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Harrison’s Manual of Medicine



Etiology and Pathogenesis
Noninflammatory diarrhea
Inflammatory Diarrhea

Etiology and Pathogenesis
Infectious diarrhea may be caused by a wide variety of microorganisms and may be mediated by toxins and/or by direct invasion of the GI mucosa. It is useful to categorize diarrheal diseases according to whether the responsible pathogens cause inflammatory or noninflammatory intestinal changes. Infections with pathogens that induce acute inflammation (e.g., Shigella species, Campylobacter jejuni, and Entamoeba histolytica) tend to involve the lower GI tract; cause small, purulent or bloody stools; and are accompanied by fever. Infections due to noninflammatory pathogens (e.g., enterotoxigenic Escherichia coli, Giardia lamblia) tend to involve the upper GI tract and cause more voluminous but nonbloody stools that do not contain PMNs.

Approach to the Patient

The history should include inquiries about fever, abdominal pain, nausea/vomiting, frequency and character of stools (whether watery or bloody; volume), food recently ingested (seafood; a possible common source, such as a picnic or restaurant), travel (exact location, duration, and nature of trip), sexual exposures, and general medical history (especially other illnesses and therapy with immunosuppressive drugs, antibiotics, or gastric-acid inhibitors). A complete physical exam should be performed, with particular attention to abdominal findings. Stool specimens should be examined grossly for consistency and the presence of blood and microscopically for the presence of PMNs. Stool should be cultured for Salmonella, Shigella, and Campylobacter if the diarrhea is inflammatory. The other diagnostic tests selected will depend on the clinical circumstances and may include an assay for Clostridium difficile cytotoxin (in the setting of recent use of antibiotics), an examination for ova and parasites (travel), and cultures for vibrios (seafood ingestion) and for Yersinia and enterohemorrhagic E. coli.

ENTEROTOXIGENIC E. coli   ETEC causes most cases of traveler’s diarrhea. The illness presents after 24–48 h of incubation as watery diarrhea, which is usually mild and is only occasionally accompanied by fever or vomiting. This diarrhea is usually self-limited (3–4 d in duration) and may be treated with oral fluid replacement (commercial or homemade solution consisting of 3.5 g of sodium chloride, 2.5 g of sodium bicarbonate, 1.5 g of potassium chloride, and 20 g of glucose per liter of water) or antimotility agents (e.g., loperamide, 4 mg at onset and 2 mg after each loose stool; up to 16 mg/d). Antibiotic therapy reduces the duration of illness to 24–36 h. Bismuth subsalicylate, which has both antimicrobial and anti-inflammatory properties, has only a minimal effect on the normal GI flora. It may be taken as 2 tablets (525 mg) every 30–60 min for up to 8 doses. TMP-SMZ (160/800 mg bid) or a quinolone such as levofloxacin (500 mg/d, for adults only) may also be used, each for a 3-d course.
CLOSTRIDIUM PERFRINGENS   C. perfringens produces a preformed toxin in food that causes illness 8–14 h after ingestion of contaminated meat, poultry, or legumes. The illness is manifest by diarrhea and crampy abdominal pain and rarely lasts >24 h. It is treated by fluid replacement, if necessary, and does not require antibiotics.
STAPHYLOCOCCUS AUREUS   Ingestion of S. aureus preformed enterotoxin causes a rapid onset (within 1–6 h) of vomiting and diarrhea. Staphylococcal food poisoning is associated epidemiologically with institutional outbreaks and high attack rates. The illness is of short duration (<12 h) and requires, at most, fluid replacement for treatment.
BACILLUS CEREUS   B. cereus produces two clinical syndromes. An emetic form, caused by a staphylococcal type of enterotoxin, resembles staphylococcal food poisoning and is epidemiologically associated with contaminated fried rice. A diarrheal form, caused by an E. coli LT–like enterotoxin, presents commonly in conjunction with abdominal cramps. The diarrheal form has a longer incubation period (8–16 h) than the emetic form.
VIBRIO CHOLERAE   Caused by toxin-producing V. cholerae, cholera occurs principally in the Ganges delta on the Indian subcontinent, in Southeast Asia, and in Africa. An ongoing epidemic in South and Central America began in 1991. The disease occurs sporadically in coastal Texas and Louisiana. Ingestion of water contaminated by human feces is the most common means of acquisition, although ingestion of contaminated food may play a role. Clinical signs developing after an incubation period of 12–48 h include profuse gray watery diarrhea, vomiting, and dehydration. Cholera is diagnosed by culture of stool on special medium. Treatment consists primarily of fluid replacement (IV or oral). Antibiotics are not necessary for cure, but tetracycline administration (2 g as a single oral dose in adults) decreases the duration and volume of fluid loss and hastens the clearance of the organism. Ciprofloxacin (30 mg/kg as a single oral dose, not to exceed 1 g) may be used for strains resistant to tetracycline. Erythromycin (40 mg/kg daily, given tid for 3 d) is the preferred treatment for children.
ROTAVIRUS   The most important cause of severe dehydrating diarrhea in children ❤ years of age worldwide, rotavirus infection presents as vomiting of <24 h duration, diarrhea, and low-grade fever. Rotaviruses may also be associated with mild diarrhea in adults (household contacts), elderly pts, and immunocompromised persons. Rotavirus infection occurs more commonly in colder months and is treated by fluid replacement.
NORWALK-LIKE VIRUSES   These food- and waterborne agents cause one-third of epidemics of nonbacterial diarrhea in developed countries. Disease occurs year-round, mainly affecting older children and adults. The illness is usually mild and does not require treatment.
G. Lamblia and Cryptosporidium See Chap. 110.
CAMPYLOBACTER   C. jejuni is a leading cause of food-borne diarrhea in the U.S. and is also associated with exposure to infected (often asymptomatic) animals and with travel to developing countries. In the U.S., ingestion of contaminated poultry that has not been sufficiently cooked accounts for 50–70% of cases. After an incubation period of 2–4 d, the illness presents as fever, crampy abdominal pain, and diarrhea. It is generally self-limited but may persist for >1 week in up to 20% of pts. Similar disease may be caused by related species of Campylobacter (e.g., C. coli, C. upsaliensis). Diagnosis requires culture of the pathogen from stool on special medium at 42°C. Treatment consists of fluid and electrolyte repletion. In severe cases, erythromycin (250 mg PO qid for 5–7 d) may be used. C. fetus is an occasional agent of diarrhea that can cause septicemia in immunocompromised hosts.
SHIGELLA   Shigellosis is caused most often by S. sonnei in the U.S. and by S. flexneri and S. dysenteriae in the developing world. Person-to-person transmission is common, and 20–40% of household contacts develop disease. The prevalence is greatest among children and homosexual men. Although referred to as bacillary dysentery, shigellosis has clinical manifestations ranging from mild watery diarrhea to severe dysentery, often accompanied by fever, with onset after an incubation period of 1–7 d. Without treatment, fever persists for 3–4 d and diarrhea for 1–2 weeks. Hemolytic-uremic syndrome is a rare but serious complication of shigellosis. The diagnosis of shigellosis is based on the finding of fecal leukocytes and the culture of the organism from stool. Treatment includes fluid replacement and antibiotic administration. Resistance to ampicillin is now common among shigellae, and resistance to TMP-SMZ is increasing in frequency. Susceptible isolates may still be treated with one of these agents (ampicillin, 500 mg qid; TMP-SMZ, 160/800 mg bid for 5 d) or with ciprofloxacin (500 mg bid; for adults only for 3 d) or IV ceftriaxone (50 mg/kg qd for 5 d). Antimotility agents should be avoided in the dysenteric phase of the disease.
ENTEROHEMORRHAGIC E. COLI   Certain E. coli organisms, particularly serotype O157:H7, produce a Shiga-like toxin and cause a syndrome of bloody diarrhea. Outbreaks are frequently food-borne. Hemolytic-uremic syndrome is a rare but serious complication of infection with EHEC. The diagnosis may be made by identification of the organism in stool cultured on special medium.
CLOSTRIDIUM DIFFICILE   Infection with the cytotoxin-producing anaerobe C. difficile is commonly associated with antibiotic use and classically causes pseudomembranous colitis. Clinical manifestations include fever, elevated WBC count, and diarrhea. The infection is diagnosed by the detection of cytotoxin in stool specimens. Treatment should include the discontinuation of any offending antibiotics and the administration of metronidazole (500 mg PO tid for 10–14 d). Vancomycin (125 mg PO qid) may be substituted in refractory cases but is generally avoided because of concerns about the development of vancomycin-resistant enterococci.
VIBRIO PARAHAEMOLYTICUS   Present in coastal waters throughout the world, V. parahaemolyticus causes disease most frequently in association with the consumption of raw or under-cooked seafood. After an incubation period of 4 h to 4 d, it most commonly produces acute watery diarrhea accompanied by abdominal cramps, nausea, and vomiting and sometimes by fever and chills. The diagnosis is made by culture of the organism on special medium and must be suspected on the basis of exposure to seafood or the sea. Treatment of severe cases consists of fluid repletion and antibiotic administration (tetracycline, 500 mg qid).
E. HISTOLYTICA See Chap. 110.
SALMONELLA   Salmonellae are acquired by consumption of contaminated food or drink, most commonly from eggs or poultry, and may cause clinical illness ranging from gastroenteritis to enteric fever. S. typhimurium and S. enteritidis cause most cases of human disease in the U.S. Pts at increased risk for salmonellosis include those with decreased stomach acidity (antacid use, achlorhydric disease) and those with decreased intestinal integrity (inflammatory bowel disease, history of GI surgery, antibiotic use). Gastroenteritis is the most common manifestation. After an incubation period of 6–48 h, diarrhea develops and may be accompanied by abdominal cramps, nausea, vomiting, and fever. Stools may show fecal leukocytes and are sometimes frankly dysenteric. Illness is usually mild and self-limited but may become severe in elderly pts or neonates as well as in immunocompromised pts (e.g., those with HIV infection or sickle cell disease). The diagnosis is based on culture of stool or blood.
Bacteremia/Enteric Fevers   Up to 5% of pts with nontyphoidal Salmonella gastroenteritis have positive blood cultures, and 5–10% of these bacteremic persons develop localized infections. This illness is similar to typhoid fever (see below) but may be more acute and is not associated with classic manifestations of typhoid such as rose spots, leukopenia, and relative bradycardia. This syndrome, frequently associated with S. choleraesuis or S. dublin, is serious and carries a high mortality. Pts with HIV infection have a high risk of Salmonella (particularly S. typhimurium) bacteremia, which may be refractory to treatment.
Localization of Systemic Infection   Bloodborne salmonellae, usually present following GI infection, can invade any tissue or organ. Salmonellae have a propensity for vascular sites. Arterial infection may occur in preexisting arteriosclerotic aortic aneurysms, especially in men over age 50. Osteomyelitis (associated with sickle cell disease), hepatobiliary infection, splenic abscess, cholecystitis, and UTI are all examples of localized Salmonella infection.
Typhoid Fever   This form of enteric fever, caused by the exclusively human pathogen S. typhi (and less commonly by S. paratyphi), is linked epidemiologically to the ingestion of contaminated food, water, or milk and occurs most frequently in travelers. The risk of infection is increased by antibiotic use, malnutrition, and HIV infection. After an average incubation period of 3–21 d, clinical manifestations include prolonged fever and the nonspecific symptoms of chills, headache, malaise, anorexia, and (rarely) an altered sensorium. Findings on physical exam include rose spots (a salmon-colored maculopapular rash, primarily on the trunk and chest), relative bradycardia, and hepatosplenomegaly. Complications include intestinal perforation, GI bleeding, and localized infection (meningitis, hepatitis, hepatic and splenic abscesses, cholecystitis, nephritis, myocarditis, endocarditis, pneumonia, parotitis, orchitis). Chronic carriage develops in 1–5% and relapse in ~10% of treated immunocompetent pts. Diagnosis depends on isolation of the organism from blood (with a 90% positivity rate in the first week and a decline thereafter), stool (greater positivity by the third week in untreated pts), urine, bone marrow, and gastric or intestinal secretions. Serologic (Widal) testing is less reliable and not clinically useful.

Uncomplicated Salmonella gastroenteritis does not require antibiotic treatment, and such treatment may in fact increase rates of relapse and prolong carriage. However, treatment should be considered in neonates, pts >50 years old, transplant recipients, pts with prosthetic joints or vascular grafts, and persons with underlying immunosuppression (HIV disease, lymphoma, malignancy, sickle cell disease). The treatment of these pts includes a third- generation cephalosporin (e.g., ceftriaxone, 1–2 g/d) and/or ciprofloxacin (500 mg bid) for 2–3 d or until defervescence. For focal infections or bacteremia, the pt should be treated for 7–14 d or — if immunocompromised—even longer. Many strains of Salmonella are resistant to ampicillin, chloramphenicol, and TMP-SMZ. Typhoid fever may be treated with ceftriaxone (1–2 g/d IV) or ciprofloxacin (500 mg PO bid) for 10–14 d. Other agents effective against sensitive typhoid include amoxicillin (1–1.5 g PO qid) and TMP-SMZ (160/800 mg PO qid), each for 2 weeks. Glucocorticoids (dexamethasone, loading dose of 3 mg/kg followed by 1 mg/kg q6h for 24–48 h) may have an adjunctive role in severe typhoid.


For a more detailed discussion, see Butterton JR, Calderwood SB: Acute Infectious Diarrheal Diseases and Bacterial Food Poisoning, Chap. 131, p. 834; Kasper DL, Zaleznik DF: Gas Gangrene, Antibiotic-Associated Colitis, and Other Clostridial Infections, Chap. 145, p. 922; Lesser CF, Miller SI: Salmonellosis, Chap. 156, p. 970; Keusch GT: Shigellosis, Chap. 157, p. 975; Blaser MJ: Infections Due to Campylobacter and Related Species, Chap. 158, p. 978; Keusch GT, Deresiewicz RL, Waldor MK: Cholera and Other Vibrioses, Chap. 159, p. 980; and Greenberg HB: Viral Gastroenteritis, Chap. 192, p. 1135, in HPIM-15.


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