Approach to Diarrhea in Returned Travelers

Exposure History and Risk Factors

Many factors influence the acquisition of TD, including geographic location, type of travel, and host factors. Of these factors, travel destination and duration are the most important determinants of attack rate. Highest risk of TD is associated with travel for more than 2 weeks to South and Southeast Asia, sub-Saharan Africa, the Middle East, and Latin America. Gathering information regarding the patient's travel arrangements is important in determining if the patient is suffering from TD and may narrow the list of potential pathogens. While ETEC and enteroaggregative E. coli (EAEC) are the most common causes of TD, especially in Africa and Latin America, the invasive pathogens Campylobacter , Vibrio , and Salmonella are just as common in South and Southeast Asia. High rates of TD have been associated with those visiting family and relatives, trekkers and campers, and travelers on adventure tours or cruise ships.

Information about consumption of street food and local water sources increases the risk of TD but is unhelpful in ascertaining the TD etiology. A history of shellfish or seafood consumption may be useful, as they are common sources of Vibrio . In addition, hepatitis A virus and noroviruses may be acquired through contaminated shellfish. Acute hepatitis A viral infection is associated with an average of 30 days of missed work and 1% mortality in adults.

Direct contact with animals should raise the suspicion for Campylobacter , shiga toxin–producing E. coli (STEC), and Giardia infections. Treatment with antibiotics for TD adds the risk of antibiotic-associated diarrhea caused by Clostridium difficile . If antibiotics were administered and an initial response obtained, the recurrence of symptoms may represent recrudescence of resistant bacteria, reinfection with similar or different pathogens, or a post-infectious process. Reviewing the patient's vaccination history is also important; those vaccinated against rotavirus and hepatitis A would be protected against infections caused by these agents. However, given the relatively low efficacy of typhoid fever vaccine (50-80% for both the oral and injectable forms), this diagnosis should remain in the differential diagnosis for returned travelers with signs and symptoms consistent with this.

Host factors can also play a role in the risk of TD, including age, reduced gastric acidity, blood type group O, and other genetic factors. Infants and toddlers can acquire infection though oral contact with nonfood items. Recent studies have suggested that individuals who produce higher amounts of the inflammatory mediators interleukin 8 AA, lactoferrin, and interleukin 10 may be more susceptible to TD. Polymorphisms in the CD14 receptor and osteoprotegerin have also been associated with increased susceptibility to TD. Immunocompromised individuals are at risk for prolonged illness with typical agents and infection with atypical organisms such as microsporidia.

Finally, the likelihood of the patient transmitting infectious diarrhea to other contacts must be explored. Food handlers and institutional caregivers with any type of diarrhea, including TD, should be evaluated regardless of the length of symptoms and their employment deferred until symptoms resolve to avoid a potential outbreak.

Clinical Presentation and Evaluation

The severity of the illness dictates the level of evaluation required of an ill patient with diarrhea. The first consideration to be made is the need for hospitalization. The combination of orthostatic hemodynamic changes and an inability to maintain oral rehydration necessitates intravenous rehydration and possible hospitalization. If significant systemic toxicity is present, stool and blood cultures should be obtained along with initiation of empiric parenteral antibiotics.

That being said, the average case of TD is not severe (averaging 4.6 stools/day), and symptoms are often those of nausea and cramping abdominal pain. The presence of high fever and/or blood or pus in stool suggest an invasive pathogen such as Salmonella , Shigella , Campylobacter , STEC, or Entamoeba histolytica and decrease the likelihood of non-invasive pathogens such as ETEC , norovirus, Giardia , and Vibrio spp., which tend to cause profuse watery diarrhea and abdominal cramps, without fever or bloody stools. Blood may not be present in all patients infected with invasive organisms, and concurrent infection with more than one enteric pathogen may occur. Persistent watery diarrhea for longer than 14 days, without fever, suggests giardiasis as well as other parasitic infections such as Cryptosporidium , microsporidia, and Cyclospora .

The physical examination does not usually aid in determining the etiology of travel-acquired diarrhea, although it is useful to assess the general condition of the patient and to exclude other conditions that may present with diarrhea. In TD, the abdomen is typically not tender to palpation, and bowel tones are hyperactive. Focal abdominal tenderness dictates expanding the differential diagnosis to include appendicitis, biliary disease, peptic ulcer disease, pancreatitis, diverticulitis, small bowel perforation and inflammatory bowel disease (IBD). Hepatic tenderness in a traveler with diarrhea could be suggestive of acute viral hepatitis or amebic liver abscess. Unrecognized chronic human immunodeficiency virus infection may present with gastrointestinal complaints. Occult or gross blood in the stool indicates the presence of an invasive organism. If only non-invasive pathogens are identified in stool samples, a non-infectious cause for gastrointestinal bleeding should be considered, including IBD and malignancy.

Physicians seeing travelers with chronic gastrointestinal complaints need to maintain an index of suspicion for previously unrecognized gastrointestinal disease, particularly IBD and irritable bowel syndrome (IBS). Infections with Salmonella , Shigella , or Campylobacter may trigger or exacerbate IBD. Ulcerative colitis or Crohn disease should be suspected in patients with bloody diarrhea, accompanied by systemic signs such as weight loss, oral or perianal lesions, and extraintestinal manifestations including arthropathies or ophthalmologic symptoms. IBD becomes more likely when symptoms have persisted more than 2 months without a microbiologic diagnosis. IBS is one of the most common post-infectious diarrhea processes in returning travelers and may be associated with intermittent cramping pain, bloating, and gas. If IBD or IBS is a consideration, further evaluation should be performed in consultation with a gastroenterologist.

Diagnostic Studies

The decision to perform laboratory studies in the traveler with diarrhea should be based on the duration of symptoms, severity of the illness, and type of diarrhea present: inflammatory (blood or white blood cells present) versus non-inflammatory (primarily watery), as outlined in Table 31.1 . The traveler seeking medical attention who has had fewer than 5 days of diarrhea does not require investigations unless there is significant fever, abdominal pain, dehydration, blood or mucus is present in the stool, or if the patient is immunocompromised. Before ordering stool studies, it is important to be aware of the capabilities and protocols of the clinical microbiology laboratory at your institution, including testing options, recommended stool sample volume, and preferred stool specimen transport method. Table 31.2 lists the common causes of TD, associated symptoms, and diagnostic testing.

It is important to educate patients on proper collection of stool samples for laboratory testing, as submission of improperly collected specimens will compromise testing results. The stool specimen should be caught directly in a standard pint-sized specimen container or in a larger clean, dry container. Fecal specimens contaminated with urine or toilet paper or retrieved from the toilet bowl are not satisfactory. It is ideal for stool specimens to arrive in the laboratory within 1-2 hours post collection to ensure reliability of microscopy and culture results. If this is not feasible, specimens for bacterial culture should be placed in an appropriate transport medium, such as Cary-Blair. When collecting stools to be examined for parasites, patients should be instructed to collect only one stool sample per day and at least three samples within a 10-day period if the first specimen is negative. It is recommended that stool specimens for ova and parasite examination be sent to the laboratory in a fixative. Preservative kits usually contain two different fixatives: formalin to preserve helminths and coccidian parasites and polyvinyl alcohol for staining to visualize protozoa. Single vial preservatives are now available, such as the alcohol-based Ecofix™ (Meridian Bioscience, Cincinnati, OH), which can be utilized for both the examination of helminths and staining for intestinal protozoa. It is important to note that the transport media used for bacterial cultures are not suitable for parasite examination and that fixed specimens cannot be used for bacterial culture. Thus, if bacterial culture and parasite examination are desired, separate fecal specimens are required, each in the appropriate transport container.

The determination of white blood cells (WBC) in the stool can be helpful in the evaluation of patients with diarrhea. The presence of WBC suggests an inflammatory process in the gastrointestinal tract, possibly due to an invasive infection. The detection of fecal leukocytes in stool samples can be achieved by microscopic examination of a stool smear stained with methylene blue or by using a commercially available enzyme immunoassay (EIA) for lactoferrin. The sensitivity/specificity of fecal leukocytes by microscopy or lactoferrin for predicting inflammatory diarrhea are 73%/84%, and 92%/79%, respectively.

TD studies have shown that the most commonly identified bacterial pathogens are ETEC, Salmonella , Shigella , and Campylobacter , which account for 45-50% of cases. Because bacteria are the most commonly reported cause of TD, stool culture has traditionally served as the backbone for a TD diagnostic work-up. While stool cultures are a commonly ordered test, they are not performed the same way at every hospital laboratory. Stool cultures are designed to optimize the recovery of Salmonella , Shigella , Campylobacter , and STEC, including E. coli O157:H7. Some laboratories will also isolate Aeromonas , Plesiomonas , Yersinia , and/or Vibrio from stool, whereas others will do so only on special request. In view of this, it is crucial to know how your laboratory performs stool cultures to ensure that the enteric pathogens being considered will be recovered. It is important to note that the most common cause of TD, ETEC, is difficult to isolate in stool culture, as there is no reliable way to discriminate between ETEC and endogenous E. coli by culture alone. Nucleic acid testing (NAT) platforms are available that will detect ETEC in stool samples as a single target or as part of a multiplex panel along with Salmonella , Shigella , and Campylobacter . Many laboratories will include an antigen-based assay or NAT to detect Shiga toxin in all stool cultures to aid in detecting STEC. However, STEC is an uncommon cause of TD, although it has been seen in outbreaks such as the one in Germany and France in 2011. Another illness to consider in patients with TD is Clostridium difficile colitis, based on history of antibiotics use or previous C. difficile infections. Detection of C. difficile from stool specimens is achieved by detecting toxins A and B using commercially available EIA or NAT methodologies. In addition to feces, cultures of blood, bone marrow, and/or urine samples should be performed in patients with symptoms consistent with disseminated Salmonella . Two negative stool cultures from specimens collected on separate days, rules out the majority of bacterial pathogens in patients with diarrhea.

Identification of bacteria and yeast using matrix-assisted laser desorption ionization time of flight mass spectroscopy (MALDI-TOF MS) has become increasingly available in clinical laboratories throughout the world including the United States. Currently, there are two commercially available systems: VITEK® MS (BioMérieux Inc.) and the MALDI Biotyper CA System (Bruker Daltonics Inc.). Each system includes a mass spectrometer, software, and database including a list of microorganisms that are cleared for identification. MALDI-TOF MS based bacterial identification takes minutes to perform and is significantly cheaper to operate than nucleic acid based identification methods such as 16S rRNA sequencing and multiplex panels, leading to a de-emphasis of biochemical-based bacterial identification. However, despite the robust nature of this technology, it cannot reliable differentiate E. coli from Shigella spp as these are highly related organisms at the molecular level. Thus, there may always be a need for biochemical identification in certain situations.

One major advantage of isolating stool bacterial pathogens is the ability to perform antimicrobial susceptibility testing. This is particularly important in travelers returning from parts of the world known to harbor multidrug-resistant (MDR) bacterial pathogens. MDR Salmonella have become more common in Asia and sub-Saharan Africa. Campylobacter resistance to fluoroquinolones has become a concern in Southeast Asia, with resistance rates up to 80%. Additionally, Enterobacteriaceae producing extended spectrum beta-lactamases and, more recently, carbapenem-resistant Enterobacteriaceae are becoming more prevalent in many parts of the world.

Parasitic infections are estimated to be responsible for 5-10% of TD cases. The index of suspicion for an enteric parasite should increase in travelers with diarrhea lasting longer than 1 week. Microscopic examination of stool for ova and parasites indicating infection is performed by examination of a stool specimen on two glass slides prepared using two different methods. One slide is prepared using concentrated, preserved stool and examined with or without the addition of iodine, looking for helminths and their eggs, or ova. The second slide is of preserved stool stained with trichrome, which facilitates identification of intestinal flagellates and amebic parasites. Microsporidia, Cryptosporidium , Cystoisospora , and Cyclospora are best visualized using special stains other than trichrome. If these organisms are suspected, the laboratory must be notified so the appropriate stains are included. Reliable detection of parasites by microscopy requires examination of multiple (at least three) fecal specimens, since parasites may be excreted intermittently and infections with multiple parasites may not be detected with one or two specimens. Strongyloides may require up to seven stool examinations and the use of special methods such as the Baermann technique or agar plate culture.

As an adjunct to microscopic stool examination, many laboratories utilize EIAs or fluorescent antibody tests for the detection of Giardia and Cryptosporidium antigens in stool because they are more sensitive than microscopic examination and are easier to perform. Stool antigen testing typically requires only one specimen to be diagnostic and effectively rules out infection with two negative results from separate specimens collected on different days. The sensitivity and specificity of Giardia EIAs are greater than 95%, while the performance of the Cryptosporidium EIAs are more variable, with sensitivity and specificity ranging from 80 to 99%.

It is estimated that 5-15% of cases of TD are due to viral infections, the majority of which are norovirus and rotavirus. Diagnostic work-up in these patients is unnecessary, since viral infections are self-limited and there are no directed therapies that will shorten the duration of illness or decrease viral shedding. Immunocompromised individuals are a patient group in whom diagnostic work-up may be beneficial, because determining the etiology of the diarrhea would limit further diagnostic work-up. In travelers in whom viral diagnostic work-up is warranted, stool can be assessed for rotavirus using commercially available EIAs; some laboratories offer NAT for norovirus and rotavirus. Hepatitis A is another viral cause of diarrhea that would be important to consider in unvaccinated individuals and is diagnosed using serology.

The causes of protracted diarrhea and ongoing gastrointestinal complaints will usually reveal themselves after clinical examination and laboratory studies outlined in this section. However, in approximately 30% of cases of traveler's diarrhea, no pathogen can be identified despite multiple, thorough laboratory evaluations. In these instances, consultation with a gastroenterologist is recommended to assist with further diagnostic evaluation. A complete blood count should be obtained to assess for signs of systemic inflammation, suggested by a high WBC and/or eosinophilia, and to assess for anemia from ongoing gastrointestinal blood loss or malabsorption. If tropical sprue or other malabsorption syndromes are being considered, testing for lactose tolerance and D-xylose absorption may be considered. If deemed appropriate, a gastroenterologist can perform a colonoscopic examination to inspect the mucosa and obtain biopsies to assess for Crohn disease, ulcerative colitis, schistosomiasis, and amebiasis.

Currently, there are three FDA-cleared, multiplex NAT panels available for the detection of enteric pathogens from stool specimens: xTag® GI Pathogen Panel (Luminex Corporation, Toronto, Canada), the FilmArray ^TM GI panel (BioFire, Inc., Salt Lake City, UT), and Verigene® Enteric Pathogens (EP) Test (Nanosphere, Inc., Northbrook, IL). All three panels detect bacterial pathogens commonly isolated in stool culture ( Campylobacter spp., Salmonella spp., Shigella spp., Vibrio spp., and Yersinia enterocolitica ) and the enteric viral pathogens Norovirus and Rotavirus. The xTag® and FilmArray ^TM GI panels can also detect the protozoan parasites Cryptosporidium spp., Entamoeba histolytica , and Giardia lamblia . These assays yield results within hours and require less hands-on time than the laborious, conventional methods for identification of bacteria and parasites. However, these assays may be cost prohibitive for some laboratories and patient populations and none of the currently available multiplex NAT assays can detect helminths. While molecular assays offer improved sensitivity over culture, use of these assays remains controversial due to concerns regarding specificity, clinical correlation and lack of an isolate for antimicrobial susceptibility testing and subtyping analysis to support identification during outbreak investigations. It is important to maintain an open dialog with the clinical microbiology laboratory to ensure that the tests being ordered are the appropriate tests for the patient.