REVIEW URRENT C OPINION
An update on travelers’ diarrhea Deenaz Zaidi and Eytan Wine
Purpose of review Travelers’ diarrhea, affecting millions of travelers every year globally, continues to be a leading cause of morbidity despite advances in vaccination, prevention, and treatment. Complications of travelers’ diarrhea often present to gastroenterologists and some patients followed by gastroenterologists are at higher risk of developing travelers’ diarrhea. This review will provide an update on recent progress made in the epidemiology, pathogenesis, diagnosis, prevention, and treatment of travelers’ diarrhea. Recent findings Most causes of travelers’ diarrhea remain bacterial, but newly recognized pathogens are emerging. Patient-related and travel-related factors affect disease development risk and should guide prophylaxis and treatment. Although specific vaccines are being developed, they have not yet had a major impact on travelers’ diarrhea, and understanding their roles and limitations is especially important. Prophylaxis and treatment of populations at risk (children, chronically ill patients, and those on immunosuppressive medications) remain challenging and require a tailored approach. Summary Travelers’ diarrhea will continue to challenge patients and physicians despite the use of sanitation advice, prophylactic vaccines, and treatment with antibiotics. Effects may extend beyond the time of travel, such as postinfectious complications and exacerbation of preexisting disease. Future research should focus on novel strategies for reducing exposure to pathogens, vaccine development, early detection, and targeted treatments. Keywords gastroenteritis, travelers’ diarrhea, vaccination
INTRODUCTION Travelers’ diarrhea is a common complication that occurs through the acquisition of specific pathogens while traveling. Typically, the term is used when individuals from developed countries (e.g., North America or Europe) travel to developing countries. Travelers’ diarrhea is defined as three or more stools with or without associated fever, abdominal cramps, and vomiting within a 24-h period and is the most common travel-related morbidity. Ten to sixty percent of travelers will develop diarrhea, especially when traveling to Latin America, Africa, the Indian subcontinent, and to a lesser extent Russia, Middle East, China, and south-east Asia (8–15%) [1,2]. With more than a billion travelers globally per year, travelers’ diarrhea has huge health and economic impacts. This review will focus on recent data on epidemiology, pathophysiology, prevention, treatment, and specific conditions frequently managed by gastroenterologists in which travelers’ diarrhea may be encountered.
GLOBAL DISTRIBUTION OF TRAVELERS’ DIARRHEA According to the global travel surveillance conducted by the GeoSentinel Surveillance System (1997–2011), acute bacterial and unspecified diarrhea, chronic diarrhea of unknown cause, postinfectious irritable bowel syndrome (PI-IBS), and giardiasis were the most commonly diagnosed disorders out of 13 059 posttravel diagnoses in 10 032 cases [3 ]. A multitude of factors, such as geographical variation, prevalence of specific microbes, host &&
Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada Correspondence to Eytan Wine, MD, PhD, Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, University of Alberta, Edmonton Clinic Health Academy, Room 4–577, 11405 87th Avenue, Edmonton, AB T6G 1C9, Canada. Tel: +1 780 248 5420; fax: +1 888 353 1157; e-mail: [email protected] Curr Opin Gastroenterol 2015, 31:7–13 DOI:10.1097/MOG.0000000000000133
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Gastrointestinal infections Table 2. Major enteropathogens causing travelers’ diarrhea in various regions of the world
KEY POINTS Basic preventive measures, such as sanitation and food safety, are important, but have not eliminated travelers’ diarrhea. Up-to-date knowledge on destination-specific pathogens is important for appropriate selection of vaccines, prophylactic antibiotics, and treatment. Emerging vaccines against specific pathogens are promising, but as each could only eliminate a small portion of all infections, development of multitarget vaccines is warranted. Patients on immunosuppressive treatments (e.g., IBD and transplant) require additional measures and tailored prophylaxis and treatment.
Southern Asia (Indian subcontinent)
Latin America and Africa
Campylobacter (20%)
ETEC (33%)
ETEC (19%)
Norovirus (15%)
EAEC (16%)
EAEC (13%)
Vibrios (10%)
Shigella (8%)
Parasites (10%)
Campylobacter (4%)
Salmonella (8%)
Salmonella (4%)
Shigella (5%)
Parasites (4%)
Plesiomonas (5%)
Unknown (44%)
Norovirus (4%) Aeromonas (3%) Unknown (38%)
factors, and comorbid conditions, determine the global pattern of travelers’ diarrhea, adding to the complexity of managing travelers’ diarrhea. Management requires knowledge of host and pathogen factors and global variation to guide travelers’ diarrhea treatment. In contrast to nontravel diarrhea, most infectious causes of travelers’ diarrhea are bacterial. Some of the commonly identified pathogens causing travelers’ diarrhea include pathogenic Escherichia coli strains, Campylobacter jejuni, Shigella, Salmonella, norovirus, astrovirus, and rotavirus; enteroaggregative E. coli (EAEC), norovirus, and enterotoxigenic E. coli (ETEC) are the most common pathogens globally [4 ]. However, recently, relatively unknown pathogens, such as Aeromonas and Plesiomonas, have also been implicated [5 ]. As the cause differs worldwide, the world is divided into three travelers’ diarrhea risk regions (low, intermediate, and high; Table 1), with specific pathogens linked to each location. For example, ETEC is the causative agent of travelers’ diarrhea in most Americans traveling to Mexico or South America, whereas Giardia infections commonly occur in travelers to Russia [6 ]. Although many pathogens remain unknown, some of the leading causes, according to the geographical location, are listed in Table 2. &
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Table 1. Risk stratification of travelers’ diarrhea by region Low-risk regions
United States, Canada, Australia, New Zealand, Japan, northern and western European countries
Intermediate-risk regions
Eastern European and South African countries, some Caribbean islands.
High-risk regions
Asia, Africa, Middle East, central America, South America, Mexico.
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EAEC, enteroaggregative Escherichia coli; ETEC, enterotoxigenic Escherichia coli. Adapted from [1,2].
Less common causes are diagnostically challenging and, therefore, deserve additional attention. Schistosomiasis, acquired during travel, can present with diarrhea, developing into a chronic condition. A case report describes a French woman with Giardia lamblia who was also diagnosed with colonic schistosomiasis on colonoscopy 5 years after traveling to Laos [7]. A recent study [8 ] reported cases of acute schistosomiasis in German students who returned from Lake Tanganyika, Tanzania. As schistosomiasis is increasingly found in travelers returning from tropical regions, development of accurate, sensitive, and specific diagnostic tests is crucial, as current diagnostic tests have poor sensitivity [9]. Another uncommon cause of travelers’ diarrhea is demonstrated through a case of Plasmodium knowlesi (infects humans in south-east Asia), appearing in a Scottish traveler returning from Borneo, Malaysia, who developed diarrhea, fever, and chills 13 days after the return. Thus, in patients traveling to south-east Asia, specially those presenting with symptoms of malaria, but testing negative for malaria, specific PCR for P. knowlesi should be considered [10]. Another excellent and highly relevant example of an emerging infectious cause of diarrhea is Ebola virus, which presents with fever, severe diarrhea, and vomiting (although other systemic symptoms, including headache, myalgia, and weakness, are typically present as well). An outbreak of this highly contagious cause of hemorrhagic fever is of major global concern at the time of the writing of this review and is already affecting travel to Africa [11 ,12]. &
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The GeoSentinel Network revealed that acute nonparasitic diarrhea was among the most commonly diagnosed diseases in returning travelers from Indian Ocean islands (mainly Madagascar and Maldives) [13 ]. A study to assess travel-acquired diseases in tourists from New South Wales, Australia, indicated that shigellosis caused 48.7% of travelers’ diarrhea cases [14 ]. Some European destinations are also prone to travelers’ diarrhea; a retrospective study [15] analyzing foreign travelers to Greece ranked travelers’ diarrhea high among conditions affecting visitors. &
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PATHOGENESIS AND DETECTION OF COMMON PATHOGENS Clinical presentation is dependent on both host and pathogen factors and is a reflection of disease pathogenesis. Mechanisms of diarrhea are complex in most cases, and include combinations of osmotic, secretory, and inflammatory processes. Viruses (e.g., norovirus) and bacterial toxins will commonly cause acute watery diarrhea with vomiting. Most common bacteria strains (e.g., ETEC, EAEC, and Vibrio) cause watery diarrhea, whereas more invasive strains (e.g., Shigella, Campylobacter, and Salmonella) can lead to bloody and inflammatory diarrhea. Persistent diarrhea (>14 days) is commonly caused by parasites (e.g., Giardia, Cryptosporidium) [1,16 ]. A major challenge in identifying and studying pathogenic E. coli strains is that they share many biochemical and genetic features with the more abundant commensal strains. ETEC, one of the most common and studied diarrheal causes, especially among children, causes damage through secretion of both heat-labile and heat-stable enterotoxins [17]. Additional virulence factors, such as E. coli attaching and effacing homolog (EaeH), further contribute to pathogenesis [18 ]. EAEC is a perplexing pathogen because of a vast phylogenetic diversity. Basic virulence features include adherence to enterocytes with biofilm formation, production of enterotoxins and cytotoxins, and induction of mucosal inflammation [19]. Traditionally, research focus has been on aggregative adherence regulator (AggR), a transcriptional regulator, but differences in other EAEC virulence genes complicate the understanding of pathogenesis and diagnosis [20 ]. The pathogenesis of norovirus, the most common viral cause of diarrhea across the world and a common cause of travelers’ diarrhea, remains poorly understood due to limited cell and animal models. The control of disease is also challenged by prolonged virus shedding after the resolution of diarrhea [21 ]. Serological features of norovirus were assessed to identify vaccine targets in a cohort of &&
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American students traveling to Mexico. Pretravel mean serum levels of immunoglobulins were lower against six predominant variants of norovirus (G1–G6), relative to other viruses, suggesting an involvement in pathogenesis [22]. Serotype analysis of Shigella conducted on stool samples and rectal swabs of children below 5 years of age in Africa and Asia confirmed the predominance of Shigella sonnei and S. flexneri and showed that O antigen-based quadrivalent vaccine could offer effective protection [23 ]. Current laboratory-based immunoassays and cultures for the detection of pathogens are time consuming and with low yield. A multiplex quantitative PCR test was recently developed to detect nine travelers’ diarrhea-associated pathogens in just 4 h. The pathogens covered were Campylobacter, Yersinia, Salmonella, Vibrio cholerae, Shigella, enteropathogenic E. coli, ETEC, enterohemorrhagic E. coli, and EAEC, and were tested on stool samples from 96 travelers’ diarrhea cases. The assay’s sensitivity and specificity for the detection of these pathogens were 100%. Most travelers (76%) had at least one pathogen identified, compared with the routine methods that detected pathogens in only 17% of the travelers [16 ]. &
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LONG-TERM SEQUELAE OF TRAVELERS’ DIARRHEA: FOCUS ON EMERGING PATHOGENS Although typically an acute infection, travelers’ diarrhea can at times have detrimental long-term consequences, such as reactive arthritis, chronic diarrhea, PI-IBS [4 ] and Guillain–Barre syndrome [24]. Persistent diarrhea (>14 days) can result from infection with less common pathogens (usually parasites), triggering of a previously unknown condition [e.g., inflammatory bowel diseases (IBD)], or postinfectious complications (PI-IBS) [25 ]. Chronic diarrhea in returning travelers poses a diagnostic challenge as pathogens are different from those typically screened for (Table 3) [26 ]. Furthermore, one must recognize additional causes for chronic diarrhea. For instance, tropical sprue, which rarely presents in developed countries, should be considered a possible cause of chronic diarrhea after traveling. In a retrospective study [27 ] of patients diagnosed with either tropical sprue or celiac disease, with the same length of stay in tropical regions, both conditions had similar presentation and histological findings, but celiac disease was characterized by the presence of anti-endomysial or anti-tissue transglutaminase antibodies. This is important to appropriately guide the treatment (prolonged antibiotics or diet, respectively) [27 ].
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Gastrointestinal infections Table 3. Pathogens causing persistent travelers’ diarrhea Areas with high risk of acquisition
Pathogen Giardia lamblia
Middle East, South America, south Asia
Entamoeba histolytica
Middle East, South America, south Asia, south-east Asia
Strongyloides
Latin America, South America, Asia, Africa, Oceania, Caribbean
Schistosoma
South America, Asia, Africa
Shigella
South Asia, south-east Asia, Oceania, north Africa
Campylobacter
South-east and south Asia
Salmonella serovar typhi
Africa, south Asia
Nontyphoidal Salmonella
Oceania, south-east Asia
Guidelines for healthy travelers Prevention includes reducing exposure and travel behavior, prophylactic antibiotics, and vaccines. An example for specific destination-based recommendations is the recent FIFA 2014 World Cup, in which emphasis was made on proper food sanitation. In fact, a risk evaluation tool for food services was created based on foodborne disease data with associated statistical analysis [32 ]. Travel clinics and available public resources focus on sanitation – from drinking only sealed bottled beverages (no ice) to avoiding salad dressing and raw vegetables, peeling fruits yourself, eating fully and freshly cooked food, hand washing, etc. Such advice is associated with protection, but has not eliminated travelers’ diarrhea [5 ]. In an attempt to improve pretravel counseling for travelers’ diarrhea, a communitybased retrospective observational study [33 ] was conducted on 525 precounseled travelers. Results showed that travelers’ diarrhea was associated with longer duration of travel (>14 days). Through a quality-improvement approach, the group modified the survey to collect information about duration, comorbid conditions, accommodations at destination, and the reason for visit [33 ]. Prophylactic use of antibiotics remains controversial and should probably be limited to individuals at high risk (e.g., patients receiving immunosuppressant medications, as discussed below) [34]; however, many practitioners will provide patients with antibiotics for use if diarrhea develops (e.g., rifaximin, ciprofloxacin) [35 ]. Vaccines are obviously very attractive, but also challenging as multiple pathogens cause travelers’ diarrhea at any destination. Although vaccines against cholera are available, a recent systematic review did not recommend cholera vaccine for the prevention of travelers’ diarrhea [36]. Effective ETEC vaccines are available but others are still in development. Whole-cell/recombinant-B-subunit (Dukoral, Crucell Vaccines Canada, a division of Janssen Inc., Toronto, Ontario, Canada), a commercially available oral cholera vaccine with some cross-activity against ETEC, was prospectively shown to prevent 28% of travelers’ diarrhea cases in a Spanish study [37 ]. Although the development of a transcutaneous vaccine, using the heat-labile ETEC toxin, which is effectively delivered, had shown promise [38], it did not prevent ETEC travelers’ diarrhea [39 ]. Another study [40 ] on ETEC suggested that targeting a combination of antigens and colonizing factors is important for the development of effective vaccines. Another complex vaccine, constructed using nontoxigenic E. coli strains expressing colonizing factors, an ETEC-based B subunit protein, and nontoxic double-mutant heat-labile toxin molecule &
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Tropheryma whipplei, the infectious cause of Whipple’s disease, has also recently been associated with persistent travelers’ diarrhea. PCR analysis of stool samples collected from two French travelers to Senegal, who were T. whipplei-negative pretravel, showed the presence of T. whipplei after they returned. However, this could be an underestimation as many participants received doxycycline prophylaxis. Nevertheless, this pathogen, which is now known to also cause acute diarrhea [28], should be considered in the differential diagnosis of persistent travelers’ diarrhea [29 ]. Another potential travelers’ diarrhea pathogen, not previously considered as a cause of travelers’ diarrhea, is Clostridium difficile, highly prevalent in low-income countries. Travelers might become infected through hospitals and communities in such countries. A literature review by Neuberger et al. [30] revealed 48 cases of travelers’ diarrhea attributed to C. difficile infection. Infected travelers were mostly young, more likely to visit developing countries, acquire infection in the community, and exposed to antibiotics, especially fluoroquinolones. PI-IBS is a common sequela of infectious diarrhea and is linked to travelers’ diarrhea. A questionnaire-based prospective Swiss study [31] following 2500 travelers showed an odds ratio of 3.7 for developing IBS after travelers’ diarrhea; however, adverse life events and previous diarrhea were also risk factors and may have biased results. &
PREVENTION AND TREATMENT Below are the suggestions for the prevention and treatment of travelers’ diarrhea, tailored to individuals from different groups. 10
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An update on travelers’ diarrhea Zaidi and Wine
(dmLT) as the adjuvant, increased serological responses in mice [41]. Similarly, a phase 1 clinical trial of 36 adults has shown that oral administration of a dmTL enhanced immune responses of dmLTspecific antibodies in lymphocyte supernatant [42]. Once travelers’ diarrhea develops, treatment includes symptomatic support or relief and antibiotics. Oral rehydration remains the backbone of supportive therapy for severe watery diarrhea and is especially important when cholera or other enterotoxin-mediated infections are suspected. The use of antibiotics requires knowledge of local resistance patterns. In general, rifaximin is appropriate for noninvasive travelers’ diarrhea and fluoroquinolones are useful for most invasive infections, although azithromycin may be preferred in Asia due to antibiotics resistance of many Campylobacters [2,35 ]. &&
Role of probiotics in travelers’ diarrhea prevention There is a strong rationale for the use of probiotics for the prevention of travelers’ diarrhea, but available data are still limited and conflicting. A meta-analysis from 2007 found a risk reduction for travelers’ diarrhea (relative risk ¼ 0.85) with Saccharomyces boulardii prophylaxis. Other studies [43,44 ] suggest a role for various strains and combination, including Lactobacillus bulgaricus, L. acidophilus, Lactobacillus GG, and Streptococcus thermophilus, but a recommendation for the broad use of probiotics could not be made at this point. A recent study [45] on Agri-King Symbiotic (combination of two probiotic strains and prebiotics; Agri-King Inc, Fulton, Illinois, USA) for preventing travelers’ diarrhea failed to prove efficacy. &
Guidelines for children
and probiotics in the setting of travelers’ diarrhea in children [47 ]. &
Guidelines for immunocompromised patients Many patients followed by gastroenterologists, specifically those after solid-organ transplant and IBD patients receiving immunosuppressive drugs, require additional attention. A retrospective analysis of 277 Dutch IBD patients reported that most patients felt that their disease limited their travel and did seek travel advice. Diarrhea developed in 32%, but it was difficult to conclude whether this was travelers’ diarrhea or a flare of their disease as 19% felt that their disease flared within 2 months [48]. Another Dutch study [49], prospectively following 150 traveling pairs, in which one had IBD or was taking immunosuppressants and the companion was healthy, did not show higher rates of travelers’ diarrhea among patients, although they did report more vomiting. Fever, diarrhea, and respiratory symptoms were the most common symptoms in traveling transplant patients (8–29% of travelers). Acute rejection was rare (two cases out of more than 500), but given the clinical complexity of these individuals, seeking advice from both transplant and travel clinics prior to travel is recommended [50 ]. Live vaccinations are contraindicated with any significant immunosuppression; therefore, patients should avoid traveling to areas endemic with yellow fever. However, other types of prophylaxis, such as trimethoprim and sulfamethoxazole, passive vaccines, and antimalarials when indicated, should be encouraged. Antibiotics, especially azithromycin and fluoroquinolones, should be considered for prophylaxis for shorter travel duration (weighed against risks of antibiotic-related complications) and should certainly be provided for treatment in case travelers’ diarrhea develops [51 ]. An updated, detailed guideline from the Centers for Disease Control and Prevention serves as an excellent resource [52 ]. &&
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Recommendations for prevention and treatment of travelers’ diarrhea in the pediatric population are age-dependent. Immunizations should be optimized after consultation and according to age and destination-specific risks. Antibiotic prophylaxis is not recommended, especially for children below 2 years of age, but rather oral rehydration should be provided for diarrhea. Azithromycin is suggested as a treatment for children below 2 years of age for most destinations. Although fluoroquinolones are not recommended for children, they can be used in areas with multidrug resistance. Loperamide and bismuth subsalicylate are also an option for symptomatic treatment, but should be used with caution, especially in young children [6 ,46 ]. There have been no studies investigating the use of prebiotics &
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CONCLUSION Developing diarrhea during travel can be devastating and, in some cases, dangerous. Despite advances in epidemiology, pathogenesis, vaccines, and treatment of travelers’ diarrhea, these conditions remain a challenge to patients and practitioners. Geographic variation and a multitude of potential pathogens add complexity to prophylaxis and treatment, especially in patients with chronic illness requiring immunosuppressive medications. Changes in travel patterns, bacterial resistance, and
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Gastrointestinal infections
even global warming define travelers’ diarrhea as a moving target, requiring frequent updates. However, improvements in diagnosis and development of new vaccines, together with better guidance and good hygiene practices, will likely improve outcomes. Travel clinics and online resources should be better utilized, certainly for complex patients. Acknowledgements D.Z. is a graduate student funded by the Women and Children’s Health Research Institute. E.W. is funded by an Independent Investigator Award by Alberta Innovates Health Solutions. Conflicts of interest There are no relevant conflicts of interest.
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Estrada-Garcia T, Navarro-Garcia F. Enteroaggregative Escherichia coli pathotype: a genetically heterogeneous emerging foodborne enteropathogen. FEMS Immunol Med Microbiol 2012; 66:281–298. 20. Estrada-Garcia T, Perez-Martinez I, Bernal-Reynaga R, Zaidi MB. Enteroag& gregative coli: a pathogen bridging the north and south. Curr Trop Med Rep 2014; 1:88–96. This detailed review describes the basic and the clinical aspects of EAEC, one of the leading causes of travelers’ diarrhea, including epidemiology, pathogenesis, clinical manifestations, and treatment. 21. Karst SM, Wobus CE, Goodfellow IG, et al. Advances in norovirus biology. && Cell Host Microbe 2014; 15:668–680. This excellent review details the molecular virology, cell and animal models, pathogenesis, host immune responses, and insights into vaccine development for the most common cause of infectious diarrhea, norovirus. 22. Ajami NJ, Kavanagh OV, Ramani S, et al. Seroepidemiology of norovirusassociated travelers’ diarrhea. J Travel Med 2014; 21:6–11. 23. Livio S, Strockbine NA, Panchalingam S, et al. Shigella isolates from the & global enteric multicenter study inform vaccine development. Clin Infect Dis 2014; 159:933–941. As part of the Global Enteric Multicenter Study, this study analyzed 1130 isolates of Shigella to identify potential targets for future vaccine development that would cover a large variety of serotypes. 24. Zautner AE, Johann C, Strubel A, et al. Seroprevalence of campylobacteriosis and relevant postinfectious sequelae. Eur J Clin Microbiol Infect Dis 2014; 33:1019–1027. 25. Connor BA. Persistent travelers’ diarrhea. In: Brunette G, editor. The Yellow & Book: CDC Health Information for International Travel 2014. New York, New York: Oxford University Press; 2014. pp. 479–482. This Centers for Disease Control and Prevention’s ‘Yellow Book’ chapter focuses on persistent travelers’ diarrhea and provides background for understanding the relationship between travelers’ diarrhea and PI-IBS. It is available through the following link: http://wwwnc.cdc.gov/travel/yellowbook/2014/chapter-5-posttravel-evaluation/persistent-travelers-diarrhea. 26. Ross AGP, Olds GR, Cripps AW, et al. Enteropathogens and chronic illness && in returning travelers. N Engl J Med 2013; 368:1817–1825. This detailed review on chronic complications of travelers’ diarrhea highlights leading parasitic and bacterial pathogens, in relation to travel destination, and discusses the diagnosis and treatment. 27. Langenberg MCC, Wismans PJ, van Genderen PJJ. Distinguishing tropical & sprue from celiac disease in returning travellers with chronic diarrhoea: a diagnostic challenge? Travel Med Infect Dis 2014; 12:401–405. In this interesting report, comparison is made between the related diagnoses – celiac disease and tropical sprue. 28. Raoult D, Fenollar F, Rolain JM, et al. Tropheryma whipplei in children with gastroenteritis. Emerg Infect Dis 2010; 16:776–782. 29. Gautret P, Lagier J-C, Benkouiten S, et al. Does Tropheryma whipplei & contribute to travelers’ diarrhea?: a PCR analysis of paired stool samples in French travelers to Senegal. Travel Med Infect Dis 2014; 12:264–267. Tropheryma whipplei is traditionally thought to cause chronic diarrhea. In this study, it is discussed as a cause of acute symptoms in the context of returning travelers.
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An update on travelers’ diarrhea Zaidi and Wine 30. Neuberger A, Saadi T, Shetern A, Schwartz E. Clostridium difficile infection in travelers: a neglected pathogen? J Travel Med 2013; 20:37–43. 31. Pitzurra R, Fried M, Rogler G, et al. Irritable bowel syndrome among a cohort of European travelers to resource-limited destinations. J Travel Med 2011; 18:250–256. 32. Gallego V, Berberian G, Lloveras S, et al. The 2014 FIFA World Cup: & communicable disease risks and advice for visitors to Brazil – A review from the Latin American Society for Travel Medicine (SLAMVI). Travel Med Infect Dis 2014; 12:208–218. In preparation for the 2014 FIFA World Cup in Brazil, this timely study summarized the major communicable diseases that travelers may encounter and how to reduce risk of exposure; this advice is probably applicable to other travel destinations. 33. Mackaness CA, Osborne A, Verma D, et al. A quality improvement initiative && using a novel travel survey to promote patient-centered counseling. J Travel Med 2013; 20:237–242. Recognizing the limited ability of current approaches to prevent travelers’ diarrhea, this study outlines a quality improvement approach for guiding travelers through the analysis of a survey. 34. Alajbegovic S, Sanders JW, Atherly DE, Riddle MS. Effectiveness of rifaximin and fluoroquinolones in preventing travelers’ diarrhea (TD): a systematic review and meta-analysis. Syst Rev 2012; 1:39. 35. Nair D. Travelers’ diarrhea: prevention, treatment, and posttrip evaluation. && J Fam Pract 2013; 62:356–361. This practical guide for the practitioner provides simple and supported advice on prevention and management of travelers’ diarrhea. It includes details on choice and doses of antibiotics. 36. Nickonchuk T, Lindblad AJ, Kolber MR. Oral cholera vaccine for traveler’s diarrhea prophylaxis. Can Fam Physician 2014; 60:451. 37. Lo´pez-Gigosos R, Campins M, Calvo MJ, et al. Effectiveness of the WC/rBS & oral cholera vaccine in the prevention of traveler’s diarrhea: a prospective cohort study. Hum Vaccin Immunother 2013; 9:692–698. In this prospective, randomized study on the whole-cell/recombinant-B-subunit Cholera/ETEC vaccine, two of every seven cases of traveler’s diarrhea were prevented by the vaccine. 38. Frech SA, Dupont HL, Bourgeois AL, et al. Use of a patch containing heatlabile toxin from Escherichia coli against travellers’ diarrhoea: a phase II, randomised, double-blind, placebo-controlled field trial. Lancet 2008; 371:2019–2025. 39. Behrens RH, Cramer JP, Jelinek T, et al. Efficacy and safety of a patch vaccine & containing heat-labile toxin from Escherichia coli against travellers’ diarrhoea: a phase 3, randomised, double-blind, placebo-controlled field trial in travellers from Europe to Mexico and Guatemala. Lancet Infect Dis 2014; 14:197–204. This randomized double-blind, placebo-controlled trial on an ETEC heat-labile toxin-based vaccine patch was negative. Although the vaccine was effectively absorbed, it did not reduce travelers’ diarrhea in the treatment group. 40. Rivera FP, Medina AM, Aldasoro E, et al. Genotypic characterization of & enterotoxigenic Escherichia coli strains causing traveler’s diarrhea. J Clin Microbiol 2013; 51:633–635. In an attempt to identify vaccine targets for ETEC, this study surveyed 52 clinical isolates and characterized common colonization factors.
41. Holmgren J, Bourgeois L, Carlin N, et al. Development and preclinical evaluation of safety and immunogenicity of an oral ETEC vaccine containing inactivated E. coli bacteria overexpressing colonization factors CFA/I, CS3 CS5 and CS6 combined with a hybrid LT/CT B subunit antigen, administered alone and together with dmLT. Vaccine 2013; 31:2457–2464. 42. El-Kamary SS, Cohen MB, Bourgeois a L, et al. Safety and immunogenicity of a single oral dose of recombinant double mutant heat-labile toxin derived from enterotoxigenic Escherichia coli. Clin Vaccine Immunol 2013; 20:1764– 1770. 43. McFarland LV. Meta-analysis of probiotics for the prevention of traveler’s diarrhea. Travel Med Infect Dis 2007; 5:97–105. 44. Sarowska J, Choroszy-Kro´l I, Regulska-Ilow B, et al. The therapeutic effect of & probiotic bacteria on gastrointestinal diseases. Adv Clin Exp Med 2013; 22:759–766. This review article details current knowledge on probiotic use for intestinal conditions with some comments on travelers’ diarrhea. 45. Virk A, Mandrekar J, Berbari EF, et al. A randomized, double blind, placebocontrolled trial of an oral synbiotic (AKSB) for prevention of travelers’ diarrhea. J Travel Med 2013; 20:88–94. 46. Fox TG, Manaloor JJ, Christenson JC. Travel-related infections in children. & Pediatr Clin North Am 2013; 60:507–527. This review discusses pediatric-specific considerations related to travel, including travelers’ diarrhea. 47. Vandenplas Y, De Greef E, Devreker T, et al. Probiotics and prebiotics in & infants and children. Curr Infect Dis Rep 2013; 15:251–262. This review on probiotics use in children includes a section on probiotics for travelers’ diarrhea, highlighting the paucity of data. 48. Soonawala D, van Eggermond AM, Fidder H, Visser LG. Pretravel preparation and travel-related morbidity in patients with inflammatory bowel disease. Inflamm Bowel Dis 2012; 18:2079–2085. 49. Baaten GG, Geskus RB, Kint JA, et al. Symptoms of infectious diseases in immunocompromised travelers: a prospective study with matched controls. J Travel Med 2011; 18:318–326. 50. Rosen J. Travel medicine and the solid-organ transplant recipient. Infect Dis && Clin North Am 2013; 27:429–457. Focusing on patients after solid-organ transplant, this study provides an excellent resource, including risk assessment and practical vaccination and treatment advice with a section on travelers’ diarrhea in this setting. 51. Askling HH, Dalm VA. The medically immunocompromised adult traveler and & pretravel counseling: status quo 2014. Travel Med Infect Dis 2014; 12:219– 228. This review highlights travel-related concerns in immunocompromised patients. First, different classes of immunosuppressive medications are defined and then advice on prophylaxis and treatment is provided. 52. Kotton CN, Freedman DO. Immunocompromised travelers. In: Brunette GW, && editor. The Yellow Book: CDC Health Information for International Travel 2014. New York, New York: Oxford University Press; 2014. pp. 544–556. This Centers for Disease Control and Prevention’s ‘Yellow Book’ chapter on immunocompromised travelers is an excellent resource on different levels of immune deficiency and their impact on vaccination and travel advice.
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An update on travelers’ diarrhea Deenaz Zaidi and Eytan Wine
Purpose of review Travelers’ diarrhea, affecting millions of travelers every year globally, continues to be a leading cause of morbidity despite advances in vaccination, prevention, and treatment. Complications of travelers’ diarrhea often present to gastroenterologists and some patients followed by gastroenterologists are at higher risk of developing travelers’ diarrhea. This review will provide an update on recent progress made in the epidemiology, pathogenesis, diagnosis, prevention, and treatment of travelers’ diarrhea. Recent findings Most causes of travelers’ diarrhea remain bacterial, but newly recognized pathogens are emerging. Patient-related and travel-related factors affect disease development risk and should guide prophylaxis and treatment. Although specific vaccines are being developed, they have not yet had a major impact on travelers’ diarrhea, and understanding their roles and limitations is especially important. Prophylaxis and treatment of populations at risk (children, chronically ill patients, and those on immunosuppressive medications) remain challenging and require a tailored approach. Summary Travelers’ diarrhea will continue to challenge patients and physicians despite the use of sanitation advice, prophylactic vaccines, and treatment with antibiotics. Effects may extend beyond the time of travel, such as postinfectious complications and exacerbation of preexisting disease. Future research should focus on novel strategies for reducing exposure to pathogens, vaccine development, early detection, and targeted treatments. Keywords gastroenteritis, travelers’ diarrhea, vaccination
INTRODUCTION Travelers’ diarrhea is a common complication that occurs through the acquisition of specific pathogens while traveling. Typically, the term is used when individuals from developed countries (e.g., North America or Europe) travel to developing countries. Travelers’ diarrhea is defined as three or more stools with or without associated fever, abdominal cramps, and vomiting within a 24-h period and is the most common travel-related morbidity. Ten to sixty percent of travelers will develop diarrhea, especially when traveling to Latin America, Africa, the Indian subcontinent, and to a lesser extent Russia, Middle East, China, and south-east Asia (8–15%) [1,2]. With more than a billion travelers globally per year, travelers’ diarrhea has huge health and economic impacts. This review will focus on recent data on epidemiology, pathophysiology, prevention, treatment, and specific conditions frequently managed by gastroenterologists in which travelers’ diarrhea may be encountered.
GLOBAL DISTRIBUTION OF TRAVELERS’ DIARRHEA According to the global travel surveillance conducted by the GeoSentinel Surveillance System (1997–2011), acute bacterial and unspecified diarrhea, chronic diarrhea of unknown cause, postinfectious irritable bowel syndrome (PI-IBS), and giardiasis were the most commonly diagnosed disorders out of 13 059 posttravel diagnoses in 10 032 cases [3 ]. A multitude of factors, such as geographical variation, prevalence of specific microbes, host &&
Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada Correspondence to Eytan Wine, MD, PhD, Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, University of Alberta, Edmonton Clinic Health Academy, Room 4–577, 11405 87th Avenue, Edmonton, AB T6G 1C9, Canada. Tel: +1 780 248 5420; fax: +1 888 353 1157; e-mail: [email protected] Curr Opin Gastroenterol 2015, 31:7–13 DOI:10.1097/MOG.0000000000000133
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Gastrointestinal infections Table 2. Major enteropathogens causing travelers’ diarrhea in various regions of the world
KEY POINTS Basic preventive measures, such as sanitation and food safety, are important, but have not eliminated travelers’ diarrhea. Up-to-date knowledge on destination-specific pathogens is important for appropriate selection of vaccines, prophylactic antibiotics, and treatment. Emerging vaccines against specific pathogens are promising, but as each could only eliminate a small portion of all infections, development of multitarget vaccines is warranted. Patients on immunosuppressive treatments (e.g., IBD and transplant) require additional measures and tailored prophylaxis and treatment.
Southern Asia (Indian subcontinent)
Latin America and Africa
Campylobacter (20%)
ETEC (33%)
ETEC (19%)
Norovirus (15%)
EAEC (16%)
EAEC (13%)
Vibrios (10%)
Shigella (8%)
Parasites (10%)
Campylobacter (4%)
Salmonella (8%)
Salmonella (4%)
Shigella (5%)
Parasites (4%)
Plesiomonas (5%)
Unknown (44%)
Norovirus (4%) Aeromonas (3%) Unknown (38%)
factors, and comorbid conditions, determine the global pattern of travelers’ diarrhea, adding to the complexity of managing travelers’ diarrhea. Management requires knowledge of host and pathogen factors and global variation to guide travelers’ diarrhea treatment. In contrast to nontravel diarrhea, most infectious causes of travelers’ diarrhea are bacterial. Some of the commonly identified pathogens causing travelers’ diarrhea include pathogenic Escherichia coli strains, Campylobacter jejuni, Shigella, Salmonella, norovirus, astrovirus, and rotavirus; enteroaggregative E. coli (EAEC), norovirus, and enterotoxigenic E. coli (ETEC) are the most common pathogens globally [4 ]. However, recently, relatively unknown pathogens, such as Aeromonas and Plesiomonas, have also been implicated [5 ]. As the cause differs worldwide, the world is divided into three travelers’ diarrhea risk regions (low, intermediate, and high; Table 1), with specific pathogens linked to each location. For example, ETEC is the causative agent of travelers’ diarrhea in most Americans traveling to Mexico or South America, whereas Giardia infections commonly occur in travelers to Russia [6 ]. Although many pathogens remain unknown, some of the leading causes, according to the geographical location, are listed in Table 2. &
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Table 1. Risk stratification of travelers’ diarrhea by region Low-risk regions
United States, Canada, Australia, New Zealand, Japan, northern and western European countries
Intermediate-risk regions
Eastern European and South African countries, some Caribbean islands.
High-risk regions
Asia, Africa, Middle East, central America, South America, Mexico.
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EAEC, enteroaggregative Escherichia coli; ETEC, enterotoxigenic Escherichia coli. Adapted from [1,2].
Less common causes are diagnostically challenging and, therefore, deserve additional attention. Schistosomiasis, acquired during travel, can present with diarrhea, developing into a chronic condition. A case report describes a French woman with Giardia lamblia who was also diagnosed with colonic schistosomiasis on colonoscopy 5 years after traveling to Laos [7]. A recent study [8 ] reported cases of acute schistosomiasis in German students who returned from Lake Tanganyika, Tanzania. As schistosomiasis is increasingly found in travelers returning from tropical regions, development of accurate, sensitive, and specific diagnostic tests is crucial, as current diagnostic tests have poor sensitivity [9]. Another uncommon cause of travelers’ diarrhea is demonstrated through a case of Plasmodium knowlesi (infects humans in south-east Asia), appearing in a Scottish traveler returning from Borneo, Malaysia, who developed diarrhea, fever, and chills 13 days after the return. Thus, in patients traveling to south-east Asia, specially those presenting with symptoms of malaria, but testing negative for malaria, specific PCR for P. knowlesi should be considered [10]. Another excellent and highly relevant example of an emerging infectious cause of diarrhea is Ebola virus, which presents with fever, severe diarrhea, and vomiting (although other systemic symptoms, including headache, myalgia, and weakness, are typically present as well). An outbreak of this highly contagious cause of hemorrhagic fever is of major global concern at the time of the writing of this review and is already affecting travel to Africa [11 ,12]. &
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An update on travelers’ diarrhea Zaidi and Wine
The GeoSentinel Network revealed that acute nonparasitic diarrhea was among the most commonly diagnosed diseases in returning travelers from Indian Ocean islands (mainly Madagascar and Maldives) [13 ]. A study to assess travel-acquired diseases in tourists from New South Wales, Australia, indicated that shigellosis caused 48.7% of travelers’ diarrhea cases [14 ]. Some European destinations are also prone to travelers’ diarrhea; a retrospective study [15] analyzing foreign travelers to Greece ranked travelers’ diarrhea high among conditions affecting visitors. &
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PATHOGENESIS AND DETECTION OF COMMON PATHOGENS Clinical presentation is dependent on both host and pathogen factors and is a reflection of disease pathogenesis. Mechanisms of diarrhea are complex in most cases, and include combinations of osmotic, secretory, and inflammatory processes. Viruses (e.g., norovirus) and bacterial toxins will commonly cause acute watery diarrhea with vomiting. Most common bacteria strains (e.g., ETEC, EAEC, and Vibrio) cause watery diarrhea, whereas more invasive strains (e.g., Shigella, Campylobacter, and Salmonella) can lead to bloody and inflammatory diarrhea. Persistent diarrhea (>14 days) is commonly caused by parasites (e.g., Giardia, Cryptosporidium) [1,16 ]. A major challenge in identifying and studying pathogenic E. coli strains is that they share many biochemical and genetic features with the more abundant commensal strains. ETEC, one of the most common and studied diarrheal causes, especially among children, causes damage through secretion of both heat-labile and heat-stable enterotoxins [17]. Additional virulence factors, such as E. coli attaching and effacing homolog (EaeH), further contribute to pathogenesis [18 ]. EAEC is a perplexing pathogen because of a vast phylogenetic diversity. Basic virulence features include adherence to enterocytes with biofilm formation, production of enterotoxins and cytotoxins, and induction of mucosal inflammation [19]. Traditionally, research focus has been on aggregative adherence regulator (AggR), a transcriptional regulator, but differences in other EAEC virulence genes complicate the understanding of pathogenesis and diagnosis [20 ]. The pathogenesis of norovirus, the most common viral cause of diarrhea across the world and a common cause of travelers’ diarrhea, remains poorly understood due to limited cell and animal models. The control of disease is also challenged by prolonged virus shedding after the resolution of diarrhea [21 ]. Serological features of norovirus were assessed to identify vaccine targets in a cohort of &&
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American students traveling to Mexico. Pretravel mean serum levels of immunoglobulins were lower against six predominant variants of norovirus (G1–G6), relative to other viruses, suggesting an involvement in pathogenesis [22]. Serotype analysis of Shigella conducted on stool samples and rectal swabs of children below 5 years of age in Africa and Asia confirmed the predominance of Shigella sonnei and S. flexneri and showed that O antigen-based quadrivalent vaccine could offer effective protection [23 ]. Current laboratory-based immunoassays and cultures for the detection of pathogens are time consuming and with low yield. A multiplex quantitative PCR test was recently developed to detect nine travelers’ diarrhea-associated pathogens in just 4 h. The pathogens covered were Campylobacter, Yersinia, Salmonella, Vibrio cholerae, Shigella, enteropathogenic E. coli, ETEC, enterohemorrhagic E. coli, and EAEC, and were tested on stool samples from 96 travelers’ diarrhea cases. The assay’s sensitivity and specificity for the detection of these pathogens were 100%. Most travelers (76%) had at least one pathogen identified, compared with the routine methods that detected pathogens in only 17% of the travelers [16 ]. &
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LONG-TERM SEQUELAE OF TRAVELERS’ DIARRHEA: FOCUS ON EMERGING PATHOGENS Although typically an acute infection, travelers’ diarrhea can at times have detrimental long-term consequences, such as reactive arthritis, chronic diarrhea, PI-IBS [4 ] and Guillain–Barre syndrome [24]. Persistent diarrhea (>14 days) can result from infection with less common pathogens (usually parasites), triggering of a previously unknown condition [e.g., inflammatory bowel diseases (IBD)], or postinfectious complications (PI-IBS) [25 ]. Chronic diarrhea in returning travelers poses a diagnostic challenge as pathogens are different from those typically screened for (Table 3) [26 ]. Furthermore, one must recognize additional causes for chronic diarrhea. For instance, tropical sprue, which rarely presents in developed countries, should be considered a possible cause of chronic diarrhea after traveling. In a retrospective study [27 ] of patients diagnosed with either tropical sprue or celiac disease, with the same length of stay in tropical regions, both conditions had similar presentation and histological findings, but celiac disease was characterized by the presence of anti-endomysial or anti-tissue transglutaminase antibodies. This is important to appropriately guide the treatment (prolonged antibiotics or diet, respectively) [27 ].
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Gastrointestinal infections Table 3. Pathogens causing persistent travelers’ diarrhea Areas with high risk of acquisition
Pathogen Giardia lamblia
Middle East, South America, south Asia
Entamoeba histolytica
Middle East, South America, south Asia, south-east Asia
Strongyloides
Latin America, South America, Asia, Africa, Oceania, Caribbean
Schistosoma
South America, Asia, Africa
Shigella
South Asia, south-east Asia, Oceania, north Africa
Campylobacter
South-east and south Asia
Salmonella serovar typhi
Africa, south Asia
Nontyphoidal Salmonella
Oceania, south-east Asia
Guidelines for healthy travelers Prevention includes reducing exposure and travel behavior, prophylactic antibiotics, and vaccines. An example for specific destination-based recommendations is the recent FIFA 2014 World Cup, in which emphasis was made on proper food sanitation. In fact, a risk evaluation tool for food services was created based on foodborne disease data with associated statistical analysis [32 ]. Travel clinics and available public resources focus on sanitation – from drinking only sealed bottled beverages (no ice) to avoiding salad dressing and raw vegetables, peeling fruits yourself, eating fully and freshly cooked food, hand washing, etc. Such advice is associated with protection, but has not eliminated travelers’ diarrhea [5 ]. In an attempt to improve pretravel counseling for travelers’ diarrhea, a communitybased retrospective observational study [33 ] was conducted on 525 precounseled travelers. Results showed that travelers’ diarrhea was associated with longer duration of travel (>14 days). Through a quality-improvement approach, the group modified the survey to collect information about duration, comorbid conditions, accommodations at destination, and the reason for visit [33 ]. Prophylactic use of antibiotics remains controversial and should probably be limited to individuals at high risk (e.g., patients receiving immunosuppressant medications, as discussed below) [34]; however, many practitioners will provide patients with antibiotics for use if diarrhea develops (e.g., rifaximin, ciprofloxacin) [35 ]. Vaccines are obviously very attractive, but also challenging as multiple pathogens cause travelers’ diarrhea at any destination. Although vaccines against cholera are available, a recent systematic review did not recommend cholera vaccine for the prevention of travelers’ diarrhea [36]. Effective ETEC vaccines are available but others are still in development. Whole-cell/recombinant-B-subunit (Dukoral, Crucell Vaccines Canada, a division of Janssen Inc., Toronto, Ontario, Canada), a commercially available oral cholera vaccine with some cross-activity against ETEC, was prospectively shown to prevent 28% of travelers’ diarrhea cases in a Spanish study [37 ]. Although the development of a transcutaneous vaccine, using the heat-labile ETEC toxin, which is effectively delivered, had shown promise [38], it did not prevent ETEC travelers’ diarrhea [39 ]. Another study [40 ] on ETEC suggested that targeting a combination of antigens and colonizing factors is important for the development of effective vaccines. Another complex vaccine, constructed using nontoxigenic E. coli strains expressing colonizing factors, an ETEC-based B subunit protein, and nontoxic double-mutant heat-labile toxin molecule &
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Tropheryma whipplei, the infectious cause of Whipple’s disease, has also recently been associated with persistent travelers’ diarrhea. PCR analysis of stool samples collected from two French travelers to Senegal, who were T. whipplei-negative pretravel, showed the presence of T. whipplei after they returned. However, this could be an underestimation as many participants received doxycycline prophylaxis. Nevertheless, this pathogen, which is now known to also cause acute diarrhea [28], should be considered in the differential diagnosis of persistent travelers’ diarrhea [29 ]. Another potential travelers’ diarrhea pathogen, not previously considered as a cause of travelers’ diarrhea, is Clostridium difficile, highly prevalent in low-income countries. Travelers might become infected through hospitals and communities in such countries. A literature review by Neuberger et al. [30] revealed 48 cases of travelers’ diarrhea attributed to C. difficile infection. Infected travelers were mostly young, more likely to visit developing countries, acquire infection in the community, and exposed to antibiotics, especially fluoroquinolones. PI-IBS is a common sequela of infectious diarrhea and is linked to travelers’ diarrhea. A questionnaire-based prospective Swiss study [31] following 2500 travelers showed an odds ratio of 3.7 for developing IBS after travelers’ diarrhea; however, adverse life events and previous diarrhea were also risk factors and may have biased results. &
PREVENTION AND TREATMENT Below are the suggestions for the prevention and treatment of travelers’ diarrhea, tailored to individuals from different groups. 10
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An update on travelers’ diarrhea Zaidi and Wine
(dmLT) as the adjuvant, increased serological responses in mice [41]. Similarly, a phase 1 clinical trial of 36 adults has shown that oral administration of a dmTL enhanced immune responses of dmLTspecific antibodies in lymphocyte supernatant [42]. Once travelers’ diarrhea develops, treatment includes symptomatic support or relief and antibiotics. Oral rehydration remains the backbone of supportive therapy for severe watery diarrhea and is especially important when cholera or other enterotoxin-mediated infections are suspected. The use of antibiotics requires knowledge of local resistance patterns. In general, rifaximin is appropriate for noninvasive travelers’ diarrhea and fluoroquinolones are useful for most invasive infections, although azithromycin may be preferred in Asia due to antibiotics resistance of many Campylobacters [2,35 ]. &&
Role of probiotics in travelers’ diarrhea prevention There is a strong rationale for the use of probiotics for the prevention of travelers’ diarrhea, but available data are still limited and conflicting. A meta-analysis from 2007 found a risk reduction for travelers’ diarrhea (relative risk ¼ 0.85) with Saccharomyces boulardii prophylaxis. Other studies [43,44 ] suggest a role for various strains and combination, including Lactobacillus bulgaricus, L. acidophilus, Lactobacillus GG, and Streptococcus thermophilus, but a recommendation for the broad use of probiotics could not be made at this point. A recent study [45] on Agri-King Symbiotic (combination of two probiotic strains and prebiotics; Agri-King Inc, Fulton, Illinois, USA) for preventing travelers’ diarrhea failed to prove efficacy. &
Guidelines for children
and probiotics in the setting of travelers’ diarrhea in children [47 ]. &
Guidelines for immunocompromised patients Many patients followed by gastroenterologists, specifically those after solid-organ transplant and IBD patients receiving immunosuppressive drugs, require additional attention. A retrospective analysis of 277 Dutch IBD patients reported that most patients felt that their disease limited their travel and did seek travel advice. Diarrhea developed in 32%, but it was difficult to conclude whether this was travelers’ diarrhea or a flare of their disease as 19% felt that their disease flared within 2 months [48]. Another Dutch study [49], prospectively following 150 traveling pairs, in which one had IBD or was taking immunosuppressants and the companion was healthy, did not show higher rates of travelers’ diarrhea among patients, although they did report more vomiting. Fever, diarrhea, and respiratory symptoms were the most common symptoms in traveling transplant patients (8–29% of travelers). Acute rejection was rare (two cases out of more than 500), but given the clinical complexity of these individuals, seeking advice from both transplant and travel clinics prior to travel is recommended [50 ]. Live vaccinations are contraindicated with any significant immunosuppression; therefore, patients should avoid traveling to areas endemic with yellow fever. However, other types of prophylaxis, such as trimethoprim and sulfamethoxazole, passive vaccines, and antimalarials when indicated, should be encouraged. Antibiotics, especially azithromycin and fluoroquinolones, should be considered for prophylaxis for shorter travel duration (weighed against risks of antibiotic-related complications) and should certainly be provided for treatment in case travelers’ diarrhea develops [51 ]. An updated, detailed guideline from the Centers for Disease Control and Prevention serves as an excellent resource [52 ]. &&
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Recommendations for prevention and treatment of travelers’ diarrhea in the pediatric population are age-dependent. Immunizations should be optimized after consultation and according to age and destination-specific risks. Antibiotic prophylaxis is not recommended, especially for children below 2 years of age, but rather oral rehydration should be provided for diarrhea. Azithromycin is suggested as a treatment for children below 2 years of age for most destinations. Although fluoroquinolones are not recommended for children, they can be used in areas with multidrug resistance. Loperamide and bismuth subsalicylate are also an option for symptomatic treatment, but should be used with caution, especially in young children [6 ,46 ]. There have been no studies investigating the use of prebiotics &
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CONCLUSION Developing diarrhea during travel can be devastating and, in some cases, dangerous. Despite advances in epidemiology, pathogenesis, vaccines, and treatment of travelers’ diarrhea, these conditions remain a challenge to patients and practitioners. Geographic variation and a multitude of potential pathogens add complexity to prophylaxis and treatment, especially in patients with chronic illness requiring immunosuppressive medications. Changes in travel patterns, bacterial resistance, and
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Gastrointestinal infections
even global warming define travelers’ diarrhea as a moving target, requiring frequent updates. However, improvements in diagnosis and development of new vaccines, together with better guidance and good hygiene practices, will likely improve outcomes. Travel clinics and online resources should be better utilized, certainly for complex patients. Acknowledgements D.Z. is a graduate student funded by the Women and Children’s Health Research Institute. E.W. is funded by an Independent Investigator Award by Alberta Innovates Health Solutions. Conflicts of interest There are no relevant conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. DuPont HL. Systematic review: the epidemiology and clinical features of travellers’ diarrhoea. Aliment Pharmacol Ther 2009; 30:187–196. 2. Shah N, DuPont HL, Ramsey DJ. Global etiology of travelers’ diarrhea: systematic review from 1973 to the present. Am J Trop Med Hyg 2009; 80:609–614. 3. Harvey K, Esposito DH, Han P, et al., Centers for Disease Control and && Prevention (CDC). Surveillance for travel-related disease: GeoSentinel Surveillance System, United States, 1997-2011. MMWR Surveill Summ 2013; 62:1–23. This report describes the utility of the remarkable GeoSentinel Surveillance System, a global travel clinic-based database with contributions from 40 countries, across six continents. Such robust data will continue to yield valuable data for future analyses. 4. Connor BA, Riddle MS. Postinfectious sequelae of travelers’ diarrhea. J Travel & Med 2013; 20:303–312. This thoughtful review focuses on long-term complications, such as reactive arthritis, Guillain-Barre´ syndrome, and PI-IBS, of travelers’ diarrhea. 5. Connor BA. Travelers’ diarrhea. In: Brunette GW, editor. The Yellow Book: && CDC Health Information for International Travel 2014. New York, New York: Oxford University Press; 2014. pp. 57–62. Chapter 2 of the Centers for Disease Control and Prevention’s ‘Yellow Book’ is an essential tool with practical, easy to follow, details on travelers’ diarrhea with links to other relevant chapters. It is available online at the following address: http:// wwwnc.cdc.gov/travel/yellowbook/2014/chapter-2-the-pretravel-consultation/ travelers-diarrhea 6. Doan S, Steele RW. Advice for families traveling to developing countries with & young children. Clin Pediatr (Phila) 2013; 52:803–811. As suggested by the title, this review is a useful tool for planning family travel and mainly focuses on vaccines and prophylactic measures. 7. Campa P, Develoux M, Belkadi G, et al. Chronic Schistosoma mekongi in a traveler: a case report and review of the literature. J Travel Med 2014; 21:361–363. 8. Steiner F, Ignatius R, Friedrich-Jaenicke B, et al. Acute schistosomiasis in & European students returning from fieldwork at Lake Tanganyika Tanzania. J Travel Med 2013; 20:380–383. This study reports on eight of 16 students exposed to a lake in Tanzania who developed schistosomiasis. Given that this is not frequently reported in travelers, this could impact advice on traveling behavior and returning traveler diagnostic workup. 9. Meltzer E, Schwartz E. Schistosomiasis: current epidemiology and management in travelers. Curr Infect Dis Rep 2013; 15:211–215. 10. Cordina CJ, Culleton R, Jones BL, et al. Plasmodium knowlesi: clinical presentation and laboratory diagnosis of the first human case in a Scottish traveler. J Travel Med 2014; 21:357–360. 11. Baize S, Pannetier D, Oestereich L, et al. Emergence of Zaire ebola virus & disease in Guinea. N Engl J Med (in press). Ebola virus hemorrhagic fever presents with severe diarrhea, as reported in this preliminary report.
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12. Dixon MG, Schafer IJ. Ebola viral disease outbreak: west Africa 2014. MMWR Morb Mortal Wkly Rep 2014; 63:548–551. 13. Savini H, Gautret P, Gaudart J, et al. GeoSentinel Surveillance Network. & Travel-associated diseases, Indian Ocean Islands, 1997-2010. Emerg Infect Dis 2013; 19:1297–1301. Utilizing the GeoSentinel Surveillance System described in [3&&], this article describes 1415 returning travelers from the Indian Ocean islands and their clinical presentation. 14. Gunaratnam P, Tobin S, Seale H, McAnulty JM. Infectious diseases in & returned travellers, NSW, 2010-2011. N S W Public Health Bull 2014; 24:171–175. In contrast to destination-based analysis, this report presents clinical features according to the country of origin of the travelers and may serve as a tool for local travel clinics. 15. Plessa E, Tansarli GS, Xanthopoulos D, Falagas ME. Morbidity and outcomes of foreign travelers in Zakynthos island Greece: a retrospective study. PLoS One 2014; 9:e94416. 16. Antikainen J, Kantele A, Pakkanen SH, et al. A quantitative polymerase chain && reaction assay for rapid detection of 9 pathogens directly from stools of travelers with diarrhea. Clin Gastroenterol Hepatol 2013; 11:1300.e3– 1307.e3. This study presents a rapid, quantitative PCR-based assay for identifying nine major bacterial pathogens, all common causes of travelers’ diarrhea. Although the report still needs to be validated, it does provide impressive accuracy and pathogen detection rates. 17. Munson GP. Virulence regulons of enterotoxigenic Escherichia coli. Immunol Res 2013; 57:229–236. 18. Sheikh A, Lou Q, Roy K, et al. Contribution of the highly conserved EaeH & surface protein to enterotoxigenic Escherichia coli pathogenesis. Infect Immun 2014; 82:3657–3666. Bacterial pathogenesis is a key to the development of novel vaccines. EaeH, a bacterial adhesin involved in colonization and delivery of enterotoxin, is presented as a potential target for vaccine development. 19. Estrada-Garcia T, Navarro-Garcia F. Enteroaggregative Escherichia coli pathotype: a genetically heterogeneous emerging foodborne enteropathogen. FEMS Immunol Med Microbiol 2012; 66:281–298. 20. Estrada-Garcia T, Perez-Martinez I, Bernal-Reynaga R, Zaidi MB. Enteroag& gregative coli: a pathogen bridging the north and south. Curr Trop Med Rep 2014; 1:88–96. This detailed review describes the basic and the clinical aspects of EAEC, one of the leading causes of travelers’ diarrhea, including epidemiology, pathogenesis, clinical manifestations, and treatment. 21. Karst SM, Wobus CE, Goodfellow IG, et al. Advances in norovirus biology. && Cell Host Microbe 2014; 15:668–680. This excellent review details the molecular virology, cell and animal models, pathogenesis, host immune responses, and insights into vaccine development for the most common cause of infectious diarrhea, norovirus. 22. Ajami NJ, Kavanagh OV, Ramani S, et al. Seroepidemiology of norovirusassociated travelers’ diarrhea. J Travel Med 2014; 21:6–11. 23. Livio S, Strockbine NA, Panchalingam S, et al. Shigella isolates from the & global enteric multicenter study inform vaccine development. Clin Infect Dis 2014; 159:933–941. As part of the Global Enteric Multicenter Study, this study analyzed 1130 isolates of Shigella to identify potential targets for future vaccine development that would cover a large variety of serotypes. 24. Zautner AE, Johann C, Strubel A, et al. Seroprevalence of campylobacteriosis and relevant postinfectious sequelae. Eur J Clin Microbiol Infect Dis 2014; 33:1019–1027. 25. Connor BA. Persistent travelers’ diarrhea. In: Brunette G, editor. The Yellow & Book: CDC Health Information for International Travel 2014. New York, New York: Oxford University Press; 2014. pp. 479–482. This Centers for Disease Control and Prevention’s ‘Yellow Book’ chapter focuses on persistent travelers’ diarrhea and provides background for understanding the relationship between travelers’ diarrhea and PI-IBS. It is available through the following link: http://wwwnc.cdc.gov/travel/yellowbook/2014/chapter-5-posttravel-evaluation/persistent-travelers-diarrhea. 26. Ross AGP, Olds GR, Cripps AW, et al. Enteropathogens and chronic illness && in returning travelers. N Engl J Med 2013; 368:1817–1825. This detailed review on chronic complications of travelers’ diarrhea highlights leading parasitic and bacterial pathogens, in relation to travel destination, and discusses the diagnosis and treatment. 27. Langenberg MCC, Wismans PJ, van Genderen PJJ. Distinguishing tropical & sprue from celiac disease in returning travellers with chronic diarrhoea: a diagnostic challenge? Travel Med Infect Dis 2014; 12:401–405. In this interesting report, comparison is made between the related diagnoses – celiac disease and tropical sprue. 28. Raoult D, Fenollar F, Rolain JM, et al. Tropheryma whipplei in children with gastroenteritis. Emerg Infect Dis 2010; 16:776–782. 29. Gautret P, Lagier J-C, Benkouiten S, et al. Does Tropheryma whipplei & contribute to travelers’ diarrhea?: a PCR analysis of paired stool samples in French travelers to Senegal. Travel Med Infect Dis 2014; 12:264–267. Tropheryma whipplei is traditionally thought to cause chronic diarrhea. In this study, it is discussed as a cause of acute symptoms in the context of returning travelers.
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An update on travelers’ diarrhea Zaidi and Wine 30. Neuberger A, Saadi T, Shetern A, Schwartz E. Clostridium difficile infection in travelers: a neglected pathogen? J Travel Med 2013; 20:37–43. 31. Pitzurra R, Fried M, Rogler G, et al. Irritable bowel syndrome among a cohort of European travelers to resource-limited destinations. J Travel Med 2011; 18:250–256. 32. Gallego V, Berberian G, Lloveras S, et al. The 2014 FIFA World Cup: & communicable disease risks and advice for visitors to Brazil – A review from the Latin American Society for Travel Medicine (SLAMVI). Travel Med Infect Dis 2014; 12:208–218. In preparation for the 2014 FIFA World Cup in Brazil, this timely study summarized the major communicable diseases that travelers may encounter and how to reduce risk of exposure; this advice is probably applicable to other travel destinations. 33. Mackaness CA, Osborne A, Verma D, et al. A quality improvement initiative && using a novel travel survey to promote patient-centered counseling. J Travel Med 2013; 20:237–242. Recognizing the limited ability of current approaches to prevent travelers’ diarrhea, this study outlines a quality improvement approach for guiding travelers through the analysis of a survey. 34. Alajbegovic S, Sanders JW, Atherly DE, Riddle MS. Effectiveness of rifaximin and fluoroquinolones in preventing travelers’ diarrhea (TD): a systematic review and meta-analysis. Syst Rev 2012; 1:39. 35. Nair D. Travelers’ diarrhea: prevention, treatment, and posttrip evaluation. && J Fam Pract 2013; 62:356–361. This practical guide for the practitioner provides simple and supported advice on prevention and management of travelers’ diarrhea. It includes details on choice and doses of antibiotics. 36. Nickonchuk T, Lindblad AJ, Kolber MR. Oral cholera vaccine for traveler’s diarrhea prophylaxis. Can Fam Physician 2014; 60:451. 37. Lo´pez-Gigosos R, Campins M, Calvo MJ, et al. Effectiveness of the WC/rBS & oral cholera vaccine in the prevention of traveler’s diarrhea: a prospective cohort study. Hum Vaccin Immunother 2013; 9:692–698. In this prospective, randomized study on the whole-cell/recombinant-B-subunit Cholera/ETEC vaccine, two of every seven cases of traveler’s diarrhea were prevented by the vaccine. 38. Frech SA, Dupont HL, Bourgeois AL, et al. Use of a patch containing heatlabile toxin from Escherichia coli against travellers’ diarrhoea: a phase II, randomised, double-blind, placebo-controlled field trial. Lancet 2008; 371:2019–2025. 39. Behrens RH, Cramer JP, Jelinek T, et al. Efficacy and safety of a patch vaccine & containing heat-labile toxin from Escherichia coli against travellers’ diarrhoea: a phase 3, randomised, double-blind, placebo-controlled field trial in travellers from Europe to Mexico and Guatemala. Lancet Infect Dis 2014; 14:197–204. This randomized double-blind, placebo-controlled trial on an ETEC heat-labile toxin-based vaccine patch was negative. Although the vaccine was effectively absorbed, it did not reduce travelers’ diarrhea in the treatment group. 40. Rivera FP, Medina AM, Aldasoro E, et al. Genotypic characterization of & enterotoxigenic Escherichia coli strains causing traveler’s diarrhea. J Clin Microbiol 2013; 51:633–635. In an attempt to identify vaccine targets for ETEC, this study surveyed 52 clinical isolates and characterized common colonization factors.
41. Holmgren J, Bourgeois L, Carlin N, et al. Development and preclinical evaluation of safety and immunogenicity of an oral ETEC vaccine containing inactivated E. coli bacteria overexpressing colonization factors CFA/I, CS3 CS5 and CS6 combined with a hybrid LT/CT B subunit antigen, administered alone and together with dmLT. Vaccine 2013; 31:2457–2464. 42. El-Kamary SS, Cohen MB, Bourgeois a L, et al. Safety and immunogenicity of a single oral dose of recombinant double mutant heat-labile toxin derived from enterotoxigenic Escherichia coli. Clin Vaccine Immunol 2013; 20:1764– 1770. 43. McFarland LV. Meta-analysis of probiotics for the prevention of traveler’s diarrhea. Travel Med Infect Dis 2007; 5:97–105. 44. Sarowska J, Choroszy-Kro´l I, Regulska-Ilow B, et al. The therapeutic effect of & probiotic bacteria on gastrointestinal diseases. Adv Clin Exp Med 2013; 22:759–766. This review article details current knowledge on probiotic use for intestinal conditions with some comments on travelers’ diarrhea. 45. Virk A, Mandrekar J, Berbari EF, et al. A randomized, double blind, placebocontrolled trial of an oral synbiotic (AKSB) for prevention of travelers’ diarrhea. J Travel Med 2013; 20:88–94. 46. Fox TG, Manaloor JJ, Christenson JC. Travel-related infections in children. & Pediatr Clin North Am 2013; 60:507–527. This review discusses pediatric-specific considerations related to travel, including travelers’ diarrhea. 47. Vandenplas Y, De Greef E, Devreker T, et al. Probiotics and prebiotics in & infants and children. Curr Infect Dis Rep 2013; 15:251–262. This review on probiotics use in children includes a section on probiotics for travelers’ diarrhea, highlighting the paucity of data. 48. Soonawala D, van Eggermond AM, Fidder H, Visser LG. Pretravel preparation and travel-related morbidity in patients with inflammatory bowel disease. Inflamm Bowel Dis 2012; 18:2079–2085. 49. Baaten GG, Geskus RB, Kint JA, et al. Symptoms of infectious diseases in immunocompromised travelers: a prospective study with matched controls. J Travel Med 2011; 18:318–326. 50. Rosen J. Travel medicine and the solid-organ transplant recipient. Infect Dis && Clin North Am 2013; 27:429–457. Focusing on patients after solid-organ transplant, this study provides an excellent resource, including risk assessment and practical vaccination and treatment advice with a section on travelers’ diarrhea in this setting. 51. Askling HH, Dalm VA. The medically immunocompromised adult traveler and & pretravel counseling: status quo 2014. Travel Med Infect Dis 2014; 12:219– 228. This review highlights travel-related concerns in immunocompromised patients. First, different classes of immunosuppressive medications are defined and then advice on prophylaxis and treatment is provided. 52. Kotton CN, Freedman DO. Immunocompromised travelers. In: Brunette GW, && editor. The Yellow Book: CDC Health Information for International Travel 2014. New York, New York: Oxford University Press; 2014. pp. 544–556. This Centers for Disease Control and Prevention’s ‘Yellow Book’ chapter on immunocompromised travelers is an excellent resource on different levels of immune deficiency and their impact on vaccination and travel advice.
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