Diarrhea

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Definition and causes
Normal bowel frequency ranges from three times a day to three times a week in the normal population. Increased stooling, with stool consistency less solid than normal, constitutes a satisfactory, if somewhat imprecise, definition of diarrhea. Acute diarrhea is defined as a greater number of stools of decreased form from the normal lasting for less than 14 days. If the illness persists for more than 14 days, it is called persistent. If the duration of symptoms is longer than 1 month, it is considered chronic diarrhea. Most cases of acute diarrhea are self limited, caused by infectious agents (e.g. viruses, bacteria, parasites), and do not require medication unless the patient is immunocompromised.

Pathophysiology
Approximately 8 to 9 L of fluid enter the intestines daily—1 to 2 L represents food and liquid intake, and the rest is from endogenous sources such as salivary, gastric, pancreatic, biliary, and intestinal secretions. Most of the fluid, about 6 to 7 L, is absorbed in the small intestine, and only about 1 to 2 L is presented to the colon. Most of this is absorbed as it passes through the colon, leaving a stool output of about 100 to 200 g/day. Although many organisms simply impair the normal absorptive processes in the small intestine and colon, others, organisms, such as vibrio cholera, secrete a toxin that causes the colonic mucosa to secrete, rather than absorb, fluid and electrolytes. Voluminous diarrhea may result.

Diarrhea-causing pathogens are usually transmitted through the fecal-oral route. Risk factors for this type of transmission include improper disposal of feces and lack of proper hand washing following defecation and feces contact before handling food. Other risk factors include improper food hygiene, inadequate food refrigeration, food exposure to flies, and consumption of contaminated water. Multiple host factors that determine the level of illness once exposure to infectious agents has occurred include age, personal hygiene, gastric acidity and other barriers, intestinal motility, enteric microflora, immunity, and intestinal receptors.

Viruses (e.g., adenovirus, rotavirus, Norwalk virus) are the most common cause of diarrhea in the United States. Escherichia coli, Clostridium difficile and Campylobacter, Salmonella, and Shigella spp. are common bacterial causes. Bacillus cereus, Clostridium perfringens, Staphylococcus aureus, Salmonella spp., and others cause food poisoning. Entamoeba histolytica and Giardia, Cryptosporidium, and Cyclospora spp. are parasitic or protozoal agents that cause diarrhea.

Acute watery diarrhea is most commonly seen with traveler's diarrhea caused by enterotoxigenic E. coli (ETEC), parasite-induced diarrhea from Giardia and Cryptosporidium spp. and, in cases of food poisoning (ingestion of preformed toxins), from B. cereus and S. aureus.

Some infectious agents cause mucosal inflammation, which may be mild or severe. Bacteria such as enteroadherent or enteropathogenic E. coli and viruses such as rotavirus, Norwalk agent, and HIV can cause minimal to moderate inflammation. Bacteria that destroy enterocytes such as Shigella, enteroinvasive E. coli, the parasite Entamoeba histolytica and bacteria that penetrate the mucosa such as Salmonella, Campylobacter jejuni, and Yersinia enterocolitica result in moderate to severe inflammation with or without ulceration.

Ingestion of preformed toxin produced by bacteria such as B. cereus, S. aureus, and Clostridium perfringens can result in acute jejunitis. Aeromonas, Shigella, and Vibrio spp. (e.g., V. parahaemolyticus) produce enterotoxins and also invade the intestinal mucosa. Patients therefore often present with watery diarrhea, followed within hours or days by bloody diarrhea. Bacteria that produce inflammation from cytotoxins include Clostridium difficile and hemorrhagic E. coli 0157:H7.

Exudative diarrhea results from extensive injury of the small bowel or colon mucosa as a result of inflammation or ulceration, leading to a loss of mucus, serum proteins, and blood into the bowel lumen. Increased fecal water and electrolyte excretion results from impaired water and electrolyte absorption by the inflamed intestine rather than from secretion of water and electrolytes into the exudates.

Noninfectious causes of diarrhea include inflammatory bowel disease, irritable bowel syndrome, ischemic bowel disease, partial small bowel obstruction, pelvic abscess in the rectosigmoid area, fecal impaction, and the ingestion of poorly absorbable sugars, such as lactulose and acute alcohol ingestion. Diarrhea is one of the most frequent adverse effects of prescription medications; it is important to note that drug-related diarrhea usually occurs after a new drug is initiated or the dosage increased.

Signs and symptoms
Clinical features sometimes provide a clue as to the cause. Diarrhea caused by small intestine disease is typically high volume, watery, and often associated with malabsorption. Dehydration is frequent. Diarrhea caused by colonic involvement is more often associated with frequent small-volume stools, the presence of blood, and a sensation of urgency.
Important factors in evaluating acute diarrhea include travel history, sources of water (e.g., well water), recent food intake, history of profuse diarrheal episodes, dehydration, fever, hematochezia, nausea, vomiting, and abdominal pain. Important clinical features include abrupt versus gradual onset of symptoms, symptom duration, including bowel movement frequency, stool quantities, dysentery with fever, tenesmus, hematochezia or pus in the stool, signs of volume depletion, including thirst, tachycardia, orthostasis, decreased urine output, skin turgor, and lethargy or confusion, or both.
Patients ingesting toxins or those with toxigenic infection typically have nausea and vomiting as prominent symptoms, along with watery diarrhea, but rarely have a high fever. Vomiting that begins within 6 hours of ingesting a food should suggest food poisoning caused by preformed toxin from bacteria such as S. aureus or B. cereus. If diarrhea disease begins within 8 to 14 hours of food ingestion, C. perfringens should be suspected. When the incubation period is longer than 14 hours and vomiting is also a significant symptom, along with the diarrhea, viral agents should be considered. Parasites that do not invade the intestinal mucosa, such as Giardia lamblia and Cryptosporidium, usually cause only mild abdominal discomfort. Giardiasis may be associated with mild steatorrhea, gaseousness, and bloating.

Infection with invasive bacteria such as Campylobacter, Salmonella, and Shigella spp., and organisms that produce cytotoxins, such as C. difficile and enterohemorrhagic E. coli (serotype O157:H7), frequently result in abdominal pain, and low-grade fever; occasionally, peritoneal signs may suggest a surgical abdomen. Yersinia organisms often infect the terminal ileum and cecum and manifest with right lower quadrant pain and tenderness, suggestive of acute appendicitis.

Hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura can occur in infections with enterohemorrhagic E. coli and Shigella organisms, particularly in young children and older adults. Yersinia infection and other enteric bacterial infections may be accompanied by Reiter's syndrome (arthritis, urethritis, and conjunctivitis), thyroiditis, pericarditis, or glomerulonephritis. Enteric fever, caused by Salmonella typhi or paratyphi, is a severe systemic illness manifested initially by prolonged high fevers, prostration, confusion, and respiratory symptoms, followed by abdominal tenderness, diarrhea, and rash.

Epidemiologic risk factors should be investigated for certain diarrheal diseases and their spread. They include recent travel to an underdeveloped area, daycare center exposure, consumption of raw meat, eggs, shellfish, and unpasteurized milk products, contact with reptiles or pets with diarrhea, a history of other ill people in a shared dormitory facility, recent antibiotic use, and a history of HIV or medically induced immunosuppression. In cases of homosexual males, in addition to immunosuppression, there are two other disease transmission routes that lead to an increased susceptibility to infectious agents that cause diarrhea. These include an increased rate of fecal-oral transmission of all infectious agents spread by this route, including Shigella, Salmonella, Campylobacter, and intestinal protozoa and anal intercourse. Anal intercourse may lead to a direct rectal inoculation, resulting in proctitis associated with rectal pain, tenesmus, and passage of small-volume, bloody, mucous stools.

Diagnosis
Conducting a careful interview can provide valuable clues that will aid in diagnosing and choosing the most appropriate and cost-effective investigation. Acute diarrheas are usually infectious in origin and, for the most part, resolve with or without intervention before a diagnosis is made.

The presence of blood is a useful clue, suggesting infection by invasive organisms, inflammation, ischemia, or neoplasm. Large-volume diarrhea suggests small bowel or proximal colonic disease, whereas small frequent stools associated with urgency suggest left colon or rectal disease. All current and recent medications should be reviewed, specifically new medications, antibiotics, antacids, and alcohol abuse. Nutritional supplements should also be reviewed, including the intake of “sugar-free” foods (containing nonabsorbable carbohydrates), fat substitutes, milk products, and shellfish, and heavy intake of fruits, fruit juices, or caffeine. Food- or waterborne outbreaks of diarrhea are becoming more common. The history should include place of residence, drinking water (treated city water or well water), rural conditions, with consumption of raw milk, consumption of raw meat or fish, and exposure to farm animals that may spread Salmonella or Brucella organisms. Sexual history is important, because specific organisms can cause diarrhea in homosexual men and HIV-infected patients.

A medical evaluation of acute diarrhea is not warranted in the previously healthy individual if symptoms are mild, moderate, spontaneously improve within 48 hours, and are not accompanied by fever, chills, severe abdominal pain, or blood in the stool. On the other hand, evaluation is indicated if symptoms are severe or prolonged, the patient appears “toxic,” there is evidence of colitis (occult or gross blood in the stools, severe abdominal pain or tenderness, and fever), or empirical therapy has failed. Passage of many small-volume stools containing blood and mucus, temperature higher than 38.5° C (101.3° F), passage of more than six unformed stools in 24 hours, or a duration of illness longer than 48 hours, diarrhea with severe abdominal pain in a patient older than 50 years, diarrhea in older adults (older than 70 years) or in the immunocompromised patient (e.g., those with AIDS, after transplantation, or undergoing cancer chemotherapy) are all indications for a thorough medical and bacteriologic evaluation.

The physical examination in acute diarrhea is helpful in determining the severity of disease and hydration status. A directed physical examination may lead to a more focused evaluation. Vital signs (including temperature and orthostatic evaluation of pulse and blood pressure) and signs of volume depletion (including dry mucous membranes, decreased skin turgor, and confusion) should be carefully evaluated. A careful abdominal examination to evaluate for tenderness and distention and a stool examination to evaluate for grossly bloody stools are warranted. Nonbloody stools should be evaluated for heme positivity.

The history and physical examination can help lead to a diagnosis but, for treatment of some organisms, a specific diagnosis is required, which will lead to more specific therapy and prevention of unneeded interventions. Fecal testing should be performed in patients with a history of diarrhea longer than 1 day who have the following symptoms: fever, bloody stools, systemic illness, recent or remote antibiotic treatment, hospital admission, or signs of dehydration, as described earlier.

Studies in Select Patients with Acute Diarrhea
The following studies should be carried out:
1. Fecal leukocyte determination
2. Stool culture for enteric pathogens
3. Stool examination for ova and parasites
4. Flexible sigmoidoscopy with biopsy

Stool evaluation for fecal leukocytes (or lactoferrin, a by-product of white blood cells) is a useful initial test, because it may support a diagnosis of inflammatory diarrhea. If the test is negative, stool culture may not be necessary, but culture is indicated if the test is positive. However, clinicians should remember that inflammatory diarrhea with a noninfectious cause, such as inflammatory bowel disease, ischemic or radiation-induced colitis, and diverticulitis, can be positive for stool leukocytes.

Indications for stool culture are bloody diarrhea, a toxic-appearing patient (fever, severe abdominal pain), possible epidemic, history of traveler's diarrhea, immunosuppression, or persistent diarrhea. A positive stool culture can be considered to be a true positive. Multiple stool cultures are usually not necessary because bacteria usually shed continuously. The culture medium routinely used can identify Campylobacter, Salmonella, Shigella, and Aeromonas organisms. Stool cultures are of little value if first performed more than 72 hours after admission. In outbreaks of diarrhea secondary to Salmonella and E. coli, performance of routine culture is critical for antibiotic resistance testing and serotype subtyping. In patients with bloody diarrhea or hemolytic-uremic syndrome, the stool should be evaluated for E. coli 0157 by the presence or absence of Shiga's toxin. Stool culture for Vibrio spp. should be performed for those with diarrhea who have a previous history of shellfish ingestion within three days of onset of the illness. Cultures for Yersinia enterocolitica should be performed for at-risk populations (Asian Americans in California and African American infants) who develop diarrhea in the fall or winter. The rapid enzyme-linked immunoassay (ELISA) for C. difficile toxins A and B is most often used for high-risk patients who have taken antibiotics or have hospital-acquired diarrhea that develops three or more days after admission. The evaluation and management of antibiotic-associated diarrhea, including C. difficile, are considered elsewhere in this section (“Antibiotic-Associated Diarrhea”).

A negative stool culture in a patient with acute diarrhea with fecal leukocytes is helpful for suggesting the acute onset of idiopathic inflammatory bowel disease (e.g., Crohn's disease, mucosal ulcerative colitis). A flexible sigmoidoscopy with biopsy may provide additional support.

Stool testing for ova and parasites should be done if the patient is at risk for parasitic infection. Multiple stool collections should be collected at different times because shedding of parasites may be intermittent.

When organisms are not identified on stool cultures for ova and parasites, a sigmoidoscopy should be performed and biopsies obtained. Mucosal biopsy is helpful in differentiating infectious colitis from inflammatory bowel disease. Further investigations will depend on the results of sigmoidoscopy, severity of diarrhea, immune status of the host, and presence of systemic toxicity. A general algorithm for the evaluation and management of acute diarrhea is shown in Figure 1.
Algorithm for the evaluation of a patient with acute diarrhea.

Treatment
The principal components of the treatment of acute diarrhea are fluid and electrolyte replacement, dietary modifications, and drug therapy. All recommendations agree with the guidelines on acute infectious diarrhea in adults published by the American College of Gastroenterology.

Rehydration
In most cases of acute diarrhea, fluid and electrolyte replacement are the most important forms of therapy. If patients are otherwise healthy and are not dehydrated, adequate oral intake can be achieved with soft drinks, fruit juice, broth, soup, and salted crackers. In those with excessive fluid losses and dehydration, more aggressive measures such as IV fluids or oral rehydration therapy with isotonic electrolyte solutions containing glucose or starch should be instituted. Oral rehydration therapy is less expensive, often just as effective, and more practical than intravenous fluids. A number of oral rehydration solutions are available, including Pedialyte, Rehydralyte, Ricelyte (Infalyte), Resol, the World Health Organization formula, and the newer reduced osmolarity formula for children. An equally effective homemade mixture is ½ tsp salt (3.5 g), 1 tsp baking soda (2.5 g NaHCO3), 8 tsp sugar (40 g), and 8 oz orange juice (1.5 g KCl), diluted to 1 L with water. Fluids should be given at rates of 50 to 200 mL/kg/24 hr, depending on the patient's hydration status. IV fluids (e.g., lactated Ringer's solution) are preferred acutely for patients with severe dehydration and for those who cannot tolerate oral fluids.

Diet
Total food abstinence is unnecessary and not recommended. Foods providing calories are necessary to facilitate renewal of enterocytes. Patients should be encouraged to take frequent feedings of fruit drinks, tea, “flat” carbonated beverages, and soft, easily digested foods such as bananas, applesauce, rice, potatoes, noodles, crackers, toast, and soups. Dairy products should be avoided, because transient lactase deficiency can be caused by enteric, viral, and bacterial infections. Caffeinated beverages and alcohol, which can enhance intestinal motility and secretions, should be avoided.

Pharmacologic Measures
Antidiarrheal Agents
These can be useful for the amelioration of symptoms. The most effective agents are the opioid derivatives—loperamide, diphenoxylate—atropine, and tincture of opium. These agents inhibit intestinal peristalsis, facilitating intestinal absorption, and have antisecretory properties. Loperamide may reduce the duration of diarrhea in those with traveler's diarrhea and bacillary dysentery. These agents should be avoided in patients with fever, bloody diarrhea, and possible inflammatory diarrhea because they may be associated with prolonged fever in patients with shigellosis, toxic megacolon in patients with C. difficile infection, and the hemolytic-uremic syndrome in children with Shiga toxin–producing E. coli.

Bismuth subsalicylate, somewhat less effective than loperamide, is effective in relieving symptoms of diarrhea, nausea, and abdominal pain in patients with traveler's diarrhea. Bismuth subsalicylate is contraindicated in HIV-infected patients because it may cause bismuth encephalopathy.

Antimicrobial Treatment
Because most patients have mild, self-limited disease caused by viruses or noninvasive bacteria, routine empirical treatment is not warranted. Empirical treatment is indicated for those patients with suspected invasive bacterial infection, traveler's diarrhea, or immunosuppression. Empirical antibiotic treatment is also appropriate specifically for early Campylobacter infections and C. difficile–associated diarrhea as well as for the febrile patient with fecal leukocytes and hemoccult-positive stools. Empirical treatment for Giardia can be prescribed for those with a 2-week or longer history of diarrhea.