Epidemiology

Fecal–oral contamination through ingestion of contaminated water and food (waterborne or foodborne) is the usual route of transmission of the enteric pathogens causing acute infectious diarrhea. The relative importance of food and water depends mainly on location and precautions taken. The majority of pathogens that cause traveler’s diarrhea (TD) or wilderness-acquired diarrhea can be either foodborne or waterborne; however, waterborne pathogens from drinking untreated surface water or from an inadvertent ingestion during water recreational activity probably account for most infectious diarrhea acquired in the U.S. wilderness. Prevention of infection from all these pathogens includes proper sanitation and water disinfection. Person-to-person transmission is seen with pathogens that have small infectious doses, such as Shigella species, hepatitis A virus, Giardia, and noroviruses. These infections are most common in select populations whose habits expose them to high levels of pathogens (e.g., infants in day care centers, homosexuals, persons with minimal access to water); prevention of these illnesses includes adequate hand washing and personal hygiene. Other, less common routes of fecal–oral transmission are through aerosols (some viruses), contaminated hands or surfaces, and sexual activity.

In areas of Africa, Asia, and Latin America, where satisfactory sanitation is lacking, diarrhea is still the leading cause of infant morbidity and mortality. Good sanitation is related to a much lower incidence of infectious diarrhea in industrialized areas of the world. Travelers to foreign countries and wilderness areas often leave behind sanitation in the forms of flush toilets and safe tap water and do not have proximity to advanced medical care. Similar hygiene conditions are created in many other settings.

Outbreaks of infectious diarrhea in day care centers among non-toilet-trained toddlers are associated with low inoculum organisms, including Shigella, Cryptosporidium, Giardia and the viral pathogens. Hospitals, especially intensive care units and pediatric wards, institutions for mentally handicapped patients, and nursing homes are also locations with a high incidence of diarrheal diseases. Clostridium difficile is the most important definable pathogen in those settings.¹⁶⁰ Salmonella species, rotavirus, and enteropathogenic Escherichia coli (EPEC) may on occasion cause nosocomial outbreaks.

Antimicrobial therapy is indicated for moderate to severe TD. When a specific bacterial or parasitic pathogen is identified (see later details), C. difficile infection (CDI) is frequently related to recent use of an antimicrobial agent (or cytotoxic agent) in debilitated hospitalized patients with a high rate of CDI recurrence.⁷⁵

In developing areas of the world, children under 5 years of age have the highest morbidity of diarrhea, and infants under 1 year of age experience the highest mortality rates.⁴⁰ The enteropathogens more common in infectious diarrhea during childhood are rotavirus, enterotoxigenic E. coli (ETEC), enteropathogenic E. coli (EPEC), enteroaggregative E. coli (EAEC), Campylobacter spp., and Giardia. Residents in industrialized countries, such as the United States, have only one to two bouts of diarrhea per person per year, with no difference between age groups. Complications, including death, are more common in elderly persons.¹²²

Organisms are shed in the stools during asymptomatic and symptomatic infection and for a period after illness. Long-term fecal shedding or chronic carrier states are reported to be important only for typhoid fever, whereas in other intestinal protozoal infections, the parasite may be persistently shed, as is seen in amebiasis, giardiasis and cryptosporidiosis. These cases may act as reservoirs for spreading infection, even in areas with low risk for infection. A few enteric pathogens have animal reservoirs and are spread to exposed persons. These zoonotic organisms include Salmonella spp., Yersinia, Campylobacter, Giardia, Balantidium coli, Sarcocystis, and Cryptosporidium.

Food intoxication, caused by ingestion of preformed toxins from Staphylococcus aureus or Bacillus cereus, typically has a short incubation period (2 to 7 hours) and causes common source outbreaks involving multiple persons.⁴¹ Infection and diarrhea caused by a living enteropathogen must first traverse the stomach and infect the small bowel or colon, explaining a longer incubation period of 14 or more hours, usually more than 1 day.

Immunocompromised patients, including those with advanced infection by the human immunodeficiency virus (HIV), and persons with metastatic cancer are prone to acquire infection by a wide variety of enteropathogens, to develop infectious diarrhea, and to experience recurrent infections. Advanced AIDS is associated with chronic diarrhea secondary to ultrastructural changes in gut morphology and malabsorption, or because of reduced immunity and coinfection with enteropathogens. The agents responsible for diarrheal diseases in advanced AIDS include Mycobacterium avium-intracellulare complex, Cryptosporidium, Giardia, Isospora, Cyclospora, Microsporidium, cytomegalovirus, herpes simplex virus, and HIV itself (so called “AIDS enteropathy”). Treatment of HIV with highly active antiretroviral therapy and treatment of the enteric infection(s) are associated with improved symptomatology and decreased rates of infection.

Most cases of acute diarrhea are caused by infectious microorganisms, including bacteria, viruses, and protozoa. Fungal agents have been reported rarely. Table 68-1 lists the etiologic agents often associated with travel to developing tropical areas or with wilderness travel in an industrialized region. Foodborne illness may consist of food “poisoning” or food “infection.” In food poisoning, an intoxication results when toxins produced by bacteria are found in food in sufficient concentrations to produce symptoms. A rare cause of food poisoning that results in paralysis is botulism, caused when the neurotoxin of Clostridium botulinum is ingested. Other foodborne pathogens are viruses, including rotavirus and small round viruses (noroviruses, astrovirus, etc.), and intestinal protozoal agents, including Giardia, Entamoeba histolytica, and Cryptosporidium.

TABLE 68-1 Enteropathogens Found in Tropical and Wilderness Travel

Pathophysiology

Three intestinal mechanisms lead to acute diarrhea. The most common pathophysiologic mechanism in acute infectious diarrhea is alteration of fluid and electrolyte movement from the serosal to the mucosal surface of the gut (secretory diarrhea). This alteration may occur as a result of cyclic nucleotide stimulation (as a second messenger) or by an inflammatory process that is associated with release of proinflammatory cytokines. The second mechanism is malabsorption or presence of nonabsorbable substances in the lumen of the bowel, including lactase deficiency and AIDS-associated malabsorption. The third mechanism of diarrhea is altered intestinal motility. Secretory mechanisms best explain acute infectious diarrhea, while malabsorption and altered motility are more important in chronic forms of diarrhea, such as tropical and nontropical sprue, Whipple’s disease, intestinal scleroderma, irritable bowel syndrome and inflammatory bowel disease. Table 68-2 shows the virulence factors of the most important enteric pathogens related to infectious diarrhea.

TABLE 68-2 Bacterial Enteropathogens: Virulence Properties

In secretory diarrhea, the unformed stools are usually of large volume and small in number (characteristically less than six bowel movements per day). Stools do not contain blood and fever is unusual. Examples of pathogens in this group are Vibrio cholerae, ETEC, preformed enterotoxins, noroviruses, rotavirus, Giardia, and Cryptosporidium. Dehydration is the major complication, especially in the extremes of age. Without adequate therapy, secretory diarrhea can be followed by renal insufficiency. Invasive pathogens involving the distal ileum and colon damage the mucosa and elicit an inflammatory response that is associated with secretory diarrhea and colitis. In this form of colitis, stools are typically liquid, small-volume, and may contain blood and many leukocytes. The common microorganisms in this group are Shigella, Salmonella, EIEC, Shiga-toxin producing E. coli (STEC), Yersinia enterocolitica, Campylobacter spp., Aeromonas, Vibrio parahaemolyticus, and E. histolytica. Complications include dehydration and systemic involvement, especially in children with malnutrition.¹⁵¹

Definition

TD refers to an illness contracted while traveling, although in 15% of sufferers symptoms first become ill after returning home. Most clinical studies define TD as passage of three or more unformed stools in a 24-hour period in association with one or more enteric symptoms, such as abdominal cramps, fever, fecal urgency, tenesmus, bloody–mucoid stools, nausea, and vomiting.⁴⁵

Etiology

Because the incidence of TD reflects in part the extent of environmental contamination with feces, the etiologic agents are pathogens causing illness in local children. A list of etiologic agents important in TD is provided in Table 68-3). Twenty years ago, specific pathogens were found in only 20% of cases. Currently, etiologic agents can be identified in up to 80% of TD episodes.¹⁰³ In most studies, however, causative pathogens are not identified in 20% to 40% of cases. In most of these cases, antimicrobial therapy shortens illness, suggesting that this subset of diarrhea is caused by undetected bacterial pathogens.⁵³ Overall, the major etiologic agents and their frequency of isolation are remarkably similar worldwide.

TABLE 68-3 Major Pathogens in Traveler’s Diarrhea (Travel to Developing Tropical Regions)

ETEC is the most common cause of TD worldwide,¹⁷⁷ accounting for about one-third to one-half of cases. Since the last edition of this book, EAEC has been identified as the second most common bacterial cause of TD, causing up to 30% of TD cases in some areas of the world.³ One study has shown that the source of both types of E. coli is food. Viable ETEC and EAEC were found in hot sauces served on the table in popular restaurants in Guadalajara, Mexico.⁴ Shigella and Campylobacter species cause around 20% of illness. Other causes of TD include Salmonella (4% to 5% of cases), Vibrio, Aeromonas, Plesiomonas, viruses (10%), and parasites.¹⁷⁷ Specific pathogens may predominate at a particular time or location.

Clinical Syndromes

Table 68-4 outlines the major syndromes in patients with enteric infection. The typical clinical syndrome experienced by travelers with diarrhea secondary to the major infectious causes (e.g., ETEC) begins abruptly with abdominal cramping and watery diarrhea. Most cases are mild, consisting of passage of one to two unformed stools per day associated with symptoms that are tolerable and do not interfere with normal activities. Approximately 30% of affected persons experience moderately severe illness, with three to five unformed stools per day and distressing symptoms that force a change in activities or itinerary. Only 1% to 3% of persons with TD occurring in Latin America or Africa experience febrile dysenteric illness,^64,129 whereas approximately 9% of travelers with diarrhea acquired in Asia (Indian subcontinent) develop this more serious form of illness.¹⁸⁷ TD may lead to a chronic illness⁴³ and postinfectious irritable bowel syndrome (PI-IBS).^147,190 TD should be considered a self-limited nonfatal condition. An illness associated with vomiting without important diarrhea is commonly seen in travelers and is characteristically due to noroviruses.^6,113 Symptoms lasting more than 1 to 2 weeks suggest a protozoan etiology such as Giardia, E. histolytica, Cryptosporidium or other parasite.⁴³

TABLE 68-4 Clinical Syndromes in Enteric Disease

An important part of the initial assessment is to measure the level of hydration, which includes a determination of vital signs, orthostatic pulse and blood pressure, mental status, skin turgor, hydration of mucous membranes, and urine output. Dehydration is most common in pediatric and elder populations.

Fever is a reaction to an intestinal inflammatory process. High fever suggests a pathogen invasive to the intestinal mucosa, which classically includes bacterial enteropathogens such as Shigella, Salmonella, and Campylobacter spp. Fever can also be produced by strains of EIEC, V. parahaemolyticus, Aeromonas, C. difficile, and viral pathogens.

Vomiting as the predominant symptom in a traveler usually suggests norovirus infection. Vomiting is also seen in “food poisoning” secondary to consumption of pre-formed enterotoxin produced by S. aureus or B. cereus.

Dysentery is defined as the passage of small-volume stools with gross blood and mucus. Common causes include Shigella, C. jejuni, Salmonella, Aeromonas, V. parahaemolyticus, Y. enterocolitica, EIEC, STEC, E. histolytica, and preexistent inflammatory bowel disease.

The abdominal examination in persons with TD often shows mild tenderness but should not demonstrate signs of peritoneal irritation. A rectal examination may reveal tenderness in enterocolitis, and the victim may have painful external hemorrhoids, a result of the excessive rate of stooling.

Some enteric pathogens produce both diarrheal and systemic diseases, such as hemolytic–uremic syndrome related to infection with shigellosis or STEC, Reiter’s syndrome, or glomerulonephritis related to Y. enterocolitica, and sepsis seen with bacteremic salmonellosis caused by Salmonella typhi, Salmonella paratyphi, and nontyphoid strains of Salmonella.

Persistent and Chronic Diarrhea

Diarrhea may persist after the traveler returns home. Up to 3% of persons with TD in high-risk areas will develop persistent diarrhea.⁴³ Persistent diarrhea is defined as illness lasting 14 days or longer, whereas diarrhea is considered chronic when the illness has lasted 30 days or longer. The etiology of persistent or chronic diarrhea often differs from that of acute diarrhea. Important causes of persistent diarrhea include (1) protozoal parasitic agents (Giardia, Cryptosporidium, Cyclospora, and E. histolytica), (2) bacterial infection (Salmonella, Shigella, Campylobacter, and Y. enterocolitica), (3) lactase deficiency induced by a small bowel pathogen (Giardia, rotavirus, or norovirus), and (4) a small bowel bacterial overgrowth syndrome secondary to small bowel motility inhibition (as a result of enteric infection) or secondary to antimicrobial use. Occasionally, other parasitic enteric infections can cause more persistent illness. These include Strongyloides stercoralis, Trichuris trichiura, and severe infection by Necator americanus or Ancylostoma duodenale. In rare cases, more protracted diarrhea may be a prominent symptom in persons with schistosomiasis, Plasmodium falciparum malaria, leishmaniasis, or African trypanosomiasis.

When chronic diarrhea follows a bout of TD, a pathogen is not identified and the patient fails to respond to empiric antimicrobial therapy, PI-IBS, or activation of an underlying condition such as inflammatory bowel disease or celiac or tropical sprue should be considered. Even with eradication of microbial pathogens with antimicrobial therapy, bowel habits may not return to normal for several weeks. This represents slow repair of the damage to the intestinal mucosa. Small bowel bacterial overgrowth has been identified in patients with persistent diarrhea after a bout of TD. Finally, there first occurred in the 1980s an idiopathic form of chronic diarrhea called Brainerd diarrhea after the name of the city in Minnesota where the first outbreak was identified.¹⁵⁰ The known vehicles of transmission of Brainerd diarrhea are raw (unpasteurized) milk¹⁵⁰ and untreated water, such as well water.¹⁵² There is no diagnostic test or therapy, and the diagnosis is suspected based on the epidemiologic history (exposure to unpasteurized milk or untreated water just before onset of illness). Although the average duration of Brainerd diarrhea is 2 years, persons with this condition invariably become totally well.

The approach to evaluate persistent or chronic diarrhea in travelers should begin with diagnostic tests for conventional bacterial pathogens in stools and at least three parasitologic evaluations of freshly passed stools. Dietary modification in all cases should initially include avoidance of milk and dairy products because of the possibility of lactase deficiency. Treatment should be specific, following the results of the microbiologic tests. Because most of these chronic forms of diarrhea are self-limited, it is unwise to employ empiric antibiotics in these patients. A single, limited empiric trial with metronidazole for possible Giardia infection is considered an option by some experts if all tests are negative.

Laboratory Tests and Procedures

Several laboratory tests are useful in evaluating patients with diarrheal disease (Table 68-5). In clinical practice, laboratory testing is reserved for illness continuing after the patient returns home or when empiric treatment is unsuccessful. Persons with milder forms of diarrhea usually need only clinical evaluation; etiologic assessment is unnecessary. Laboratory tests are reserved for persons with moderate to severe diarrhea and those with persistent illness.

TABLE 68-5 Indications for Laboratory Test in Diarrheal Diseases and Possible Diagnoses

The presence of fecal leukocytes is a reliable indicator of diffuse colonic inflammation. For moderate to severe illness, this is the most rapid, useful test and the ideal screening procedure. A large number of polymorphonuclear leukocytes (PMNs) per high-power field using dilute methylene blue stain or trichrome stain (which also helps with identification of parasites) can be helpful in making an etiologic diagnosis (Figure 68-1) of Shigella, Salmonella, or Campylobacter spp.⁸⁸ Other organisms and conditions that may lead to presence of fecal leukocytes in the stools are C. difficile, Aeromonas, Y. enterocolitica, V. parahaemolyticus, EIEC, idiopathic ulcerative colitis, and allergic colitis.

FIGURE 68-1 Methylene blue stain of a fecal smear from a patient with bacillary dysentery (×400). Numerous polymorphonuclear leukocytes are present. This indicates the presence of diffuse colonic inflammation.

Lactoferrin is found in granules of neutrophils and can be identified in fecal samples by commercial immunoassay method (Leukotest, TechLab). This test does not require a freshly collected stool sample or an experienced technician, and is more sensitive than is microscopic examination of fecal leukocytes.²¹

Bacterial infection is specifically diagnosed by stool culture, although routine stool testing identifies few pathogens. A routine laboratory should be able to recover Shigella, Salmonella, and Campylobacter from a stool culture and, if specifically requested, V. cholerae, V. parahaemolyticus, Aeromonas, Y. enterocolitica, and C. difficile. The major indication for performing a stool culture is the presence of febrile and dysenteric disease.

Blood culture(s) should be performed in all patients who are hospitalized with gastrointestinal (GI) illness or those with significant fever, especially when combined with degrees of systemic toxicity. Systemic infections by S. typhi and non-typhi Salmonella, Shigella, Campylobacter fetus, and Y. enterocolitica may be diagnosed by blood culture.

Patients with persistent TD should be studied for presence of parasitic infection. Immunologic techniques to detect antigens of protozoan parasites are more efficient than are stool examinations for ova and parasites and are in common use for parasites that inhabit the duodenum (e.g., Giardia, Cryptosporidium, E. histolytica, Microsporidia).^86,128 At times, intestinal parasites are better detected using a sample from duodenal aspiration or intestinal biopsy.^86,128

In select cases, particularly clinical colitis and diarrhea persisting for 14 days or longer, flexible sigmoidoscopy or colonoscopy should be considered to study colonic lesions and collect samples for culture and microscopy. Lower GI tract endoscopy is particularly useful when stools contain many leukocytes per high-power field. Colonic mucosal changes may not be specific, except when pseudomembranes are sought in CDI. In homosexual male patients with acute diarrhea, examination of the distal colon may show evidence of proctitis (mucosal inflammation in the distal 15 cm of the colon), proctocolitis (inflammation beyond 15 cm), or enteritis. If there are no leukocytes in stool exam or if colonoscopy is negative, esophagogastroduodenoscopy (EGD) should be considered, looking at duodenal mucus for Giardia lamblia. Tests for malabsorption and biopsy of the small bowel mucosa may be useful in making a diagnosis.

Treatment

In all cases of diarrhea, fluid and electrolyte replacement should be the primary therapy. This is particularly important in persons with cholera-like diarrhea or when diarrhea is seen in extremes of age (infants and the elderly). Outpatient treatment with instructions for oral rehydration can be used in the vast majority of adults and children. Significant dehydration from diarrhea in travelers is unusual.

Treatment with intravenous (IV) fluids is indicated for

Supplemental nutrition is beneficial (essential in undernourished populations) and can be given as soon as fluid deficit losses are replaced, usually after the first 4 hours. In the face of more severe forms of acute diarrheal disease, the intestinal tract may not be able to process complex dietary products, so patients are often told to avoid solid foods and eat easily digested foods. As stooling decreases and appetite improves, staple foods, such as cereals, bananas, crackers, toasts, lentils, potatoes, and other cooked vegetables, are well tolerated and can be gradually added to the diet to facilitate enterocyte renewal, with subsequent progression to white meats, fruits, and vegetables. Dairy products and red meat are recommended only after diarrhea has resolved, usually after 2 to 3 days. Only foods and drinks that prolong diarrhea or increase intestinal motility should be avoided, such as those that contain lactose, caffeine, alcohol, high fiber, and fats. Breastfeeding of infants should be continued or should be resumed as soon as possible. Patients with TD should avoid excessive physical activity to reduce the risk of fluid loss and dehydration.

The major cause of morbidity and mortality from acute diarrheal disease is depletion of body water and electrolytes. Rehydration is an essential part of therapy, especially in the extremes of age and during pregnancy. Most patients with TD do not become dehydrated, and hydration can be maintained by ingesting fluids such as sodas, juices, soup, and potable water in conjunction with a source of electrolytes (e.g., salted crackers).

Fluid status in the field must be guided by physical signs related to hydration, including pulse, mucous membranes, skin turgor, and urine output. Urine color and volume are excellent measures. For travelers in the wilderness or tropics, fluid replacement must equal basic needs plus volume of diarrhea plus estimated sweat loss.

Prevention and Prophylaxis

Chemoprophylaxis

Chemoprophylaxis with antibiotics was shown in the 1950s and 1960s to effectively prevent TD among international travelers.¹¹¹ This was the first evidence that bacterial pathogens were the most important causes of TD. Preventive antibiotics are generally recommended to be used for trips of 2 weeks or less and will require a prescription from a physician (Table 68-9). Because of safety and efficacy, rifaximin is the optimal drug when prophylaxis is employed: the dose is one 200 mg tablet twice a day with major daily meals for trips up to 2 weeks in length. Another effective dosage formulation of rifaximin is a 550 mg tablet taken once for breakfast each day of the trip to high-risk regions. The medication should be started the day of arrival to a high-risk region and can be stopped once leaving the area. Most wilderness travelers taking their own food or preparing their own food are not at high enough risk for TD to justify chemoprophylaxis with antibiotics.

TABLE 68-9 Prophylactic Medications for Prevention of Traveler’s Diarrhea*

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