Traveler’s Diarrhea Recommendations for Solid Organ Transplant Recipients and Donors

Diarrhea is the most common illness in people traveling from resource-rich to resource-limited regions of the world.1 Most episodes of traveler’s diarrhea (TD) are benign and self-limited, but may require extra care in immunosuppressed patients.2,3 The major associated problem is dehydration, which can be exacerbated by immunosuppressive agents. TD refers to diarrhea that develops during or within 10 days of returning from travel to resource-limited countries or regions. For epidemiological purposes, it is traditionally categorized into 3 forms: severe, moderate, and mild.4 Severe TD refers to the passage of 6 or more unformed stools in a 24-hour period irrespective of the presence of at least 1 of these other symptoms: nausea, vomiting, abdominal pain or cramps, fever, or blood in stools. Moderate TD is defined as the passage of 1 or 2 unformed stools in 24 hours, plus at least 1 of the above symptoms or 3 to 5 unformed stools in 24 hours without other symptoms. Passage of 1 or 2 unformed stools in 24 hours without other symptoms is considered mild. Recently, a more functional classification has been proposed, taking into account the tolerability of the diarrheal illness and functional impairment of the patient that it causes.5,6 EPIDEMIOLOGY The incidence of TD is approximately 10% to 40%, depending on the travel destination. There have been few systematic studies in transplant recipients, so much of the discussion below is extrapolated from studies in all travelers. In immunosuppressed travelers, rates of infection are not necessarily higher, but the severity of illness can be increased.3,7 The viral, bacterial, and parasitic organisms that cause TD are usually transmitted by food and water, and the risk of TD is the highest in regions where sanitation and hygienic practices are poor. South and Southeast Asia, Africa (except South Africa), South and Central America, and Mexico are considered high risk (incidence greater than 20%). Regions that are moderate risk (10-20%) include Caribbean Islands, South Africa, Central and East Asia, Eastern Europe, and the Middle East, including Israel. Northern and Western Europe, Australia and New Zealand, the United States, Canada, Singapore, and Japan are classified as low-risk areas (less than 10%).4 Two decades ago, the incidence of TD was about 60%8,9 but it has decreased in countries with increasing economies and in some previously high-risk destinations with improved tourism infrastructure. South Asia, India, Nepal, and West/Central Africa remain the destinations with the highest risk. The largest experience in travelers returning with disease acquired during travel to developing countries comes from GeoSentinel, the global surveillance network of the International Society of Travel Medicine and the United States Centers for Disease Control and Prevention10,11 Since GeoSentinel’s inception in 1995, it has grown to include more than 50 reporting sites in 24 countries on 6 continents, with over 200 000 patient records collected. Retrospective observational studies from the GeoSentinel network showed that rates of gastrointestinal infection reported in travelers returning to high-income settings, such as Western and Northern Europe, were inversely related to the income level of the country they had visited.3,12,13 These studies are particularly valuable for providing insight into the etiology and risk factors for the development of prolonged diarrhea in returned travelers. These differ from the bacterial and viral causes of the more common short-lived diarrhea typically experienced by travelers earlier during their travel. Risk Groups Environmental Factors The risk of having diarrhea is highest during the first 7 days of travel and then progressively decreases. As well as destination, style of travel and available budget are important as they often determine where a traveler purchases meals. Backpackers often favor street vendors, which are known to have a high-risk of contaminated food.14 Buffet-style foods exposed to warm environmental conditions, even those served in a 5-star hotel, are also associated with a high incidence of TD.15 The risk of TD varies depending on the season, with a higher risk during warmer and wetter seasons.16 Host Factors Genetic factors associated with an increased risk of TD are being increasingly recognized and are also being linked with susceptibility to postdiarrheal irritable bowel syndrome.17 For example, polymorphisms in genes controlling production of the proinflamatory cytokine interleukin 8 and lactoferrin correlate with greater intestinal inflammation and symptoms in US travelers to Mexico.18,19 Osteoprotegerin, an immunoregulatory member of the tumor necrosis factor receptor superfamily, may function as an antiinflammatory modulator that increases susceptibility to TD and CD14, a receptor for bacterial lipopolysaccharide binding, is associated with the innate immune response to enteric infection and inflammation. Single-nucleotide polymorphisms of these may increase susceptibility to TD.20,21 Possession of different blood group ABO(H) histocompatibility antigens has long been associated with susceptibility to bacterial enteropathogens, such as Vibrio cholerae, and more recently absence mutations in the related FUT2 gene, which provides ligands for virus binding, have been shown to reduce susceptibility to Norovirus infection.22,23 Younger travelers tend to have a greater risk of acquiring TD, probably because they eat more food, resulting in the ingestion of a larger quantity of pathogens.24 Also, younger travelers are more adventurous.24 Anything that reduces the gastric acid barrier to pathogens increases the risk of a wide variety of gastrointestinal infections from cholera to Clostridium difficile. This includes gastric sugery for peptic ulcer disease, antacids, H2 receptor antagonists and protein pump inhibitors. Many transplant recipients will be taking these medications.25,26 ETIOLOGY Because there are few studies of travel-related diarrhea in transplant patients, the following discussion extrapolates from more general studies in travelers, highlighting areas of known or potential differences in the immunosuppressed. Although causes of diarrhea in solid-organ transplant recipients are similar to those in the general population, there are some differences, such as a higher incidence of drug-induced diarrhea and opportunistic infections in transplant patients.25 In a study of 52 diarrheal episodes among 43 solid-organ transplant recipients, the cause was determined in 43 (83%) recipients. Infectious etiologies accounted for 77% of cases, whereas drug-related diarrhea occurred in 23%.26 The relative importance of different pathogens in traveler's diarrhea greatly varies per the region visited and the season of travel.1 As in the general population, bacterial agents are the most frequent cause of TD in transplant patients.27 The most common causes are enterotoxigenic Escherichia coli (ETEC) and enteroaggregative E. coli, followed by Shigella, Salmonella, Campylobacter, Aeromonas, noncholeric vibrios, and Plesiomonas spp.1 In Asia, Campylobacter jejuni is a particularly frequent cause of traveler's diarrhea.28 Although viruses are rarely identified as the cause of traveler's diarrhea, their true importance is probably underappreciated because specific diagnostic tests (such as polymerase chain reaction) are not often performed in routine clinical practice.29 Noroviruses are recognized to be a leading cause of acute viral gastroenteritis worldwide and have been implicated in TD in visitors to Mexico, especially during the winter.30 Although noroviruses are increasingly being recognized as a significant cause of both acute and chronic diarrhea in solid-organ transplant recipients, their role as a cause of TD has not been specifically analyzed.31,32 Rotaviruses are known not only as a cause of TD but also of severe gastroenteritis in immunocompromised hosts, including transplant patients.33 Certain parasitic infections (Cryptosporidium spp, Cystoisospora belli, Cyclospora spp, Microsporidia, Giardia intestinalis) are highly prevalent in developing regions, and may be a significant cause of gastroenteritis in solid-organ recipients.34 However, most of the available information on diarrhea due to intestinal protozoa in transplant patients is derived from case reports or small series from single institutions.35,36 Cryptosporidium and Giardia the most common parasites infecting transplant recipients, especially in travelers to endemic regions.34 Cryptosporidial infection is a common cause of infective diarrhea in transplant recipients in endemic areas, such as India, the Middle East, and South America. In India, its prevalence was estimated to be over 20% in a study conducted by Udgiri et al.36 The microsporidia most often linked to gastrointestinal illnesses are Enterocytozoon bieneusi and Encephalitozoon intestinalis. However, Entameba histolytica is rarely identified in transplant recipients.34 Strongyloides stercoralis is a gut nematode that causes chronic gastrointestinal and skin manifestations due to its autoinfective lifecycle. Transplant recipients are at risk for developing Strongyloides hyperinfection syndrome secondary to chronic intestinal infection, acquisition of primary Strongyloides infection in tropical and subtropical areas, or allograft transmission.37 Coinfection is a common feature of parasitic infection in the setting of transplantation, and invasive disease may be associated with disseminated viral or bacterial infections.34 CLINICAL MANIFESTATIONS TD is characterized by an increase in frequency of bowel movements and a change in consistency of the stool (soft to liquid) that usually begins within 2 to 3 days of arrival. More than 90% of illnesses start within the first 2 weeks.1,6,28 Three overlapping syndromes may be discerned. The first is short-lived watery diarrhea with little or no fever. This may be triggered by invasive pathogens, and be associated with secretory diarrhea. The second syndrome is a more prolonged disease, which may be accompanied by bloody diarrhea (dysentery) and fever. The third is chronic diarrhea lasting for more than 1 month, which affects 1% to 3% of patients with diarrhea. This syndrome is often associated with parasitic infections, but also can be due to invasive bacterial pathogens, such as Shigella, Salmonella, and Campylobacter.11,12 Giardiasis and amebiasis can be linked with chronic diarrhea in solid-organ transplant recipients. Giardia usually causes enteritis with watery diarrhea, malabsorption, bloating and flatulence, whereas amebiasis produces more often colitis with bloody stools.25 Intestinal microsporidiosis is also a well-known cause of chronic diarrhea and wasting in immunocompromised hosts.38 Diarrhea in organ transplant recipients is a potentially debilitating condition that can lead to severe dehydration, which compromises renal function, a marked increase in toxicity of immunosuppressants, and organ rejection, producing a negative impact on the recipient’s quality of life.26,39 Long-term complications of TD can occur, such as postinfectious irritable bowel syndrome, reactive arthritis often associated with HLA-B27, and Guillain-Barré syndrome.3 It is not clear whether long-term sequelae such as irritable bowel syndrome are more common or severe in solid-organ transplant recipients compared with other travelers. DIAGNOSIS APPROACH Most self-limited episodes of diarrhea while traveling will not require investigation, but a different approach is needed for diarrhea that persists. This approach is sometimes limited to investigation of those that continue to have diarrhea after empiric treatment for common pathogens, such as Giardia.40 Discriminating between immunosuppression-related and infection-related gastrointestinal complications after transplantation can be difficult and is often based on the patient’s net state immunosuppression, the presence of anatomic abnormalities and the patient’s epidemiologic exposures.41 For this reason, we advocate a low threshold for laboratory workup of transplant patients with travel-related diarrhea, to include both travel and other causes. Diagnosis and management of posttransplant diarrhea should include stool culture, stool C. difficile assessment, and blood Cytomegalovirus (CMV) quantitative viral load. A stepwise approach to the general diagnosis of diarrhea in solid organ recipients has been described elsewhere.41 Importantly, transplant recipients suffering from diarrhea refractory to standard treatment, especially those at risk for additional waterborne diseases, should undergo a full evaluation for intestinal parasitic infection.42 This includes fecal testing for leukocytes, ova, and parasites; appropriate stains for Cryptosporidium spp, Cystoisospora belli and Cyclospora cayetanensis; Giardia and Cryptosporidium antigen screen or enzyme immunoassay; and Norovirus detection by polymerase chain reaction. Although new multipathogen molecular tests are very promising, they need further validation and standardization before becoming widely implemented.1,6,42 TREATMENT The majority of food-borne illnesses, including TD, are self-limited, and require mainly supportive management and fluid replacement. Fluids and electrolytes should be replaced aggressively because diarrhea-induced dehydration can result in renal insufficiency and enhance the potential toxicities of antirejection medications. Antimotility agents, such as loperamide, are also recommended with good evidence for added efficacy when used in combination with antibacterial therapy.43 Bismuth subsalicylate has been used to treat TD, but should be used with caution in solid-organ transplant patients because it is converted to salicylic acid and bismuth salts, and these can result in toxicity among transplant patients with diminished renal function. Solid-organ transplant recipients may be at increased risk of complications, including bloodstream infection (with potential seeding at distant sites). Dehydration can potentiate the nephrotoxic effects of calcineurin inhibitors. More aggressive treatment of TD is therefore recommended for solid-organ transplant recipients.44 Although randomized controlled clinical trials have not been performed specifically in transplant recipients, the clinical benefit of treating TD has been demonstrated in numerous studies performed in the nontransplant population.45,46 In a meta-analysis of controlled trials, antibiotic treatment was significantly associated with shorter duration of diarrhea, although it also led to higher incidence of side effects.46 Data from these studies in nontransplant population serve as evidence to support these recommendations for the management of transplant patients with TD. Empiric antibiotic therapy is recommended for those with moderate to severe frequency of TD (3 or more stools per day), and for all those with invasive symptoms (eg, bloody stools) and systemic illness (eg, fever).1,6,47 However, short lived mild diarrhea (1-2 stools per day) without systemic symptoms, that is tolerated by the patient, rarely requires antimicrobial therapy. Antibiotic regimens are chosen to target the most common bacterial pathogens, including ETEC and enteroaggregative E. coli, followed by Salmonella, Shigella and Campylobacter jejuni. These usually cover the less commonly encountered causes, such as Aeromonas spp, Plesiomonas spp, and Vibrio spp.27,48,49 The first-line empiric drug regimens against these bacterial pathogens are ciprofloxacin, levofloxacin, and azithromycin (Table 1). In general, ciprofloxacin is the standard empiric drug for self-treatment of TD except for travelers to South and Southeast Asia, where azithromycin is the preferred drug.1,6 In separate studies, single doses of ciprofloxacin (500 mg orally), levofloxacin (500 mg orally), and azithromycin (1000 mg orally) were effective in reducing the severity and duration of diarrhea in most travelers.50-52 Multiple doses taken over a course of 3 to 7 days have also been recommended44 (Table 1). In some studies, however, azithromycin had efficacy than a and had less side for empiric and antimicrobial treatment of of empiric should into the in a specific For example, the of for empiric treatment of TD and other bacterial infections has led to the and of ciprofloxacin especially among Campylobacter There is increasing to among Campylobacter in and azithromycin is recommended as first-line empiric treatment of diarrhea among travelers in and Southeast In a randomized azithromycin treatment in a than levofloxacin treatment of TD in where the was Campylobacter There have also been increasing reports of and among travelers returning from The potential for should be considered in the treatment of TD among transplant recipients. Although has been for the treatment of traveler's diarrhea by bacterial pathogens, some caution against its among solid-organ transplant recipients due to its potential for with However, is a that is not to the The role of as empiric therapy is because patients are often to from the invasive of diarrhea, so a second antimicrobial need to be a may and reduce leading to higher systemic that can as and may be further by diarrhea-induced These not the of but the role of and and of immunosuppressive drug in solid-organ transplant patients with TD. TD not after empiric antibacterial solid-organ transplant patients should and have their stools for bacterial pathogens other potential causes susceptibility testing should be performed for bacterial to antibiotic therapy (Table 1). infections account for 1% to 20% of all of TD, including Cryptosporidium spp, Cyclospora Cystoisospora belli and Entameba In to the symptoms for bacterial and viral diarrhea, the is more for parasitic for the most common parasitic cause of TD, include or (Table parasites have been reported with increasing frequency in of the particularly in infections acquired in These may require treatment with agents such as or Entameba infections are also with or usually with a such as (Table 1). Cryptosporidium infections are often self-limited, but may be considered for severe Cyclospora and Cystoisospora infections are with (Table 1). causes of TD are often self-limited, but severe and should reducing the of may also to cause gastrointestinal disease that most often as diarrhea, with travel. is with or mg for at least pathogens that may with diarrhea during travel include C. especially among solid-organ transplant recipients are at risk due to of antibiotic of C. difficile of mg (500 mg or or mg depending on and causes of diarrhea may be among solid-organ transplant recipients, sometimes as an of of diarrhea in the or of the drug with immunosuppressive therapy. risk should be about potential for all travelers, particularly those with Transplant patients have gastrointestinal is in may need about the of travel to high-risk should be about and There is good evidence that before food reduces the risk of diarrheal disease and travelers should or for where may not be available for of the or at the of reduces the incidence of diarrheal disease in settings, and travelers to areas with sanitation may need to or both wide variety are should be to in and to that the is they are and to a from the to pathogens on the of the or in may be of and and should be and should be used to may potentiate diarrhea and The is to all that have not been or foods are foods that have been food and therefore visited by and food in that is by a street and served on may be than food in a The it or the need to of and other foods by of However, much food is not to a high to all experience and have shown by travelers with about food and and little impact of such on the incidence of should be considered for this high-risk The evidence for of and is and they are not widely or similar agents have been recommended by some in the but there is no evidence to support their in to Bismuth has moderate efficacy in travelers diarrhea but has to be taken has associated such as the and and should be by people with has been reported in patients with renal as this is common in solid-organ transplant recipients, bismuth is a less for this group of travelers. with is highly effective in traveler’s diarrhea, that at the are the of such agents for lasting more than after which most but not all risk of TD has and such to for or As solid-organ transplant patients are at increased risk of complications of TD, there may be more to but this has to be against the risk of of and The acquisition of is an increasingly important of travel. There is increasing evidence that even travel to the a high risk of acquiring pathogens and that this risk is increased in those that Although this is not for the per it for solid-organ transplant patients and may of pathogens in their and The systemic agents usually recommended are such as ciprofloxacin taken in standard doses for short In such as and India, where is azithromycin be preferred for but with be The antimicrobial is increasingly recommended for but its potential for in treatment is very limited in solid-organ transplant patients as invasive pathogens not be about a role for is only for the small of travelers will be in where cholera is a for example, in It not against other causes of TD and should not be recommended for that and on against other TD, have been to even when good As effective against Norovirus infection travelers will be a very good group in which to particularly in known high-risk such as However, these are not In most evidence about and treatment of TD in solid-organ transplant patients is extrapolated from other of travelers. The higher risk of illness in transplant patients more aggressive and than in other travelers but this should be by of patient should have an risk for and on it may be to to the from countries have potential risk for of of Salmonella, Shigella, ETEC bacterial enteric but the risk of from such they should be for intestinal parasites and before with diarrhea should be and the diagnosis and appropriate

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