Even today diarrheal illness is a common cause of morbidity and mortality. Infectious agents cause more than 200 million cases of diarrhea in the United States yearly.³ Although it is a major cause of mortality in developing nations, infectious diarrhea also has significant costs in developed nations in terms of hospitalization and lost time.⁴ Intestinal infection is the most common cause of diarrhea worldwide and is responsible for the deaths of 3 to 4 million individuals annually, the majority of whom are preschool-age children.⁵ According to the World Health Organization, nearly 2 million children die each year because of diarrheal illness.¹ Despite these alarming statistics, approximately 90% of cases of acute diarrhea are mild and self-limited and respond within 5 days to simple rehydration therapy or antidiarrheal agents.⁶

Infectious Agents and Symptoms

An increasingly wide variety of viral and bacterial agents are being recognized as causes of serious diarrheal illness.³ Overall, the causes of infectious diarrhea can be categorized as viral, bacterial, or parasitic. In general, these pathogens create a diarrheal effect by inhibiting intestinal absorption and increasing secretion; in causing inflammation, they promote secretory and exudative diarrheal symptoms.

Viral Agents

Viruses are important causes of diarrhea. In healthy adults, the clinical manifestation of viral diarrhea is generally an acute, self-limited gastroenteritis. Although at least 25 different bacteria and protozoa can cause an identical clinical syndrome, greater than 75% of diarrhea-associated cases of gastroenteritis are caused by viruses. Viruses are suspected when vomiting is prominent, the incubation period is longer than 14 hours, and the entire illness is over in less than 72 hours. Viral pathogens are likely when there are no warning signs of bacterial infection (such as high fever, bloody diarrhea, severe abdominal pain, more than 6 stools in 24 hours) and there are no epidemiologic clues from the history (i.e., travel, sexual contact, antibiotic use) suggesting an alternative diagnosis.⁷

Rotavirus

Rotavirus is one of the most ubiquitous agents of diarrhea. It can contribute to an acute, dehydrating diarrhea in children and is estimated to cause more than 800,000 annual deaths of young children in developing countries.⁸ Rotavirus-associated diarrheal disease is seasonal; in the United States it begins in the autumn in the Southwest and ends in the spring in the Northeast. Rotaviruses are spread via a fecal–oral route that includes person-to-person transmission. Although the precise mechanisms of disease have yet to be fully elucidated, rotaviruses are known to infect the villous enterocytes of the small intestine and cause a watery diarrhea. In addition to diarrhea, patients often have fever and vomiting.⁹

Bacterial Agents

Escherichia coli

At least four distinct varieties of diarrheogenic Escherichia coli exist: enterotoxigenic (ETEC), enterohemorrhagic (EHEC), enteroinvasive (EIEC), and enteroadherent. In North America, the most prominent diarrheogenic E. coli is the EHEC serotype, E. coli O157:H7.⁹ Contaminated ground beef is the most common vehicle of transmission because contaminating bacteria are distributed throughout the meat during grinding and are not killed if hamburgers are undercooked. After an incubation period from 1 to 8 days, typical symptoms include abdominal cramping and diarrhea that can present as mild, moderate, or severe. Early in the disease course, bowel movements may be loose and watery; in time, however, they may contain gross blood. A subset of patients, often children, may develop the severe, life-threatening hemolytic-uremic syndrome, characterized by the clinical triad of hemolytic anemia, renal failure, and thrombocytopenia.⁹

Campylobacter jejuni

Campylobacter is part of the intestinal flora in many mammals. Contaminated and improperly cooked meat contributes significantly to the spread of disease. Unpasteurized dairy products, contaminated water, and other foods also may encourage transmission. Symptoms begin 1 to 7 days after ingestion of the bacteria and consist of fever, headache, and malaise. These may herald the onset of diarrhea and abdominal cramps by 1 to 2 days. The nature of the diarrhea varies from watery to bloody. Campylobacter enterocolitis is usually acute and self-limited over 7 to 10 days. Rarely, relapses, complications, severe disease, and death may occur.⁹

Clostridium difficile

C. difficile infection has become the most common cause of infectious diarrhea in hospitalized patients ¹⁰ and is most likely to affect the elderly. Clostridium can be catalyzed by the use of antibiotics.

Salmonella

The spread of resistant Salmonella strains continues to increase worldwide ¹¹ and there are more than 2200 currently known serotypes. Spread chiefly through contaminated food, salmonella enteritidis accounts for 85% of all salmonella infections in the United States. Other prominent salmonella infections include Salmonella typhi and Salmonella paratyphi, which are responsible for typhoid fever. Nontyphoidal salmonellosis may present as fever, gastroenteritis-related diarrhea, and localized infections of the gastrointestinal tract, endothelial surfaces, pericardium, meninges, lungs, joints, bones, urinary tract, or soft tissues. Typhoidal symptoms include a gradual onset of fever, headache, arthalgias, pharyngitis, constipation, anorexia, and abdominal discomfort.

Shigella

Among the bacterial enteric pathogens, Shigella is unique in that ingestion of fewer than 200 organisms and possibly as few as 10 organisms may cause clinically apparent disease. Shigella, like other enteric pathogens, may be transmitted through contaminated food and water. However, person-to-person spread and transmission by flies may also occur, because so few organisms are necessary to cause disease.⁹ The incubation period is usually 1 to 4 days. Adults present with nonbloody diarrhea with or without fever and possible gripping abdominal pain, urgency, and relief with defecation. As the infection progresses, episodes may increase with the presence of mucus and blood in the stool. Infections often resolve spontaneously in 4 to 8 days for mild cases or 3 to 6 weeks in severe cases.

Yersinia enterocolitica

Yersinia enterocolitica, like Salmonella and Shigella, is a member of the Enterobacteriaceae family. Yersinia species are significantly less frequent causes of bacterial enterocolitis in North America than elsewhere. Pathogenic strains of Y. enterocolitica are usually transmitted through fecally contaminated food or water but infrequently are transmitted by contaminated blood products. A 4-day to 7-day incubation period occurs, followed by watery to bloody diarrhea. This organism is invasive and demonstrates a propensity for lymphoid tissues, causing mesenteric lymphadenitis that may be clinically mistaken for acute appendicitis.⁹ Disease usually resolves within 1 to 4 weeks, but occasionally complicating septicemia may develop, usually in patients with underlying disease.

Laribacter hong-kongensis ¹²

Described and characterized in 2001, Laribacter hong-kongensis is a novel genus and species originally isolated from the blood and empyema pus cultures of a cirrhotic patient with bacteremic empyema thoracis. Since then, it has been described in six patients with diarrhea in Hong Kong and Switzerland. Although more extensive epidemiologic studies are necessary, there is reason to consider its role in future studies of diarrheal outbreaks worldwide.

Parasitic Agents

Diarrheal diseases caused by parasites still constitute the greatest single worldwide cause of illness and death. The problem is more severe in underdeveloped countries with poor sanitation, but even in the United States diarrheal diseases are a major cause of sickness and death. Furthermore, the ease and frequency of worldwide travel and increased migration to the United States are resulting in growing numbers of parasitic infections. In addition to normal inhabitants of the gastrointestinal system acting as parasites, there are also significant diarrheal diseases associated with protozoa and helminthes.

Giardia lamblia is the most frequent cause of parasitic enteritis in the United States and should be suspected in cases where history suggests recent hiking and drinking out of streams. Waterborne infection is also important in the developed world, particularly as a result of contamination of domestic water supplies with the cysts of Giardia intestinalis and Cryptosporidium parvum.⁵ Other diarrhea-associated parasites include Entamoeba histolytica, Microsporidium, Isospora belli, and Strongyloides species.

Although the most commonly reported symptoms of parasitic infection are abdominal pain and cramping with concomitant explosive diarrhea, these symptoms do not occur in all cases. In fact, a growing number of individuals are experiencing milder than usual gastrointestinal symptoms due to parasitic infections or symptoms not traditionally considered to be linked to parasitic infections. For example, in some cases of irritable bowel syndrome, indigestion, and poor digestion, parasites may be causing the symptoms. In addition, parasitic infections are often an unsuspected cause of chronic illness and fatigue.

Laboratory Diagnosis

Numerous laboratory procedures exist for the analysis of patients with diarrhea. Bacterial cultures using selective media, detection of pathogen-specific genes using polymerase chain reaction (PCR), electron microscopic examination and antigen detection for viruses, as well as direct examination with or without using special stains for protozoa are some of the plethora of diagnostic tests available. Despite this wide array, a microbiologic cause is identified in only 50% of patients at best.¹² One hospital survey of more than 30,000 stool specimens sent for testing revealed a specific pathogen in only 5.6% of cases. In descending order, the most commonly identified pathogens were Campylobacter jejuni, Salmonella, Shigella, and E. coli O157:H7.³

Confounding this issue, it has been shown that substantial variation exists in the use of stool testing, which typically does not correlate with the clinical characteristics of affected patients.^3,¹³ One study has identified several important independent variables that may be predictive of positive stool culture in adult patients with a clinical picture of infectious diarrhea. These variables are month of presentation, fever, duration of abdominal pain at presentation, and requirement of intravenous fluid therapy. Surprisingly, this study demonstrated that neither a history of bloody diarrhea nor persistent diarrhea was associated with positive stool culture.¹³

In general, persons with diarrhea should be considered for testing if they are febrile or have bloody stool. When visible blood was present in the stool, more than one third of cases were caused by Shiga toxin–producing E. coli O157:H7.³ Testing for ova and parasites is of low yield in most cases and should be run only when diarrheal illness persists for more than 7 days.³

Therapeutic Considerations

Conventional Medicines

Although appropriate in certain cases, the antibiotics and opiates used to treat diarrhea are also well known to have their limitations, as many of these drugs adversely affect gastrointestinal motility; furthermore, increasing numbers of pathogens are proving resistant to antimicrobial agents. Increasing numbers of isolates resistant to antimicrobial agents and the risk of worsened illness (e.g., hemolytic uremic syndrome with Shiga toxin–producing E. coli O157:H7) further complicate antimicrobial and antimotility drug use.³ Additionally, available antiperistaltic or antisecretory drugs to reduce the severity of diarrhea can cause serious side effects in children.⁸

Generally, selective antibiotic treatment is recommended for traveler’s diarrhea, Shigella, and Campylobacteria infection. Bismuth salts (e.g., Pepto-Bismol) can be used for travel abroad in order to coat the intestinal lining and help prevent infection. The role of antibiotic therapy in salmonellosis and E. coli O157:H7 infection remains unclear. Avoidance of antimotility agents in bloody diarrhea is emphasized, especially when illness is caused by E. coli O157:H7, which could increase the risk of subsequent hemolytic-uremic syndrome. In select at-risk populations, wider use of vaccines, including oral typhoid vaccine and oral cholera vaccine (available only outside the United States) is recommended.³

Some newer therapeutic approaches include 5-HT₂ and 5-HT₃ receptor antagonists, calcium-calmodulin antagonists, and alpha-receptor agonists. These may be useful to avoid adverse affects on gastric motilility.⁵

Underlying and Predisposing Factors

Although a pathogenic agent is often responsible for infectious diarrhea, a number of host factors can predispose individuals to experience illness. Poor digestive function, which is often characterized by low stomach acid output or achlorhydria and inadequate pancreatic enzyme output, should be explored in patients who are susceptible to infectious diarrhea. In these cases, hydrochloric acid and pancreatic enzyme supplementation may be advisable. Immunoglobulin A (IgA) antibodies help discourage epithelial adherence of pathogenic organisms. Depressed levels of secretory IgA can leave the immune system of the gastrointestinal tract feeble and unable to deal with pathogenic infection. Decreased intestinal motility, which can be caused by chronic stress and high sugar intake, can also allow microbes to flourish in an intestinal environment. Recurrent infectious diarrhea may be encouraged by food allergy and sensitivities as well.

The clinician should also be aware that many drugs may actually increase susceptibility to infectious diarrheal illness. Theses include proton pump inhibitors, antifolate drugs, and antibiotics. Hospitalized patients who receive proton pump inhibitors are at increased risk of C. difficile–induced diarrhea.¹⁴^–¹⁶ As in the case of achlorhydria, it is likely that inhibition of upper gastrointestinal digestive acids by proton pump inhibitors may allow pathogens and undigested food to reach the intestines without being properly broken down. Also, antibiotic-associated diarrhea is known to occur with broad-spectrum antibiotics.¹⁷ Antibiotics can disrupt local bowel flora, allowing pathogenic organisms to flourish, and are well-known to leave patients susceptible to diarrhea (see “Probiotics,” later).

Hydration/Electrolyte Balance

It is of paramount importance to keep the patient with diarrhea well hydrated and to assure electrolyte balance. This is most crucial in children. Of course rehydration does not treat the diarrhea itself, which will persist until the infection resolves. Signs of dehydration may include decreased or absent urination, decreased skin turgor, and dry tongue. Rehydration using solutions of glucose, sodium, and potassium is appropriate. In cases of severe dehydration with weight loss of more than 10% or unconsciousness, intravenous rehydration is indicated.¹⁸

Diet

Prevention of infectious diarrhea may be accomplished by avoiding undercooked meat or seafood, unpasteurized milk, or soft cheese.³ Once the patient has symptoms, traditional use of the “BRAT diet” can usually help decrease gastric motility. The components of this diet are foods that can slow peristalsis and tend to be more binding. These are banana, white rice, apple, plain white toast or bread, and tea.

Evidence indicates that larger, less frequent meals are more taxing to the digestive and absorptive capacities of the gastrointestinal system. In one porcine study, 3-week-old piglets were assigned to one of four dietary regimens and were subsequently all infected with rotavirus, followed 24 hours later with enteropathogenic E. coli. The dietary regimen designed to tax the digestive and absorptive capacities of the piglets (a high nutrient intake with a three times a day feeding) significantly produced the most prolonged diarrhea as well as the most advanced colonization of the gut by hemolytic enteropathogenic E. coli and persistent shedding of rotavirus. The same nutrient intake divided into 24 equal increments and administered hourly produced a less severe response. The least severe diarrhea was seen in piglets fed one third the nutrient intake either hourly or three times a day.¹⁹

Traditional dietary preparations for diarrhea such as carrot soup and products based on rice can be useful by having essentially an absorbent power. They have been known to reduce stool output and the duration of diarrhea, although they may not necessarily diminish intestinal loss of water and electrolytes.^18,²⁰

One study evaluated the effects of green banana and pectin on intestinal permeability in 57 boys with persistent diarrhea. Green banana and pectin contain nondigestible dietary sources of colonic short-chain fatty acids. The patients were given a week’s treatment with a rice-based diet containing either cooked green banana, pectin, or a rice diet alone. Intestinal permeability was assessed before and after treatment by giving a lactulose-mannitol (LM) drink and measuring urinary recovery after 5 hours. Treatment with banana significantly reduced lactulose recovery, increased mannitol recovery, and decreased the LM ratio, indicating improvement of permeability. Pectin produced similar results. Permeability changes were associated with a 50% reduction in stool weights, which correlated strongly with the LM ratio.²¹ In a study of 154 male infants aged between 1 and 30 months, commonly allergenic soy- and casein-based diets were not helpful in alleviating persistent diarrhea, whereas yogurt and broken-down amino acid formulas were helpful in encouraging a significant reduction in stool output and in the duration of diarrhea.²² Other studies also suggest, as an adjunctive measure for patients who experience vomiting, the administration of a small amount of glucose.¹⁸

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