Persistent Abdominal Symptoms in US Adults After Short-Term Stay in Mexico

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1 I S T M 153 ORIGINAL ARTICLE Persistent Abdominal Symptoms in US Adults After Short-Term Stay in Mexico Parvathy Nair, MD, PhD, Pablo C. Okhuysen, MD, Zhi-Dong Jiang, MD, DrPH, Lily G. Carlin, BS, Jaime Belkind-Gerson, MD, Jose Flores, MD, Mercedes Paredes, MD, and Herbert L. DuPont, MD Division of Epidemiology, Human Genetics and Environmental Sciences, Center for Infectious Disease, The University of Texas School of Public Health, Houston, TX, USA; Division of Infectious Diseases, The University of Texas Medical School at Houston, Houston, TX, USA; Section of Infectious Diseases, Baylor College of Medicine, Houston, TX, USA; Departmento de Enfermedades Cronicas, Instituto Nacional de Salud Publica, Cuernavaca, Mexico; Division of Gastroenterology, Hepatology and Nutrition, Massachusetts General Hospital for Children, Boston, MA, USA; Internal Medicine Service, St. Luke s Medical Center, Houston, TX, USA DOI: /jtm See the Editorial by Bradley A. Connor and Mark S. Riddle, pp of this issue. Background. Postinfectious irritable bowel syndrome (PI-IBS) has been reported as a complication of bacterial diarrhea including travelers diarrhea (TD). This study assessed the role of TD among US students in Mexico in triggering the onset of persistent abdominal symptoms (PAS) and IBS. Methods. We conducted a 6-month of a cohort of 817 US students in Mexico as short-term study to assess the frequency of PAS and IBS. Using Rome II criteria for IBS, groups of students with PAS were then categorized as PI-IBS if they met the symptom criteria for IBS or as suffering from functional abdominal disorder (FAD) if they did not meet the criteria. Results. FAD and IBS were commonly found in US students 6 months after leaving Mexico. Important variables in their development were younger adult age, longer stays in Mexico and occurrence of acute diarrhea while in Mexico. Diarrhea while in Mexico occurred more commonly for those later diagnosed with FAD, 101/196 (52%), relative risk (RR) = 1.5 [confidence interval (CI) ; p = 0.001]; IBS, 20/32 (63%), RR = 2.5 (CI ; p = 0.007); and PAS (FAD + IBS), 121/228 (53%), RR = 1.5 (CI ; p < 0.001) compared with subjects who had experienced diarrhea while in Mexico but were not diagnosed with 6 months, 227/589 (39%). Diarrhea caused by heat-labile enterotoxin-producing enterotoxigenic Escherichia coli or Providencia ssp. demonstrated a greater risk of developing PAS. Conclusions. PAS occurred commonly in a subset of younger adult travelers who stayed longer in Mexico and experienced acute diarrhea while there. Further studies with this cohort will focus on host genetic associations with the development of PAS. Irritable bowel syndrome (IBS) encompasses a wide spectrum of gastrointestinal disorders that affect 12% to 20% of the population worldwide. 1,2 In a subgroup of patients with IBS, a bout of acute diarrhea or gastroenteritis can be identified as an inciting event that results in the onset of IBS. This condition is known as postinfectious IBS (PI-IBS) and has distinctive clinical features. 3 The relative risk (RR) of acquiring PI-IBS after acute bacterial enteric infection has been reported to occur in 4 to 31% of cases. 4 Multiple studies have provided Corresponding Author: Herbert L. DuPont, MD, 1200 Herman Pressler, Suite 733, Houston, TX 77030, USA. Herbert.l.Dupont@uth.tmc.edu evidence that travelers diarrhea (TD), usually caused by one of a variety of bacterial enteropathogens, is also a risk factor for the acquisition of PI-IBS. 5,6 International travel during the previous 6 months before onset of the diagnosis of IBS was explored in a general medical population. The study found that 16% of patients with PI-IBS and 8% of overall patients with IBS in a general medicine clinic had a history of international travel 6 months before onset of their chronic intestinal disorder. 5 We conducted a 6-month study in a cohort of 817 US students traveling to Mexico with selfdescribed good health to analyze the association of TD with development of persistent abdominal symptoms (PAS) including IBS and to define the variables that predicted their occurrence International Society of Travel Medicine, Journal of Travel Medicine 2014; Volume 21 (Issue 3):

2 154 Nair et al. Materials and Methods Participants were US students who traveled to the Mexican cities of Cuernavaca and Guadalajara for shortterm (2 5 weeks) studies between June 2002 and January The subjects were consenting adults aged 18 years or older and adolescents 16 years who participated with parental consent. They were enrolled within 72 hours of arrival in Mexico and were required to stay for at least 5 days in the country to be included in the study. The exclusion criteria were history of unstable medical illness, preexisting self-identified persisting gastrointestinal symptoms, pregnancy, use of antibiotics in the past week, and lactose intolerance. The cohort was observed for the occurrence, duration, and severity of acute diarrhea during their stay in Mexico. Participants who had soft (would take the shape of a container) or watery (could be poured) stools with a frequency of three or more times in a 24-hour period were instructed to report to the clinic for stool collection and identification of enteropathogens. Stool specimens were processed for enteric pathogens by methods previously published. 6 Enterotoxigenic Escherichia coli (ETEC) was identified by colony hybridization 7 and enteroaggregative E. coli was detected by HEp2 cell adherence assay. 8 Identification of E. coli subtypes (enterotoxigenic E. coli, enteropathogenic E. coli, enteroaggregative E. coli, and enterohemorrhagic E. coli) was also conducted by polymerase chain reaction. Stool samples were examined for the presence of Cryptosporidium, Giardia, and Entamoeba by commercially available microplate ELISA Kits (Remel ProSpecT, Lenexa, KS, USA). Presence of Salmonella and Providencia ssp. was diagnosed by culture. A questionnaire based on the Rome II criterion for the diagnosis of chronic gastrointestinal symptoms was administered to the participants on enrollment and 6 months after the return to the United States. Subjects were diagnosed with PAS on the basis of their responses to the questionnaire. PAS cases were categorized as functional abdominal disease (FAD) or IBS based on frequency and severity of symptom reporting (see definitions below). This study was approved by the University of Texas Health Science Center Committee for the Protection of Human Subjects (Houston, TX, USA). Definitions PAS was defined as the presence of abdominal pain and discomfort with no obvious cause by history, with onset within the last 6 months. The symptoms reported were required to be present at least 20% of the time during the 3 months preceding the completion of the questionnaire. PAS was subclassified into IBS or FAD. IBS was defined as recurrent abdominal pain or discomfort associated with the following: (1) improvement of pain or discomfort with defecation; (2) onset associated with a change in frequency of stool; and (3) onset associated with a change in form (appearance) of stool. FAD encompassed the presence of chronic gastrointestinal symptoms that did not otherwise meet the criteria for IBS. These included diarrhea, constipation, straining while passing hard and difficultto-pass stools, bloating, distension of the abdomen or tightening of clothes after meals, passing mucus in stools, tenesmus, urgency, or a change in bowel habits. Acute TD was defined as the passage of 3 unformed stools within a 24-hour period plus one or more signs or symptoms of enteric infection (abdominal pain, cramping, excessive gas, nausea, vomiting, fever, urgency, bloody or mucous stool, or tenesmus). 9 Participants taking antidiarrheal prophylaxis, dropouts, and nonrespondents to the questionnaire were excluded from the analysis. We used STATA SE version 9 (Stata Corp., College Station, TX, USA) to perform the statistical analysis. The chi-square test of association and Fisher s exact test were used to determine statistically significant association of the sociodemographic factors, and the clinical and microbiology data with the study outcomes of PAS, FAD, and IBS. The s reported were for two-sided tests. The t-test was used to compare the means of continuous variables. RR was calculated wherever applicable. Results Between 2002 and 2008, we obtained clinical histories from a total of 817 US adults studying in Mexico for 2 to 5 weeks and again 6 months after leaving Mexico. The sociodemographic characteristics of the study group are presented in Table 1. The population represented young adults, with a preponderance of women, Table 1 Epidemiologic characteristics of the study population Characteristic, N = 817 Gender Male 227 (28) Female 590 (72) Race Caucasians 800 (98) African Americans 12 (1.5) Asians 2 (0.2) Others 3 (0.3) Ethnicity Hispanics 88 (11) Non-Hispanics 729 (89) Season of travel September to February 110 (13) March to August 797 (87) Site enrolled Guadalajara 268 (33) Cuernavaca 549 (67) Other comparisons Age (years), mean (SD) 32.0 ± 14.4 Length of stay (days), mean (SD) 23.3 ± 10.7

3 Chronic Abdominal Symptoms After Travel 155 Table 2 Symptoms Chronic abdominal symptoms among US residents present 6 months after leaving Mexico Healthy at (n = 589) (n = 196) Healthy versus (n = 32) Healthy versus IBS at (FAD + IBS) (n = 228) Healthy versus Abdominal pain 144 (24) 115 (60) < (100) < (66) <0.001 Change in bowel habits 99 (17) 79 (41) < (100) < (50) <0.001 Loose stools 148 (25) 134 (70) < (100) < (74) <0.001 Straining 99 (17) 70 (37) < (58) < (40) <0.001 Urgency 105 (18) 93 (49) < (81) < (53) <0.001 Tenesmus 115 (19) 93 (49) < (74) < (52) <0.001 Mucus in stools 95 (16) 48 (25) (55) < (29) 0.01 Bloating after eating 109 (18) 119 (62) < (55) < (66) <0.001 Loosen clothes after eating 90 (15) 60 (31) < (52) < (34) <0.001 FAD= functional abdominal disease; IBS = irritable bowel syndrome; PAS = persistent abdominal symptoms. Table 3 Distribution of selected characteristics among the North American travelers to Mexico, Variable Healthy at (n = 589) (n = 196) FAD versus RR (CI), p (n = 32) IBS versus RR (CI), p (FAD + IBS) (n = 228) PAS versus healthy RR (CI), p Male (n = 227) 170 (29) 49 (25) Ref 8 (25) Ref 57 (25) Ref Female (n = 590) 419 (71) 147 (75) 1.2 ( ), (75) 1.2 ( ), (75) 1.2 ( ), 0.3 Hispanics (n = 88) 66 (11) 21 (11) Ref 1 (3) Ref 22 (10) Ref Non-Hispanics (n = 729) 523 (89) 175 (89) 1.0 ( ), (97) 3.8 ( ), (90) 1.1 ( ), 0.6 Age (years) mean (SD) 33 ± ± 0.8 < ± ± 0.8 <0.001 Age (years) < (66) 126 (30) Ref 18 (4) Ref 144 (34) Ref (75) 43 (22) 0.6 ( ), (4) 0.8 ( ), (25) 0.7 ( ), (84) 27 (14) 0.4 ( ), < (4) 0.6 ( ), (17) 0.4 ( ), <0.001 Length of stay (days), mean (SD) 23 ± ± ± ± Season of travel September to February (n = 110) 81 (14) 26 (13) Ref 3 (9) Ref 29 (13) Ref March to August (n = 707) 508 (86) 170 (87) 1.0 ( ), (91) 1.5 ( ), (87) 1.1 ( ), 0.7 FAD= functional abdominal disease; IBS = irritable bowel syndrome; PAS = persistent abdominal symptoms. spending an average of just over 3 weeks in Mexico, most often during the spring and summer seasons. In Table 2 the presence (or absence) of chronic abdominal complaints are recorded for those found to be suffering (or not) from defined gastrointestinal syndromes 6 months after leaving Mexico. Subjects meeting the criteria for PAS (either FAD or IBS) more frequently complained of gastrointestinal symptoms compared with subjects not fitting the diagnosis of PAS. The overall incidence of PI-IBS in subjects at 6-month was 4%. The incidence of PI-IBS without TD while in Mexico was 3.2% compared with 5.7% in subjects who had TD while in Mexico. Thus, 3% of individuals developed PI-IBS as a result of TD. Men and women experienced PAS and IBS with approximately equal frequency. Hispanics and non- Hispanics were equally affected (Table 3). The timing of travel (spring and summer vs fall and winter) did not influence the occurrence of persistent abdominal complaints. Two variables correlating with increasing rates of persistent symptoms were younger age (for FAD or IBS) and longer length of stay in Mexico (for FAD) as shown in Table 3. When compared with the reference age strata of travelers aged 16 to 24 years, travelers in the 25 to 44 years had a RR reduction of 20% in PAS. This RR reduction was decreased to 40% for participants in the 45 years of age group. Diarrhea more commonly occurred while in Mexico for those later diagnosed with FAD, 101/196 (52%), RR = 1.5 [confidence interval (CI) ; p = 0.001]; IBS, 20/32 (63%), RR = 2.5 (CI ; p = 0.007); and PAS, 121/228 (53%), RR = 1.5 (CI ; p < 0.001), compared with those who were healthy when later surveyed, where diarrhea was reported to have occurred in Mexico in 227/589 (39%) (see Table 4). The number of unformed stools passed per day while in Mexico was increased for subjects found later to have FAD (p = 0.008) and PAS (FAD plus IBS subjects combined) (p = 0.004). The number of watery stools passed per day while in Mexico was not related to PAS. Development of diarrhea in Mexico and the

4 156 Nair et al. Table 4 Association of diarrhea in Mexico with persistent abdominal symptoms among US travelers 6 months after return Characteristics of travelers diarrhea Healthy at (n = 589), (n = 196), FAD versus healthy RR (95% CI), (n = 32), IBS versus healthy RR (95% CI), (FAD + IBS) (n = 228), PAS versus healthy RR (95% CI), Diarrhea status in Mexico Travelers diarrhea No (n = 469) 362 (61) 95 (48) 12 (38) 107 (47) Yes (n = 348) 227 (39) 101 (52) 1.5 ( ), (63) 2.5 ( ), (53) 1.5 ( ), <0.001 Unformed stools per day 0.36 ± ± ± ± of stay in Mexico Adjusted watery stools per day of stay in Mexico 0.14 ± ± ± ± FAD = functional abdominal disease; IBS = irritable bowel syndrome; PAS = persistent abdominal symptoms. Table 5 Enteric pathogens associated with the development of PAS Enteric pathogen identified Healthy at,, FAD versus, IBS versus (FAD + IBS), PAS versus Enteroaggregative Escherichia coli (EAEC) 64/171 (37) 24/68 (35) 0.8 3/10 (30) /78 (35) 0.8 Enterotoxigenic E. coli (ETEC) 57/169 (34) 28/64 (44) 0.2 2/10 (20) /74 (41) 0.3 ETEC-LT 18/169 (11) 13/64 (20) /10 (20) /74 (20) 0.06 ETEC-ST 13/169 (8) 9/64 (14) 0.1 0/10 (0) NA 9/74 (12) 0.2 ETEC-ST/LT 26/169 (15) 6/64 (9) 0.5 0/10 (0) NA 6/74 (8) 0.2 Enteropathogenic E. coli (EPEC) 32/88 (36) 13/37 (35) 1.0 3/6 (50) /43 (37) 1.0 Enterohemorrhagic E. coli (EHEC) 14/88 (16) 5/37 (14) 1.0 1/6 (17) 1.0 6/43 (14) 1.0 Salmonella ssp. 3/143 (2) 3/70 (4) /11 (10) /81 (5) 0.21 Providencia ssp. 0/131 (0) 3/62 (5) /8 (0) NA 3/70 (4) 0.04 Cryptosporidium spp. 6/146 (4) 6/65 (9) 0.2 1/10 (10) 0.4 7/75 (9) 0.1 FAD = functional abdominal disease; IBS = irritable bowel syndrome; PAS = persistent abdominal symptoms; LT = heat-labile enterotoxin positive; ST = heat-stable enterotoxin positive; ST/LT = both ST and LT positive. occurrence of multiple bouts of illness were greater in subjects later diagnosed with FAD (RR; 95% CI: 2.3; ; p < 0.001) and PAS (RR; 95% CI: 2.2; ; p <0.001) (data not shown in tables). As shown in Table 5, statistically significant associations were found between diarrhea due to heatlabile enterotoxin (LT)-producing ETEC (p = 0.05) and Providencia ssp. (p = 0.03). An association of development of PAS was not seen for TD due to other defined pathogens. Shigella spp. and Campylobacter spp. were not identified in subjects with TD acquired in Mexico. Discussion Based on a questionnaire completed 6 months after leaving Mexico, chronic abdominal complaints were commonly found in a large group of young adults traveling to Mexico from the United States. An earlier evaluation of a similar cohort of students reported an 18% frequency of persistent diarrhea 6 months after leaving Mexico, which is consistent with the present findings. 10 In this study, we found a 4% incidence of PI- 6-month of previously healthy travelers who did not report abdominal complaints at study enrollment. As reported in other studies, diarrhea-predominant disease was the most frequently observed subtype of PI-IBS that followed enteric infection. 3,11 In this study, TD was a significant risk factor for the development of PAS including PI-IBS. The risk of developing FAD and IBS among subjects who reported TD while at Mexico was 1.5 to 2.5 times greater compared with subjects who were healthy during their earlier travel. A literature review of studies on PI-IBS identified a sevenfold increase in the risk of acquiring IBS after a bout of acute infectious diarrhea. 12 A 1-year of children following water contamination by E. coli 0157:H7 and Campylobacter species revealed a 10.5% incidence of PI-IBS among those exposed compared with 2.5% among controls. 35 An 8-year of adults in the same study found that 15.4% of those who had acute gastroenteritis in the epidemic continued to report symptoms consistent with IBS. 36

5 Chronic Abdominal Symptoms After Travel 157 Other studies have noted an increased risk of PI-IBS development for younger age groups, females, subjects with preexistent anxiety and depression, 3,13 a longer duration of enteric symptoms with the inciting infection, 14 Campylobacter enteritis, 15 salmonellosis, 16 and shigellosis. 17,18 We hypothesize that infections of the gut by invasive bacterial enteric pathogens produce intestinal inflammation that appears to be an important event predisposing to PAS Small bowel motility changes can trigger the overgrowth of abnormal bacterial flora causing small intestinal bacterial overgrowth, which is found in idiopathic forms of IBS Other findings in subjects with IBS include mast cell activation and release of mast cell intermediaries that have physiologic effects in the gut 21,26,27 and alteration of serotonin metabolism with release of 5-hydroxytryptamine. 28,29 No significant difference in gender distribution was noted among IBS and FAD subsets in our population, a possible reason being the exclusion of subjects with chronic abdominal symptoms at baseline and the strong association of PAS with infectious diarrhea, which affects men and women equally. The risk of developing PAS was higher among younger subjects that may be attributed to the age-related lifestyle factors 30,31 such as a more adventurous dietary intake or a higher volume of potentially contaminated food being consumed. Another possible explanation for decreasing PAS incidence with age is that the large bowel lymphocyte and mast cell numbers decrease with age, which reduces the inflammatory response 32 or preexisting immunity to enteropathogens. The isolation rates of Salmonella ssp., Shigella spp., and Campylobacter spp. were either low or absent. We found a significant association of LT-producing ETEC and Providencia ssp. with FAD. A nonsignificant trend toward higher frequency of Salmonella infection among PAS cases compared with healthy subjects was observed. On the basis of this study and a previous one by our group carried out in Mexico, where the predominant cause of TD is ETEC, 10 we believe that ETEC should be considered as a cause of PI-IBS. Although the Rome II criteria are acceptable for epidemiologic studies of IBS, this study has several limitations. First, a rigorous assessment for gastrointestinal disease and enteric pathogens was not done at baseline. The assessment for PI-IBS was done by a mailed questionnaire and subjects were not evaluated in person by a study physician or for the presence of enteropathogens at 6-month followup. Other limitations are that the questionnaire did not seek for symptoms that were atypical of IBS (ie, pain interfering with sleep, bloody stools, weight loss, fever, and nocturnal diarrhea) that could be red flags suggestive of other pathology. Also, we did not inquire for the presence of chronic upper gastrointestinal symptoms. By doing so, we could have explored the possibility of the postinfectious onset of gastroesophageal reflux disease following norovirus infection as has been suggested by others. 2 In conclusion, we found that acute TD was a risk factor for the development of FAD and IBS. Further studies should be targeted at unraveling the interactions between host, environment, and pathogens, as well as to identify prognostic factors in a larger population base to facilitate a better understanding of the natural history of PAS among travelers. Studies are needed to determine if it is possible to prevent PAS development in international travelers with prophylactic antibiotics or vaccines. 33 Before these study results are available, we believe that greater emphasis should be placed on the prevention and early treatment of acute enteric infections to prevent morbidity and possibly reduce the occurrence of PAS. Declaration of Interests The authors state that they have no conflicts of interest. 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