Persistent Travelers’ Diarrhea
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 travelers’ diarrhea generally falls into one of the following broad categories: 1) persistent 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. Travelers may experience prolonged diarrheal symptoms if they are immunosuppressed, are infected sequentially with diarrheal pathogens, or are infected with protozoan parasites. Parasites as a group are the pathogens most likely to be isolated from patients with persistent diarrhea, and their probability relative to bacterial infections 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 by far the most likely persistent 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. The diagnosis can often be made through stool microscopy, antigen detection, or immunofluorescence, but 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 intestinal parasites that may be rare causes of persistent symptoms include Microsporidia, Dientamoeba fragilis , and Cystoisospora .
Individual bacterial infections rarely cause persistence of symptoms, although persistent diarrhea has been reported in children infected with enteroaggregative or enteropathogenic Escherichia coli and among people with diarrhea due to Clostridium difficile. C. difficile –associated diarrhea may follow treatment of a bacterial pathogen with a fluoroquinolone or other antibiotic, or may even follow 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 work-up of persistent travelers’ diarrhea should always include a C. difficile stool toxin assay. Treatment of C. difficile infection is with metronidazole, oral vancomycin, or fidaxomicin, although increasing reports of resistance to the first 2 drugs have been noted.
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 tropical areas. The incidence of tropical sprue appears to have declined dramatically over the past 2 decades and is rarely diagnosed 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.
Underlying Gastrointestinal Disease
In some cases, persistence of gastrointestinal symptoms relates to chronic underlying gastrointestinal disease or 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 the person’s microbiota, which triggers inflammatory bowel disease in genetically susceptible people.
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. Colorectal cancer should be considered, particularly in patients passing occult or gross blood rectally or with the onset of a new iron-deficiency anemia.
In a certain percentage of patients who present with persistent gastrointestinal symptoms, no specific source will be found. Patients may experience temporary enteropathy following an acute diarrheal infection, with 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 symptoms of irritable bowel syndrome (IBS) can be traced to an acute bout of gastroenteritis. IBS that develops after acute enteritis has been termed postinfectious (PI)-IBS. To be labeled PI-IBS, symptoms should follow an episode of gastroenteritis or travelers’ diarrhea if the work-up for microbial pathogens and underlying gastrointestinal disease is negative. Whether the use of antibiotics to treat acute TD 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 simultaneously detect multiple bacterial, parasitic, and viral enteropathogens. This may be particularly helpful when persistent diarrhea is caused by a parasite or C. difficile .
Overall, these assays have high sensitivity and specificity; however, the clinical and financial effect of these molecular panels has not yet been fully assessed, and molecular testing may, in some cases, detect colonization rather than infection, making it difficult for clinicians to interpret the results.
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 , as well as Giardia antigen testing; 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 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. If stools are bloody or when disease is caused by C. difficile , antidiarrheal medications such as loperamide or diphenoxylate should not be used in children and should be used 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.
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Bradley A. Connor