A 24-year-old man college student presents with severe diarrhea and abdominal cramps, both of which appeared quite suddenly the day before he comes to your office for advice. He is not experiencing vomiting or nausea. His diarrhea is watery and, on gross examination, does not appear to be bloody. Vital signs are T = 37.2 C, P = 80, R = 18, BP = 120/85 mm Hg. The physical examination is unremarkable. A stool smear is prepared and examined microscopically, but there is no visible evidence for the presence of red blood cells or leukocytes in this specimen. Protozoan cysts or ova are not seen either. On taking the patient's history, you find out that he returned from a short trip to Mexico the day before his symptoms suddenly appeared. He says that he only ate thoroughly cooked food and only drank bottled soft drinks or beer during his trip. However, it was very hot, so he always asked that his soft drinks be served on ice.

Question 2.1: What is your preliminary diagnosis?

The patient appears to have some type of acute gastroenteritis. The lack of leukocytes or blood in the stool argues against an inflammatory disease (in which the causative agent invades intestinal epithelial cells or damages them by producing a cytotoxin). This is most likely to be a non-inflammatory gastroenteritis, perhaps caused by an agent that produces an enterotoxin. Among the likely causative agents are bacteria (Vibrio cholerae, Clostridium perfringens, Bacillus cereus, enterotoxigenic or enterohemorrhagic Escherichia coli, Staphylococcus aureus, and others), viruses (rotavirus, Norwalk like viruses, enteric adenoviruses) and parasites (Giardia lamblia, Cryptosporidium spp, Cyclospora spp, etc.). Non microbial toxins (e.g., mushrooms or heavy metals) are also possible. The lack of cysts or ova in the stool argues against parasitic causative agents. The incubation period (>16 h) argues against Bacillus cereus, Clostridium perfringens, and staphylococcal food poisoning, but this in itself is not definitive. In actuality, it is not possible to accurately identify the specific causative agent without additional information.

Question 2.2: What tests can you do to narrow the diagnosis?

To confirm your local microscopic observations, the lab should be asked to test a stool specimen for fecal leukocytes. A routine stool culture for gastrointestinal pathogens could also be ordered. If there is any recent history of cholera in the part of Mexico visited by the patient, the lab should also be asked to test for Vibrio cholerae.

Test Results

The lab confirms that the stool does not contain significant numbers of leukocytes. The stool culture for common gastrointestinal pathogens (Salmonella, Shigella, etc.) is negative, as is the test for cholera. The lab does report high numbers of Escherichia coli in the stool.

Question 2.3: What is most likely causative agent?

Given the patient's history and symptoms, and the apparent incubation period, he most likely has a classic case of traveler's diarrhea. The most likely cause of traveler's diarrhea can vary greatly from one location to another. If one eliminates protozoan and inflammatory bacterial pathogens (which appears to be justified based on the test results), the most likely causative agent for a case related to travel in Central or South America is an enterotoxigenic strain of Escherichia coli (i.e., ETEC). (If the patient had traveled to Asia, an ETEC infection would be much less likely.) The next most likely causes of this patient's problem would be a Norwalk-like virus or enterohemorrhagic Escherichia coli (assuming a comparatively mild case). Norwalk like viral infections can involve nausea and vomiting (not seen in this case). ELISA and PCR-based assays for detection of Norwalk like viruses have been developed but are not yet widely available. Specific tests can be used to detect the Shiga toxin produced by enterohemorrhagic E. coli (EHEC), if necessary.

Question 2.4: How does this causative agent produce disease?

ETEC strains use an adhesin (colonization factor antigen; Cfa), to attach to the mucosal surfaces in the intestine. The bacterium does not invade epithelial cells. Rather, it produces either or both of two enterotoxins: the heat-stable toxin (ST) and the heat-labile toxin (LT). Both of these toxins act by changing the net fluid transport in the gut from absorption to secretion. LT is structurally similar to cholera toxin and activates the adenylate cyclase-cyclic AMP system in the same manner and for the life of the affected cell. However, the amount of water secreted is usually far less than with the cholera toxin. ST interacts with and activates a guanylate cyclase of intestinal cells, which leads to an increase of cyclic GMP and altered sodium and chloride transport, much like LT and cholera toxins. However, the effects on guanylate cyclase are turned off if the toxin is washed away from the cell.

Question 2.5: How is this disease acquired?

This form of traveler's diarrhea is most often transmitted via the indirect fecal-oral route in food or water contaminated with human fecal material. The most likely source of infection in this patient's case would be the ice cubes used in his soft drinks. Unfortunately, in being careful about what he ate and drank, he forgot that ice cubes would most likely be made from the local tap water (or an even less healthy source of water).

Question 2.6: How should this case be treated?

Most cases of ETEC-related traveler's diarrhea are self-limiting in adults within 3-4 days. Antibiotics can shorten the course of the disease in severe cases. Possible regimens include doxycycline (100 mg PO bid for 3 days), ciprofloxacin (500 mg PO bid for 5 days), or sulfamethoxazole-trimethoprim (one DS tab bid for 3 days). Replacement of fluids may be required in severe cases.