Author(s): Bradley Connor

Although most cases of travelers’ diarrhea (TD) are acute and self-limited, a certain percentage of people afflicted will develop persistent (>14 days) gastrointestinal (GI) symptoms. Details on the management of acute TD are available in Sec. 2, Ch. 6, Travelers’ Diarrhea.

Pathogenesis

The pathogenesis of persistent diarrhea in returned travelers generally falls into one 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 postinfectious phenomenon.

Ongoing Infection

Most cases of TD are the result of bacterial infection and are short-lived and self-limited. In addition to immunosuppression and sequential infection with diarrheal pathogens, ongoing infection with protozoan parasites can cause prolonged diarrheal symptoms.

Bacterial

Individual bacterial infections rarely cause persistent symptoms, but travelers infected with Clostridioides difficile or enteroaggregative or enteropathogenic Escherichia coli (see Sec. 5, Part 1, Ch. 7, Diarrheagenic Escherichia coli) can experience ongoing diarrhea. C. difficile–associated diarrhea can occur after treatment of a bacterial pathogen with a fluoroquinolone or other antibiotic, or after 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 work-up of persistent TD should always include a C. difficile stool toxin assay. Clinicians can prescribe oral vancomycin, fidaxomicin, or, less optimally, metronidazole to treat C. difficile.

Parasitic

As a group, parasites are the pathogens most likely to be isolated from patients with persistent diarrhea. The probability of a traveler having a protozoal infection, relative to a bacterial one, 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 (see Sec. 5, Part 3, Ch. 12, Giardiasis) is the most likely parasitic pathogen to cause persistent diarrhea. Suspect giardiasis particularly in patients with upper GI–predominant symptoms. Untreated, symptoms can last for months, even in immunocompetent hosts.

PCR-based diagnostics, particularly the multiplex DNA extraction PCR, are becoming the diagnostic methods of choice to identify Giardia and other protozoal pathogens, including Cryptosporidium, Cyclospora, and Entamoeba histolytica. Diagnosis also can be made by stool microscopy, antigen detection, or immunofluorescence. In the absence of diagnostics (given the high prevalence of Giardia as a cause for persistent TD), empiric therapy is a reasonable option in the clinical setting. Rare causes of persistent symptoms include the intestinal parasites Cystoisospora, Dientamoeba fragilis, and Microsporidia.

Tropical Sprue & Brainerd Diarrhea

Persistent TD also has been associated with tropical sprue and Brainerd diarrhea. 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 2 decades. Diagnosed only rarely in travelers, its cause is unknown.

Brainerd diarrhea is a syndrome of acute onset of watery diarrhea lasting ≥4 weeks. Symptoms include 10–20 episodes of explosive, watery diarrhea per day, fecal incontinence, abdominal cramping, gas, and fatigue. Nausea, vomiting, and fever are rare. Although the cause is believed to be infectious, a culprit pathogen has yet to be identified, and antimicrobial therapy is ineffective as treatment. Investigation of an outbreak of Brainerd diarrhea among passengers on a cruise ship to the Galápagos Islands in 1992 identified that individuals with persistent diarrhea (range: 7 to >42 months) were more likely to have consumed contaminated water or eaten raw fruits or vegetables washed with contaminated water.

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, clinicians might need to conduct a comprehensive search for other underlying causes of chronic 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.

Postinfectious Phenomena

In a certain percentage of patients who present with persistent GI symptoms, clinicians 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 postinfectious IBS (PI-IBS). PI-IBS symptoms can occur after an episode of gastroenteritis or TD. The clinical work-up 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.

Evaluation

Traditional methods of microbial diagnosis rely on the use of microscopy. Examine stool specimens collected over 3 or more days for ova and parasites; include acid-fast staining for Cryptosporidium, Cyclospora, and Cystoisospora. Giardia antigen testing and a C. difficile toxin assay are appropriate elements of a work-up. In addition, a D-xylose absorption test can determine whether patients are properly absorbing nutrients. If underlying gastrointestinal 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 gastrointestinal tracts, with biopsies, might be indicated.

Diagnostic tests to determine specific microbial etiologies in cases of persistent diarrhea have advanced in the past number of years. One of the most useful tools is high-throughput multiplex DNA extraction PCR. This technology uses a single stool specimen to detect multiple bacterial, parasitic, and viral enteropathogens simultaneously. Except for Cryptosporidium, these assays have high sensitivity and specificity; the clinical ramifications and the economic impact of using these diagnostic molecular panels have not been determined fully, however. In some cases, molecular testing detects colonization rather than infection, making it difficult for clinicians to interpret and apply the results properly.

Management

Specific treatment of identified enteropathogens is usually indicated, and appropriate management of underlying gastrointestinal disease warranted (e.g., a gluten-free diet for celiac disease, medication for inflammatory bowel disease). Dietary modifications might help patients with malabsorption. Symptomatic treatment or the use of nonabsorbable antibiotics offer potential benefit if small intestinal bacterial overgrowth accompanies the symptom complex. Additionally, chronic diarrhea might cause fluid and electrolyte imbalances requiring medical management involving oral or intravenous replacement based on clinical presentation.