Although most cases of travelers’ diarrhea are acute and self-limited, a certain percentage of travelers will develop persistent (>14 days) gastrointestinal symptoms (see Chapter 2, Travelers’ Diarrhea). The pathogenesis of persistent diarrhea in returned travelers generally falls into one of the following broad categories: 1) ongoing infection or coinfection with a second organism not targeted by initial therapy, 2) previously undiagnosed gastrointestinal disease unmasked by the enteric infection, or 3) a postinfectious phenomenon.
Most cases of travelers’ diarrhea are the result of bacterial infection and are short-lived and self-limited. Prolonged diarrheal symptoms can be caused by immunosuppression, sequential infection with diarrheal pathogens, and infection with protozoan parasites. Parasites as a group 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 infection) increases with increasing duration of symptoms. Parasites may also be the cause of persistent diarrhea in patients already treated for a bacterial pathogen.
Giardia is the most likely persistent parasitic pathogen to be encountered. Suspicion for giardiasis should be particularly high when upper gastrointestinal symptoms predominate. Untreated, symptoms may last for months, even in immunocompetent hosts. Stool microscopy, antigen detection, or immunofluorescence are used commonly to make the diagnosis. PCR-based diagnostics (particularly the multiplex DNA extraction PCR) are becoming the diagnostic method of choice to diagnose Giardia as well as other protozoan pathogens, including Cryptosporidium, Cyclospora , and Entamoeba histolytica . In the absence of diagnostics, however, and given the high prevalence of Giardia in persistent travelers’ diarrhea, empiric therapy is a reasonable option in the clinical setting. Other rare causes of persistent symptoms include the intestinal parasites Microsporidia, Dientamoeba fragilis , and Cystoisospora .
Individual bacterial infections rarely cause persistent symptoms, although ongoing diarrhea has been reported in travelers infected with enteroaggregative or enteropathogenic Escherichia coli and among people with diarrhea due to Clostridioides difficile. C. difficile –associated diarrhea may follow treatment of a bacterial pathogen with a fluoroquinolone or other antibiotic, or even malaria chemoprophylaxis. This is especially important to consider in the patient with persistent travelers’ diarrhea that seems refractory to multiple courses of empiric antibiotic therapy. The initial workup of persistent travelers’ diarrhea should always include a C. difficile stool toxin assay. Treatment of C. difficile infection is with oral vancomycin, fidaxomicin, or, less optimally, metronidazole.
Persistent travelers’ diarrhea has also been associated with tropical sprue and Brainerd diarrhea. These syndromes are suspected to result from infectious diseases, but specific pathogens have not been 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, as the name implies, tropical areas. The incidence of tropical sprue appears to have declined dramatically over the past 2 decades and is diagnosed only rarely in travelers. Investigation of an outbreak of Brainerd diarrhea among passengers on a cruise ship to the Galápagos Islands of Ecuador revealed that diarrhea persisted from 7 to more than 42 months and did not respond to antimicrobial therapy. Brainerd diarrhea is one of the persistent mysteries of ongoing diarrhea.
In some cases, persistence of gastrointestinal symptoms relates to chronic underlying gastrointestinal 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, villous atrophy and crypt hyperplasia are seen in response to exposure to antigens found in wheat, leading to malabsorption. The diagnosis is made by obtaining serologic tests, including tissue transglutaminase antibodies. A biopsy of the small bowel showing villous atrophy confirms the diagnosis. Treatment is with a gluten-free diet.
Idiopathic inflammatory bowel disease, both Crohn’s disease and ulcerative colitis, may be seen after acute bouts of travelers’ diarrhea. One prevailing hypothesis is that an initiating exogenous pathogen changes microbiota of the gut, which triggers inflammatory bowel disease in genetically susceptible people. Microscopic colitis may be seen after travelers’ diarrhea as well.
Depending on the clinical setting and age group, it may be necessary to do a more 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 those with new-onset iron-deficiency anemia.
In a certain percentage of patients who present with persistent gastrointestinal symptoms, no specific source will be found. Following an acute diarrheal infection, patients may experience temporary enteropathy characterized by villous atrophy, decreased absorptive surface area, and disaccharidase deficiencies. This can lead to osmotic diarrhea, particularly when large amounts of lactose, sucrose, sorbitol, or fructose are consumed. Use of antimicrobial medications during the initial days of diarrhea may also lead to alterations in intestinal flora and diarrhea symptoms.
Occasionally, the onset of irritable bowel syndrome (IBS) symptoms follows an acute bout of gastroenteritis, so-called postinfectious IBS (PI-IBS). To be labeled PI-IBS, symptoms should follow an episode of gastroenteritis or travelers’ diarrhea if the workup for microbial pathogens and underlying gastrointestinal disease is negative. Whether the use of antibiotics to treat acute travelers’ diarrhea decreases or increases the likelihood of PI-IBS is unknown.
Diagnostics to determine specific microbial etiologies in cases of persistent diarrhea have advanced in the past number of years. Among the most useful tools in microbial diagnosis is the high-throughput multiplex DNA extraction PCR. This technology uses a single stool specimen to detect multiple bacterial, parasitic, and viral enteropathogens simultaneously.
Except in the case of Cryptosporidium , these assays have high sensitivity and specificity; however, the clinical ramifications and the economic impact of using these diagnostic molecular panels has yet to be assessed fully. In some cases, molecular testing may detect colonization rather than infection, making it difficult for clinicians interpret and apply the results properly.
Traditional methods of microbial diagnosis have relied on the use of microscopy; 3 or more stool specimens should be examined for ova and parasites, including acid-fast stains for Cryptosporidium, Cyclospora , and Cystoisospora . Clinicians should also obtain Giardia antigen testing, a C. difficile toxin assay, and a D-xylose absorption test to determine if nutrients are being properly absorbed. If underlying gastrointestinal disease is suspected, an initial evaluation should include serologic tests for celiac and consideration of inflammatory bowel disease. Subsequently, other studies to visualize both the upper and lower gastrointestinal tracts, with biopsies, may be indicated.
Dietary modifications may help those with malabsorption. Avoid using antidiarrheal medications (e.g., loperamide or diphenoxylate) to treat children having bloody stools or disease caused by C. difficile ; use these same drugs cautiously, if at all, in adults. Probiotic medications have been shown to reduce the duration of persistent diarrhea among children in some settings. Antimicrobial medications may be useful in treating persistent diarrhea caused by parasites. Nonabsorbable antibiotics may help if small intestinal bacterial overgrowth accompanies the symptom complex.
Bradley A. Connor