Traveler's diarrhea

Diarrheal illness is a major health problem associated with international travel in terms of frequency and economic impact. Traveler's diarrhea refers to an enteric ill-ness acquired when a person travels from a developed to a developing country, but can include any travel-associated diarrheal disease. Today, over 50 million people travel each year from developed countries to developing countries and 20–50% of these travelers report having diarrhea during the first 2 weeks of their stay. The chances of acquiring this condition depend on well-known risk factors, such as origin and destination of travel, travel season, and various host factors.1-3 Traveler's diarrhea is an important factor in tourism because the threat of illness may deter travelers from a high-risk area, and is also an important economic factor for the host country due to the influence on foreign investment and business ventures. There has been no significant decline in the incidence of traveler's diarrhea since the 1970s, despite efforts made by the tourism industry to improve local infrastructure (e.g. water treatment, sanitation and healthcare).2,3 Traveler's diarrhea is defined as the passage of three or more unformed stools in 24 h during or shortly after travel, or any number of loose stools if accompanied by fever, cramping, abdominal pain or vomiting.4,5 This definition has allowed standardization for research but many travelers experience milder symptoms that do not fit this definition; 25% of tourists in one study reported a change in stool consistency but passed only 1–2 motions per day.6 The definition can be widened to include more trivial bowel disturbances that are sufficient enough to disrupt a business commitment or travel plans. Dysentery in travelers is defined as any number of loose stools accompanied by blood. Geographical destination is the most important determinant of risk; the geographical variation in prevalence rates of diarrhea will depend on local water quality, sewage disposal, asymptomatic carriage of enteropathogens by the local population (especially food handlers), catering standards in hotels and restaurants or other food outlets. Geographicaql destination can be classified according to the degree of risk of acquiring diarrhea.7 High-risk destinations include Latin America, Africa, the Middle East and Asia (attack rates are 20–50%); intermediate-risk places include southern Europe, China, Russia, and the Caribbean (attack rates are 0–15%); while low risk destinations include Canada, USA, northern Europe, Australia, New Zealand and Japan (attack rates are 2–4%). Seasonality can be an important factor; the risk appears to be higher for Escherichia coli-induced traveler's diarrhea in the rainy season and summer time in some regions, but not for Campylobacter jejuni.8 Mode of travel influences exposure to enteropathogens. For example, the risk is increased for back-packers and soldiers, possibly due to greater ingestion of potentially contaminated food and water, and a more adventurous lifestyle.9 Extremes of age increase the risk of traveler's diarrhea because of decreased immunity and greater fecal/oral contamination. Immunodeficiency states (persons with AIDS, IgA deficiency) increase the risk. Gastric acid is an important barrier to the transfer of orally acquired enteropathogens in the small intestine and consequently patients with hypo or achlorhydria, including those with gastric atrophy, pernicious anemia or post gastrectomy are potentially at increased risk of infection. It is now evident that users of H2 receptor antagonists and proton pump inhibitors are at increased risk of intestinal bacterial infections, especially those over 65 years of age.10 Patients with chronic gastrointestinal disorders may have an increased risk due to reduced mucosal defences. Host genetics may be important: patients with blood group O more frequently experience shigellosis and have more severe cholera. Previous travel to a high risk area during the preceding 6 months does confer some protection against traveler's diarrhea, although this is not long-lasting.11 Traveler's diarrhea is acquired through the ingestion of fecally contaminated food and less commonly water. High-risk foods include raw or poorly cooked seafood or meat, salads and raw vegetables, dairy products in areas with no refrigeration, cold buffets, food from street traders, fruits that cannot be peeled, ice-cream, ice, and local tap water. Some microorganisms can survive in food heated to 50°C (too hot to touch) and multiply as the temperature decreases.12 Several enteropathogens can survive freezing in ice cubes and multiply in soft and alcoholic drinks, even whiskey or tequila cannot reliably ‘sterilize’ ice.13,14 Person to person spread is relatively unimportant for travelers, although some viruses such as the Norwalk virus and other small round structured viruses (SRSV) may be spread by aerosol, which might contribute to the high secondary attack rates that occur in families and on cruise ships.15 Some enteropathogens, mainly bacteria and protozoa, are spread during sexual activity, particularly during intimate oro-anal contact. Risk factors for sexually transmitted intestinal infections include sexual promiscuity, sexual practices allowing fecal-oral transmission, and the carriage of enteric pathogens by asymptomatic homosexual men. Swimming pools and seawater contaminated with sewage and/or fecal microorganisms are sources of infection, particularly protozoa, and are risk factors for traveler's diarrhea. Swimming pool water can be contaminated by the feces of young children and cysts of certain parasites. Cryptosporidium parvum and Giardia intestinalis are able to survive in chlorinated water for extended periods. Freshwater lakes are not routinely monitored and many that have been tested in the UK have been contaminated with cyanobacterial toxins, thought to arise from nitrate and phosphate fertilizers and hot weather. Viral diarrhea can be acquired through water and possibly aerosol transmission. Epidemiological studies during the last 20 years have shown that the vast majority of episodes of traveler's diarrhea are due to intestinal infection; traveler's diarrhea is caused by a specific organism in approximately 80% of cases (Table 1).7,16 Prior to this, diarrhea in travelers was attributed to a ‘change in the water’ or possibly ‘traveler's nerves’ as a result of stress or overindulgence in local food or wine. The majority of cases are secondary to bacteria; enterotoxigenic Escherichia coli (ETEC) is the most frequently isolated in all parts of the world but the highest isolation rates are generally in Africa and Central America. Shigella spp. is also common in these regions, whereas Campylobacter jejuni is more common in travelers to Asia. Despite the importance of cholera as a cause of diarrhea in the Indian subcontinent and in Central and South America, it rarely affects travelers. Protozoa, viruses and helminths are also implicated but only contribute to 10–15% of the causes of traveler's diarrhea. Certain destinations are renowned for infection with specific enteropathogens, for example giardiasis in parts of eastern Europe. Although viruses are a major cause of diarrhea in children, they are much less common as the cause of traveler's diarrhea in adults. Enterotoxigenic Escherichia coli produces two major toxins: the heat labile toxin (LT) and the heat stable toxin (STa). The LT closely resembles the cholera toxin and consists of one A subunit (A1 and A2 linked by a disulfide bond) and five B subunits. The LT binds to a receptor on the enterocyte microvillous membrane, the GM1 ganglioside, which induces configurational changes in the membrane allowing entry of the enzymically active A1 subunit. The A1 subunit is an ADP-ribosyl transferase and is transported through the cytoplasm and then covalently links ADP ribose to Gs, the stimulatory component of adenylate cyclase (an enzyme located on the basolateral cell membrane), resulting in enzyme activation and increased intracellular concentrations of cyclic adenosine monophosphate (cAMP). This activates a secretory cascade involving protein kinase C, protein phosphorylation and the opening of chloride channels in the apical membrane of the enterocyte, predominantly in the crypts. As the interior of the cell is electronegative relative to the outside, an electrical driving force for chloride extrusion occurs. The STa is a much smaller molecule and acts through an apical receptor, which is directly linked to membrane-bound guanylate cyclase. The ST toxins are also ADP-ribosylating toxins but activate guanylate cyclase to increase intracellular cyclic guanylate monophosphate (cGMP). Like cAMP, cGMP causes activation of cyclic nucleotide dependent protein kinases, protein phosphorylation and the opening of chloride channels. In addition to the effects of LT and ST on chloride ion secretion, both enterotoxins also inhibit sodium and chloride absorption. Although these intracellular mechanisms have been well characterized, there is increasing evidence that both LT and STa can promote intestinal secretion through neural reflexes in the enteric nervous system.17 Small round structured viruses and rotavirus enter the villus epithelial cells and produce cytopathic changes, which eventually result in enterocyte loss. There is therefore an acute villous atrophy during the first 24–48 h of infection following which there is proliferation of crypt cells and subsequent recovery in villus morphology. Loss of enterocytes accounts for the decrease in disaccharidase activity, and hence transient lactose intolerance that can be associated with these infections. The microbial pathogens that produce dysentery express virulence factors that either allow direct invasion of the epithelial cell and/or liberate cytotoxins which produce cell death. Shigella spp., Salmonella spp., and EIEC all express invasion plasmid antigens (Ipa) on their surface which subvert the cytoskeleton of the epithelial cell allowing formation of endocytotic vesicles which transport the organism into the host cytoplasm. Cell lysis, organism multiplication occurs with liberation of cytotoxin intracellularly. The invasin and cytotoxin virulence factors are only part of a cascade of events that produces inflammation in the distal ileum and colon. Entamoeba histolytica, an important cause of dysentery, is not strictly an invasive organism. Following lectin-mediated adherence to the epithelial cell it liberates a variety of cytotoxic compounds, which rapidly produce cell death. Amoebapore is a pore-forming protein which creates high conductance ion channels in the cell membrane, allowing rapid influx of calcium and other ions leading to disequilibrium and cell death. E. histolytica then phagocytoses the dead cell and moves on to penetrate further into the mucosa. Protozoal enteropathogens such as G intestinalis, C parvum and Cyclospora spp., are all associated with varying degrees of villus architectural abnormality and an inflammatory response in the mucosa, but how they cause persistent diarrhea is not completely understood. Diarrhea can occur in the absence of morphological changes, suggesting other mechanisms must also be operating. Traveler's diarrhea may occur anytime during travel or within 10 days of return, but typically occurs on the third day after arrival, with a second episode starting approximately a week after arrival.7 Most individuals pass 3–5 loose or watery stools a day, but 20% pass > 6 watery stools a day. It is typically mild and self-limiting; the mean duration of diarrhea is 4 days with a median of 2 days, 10% last more than 1 week, 2% will persist for a month, and 1% for more than 3 months.2,18 Symptoms for those individuals with months of diarrheal symptoms following travel to high-risk but a may be for to a to of abdominal and 10% of and/or 20% of are to for 1–2 days 20% have dysentery with and diarrhea. common symptoms are fecal and is but is more common in cases with an is a major of food due to a bacterial and are associated with bacterial infections generally have and a much duration of a This with the illness of traveler's diarrhea, which for a Traveler's diarrhea can be classified into three according to acute watery and persistent diarrhea with or intestinal (Table Most episodes of acute watery diarrhea are mild and transient but can be severe with is rarely significant and symptoms are mild or In children and the may be more with is but if is symptoms such as abdominal and may be but are generally not Dysentery commonly with loose small stools with blood and The may as watery diarrhea but symptoms rapidly Dysentery is a of inflammation of the and distal ileum due to invasive enteropathogens. symptoms are common and include and pain and which can be occur in the during and frequently the diarrhea. The illness is but can be In for travelers, and can than 1% of travelers from persistent diarrhea (Table The diarrhea may have the of accompanied by loss. symptoms may be such as and infections in the small intestine can produce a disaccharidase which may as lactose There is evidence to that intestinal infection may a bowel such as bowel Some patients with have a mild but significant increase in mucosal inflammatory cells and an increase in both of which are thought to contribute to with can acute diarrheal infections, Campylobacter Salmonella spp., Shigella spp. and all individuals all of the There is a with is associated with Campylobacter jejuni infection, which now appears to be the most common cause of the in the developed symptoms have been to occur 1 and days after the of bowel predominantly and generally a is a of Shigella 1 infection and Escherichia coli infection. This is secondary to the effects of the toxin and toxins 1 and the by may from the and many other such as acute and and infections of the and and Protozoal infections such as E. may be by and of acute watery diarrhea is evident from the and the to a specific is rarely The most common organism to cause traveler's diarrhea is but as this is not routinely in the a specific is with diarrhea is due to a virus or it is important to patients with potentially diarrhea or diarrhea, and stools or is important in for those patients with stool and as the first of A stool be as a and three stool be the for by an and then for bacterial enteropathogens. diarrhea be more causes are or dysentery, and fecal by an is the for intestinalis, Cryptosporidium Cyclospora Entamoeba histolytica and the The of a stool for Giardia spp. infection is only and to with of three stool have been developed that increase the of the and direct have both been developed for Giardia spp., and for Cryptosporidium spp., with increased The is to Cyclospora and spp., as well as by and of In diarrhea when infection is mucosal from the distal gastrointestinal may be but stools on three diarrhea be for infection, a first of inflammatory bowel or for a such as or to a is at this There are to the of traveler's diarrhea. The first is to decrease exposure by and the health infrastructure of developing countries is an important but in one and the of it or the and will with is 2% of travelers to Africa and Asia able to to be heated to > or water 10 is or the of water and of high-risk foods are also include high-risk such as in and the of health on the incidence of traveler's diarrhea because there are with the to especially to and is of is not despite the protection rates by This is because of there is a risk of a for and a of may be by the the various that have been are to be the first pathogens are The increasing and of in of jejuni to has been reported from and Asia and is a of E. coli since when have been for on a a of > have an and of is on the day of and for 2 days after return, but not be for more than 3 and are as when in a low (e.g. per protection against traveler's diarrhea by to that the enteropathogens in the of study are to the have been such as nervous gastrointestinal and more severe including are not for in children and have rates or have a higher incidence of include and and The to be made on a by and may be in those most at risk. with increasing the risk or of diarrhea such as patients with bowel gastric or chronic on an important such as or days through illness decrease the of the There is in the of a an that is from the allowing high intestinal and although In a with has shown with to and for the of patients with bacterial diarrhea to or This which is in to enteric bacterial infection, be a for such as protection rates of the is a day. It has but less such as of the and and It is to because of the and has protection rates with is not a for in Europe, it is not is There are no for acute diarrheal disease. cholera is but only produces protection against protection is but may be for against Shigella spp. and Salmonella spp. are The of traveler's diarrhea is and it be for even a to a variety of the enteropathogens that are for traveler's diarrhea. The chances that a will be are to are A is defined as a microbial food to mechanisms that may a in the of these include the of or as well as the for or and of the The of protection by bacteria as have low and they have been shown to be no has been able to protection reported that to tourists to to a in the was significant only for one In the risk of traveler's diarrhea was in travelers and in the which that there was although was evident in studies of other such as and because various to in their for of the A mild but significant and and protection against traveler's diarrhea, with a was reported for travelers to Africa and have been shown to be in such as of may be an The of bacterial such as may increase the number of such as evidence is to this has any there is no for traveler's diarrhea, and of and the for such as and is the of because most cases are mild and travelers now and include and and when to and when to of and is sufficient with and or and are of food is the stools are by of in the of of and with or water are for those at risk of including young children, the or those with severe is 6 of 1 of and 1 of water. can be for and high soft be because of intolerance with associated diarrhea. with such as and are by increasing intestinal time and the for of and have a on fecal stool frequency by to is 4 with 2 after each unformed and the is in a In are and in stool although their most effects in the duration and of the illness occur when with an are not in patients with dysentery because of the risk of associated with there is evidence for this have also been thought to increase the fecal carriage of enteropathogens, but there is evidence that this is the has been shown to be in the of dysentery if in with an may have some activity, but this to is are not in children the age of 2 years because of of nervous (e.g. are as but have the to cause are the (e.g. but can be to young children and is an and is in the of traveler's the number of unformed stools by approximately This is attributed to the of it is also thought to have and As it is not a of because a number of must be it has a of to 4 it can with the of other (e.g. and has some There is an for the that will directly inhibit secretory within the mechanisms an especially those to calcium and the calcium a has been in but was because of no with has on the enteric nervous It is now well that the is in the of intestinal A number of have been in the many are thought to be in intestinal secretion and are therefore for the of watery has been implicated in the secretory by the cholera toxin and there is evidence that and receptor antagonists can inhibit secretion both in and in the of cholera has been to inhibitors of the enzyme such as which the of in the The as in the gastrointestinal by and the of This produces a in water and secretion any on intestinal has and and is in in as well as In a study in in the of acute watery diarrhea in children, was shown to be and The group a and significant in h stool stool of and duration of diarrhea. can both the and duration of diarrhea and the duration of when as an to be in to severe watery diarrhea and There is now evidence that for 3–5 days can the duration and of traveler's frequency is reduced by and the duration of illness to have the highest with the studies of or 1–2 day have shown that have with is It is for certain travelers to for are The of the of including travel and to the There are the of with other mild infections such as and infections, is to have a major on world The of for traveler's diarrhea may be less to produce although this has not been in a are for the of dysentery caused by most can but travelers to if is severe and/or there are other symptoms such as fever, or abdominal is in cases of and Campylobacter jejuni infections. In infection there is evidence that do not the of the illness if are > 4 days after the of 3 for days, is in the developing world for acute diarrhea because it and EIEC infection with evidence of can be with the for but a for has not been in infection for two do not improve especially if well after infection is and there is evidence that can promote the of due to the increased of and of toxins and leading to with young children or are to a of is and and especially be if a has for more than 24 h or has cannot be to children in of the to and are generally diarrhea days, be with a to further Most of the enteropathogens are with no cause is is to bowel such as or inflammatory bowel disease. symptoms may the of Traveler's diarrhea is a mild has a in certain of travelers. are for and and is in to severe watery diarrhea and of of diarrhea in the developing world have not in and to improve health is not only for the but also for the

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