2-wk stay (%) 95% CI IBS overall Postinfectious IBS (TD+) Unselected IBS (no TD) IBS = irritable bowel syndrome; TD = travelers diarrhea. having experienced an adverse life event and a pre-travel diarrheal episode were relevant risk factors (Table 3). Compared with other diarrheal patients, IBS patients reported more frequently multiple TD episodes abroad as well as a more severe TD course, eg, dysenteric symptoms, than other diarrheal patients. Subjective susceptibility to diarrhea was higher among IBS patients (data not shown, p 0.02). For unselected IBS, pretravel diarrhea was the only significant risk factor in the multiple logistic regression analysis (OR 3.80; 95% CI ). Any diarrheal episode increased the risk of developing IBS more than fivefold (pre-travel diarrhea or TD: OR 5.60; 95% CI ) with insignificant differences when comparing pre-travel diarrhea and TD. Experiencing multiple diarrheal attacks raised

5 254 Pitzurra et al. Table 3 Variable Risk estimates for developing IBS 6 months post-travel Univariate Odds ratio (95% CI) N = 2,476 Odds ratio (95% CI) N = 2,424 Multiple logistic regression analysis Odds ratio (95% CI) Final model, N = 2,424 Female gender 0.87 ( ) 1.05 ( ) 0.81 ( ) Age (years) 0.97 ( ) 0.97 ( ) 0.97 ( ) Newcomer, 2.39 ( ) Travel duration (weeks) 1.17 ( ) 1.13 ( ) Travel destination Africa versus Asia 1.06 ( ) Latin America versus Asia 1.52 ( ) Travel purpose (vs tourism) Visiting friends and relatives 0.53 ( ) 0.58 ( ) Business 2.18 ( ) Smoking versus no smoking 1.71 ( ) 1.68 ( ) Allergic asthma versus all other groups 3.18 ( ) 0.90 ( ) Adverse life event 3.08 ( ) 2.59 ( ) 2.58 ( ) High stress-level pre-travel 1.00 ( ) 0.73 ( ) Diarrhea pre-travel 3.38 ( ) 2.47 ( ) 2.50 ( ) Travelers diarrhea (TD) 4.23 ( ) 2.27 ( ) 3.61 ( ) 2 TD episodes 2.88 ( ) Dysentery 4.44 ( ) Duration of TD (days) 1.02 ( ) Antibiotic intake on travel 2.65 ( ) 0.84 ( ) Malaria chemoprophylaxis 0.91 ( ) 1.49 ( ) TD-risk practices abroad 1.96 ( ) 1.71 ( ) IBS = irritable bowel syndrome; TD = travelers diarrhea. Age substituted by newcomer in multiple logistic regression analysis, as newcomer is dependent from age (p < 0.001). First visit to resource-limited countries. Experienced within 12-mo pre-travel. Episode within 4-mo pre-travel and resolved pre-travel. Subjects taking antibiotic prophylaxis were excluded. Self-reported non-adherence to the adage cook it, boil it, peel it or forget it or consuming tap water abroad. the IBS risk sixfold (OR 6.01; 95% CI ) when controlled for gender, age, and an adverse life event. Concordant within all the above analyses, the risk for IBS while having experienced an adverse life event within the past 12 months was about threefold increased. For the sensitivity analysis, the results of the multiple logistic regression conducted on the total study population were compared with the results conducted on each half and the same independent risk factors were found. For a 3-month post-travel follow-up a lower overall 3-month IBS incidence rate (0.9%; 95% CI ; n = 22) was detected and the corresponding overall travel-duration-related IBS incidence for any 2-week stay was 0.6% (95% CI ). IBS Classification and Health Care Utilization The majority of IBS patients were classified as mixed IBS-M (also the majority with TD on index travel, two cases of IBS-D group with TD on index travel) (31, 81.6%), four patients (10.5%) as diarrhea-predominant IBS-D, and three (7.9%) as constipation-predominant IBS-C. Seventeen (44%) patients sought medical care, 10 of them selected a physician of their choice and the remaining 7 visited the Gastroenterology Outpatient Clinic at the University Hospital. Three of these seven patients were diagnosed with IBS, one patient was diagnosed with lactose intolerance, Blastocystis hominis was found in one patient. One patient experienced prolonged TD and one did not show up. Two of the three patients who obtained a gastroenterologist s diagnosis had IBS, while one was infested by Ascaris lumbricoides. Discussion This is the first large prospective cohort study that used the Rome III criteria to evaluate IBS among travelers to resource-limited destinations on various continents. Our data are comparable to the publications which used Rome II criteria, as in these the followup period was limited to 6 months, as in Rome III, which uses exactly the same questions. New onset of IBS assessed 6 months post-travel has occurred overall in 1.5% of subjects while 3.0% had TD-related pibs. Our IBS incidence rates are in the same range as the ones found in general population of 0.2% to 7% per year, but below the pibs rates of 4% to 36% 15,16 or 4% to 14% reported for TD-related pibs The TD attributable risk difference of 2.3% is similar to

6 IBS Among Travelers 255 the 2.6% reported in the smaller initial Ilnickyj study. 20 Our lower IBS rates among travelers may be explained by separating pre- from in-travel diarrheal episodes and by the more stringent exclusion criteria, having for instance detected 189 cases with preexisting (un)- diagnosed organic or FGID (Rome III) at recruitment. In addition, the destinations and the study populations differed, eg, we included also senior citizens and not just students. 19 The duration of TD illness in these younger populations was longer as compared with our patients, which also may have contributed to a lower IBS rate in our study. Lastly, genetic factors may play a role. Such were also considered when a higher TD incidence rate among British travelers was found. 21 Three kinds of selection bias might limit our study: Travelers consulting for pre-travel health advice might have been either somewhat hypochondriac or represent a subpopulation with special health literacy skills, as 51.3% of our customers reported a university degree. The latter would result in an underestimation of the IBS risk when compared to travelers with a different educational background, whereas for the former higher TD rates as well as a higher rate of IBS would be expected. Actually, we found a higher TD incidence rate when compared with the nonresponders TD rate, which might indicate an overestimation of our IBS incidence rate. Third, although attracting millions of visitors, some popular tourist destinations, such as Turkey, North Africa, and the Caribbean were underrepresented as travelers to those countries rarely consult for pre-travel health advice. 28 Diarrhea is a risk factor for IBS whether it occurred at home or abroad. Evidence shows that an infectious agent may trigger new onset of IBS and of other long-term sequelae, such as, eg, reactive arthritis. 29,30 Thereby, the severity and duration of IBS illness are important risk factors 23 ; however, it remains unknown whether the type of the pathogen, the inoculum, and the time interval between diarrheal attacks play a role. 31 Notably, it appears that multiple diarrheal episodes would raise the IBS risk. This might support the hypothesis of IBS being associated with increased epithelial barrier permeability and/or altered gut flora. 4 The results of the sensitivity analyses validate our risk estimates. For a more detailed subgroup analysis a different study design would be more appropriate. Such data would be needed to assess factors and syndromes associated with other low-grade inflammatory and immunological processes, such as, eg, atopy 32 or antibiotic treatment 14 which were supposed to be associated with IBS. The reported threefold increased IBS risk following the experience of a recent adverse life event corresponds to the relative risk of 2.0 found previously for IBS. 33 Contrary to some reports, female gender and smoking were not found to be significant independent risk factors for IBS. IBS patients are often reluctant to request thorough medical evaluation. Accordingly, most of our IBS patients managed their symptoms themselves. The consulting physicians rated the severity of IBS as mild. At the beginning of the symptoms the Rome III-based case definition seemed to be prone to misclassification. In about one third of our IBS cases, who had visited a physician, the medical doctors diagnosis did not confirm the IBS assessment to full extent because another diagnosis was found. This indicates that even our low rates tend to be an overestimate of clinically diagnosed IBS. Nevertheless, post-td IBS remains an issue because it represents a long-term travel sequelae in a previous healthy population. Of note, the TDassociated IBS incidence is twice the incidence rate of self-limited influenza in a comparable population of travelers. Further investigations need to focus on the pathophysiological interaction of IBS predisposing factors. Research is also needed to optimize TD self-treatment and to determine whether extensive preventive measures, eg, by drug prophylaxis, would reduce the risk of IBS among travelers. If so, those with predisposing factors could in the pre-travel consultation discuss available options to reduce the risk for IBS. Acknowledgment The study was self-funded by the Division of Communicable Diseases of the Institute of Social and Preventive Medicine at the University of Zurich, Switzerland. Declaration of Interests R. S. has obtained research sponsorships (which could indirectly be related) from Dr Falk Pharma, Intercell, Optimer, Santarus. Additionally he was sponsered as a speaker by Salix. The other authors state that they have no conflicts of interest to declare. References 1. Mayer EA. Clinical practice. Irritable bowel syndrome. N Engl J Med 2008; 358: Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006; 130: Ohman L, Simren M. Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions. Nat Rev Gastroenterol Hepatol 2010; 7: Farthing MJ. Functional diarrhea. Curr Gastroenterol Rep 2005; 7: Saito YA, Petersen GM, Locke GR 3rd, Talley NJ. The genetics of irritable bowel syndrome. 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