Travelers' Health: Travel Safe, Travel Smart

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Chapter 5Post-Travel Evaluation

Persistent Travelers’ Diarrhea

Bradley A. Connor

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). Persistent diarrhea is often associated with enteropathy and consequent malabsorption. This may lead to malnutrition, particularly among young children and the immunosuppressed. The pathogenesis of persistent travelers’ diarrhea generally falls into one of the following broad categories: 1) persistent infection or coinfection, 2) chronic underlying gastrointestinal disease unmasked by the enteric infection, or 3) a postinfectious phenomenon.

PERSISTENT INFECTION

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 appropriately 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. However, as Giardia infects the proximal small bowel, even multiple stool specimens may fail to detect it, and a duodenal aspirate may be necessary for definitive diagnosis. Given the high prevalence of Giardia in persistent travelers’ diarrhea, empiric therapy is a reasonable option in the appropriate clinical setting after negative stool microscopy and in lieu of duodenal sampling (Table 5-05). Other intestinal parasites that may cause persistent symptoms include Cryptosporidium species, Entamoeba histolytica, Isospora belli, Microsporidia, Dientamoeba fragilis, and Cyclospora cayetanensis.

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 is with metronidazole or oral vancomycin, although increasing reports of resistance to both 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. Investigation of an outbreak of Brainerd diarrhea among passengers on a cruise ship to the Galápagos Islands of Ecuador revealed that diarrhea persisted 7 to more than 42 months and did not respond to antimicrobial therapy.

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 sprue, 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 appropriate serologic tests, including tissue transglutaminase antibodies. A biopsy of the small bowel showing villous atrophy confirms the diagnosis. Treatment is with a wheat (gluten)-free diet.

Idiopathic inflammatory bowel disease, both Crohn disease and ulcerative colitis, may be seen after acute bouts of travelers’ diarrhea. One prevailing hypothesis is that an initiating endogenous pathogen triggers inflammatory bowel disease in genetically susceptible people.

In the appropriate 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.

POSTINFECTIOUS PHENOMENA

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. In the context of travelers’ diarrhea, PI-IBS has been defined as new IBS symptoms by the Rome III criteria:

≥3 months of gastrointestinal symptoms, with an onset of symptoms ≥6 months previously.
Recurrent abdominal pain or discomfort associated with ≥2 of the following features:
- Improvement with defecation
- Onset associated with a change in the frequency of stool
- Onset associated with a change in form (appearance) of stool
To be labeled PI-IBS, these symptoms should follow an episode of gastroenteritis or travelers’ diarrhea if the work-up for microbial pathogens and underlying gastrointestinal disease is negative.

EVALUATION

The hydration and nutritional status of patients with persistent travelers’ diarrhea should be assessed. Three or more stool examinations for ova and parasites, including acid-fast stains for Cryptosporidium, Cyclospora, and Isospora; Giardia antigen testing; Clostridium difficile toxin assay; D-xylose test; tests for stool reducing substances; and duodenal aspirates, may be performed. Fecal lactoferrin testing or microscopy for fecal leukocytes is often present with more severe C. difficile colitis and IBS, and noninflammatory diarrhea suggests giardiasis. Patients may also be given empiric treatment for Giardia infection. If underlying gastrointestinal disease is suspected, an initial evaluation should include serologic tests for celiac and inflammatory bowel disease. Subsequently, gastrointestinal endoscopy with duodenal aspirate and biopsies may be considered.

MANAGEMENT

Although US travelers are unlikely to become significantly dehydrated or malnourished due to persistent diarrhea, appropriate hydration and nutritional support are of foremost importance. Dietary modifications may help those with malabsorption. If stools are bloody or when disease is caused by C. difficile, antidiarrheal medications 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 (Table 5-05). Additional management strategies will depend on the specific cause of persistent diarrhea.

Table 5-05. Treatment of common intestinal protozoan parasites

PARASITE	DISEASE SEVERITY OR INDICATION	DRUG OF CHOICE	ALTERNATIVE DRUGS
Amebiasis (Entamoeba histolytica)	Asymptomatic	Iodoquinol Adults: 650 mg PO tid × 20 d Pediatric: 30–40 mg/kg/d (max 2 g) PO in 3 doses × 20 d	Paromomycin Adults: 25–35 mg/kg/d PO in 3 doses × 7 d Pediatric: 25–35 mg/kg/d PO in 3 doses × 7 d or Diloxanide furoate Adults: 500 mg PO tid × 10 d Pediatric: 20 mg/kg/d PO in 3 doses × 10 d
	Mild to moderate intestinal disease	1) Initial: Metronidazole Adults: 500–750 mg PO tid × 7–10 d Pediatric: 35–50 mg/kg/d PO in 3 doses × 7–10 d 2) Followed by: Iodoquinol Adults: 650 mg PO tid × 20 d Pediatric: 30–40 mg/kg/d (max 2 g) PO in 3 doses × 20 d	1) Initial: Tinidazole Adults: 2 g PO qd × 5 d Pediatric (age >3 y): 50 mg/kg/d (max 2 g) PO in 1 dose × 3 d 2) Followed by: Paromomycin Adults: 25–35 mg/kg/d PO in 3 doses × 7 d Pediatric: 25–35 mg/kg/d PO in 3 doses × 7 d
	Severe intestinal and extraintestinal disease	1) Initial: Metronidazole Adults: 750 mg PO tid × 7–10 d Pediatric: 35–50 mg/kg/d PO in 3 doses × 7–10 d 2) Followed by: Iodoquinol Adults: 650 mg PO tid × 20 d Pediatric: 30–40 mg/kg/d (max 2 g) PO in 3 doses × 20 d	1) Initial: Tinidazole Adults: 2 g PO qd × 5 d Pediatric (age >3 y): 50 mg/kg/d (max 2 g) PO in 1 dose × 3 d 2) Followed by: Paromomycin Adults: 25–35 mg/kg/d PO in 3 doses × 7 d Pediatric: 25–35 mg/kg/d PO in 3 doses × 7 d
Cryptosporidiosis (Cryptosporidium)	HIV-uninfected (nitazoxanide has not been shown to have efficacy in immunosuppressed people)	Nitazoxanide Adults: 500 mg PO bid × 3 d Age 1–3 y: 100 mg PO bid × 3 d Age 4–11 y: 200 mg PO bid × 3 d Age 12–18 y: 500 mg PO q12h × 3 d
Cyclosporiasis (Cyclospora cayetanensis)		Trimethoprim/ sulfamethoxazole Adults: TMP 160 mg/SMX 800 mg (1 DS tab) PO bid × 7–10 d Pediatric: TMP 5 mg/kg/SMX 25 mg/kg/d PO in 2 doses × 7–10 d
Dientamoebiasis (Dientamoeba fragilis infection)		Iodoquinol Adults: 650 mg PO tid × 20 d Pediatric: 30–40 mg/kg/d (max 2 g) PO in 3 doses × 20 d	Paromomycin Adults: 25–35 mg/kg/d PO in 3 doses × 7 d Pediatric: 25–35 mg/kg/d PO in 3 doses × 7 d or Tetracycline Adults: 500 mg PO qid × 10 d Pediatric: 40 mg/kg/d (max 2g) PO in 4 doses × 10 d or Metronidazole Adults: 500–750 mg PO tid × 10 d Pediatric: 35–50 mg/kg/d PO in 3 doses × 10 d
Giardiasis (Giardia intestinalis)		Metronidazole Adults: 250 mg PO tid × 5–7 d Pediatric: 15 mg/kg/d PO in 3 doses × 5–7 d or Tinidazole Adults: 2 g PO once Pediatric: 50 mg/kg PO once (max 2 g) or Nitazoxanide Adults: 500 mg PO bid × 3 d Age 1–3 y: 100 mg PO q12h × 3 d Age 4–11 y: 200 mg PO q12h × 3 d Age 12–18 y: 500 mg PO q12h × 3 d	Paromomycin Adults: 25–35 mg/kg/d PO in 3 doses × 5–10 d Pediatric: 25–35 mg/kg/d PO in 3 doses × 5–10 d or Furazolidone Adults: 100 mg PO qid × 7–10d Pediatric: 6 mg/kg/d PO in 4 doses × 7–10 d or Quinacrine Adults: 100 mg PO tid × 5 d Pediatric: 2 mg/kg/d PO in 3 doses × 5 d (max 300 mg/d)
Isosporiasis (Isospora belli)		Trimethoprim/ sulfamethoxazole Adults: TMP 160 mg/SMX 800 mg (1 DS tab) PO bid × 10 d Pediatric: TMP 5 mg/kg/d/SMX 25 mg/kg/d PO in 2 doses × 10 d
Microsporidiosis	Intestinal (Enterocytozoon bieneusi, Encephalitozoon [Septata] intestinalis)	Drug of choice for E. bieneusi: Fumagillin Adults: 20 mg PO tid × 14 d Drug of choice for E. intestinalis: Albendazole Adults: 400 mg PO bid × 21 d

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