Introduction
While most travelers will have onset and resolution of diarrhea during their trip, some will present with symptoms after return. Although most cases of travelers’ diarrhea (TD) are acute and self-limited, some people develop persistent (>14 days) gastrointestinal (GI) symptoms. Details on the management of TD during travel are available in the Travelers’ Diarrhea chapter.
Pathogenesis
While acute travelers’ diarrhea (i.e., diarrhea lasting less than 2 weeks) is usually self-limited and the etiologies are mostly infectious pathogens (see Travelers’ Diarrhea chapter), the pathogenesis of persistent diarrhea (i.e., diarrhea lasting 2 weeks or longer) in returned travelers generally falls into 1 of the following broad categories: ongoing infection or co-infection with a second organism not targeted by initial therapy; previously undiagnosed GI disease unmasked by the enteric infection; or a post-infectious phenomenon.
Ongoing infection
Most cases of TD are the result of bacterial or viral infection and are short-lived and self-limited. In addition to prolonged symptoms of typical pathogens among immunosuppressed persons and sequential infection with different pathogens, ongoing infection with parasites can cause prolonged diarrheal symptoms. Table 10.4.1 lists common bacterial, viral, and protozoal pathogens causing TD.
Table 10.4.1: Common bacterial, viral, and protozoal pathogens causing travelers’ diarrhea
| Bacteria | ||
|---|---|---|
| Organism | Epidemiologic Association | Antimicrobial Treatment Options |
| Aeromonas spp. | Waterborne | Fluoroquinolone1
Third-generation cephalosporin |
| Campylobacter spp. | Foodborne (poultry, milk), waterborne | Azithromycin |
| Clostridioides difficile | Fecal-oral, surfaces | Oral vancomycin Fidaxomicin |
| Escherichia coli (ETEC, EAEC, EPEC) | Foodborne, waterborne | Azithromycin
Fluoroquinolone1
|
| Escherichia coli
(EHEC, STEC) |
Avoid antimicrobials2 | |
| Plesiomonas spp. | Waterborne, contaminated seafood | Fluoroquinolone1 |
| Salmonella, non-typhoidal (see Typhoid and Paratyphoid Fever chapter) | Foodborne (poultry, milk products), contact with poultry/reptiles | Fluoroquinolone1
(see note3)
|
| Shigella spp. (Enteroinvasive Escherichia coli) | Fecal-oral: close/household contacts, anal-genital/oral/digital contact | Azithromycin
Fluoroquinolone1 (see note4)
|
| Vibrio spp. | Waterborne, contaminated seafood | Fluoroquinolone1
Doxycycline Azithromycin |
| Yersinia enterocolitica | Foodborne (pork) | Fluoroquinolone1
Third-generation cephalosporin5 |
| Viruses | ||
|---|---|---|
| Organism | Epidemiologic Association | Antimicrobial Treatment Options |
| Norovirus (see Norovirus chapter) | Fecal-oral, foodborne, waterborne household contacts, facilities/schools/ships | No antimicrobial indicated |
| Rotavirus | Fecal-oral | No antimicrobial indicated |
| Sapovirus | Fecal-oral | No antimicrobial indicated |
| Protozoans | ||
|---|---|---|
| Organism | Epidemiologic Association | Antimicrobial Treatment Options |
| Cryptosporidium parvum and hominis | Recreational water | Nitazoxanide |
| Cyclospora cayetanensis | Foodborne (vegetables, fruits) | Trimethoprim-sulfamethoxazole |
| Dientamoeba fragilis | Fecal-oral | Nitroimidazole6
Paromomycin |
| Entamoeba histolytica | Foodborne, waterborne, fecal-oral | Nitroimidazole6 plus an intraluminal agent7 |
| Giardia duodenalis | Waterborne | Nitroimidazole5 Nitazoxanide |
Notes
Abbreviations: ETEC, enterotoxigenic Escherichia coli; EAEC, enteroaggregative Escherichia coli; EPEC, enteropathogenic Escherichia coli; EHEC, enterohemorrhagic Escherichia coli; STEC, shiga toxin-producing Escherichia coli.
1Due to its narrower spectrum of activity, ciprofloxacin is slightly preferred over levofloxacin.
2Given the risk for hemolytic uremic syndrome, for patients with confirmed or suspected EHEC/STEC infection, hospitalization for aggressive fluid management and avoidance of antibiotics are recommended.
3Given risks of prolonged carriage associated with antibiotic use, antibiotics are recommended only for non-typhoidal Salmonella infection in infants, the elderly (>50 years), the immunocompromised, or those with severe disease.
4Given emergence of extensively drug-resistant strains, for patients with Shigella infection who have severe disease (e.g., bacteremia, hospitalized) or who are immunocompromised, empiric treatment with a carbapenem is recommended while awaiting results of drug susceptibility testing.
5Antibiotics are only indicated for moderate to severe illness.
6Tinidazole is preferred over metronidazole due to lower frequency of dosing and higher efficacy for some organisms.
7Intraluminal agents include paromomycin, iodoquinol, and diloxanide furoate.
Bacterial
While individual bacterial infections rarely cause persistent symptoms, travelers infected with bacteria known to cause mucosal inflammation, such as Campylobacter spp., Shigella spp., or Salmonella spp., as well as diarrheagenic Escherichia coli, can experience persistent diarrhea, including cases where the organism may be resistant against antibiotics commonly used for empiric treatment of TD (see Typhoid and Paratyphoid Fever chapter). A rare cause of post-travel persistent diarrhea is Yersinia spp., a foodborne bacterial infection which can present as a subacute febrile gastroenteritis.
Clostridioides difficile-associated diarrhea can occur after or during antibiotic use, including malaria chemoprophylaxis. The association between C. difficile and antimicrobial treatment is especially important to consider in patients with persistent TD that seems refractory to multiple courses of empiric antibiotic therapy. The initial workup of persistent TD should always include C. difficile testing. Healthcare professionals can prescribe oral vancomycin, fidaxomicin, or, less optimally, metronidazole, to treat C. difficile. Recurrent cases may be treated with fecal microbiota transplantation, now available by the oral route or as a retention enema. The monoclonal antibody bezlotoxumab is also an option.
Parasitic
As a group, parasites are the pathogens most likely to be isolated from patients with persistent diarrhea. Most parasitic infections have a less acute onset of symptoms than those caused by bacteria or viruses, and the probability of a traveler having a parasitic infection increases with increasing duration of symptoms. Parasites might also be the cause of persistent diarrhea in patients already treated for a bacterial pathogen.
Giardiasis
Giardia duodenalis is the most likely parasitic pathogen to cause persistent diarrhea. Suspect giardiasis particularly in patients with fatty stools, flatulence, or upper GI-predominant symptoms. When giardiasis is left untreated, symptoms can last for months, even in immunocompetent hosts. Diagnosis can be made by stool polymerase chain reaction (PCR), microscopy, enzyme immunoassay, or immunofluorescence (see Evaluation section below). In the absence of diagnostics (given the high prevalence of Giardia duodenalis as a cause for persistent TD), empiric therapy is a reasonable option in the appropriate clinical setting.
Amebiasis
Infection with Entamoeba histolytica, or amebiasis, can result in intestinal symptoms ranging from mild diarrhea to dysentery. Diagnosis can be made by stool PCR, microscopy, or enzyme immunoassay. Microscopy cannot distinguish between the pathogen E. histolytica and some non-pathogenic Entamoeba species such as Entamoeba dispar. Treatment is with metronidazole, followed by an intraluminal agent such as paromomycin or iodoquinol. Antibody testing for E. histolytica should be used for extra-intestinal infection only.
Cryptosporidiosis
Cryptosporidium spp. are emerging as common protozoans causing persistent diarrhea in both returning travelers and U.S. residents. Transmitted through contaminated food and water (including recreational water), most infections are asymptomatic or are self-limited. Symptoms may include watery diarrhea, nausea, or abdominal cramping. Disease may be more severe and prolonged in immunocompromised individuals. Diagnosis can be made by stool PCR, microscopy (modified acid-fast stain), immunofluorescence, or enzyme immunoassay. While most immunocompetent individuals recover with oral rehydration alone, in those with persistent symptoms, nitazoxanide may be used.
Cyclosporiasis
Cyclospora spp. may cause protozoal infection generally acquired by ingestion of contaminated food. It has been an increasingly recognized cause of persistent diarrhea in both U.S. residents and returning travelers. The oocyst of Cyclospora is resistant to chlorine disinfection. Diagnosis is through stool PCR or microscopy (modified acid-fast stain or wet mount confirmed by ultraviolet autofluorescence). Treatment is with trimethoprim-sulfamethoxazole.
Cystoisosporosis
Infection with Cystoisospora belli results in sudden onset of watery diarrhea that is self-resolving, although it may cause persistent diarrhea in immunocompromised individuals. Diagnosis can be made through detection of oocysts by stool microscopy (modified acid-fast stain). Most cases are self-resolving. Trimethoprim-sulfamethoxazole can be used if symptoms persist or if a patient is immunocompromised.
Dientamoeba fragilis infection
Dientamoeba fragilis is a protozoan that may be found in stools of both healthy individuals and in persons with abdominal symptoms. While it can be associated with diarrhea in returning travelers, its role as an intestinal pathogen is unclear. Diagnosis can be made by stool PCR or microscopy of permanently stained stool smears. Treatment options, none of which have been assessed in randomized controlled trials, include metronidazole and paromomycin.
Fungal
Microsporidiosis
Microsporidia are a group of fungi that can cause a self-limited watery diarrhea in travelers. In people living with HIV and rarely in immunocompetent persons, microsporidia can cause a chronic diarrhea. The route of transmission is not well known, and foodborne, waterborne, and animal-contact transmission have been reported. Diagnosis can be made by stool PCR or microscopy. Treatment depends on the species and includes albendazole.
Tropical sprue and brainerd diarrhea
Persistent TD also has been associated with tropical sprue and Brainerd diarrhea, both of which are believed to be caused by an infectious agent, although their culprit pathogens have yet to be identified. Tropical sprue is associated with deficiencies of vitamins absorbed in the proximal and distal small bowel and most commonly affects long-term travelers to tropical areas, as the name implies. The incidence of tropical sprue appears to have declined dramatically over the past 3 decades. Brainerd diarrhea is a syndrome of acute onset watery diarrhea lasting ≥4 weeks. Symptoms include 10–20 episodes of explosive, watery diarrhea per day, as well as fecal incontinence, abdominal cramping, gas, and fatigue. Nausea, vomiting, and fever are rare.
Underlying gastrointestinal disease
Celiac disease
In some cases, persistent symptoms relate to chronic underlying GI disease or to a susceptibility unmasked by the enteric infection. Most prominent among these is celiac disease, a systemic disease manifesting primarily with small bowel changes. In genetically susceptible people, exposure to antigens found in wheat causes villous atrophy, crypt hyperplasia, and malabsorption. Serologic tests, including tissue transglutaminase antibody testing, support the diagnosis; a small bowel biopsy showing villous atrophy confirms the diagnosis. Patients can be treated with a gluten-free diet.
Colorectal cancer
Depending on the clinical setting and age group, healthcare professionals might need to conduct a comprehensive search for other underlying causes of persistent diarrhea. Consider colorectal cancer in the differential diagnosis of patients passing occult or gross blood rectally or in patients with new-onset iron-deficiency anemia.
Inflammatory bowel disease
Idiopathic inflammatory bowel disease, including Crohn’s disease, microscopic colitis, and ulcerative colitis, can occur after acute bouts of TD. One prevailing hypothesis is that in genetically susceptible people, an initiating exogenous pathogen changes the microbiota of the gut, thereby triggering inflammatory bowel disease.
Lactose intolerance
Lactose intolerance is a syndrome caused by deficiency of lactase. Its prevalence varies across racial and ethnic groups, with the highest in Asian, African, and Native Americans, and increases with age. Symptoms include abdominal pain, flatulence, bloating, nausea, or diarrhea within hours after ingestion of lactose-containing foods.
Post-infectious phenomena
In some patients who present with persistent GI symptoms, healthcare professionals will not find a specific cause. After an acute diarrheal infection, patients might experience a temporary enteropathy characterized by villous atrophy, decreased absorptive surface area, and disaccharidase deficiencies, which can lead to osmotic diarrhea, particularly after consuming large amounts of fructose, lactose, sorbitol, or sucrose. Use of antimicrobial medications during the initial days of diarrhea might also lead to alterations in intestinal flora and diarrhea symptoms.
Occasionally, onset of irritable bowel syndrome (IBS) symptoms occurs after a bout of acute gastroenteritis, known as post-infectious IBS (PI-IBS). PI-IBS symptoms can occur after an episode of gastroenteritis or TD. The clinical workup for microbial pathogens and underlying GI disease in patients with PI-IBS will be negative. Whether using antibiotics to treat acute TD increases or decreases the likelihood of PI-IBS is unknown.
Small intestinal bacterial overgrowth is characterized by an excess of bacteria in the small intestine and is associated with intestinal motility disorders. Symptoms may include IBS-type symptoms such as abdominal discomfort, persistent diarrhea, or flatulence, and, in some cases, manifestations of nutrient malabsorption. Diagnosis is by carbohydrate breath testing, and treatment is with antibiotics.
Evaluation
Traditional methods of microbial diagnosis of diarrheal illness include stool culture, antigen detection using enzyme immunoassays, and microscopy. For detection of bacteria, routine stool culture will identify Campylobacter, Shigella, Salmonella, Aeromonas, and Plesiomonas. Special culture methods are required for Yersinia and Vibrio species. Diagnosis of C. difficile can be made by antigen detection and PCR. Identification of STEC/EHEC (E. coli O157:H7) is by culture and detection of Shiga-like toxin. Giardia and Cryptosporidium can be detected by antigen testing, and examination of serial stool specimens collected over 3 or more days for ova and parasites is appropriate for evaluation of persistent diarrhea when parasites are suspected, including the use of acid-fast staining for Cryptosporidium, Cyclospora, or Cystoisospora. In addition, a D-xylose absorption test can determine whether patients are properly absorbing nutrients. If underlying GI disease is suspected, include serologic testing for celiac disease and consider inflammatory bowel disease during initial evaluation. Subsequently, studies to visualize both the upper and lower GI tracts, with biopsies, might be indicated.
Diagnostic tests to determine specific microbial etiologies in cases of post-travel diarrhea have advanced in the past number of years. While culture, microscopy, and antigen detection have been the mainstay of diagnostics, PCR-based diagnostics (including as part of multiplex panels, which uses a single stool specimen to detect multiple enteropathogens simultaneously) are becoming increasingly available for detection of bacterial, viral, fungal, and protozoal pathogens. While these assays have high sensitivity and specificity, the clinical utility and economic impact of these diagnostic molecular panels have not been determined fully. In some cases, molecular testing detects colonization rather than infection, potentially making it difficult for healthcare professionals to interpret and apply the results properly. For persistent diarrhea, the use of a protozoa-dedicated multiplex panel would be most appropriate because bacteria and viruses are unlikely causes.
