321 Gastroenteritis Larry K. Pickering John D.

Snyder Infections of the gastrointestinal tract are caused by a wide variety of enteropathogens, including bacteria, viruses, and parasites. Clinical manifestations depend on the organism and host response to infection and include asymptomatic infection, watery diarrhea, bloody diarrhea, chronic diarrhea, and extraintestinal manifestations of infection. A presumptive etiologic diagnosis can be established from epidemiologic clues, clinical manifestations, physical examination, and knowledge of the pathophysiologic mechanisms of enteropathogens. Laboratory studies used to identify diarrheal pathogens are often not required because most episodes are self-limited. All patients with diarrhea require fluid and electrolyte therapy, a few need other nonspecific support, and some may benefit from antimicrobial therapy. Etiology. The two basic types of acute infectious diarrhea are noninflammatory and inflammatory. Enteropathogens elicit noninflammatory diarrhea through enterotoxin production by some bacteria, destruction of villus (surface) cells by viruses, adherence by parasites, and adherence and/or translocation by bacteria. In contrast, inflammatory diarrhea usually is caused by bacteria that invade the intestine directly or produce cytotoxins. Some enteropathogens possess more than one virulence property. Acute diarrhea or diarrhea of short duration may be associated with any of the recognized bacterial, viral, or parasitic causes of enteritis (Box 321-1). Chronic or persistent diarrhea lasting 14 days or more may be due to (1) an infectious agent such as Giardia lamblia, Cryptosporidium parvum, and enteroaggregative or enteropathogenic Escherichia coli; (2) any enteropathogen that infects an immunocompromised host; or (3) residual symptoms due to damage to the intestine by an enteropathogen after an acute infection. There also are many noninfectious causes of diarrhea in children (Box 321-2). BACTERIAL ENTEROPATHOGENS. BOX 321-1. Causative Agents of Gastroenteritis BACTERIA

Aeromonas Bacillus cereus Campylobacter jejuni Clostridium perfringens Clostridium difficile Escherichia coli

Plesiomonas shigelloides Salmonella Shigella Staphylococcus aureus Vibrio cholerae 01 and 0139 Vibrio parahaemolyticus Yersinia enterocolitica

**Norwalk-like viruses *Generally associated with disease only among immunocompromised persons. VIRUSES

Astroviruses Caliciviruses Norovirus Enteric adenoviruses Rotavirus Cytomegalovirus Herpes simplex viruses PARASITES Balantidium coli Blastocystis hominis Cryptosporidium parvum Cyclospora cayetanensis Encephalitozoon intestinalis Entamoeba histolytica Enterocytozoon bieneusi Giardia lamblia Isospora belli Strongyloides stercoralis Trichuris trichiura page 1272 page 1273

Bacterial enteropathogens may cause either inflammatory or noninflammatory diarrhea, and specific enteropathogens may be associated with either clinical form. Generally, inflammatory diarrhea is associated with Aeromonas, Campylobacter jejuni, Clostridium difficile, enteroinvasive E. coli, Shiga toxin-producing E. coli (E. coli O157:H7), Plesiomonas shigelloides, Salmonella, Shigella, Vibrio parahaemolyticus, and Yersinia enterocolitica. Noninflammatory diarrhea may be caused by enteropathogenic E. coli, enterotoxigenic E. coli, Vibrio cholerae, and several of the pathogens associated with inflammatory diarrhea. Antimicrobial therapy is administered to select patients with bacterial enteritis to shorten the clinical course, to decrease excretion of the causative organism, or to prevent complications (Table 321-1). Helicobacter pylori infects gastric mucosa and is associated with gastritis, peptic ulcer disease, and gastric cancer (see Chapter 316). VIRAL ENTEROPATHOGENS. The main causes of viral gastroenteritis include rotavirus, enteric adenovirus, astrovirus, Norwalk agent-like virus, and calicivirus. Cytomegalovirus and herpes simplex virus have been associated with diarrhea and other gastrointestinal tract signs and symptoms, generally in immunocompromised hosts. PARASITIC ENTEROPATHOGENS. G. lamblia is the most common parasitic cause of diarrhea in the United States; other parasitic pathogens include Entamoeba histolytica, Strongyloides stercoralis, Balantidium coli, and sporeforming protozoa, which include Cryptosporidium parvum, Cyclospora cayetanensis, Isospora belli, Enterocytozoon bieneusi, and Encephalitozoon intestinalis. The latter three agents have been found most often in persons with AIDS. The role of Dientamoeba fragilis and Blastocystis hominis as causes of diarrhea has not been defined fully. Balantidium coli, Trichuris trichiura, and E. histolytica can produce bloody diarrhea in humans. Table 321-1. Antimicrobial Therapy for Bacterial Enteropathogens in Children Organism*Antimicrobial AgentIndication for Antimicrobial Therapy AeromonasTMP/SMZDysentery-like illness, prolonged diarrhea CampylobacterErythromycin or azithromycinEarly in the course of illness Clostridium difficile Escherichia coliMetronidazole or vancomycinModerate to severe disease EnterotoxigenicTMP/SMZSevere or prolonged illness

EnteropathogenicTMP/SMZNursery epidemics, life-threatening illness EnteroinvasiveTMP/SMZAll cases if organism susceptible SalmonellaCefotaxime or ceftriaxone or ampicillin or chloramphenicol or TMP/SMZInfants <3 mo patients, typhoid fever (Salmonella typhi), bacteremia, dissemination with localized suppuration ShigellaAmpicillin or ciprofloxacin or ofloxacin or ceftriaxoneAll cases if organism susceptible Vibrio choleraeDoxycycline or tetracyclineAll cases

*Susceptibility testing should be performed on all organisms Quinolones (ciprofloxacin or ofloxacin) may be used for persons 18 yr of age. TMP/SMZ = trimethoprim and sulfamethoxazole. BOX 321-2. Other Causes of Diarrhea FEEDING DIFFICULTY ANATOMIC DEFECTS

Malrotation Intestinal duplications Hirschsprung disease Fecal impaction Short bowel syndrome Microvillus atrophy Strictures Cystic fibrosis Shwachman syndrome Cholestasis MALABSORPTION Disaccharidase deficiencies Glucose-galactose malabsorption Pancreatic insufficiency Reduced intraluminal bile salts Hartnup disease Abetalipoproteinemia

Celiac disease ENDOCRINOPATHIES Thyrotoxicosis Addison disease Adrenogenital syndrome FOOD POISONING Heavy metals Scombroid Ciguatera Mushrooms NEOPLASMS Neuroblastomas Ganglioneuromas Pheochromocytomas Carcinoid Zollinger-Ellison syndrome Vasoactive intestinal peptide syndrome MISCELLANEOUS Nongastrointestinal infections Milk allergy Crohn disease (regional enteritis) Familial dysautonomia Immune deficiency disease Protein-losing enteropathy Ulcerative colitis Acrodermatitis enteropathica Laxative abuse Motility disorders Pellagra page 1273 page 1274

Patients with diarrhea normally do not need to have their stools examined for ova and parasites unless they (1) have a history of recent travel to an endemic area, stool cultures are negative for other enteropathogens, and diarrhea persists for more than 1 wk; (2) are part of an outbreak of diarrhea; or (3) are immunocompromised. Examination of more than one stool specimen may be necessary to establish a diagnosis. Certain medications, antidiarrheal compounds, and barium may interfere with identification of parasitic enteropathogens. Treatment of these infections depends on the clinical condition and availability of effective therapy (Table 321-2). Antimicrobial resistance is present in many parts of the world. Epidemiology. Diarrheal diseases are one of the leading causes of morbidity and mortality in children worldwide, causing 1 billion episodes of illness and 3-5 million deaths annually. The relative importance and epidemiologic characteristics of diarrheal pathogens vary by geographic location. In the United States each year, 20-35 million episodes of diarrhea occur among the 16.5 million children younger than 5 yr of age, resulting in 2.1-3.7 million physician visits, 220,000 hospitalizations, 924,000 hospital days, and 300-400 deaths. Children in developing countries become infected with a diverse group of bacterial and parasitic pathogens, whereas all children in developed as well as developing countries acquire rotavirus and, in many cases, other viral enteropathogens, G. lamblia, and C. parvum during their first 5 yr of life. The major mechanisms of transmission for diarrheal pathogens are person to person through the fecal-oral route or by ingestion of contaminated food or water. Enteropathogens that are infectious in a small inoculum (Shigella, E. coli O157:H7, enteric viruses, G. lamblia, C. parvum, and E. histolytica) may be transmitted by person-to-person contact. Factors that increase susceptibility to infection with enteropathogens include young age, immune deficiency, measles, malnutrition, travel to an endemic area, lack of breast-feeding, exposure to unsanitary conditions, ingestion of contaminated food or water, level of maternal education, and attendance at a childcare center. General Approach to Children with Acute Diarrhea. Enteric infections cause gastrointestinal tract signs and symptoms as well as extraintestinal complications, including neurologic manifestations. Gastrointestinal tract involvement may include diarrhea, abdominal cramps, and vomiting. Systemic manifestations are varied and associated with a variety of causes. Extraintestinal infections related to bacterial enteric pathogens include vulvovaginitis, urinary tract infection, endocarditis, osteomyelitis, meningitis, pneumonia, hepatitis, peritonitis, chorioamnionitis, soft tissue infection, and septic thrombophlebitis. Neurologic manifestations of infectious enteritis include paresthesias (from ingestion of fish, shellfish, monosodium glutamate), hypotonia and descending muscle weakness

(C. botulinum), and a variety of other signs and symptoms (from ingestion of fish, shellfish, and mushrooms). Immune-mediated extraintestinal manifestations of enteric pathogens usually occur after diarrhea has resolved (Table 321-3). Hemolytic uremia syndrome may follow infection with E. coli or Shigella (Chapter 510). Table 321-2. Antimicrobial Therapy for Enteric Parasites in Children OrganismAntimicrobial Agent Giardia lambliaFurazolidone or metronidazole or albendazole or quinacrine or paromomycin (pregnancy) Entamoeba histolyticaMetronidazole followed by iodoquinol Blastocystis hominisMetronidazole or iodoquinol Cryptosporidium parvumParomomycin or azithromycin may be indicated in immunocompromised hosts. Cyclospora cayetanensisTrimethoprim/sulfamethoxazole (TMP/SMZ) Isospora belliTMP/SMZ Enterocytozoon bieneusiAlbendazole Encephalitozoon intestinalisAlbendazole (minimally effective) Strongyloides stercoralisIvermectin or thiabendazole

Table 321-3. Immune-Mediated Extraintestinal Manifestations of Enteric Pathogens ManifestationRelated Enteric Pathogen(s) Reactive arthritisSalmonella, Shigella, Yersinia, Campylobacter, Cryptosporidium, Clostridium difficile Guillain-Barr syndromeCampylobacter GlomerulonephritisShigella, Campylobacter, Yersinia IgA nephropathyCampylobacter Erythema nodosumYersinia, Campylobacter, Salmonella Hemolytic anemiaCampylobacter, Yersinia

HUSS. dysenteriae 1, E. coli

HUS = hemolytic uremia syndrome. The main objectives in the approach to a child with acute diarrhea are to (1) assess the degree of dehydration and provide fluid and electrolyte replacement, (2) prevent spread of the enteropathogen, and (3) in select episodes determine the etiologic agent and provide specific therapy if indicated. Information about oral intake, frequency and volume of stool output, general appearance and activity of the child, and frequency of urination must be obtained. Data should be obtained about childcare center attendance, recent travel to a diarrhea endemic area, use of antimicrobial agents, exposure to contacts with similar symptoms, and intake of seafood, unwashed vegetables, unpasteurized milk, contaminated water, or uncooked meats. The duration and severity of diarrhea, stool consistency, presence of mucus and blood, and other associated symptomatology, such as fever, vomiting, and seizures, should be determined. Fever is suggestive of an inflammatory process and also occurs as a result of dehydration. Nausea and emesis are nonspecific symptoms, but vomiting suggests organisms that infect the upper intestine, such as enteric viruses, enterotoxin-producing bacteria, Giardia, and Cryptosporidium. Fever is common in patients with inflammatory diarrhea, abdominal pain is more severe, and tenesmus may occur in the lower abdomen and rectum, indicating involvement of the large intestine. Emesis is common in noninflammatory diarrhea; fever usually is absent or low grade; pain is crampy, periumbilical, and not severe; and diarrhea is watery, indicating upper intestinal tract involvement. Because immunocompromised patients require special consideration, information about an underlying immunodeficiency or chronic disease is important. Chronic diarrhea is defined as diarrhea lasting more than 14 days. EXAMINATION OF STOOL. Stool specimens should be examined for mucus, blood, and leukocytes, the presence of which indicates colitis. Fecal leukocytes are produced in response to bacteria that diffusely invade the colonic mucosa. A positive fecal leukocyte examination indicates the presence of an invasive or cytotoxin-producing organism such as Shigella, Salmonella, C. jejuni, invasive E. coli, C. difficile, Y. enterocolitica, V. parahaemolyticus, and possibly Aeromonas or P. shigelloides. Not all patients with colitis have positive results on fecal leukocyte examination. Patients infected with Shiga toxin-producing E. coli and E. histolytica generally have minimal fecal leukocytes. Stool cultures should be obtained as early in the course of disease as possible from patients in whom the diagnosis of hemolytic-uremic syndrome (HUS) is suspected, in patients with bloody diarrhea, if stools contain fecal leukocytes, during outbreaks of diarrhea, and in persons who have

diarrhea and are immunosuppressed. Fecal specimens that cannot immediately be plated for culture can be transported to the laboratory in a non-nutrient-holding medium such as Cary-Blair to prevent drying. Because certain bacterial agents, including Y. enterocolitica, V. cholerae, V. parahaemolyticus, Aeromonas, C. difficile, E. coli O157: H7, and Campylobacter, require modified laboratory procedures for identification, laboratory personnel should be notified when one of these organisms is the suspected etiologic agent. Serotype and toxin assays are available for further characterization of E. coli. Detection of C. difficile toxins is valuable in the diagnosis of antimicrobial-associated colitis. Proctosigmoidoscopy may be helpful in establishing a diagnosis in patients in whom symptoms of colitis are severe or the cause of an inflammatory enteritis syndrome remains obscure after initial laboratory evaluation. page 1274 page 1275 MANAGEMENT OF FLUIDS AND ELECTROLYTES AND REFEEDING (also see Chapters 47 and 48.1). Management of dehydration remains the cornerstone in the approach to patients with diarrhea. Children, especially infants, are more susceptible than adults to dehydration because of the greater basal fluid and electrolyte requirements per kilogram and because they are dependent on others to meet these demands. Patients with diarrhea and possible dehydration should be evaluated to assess the degree of dehydration as evident from clinical signs and symptoms, ongoing losses, and daily requirements. Oral hydration usually is the treatment of choice for all but the most severely dehydrated patients whose caretakers cannot administer fluids. Rapid rehydration with replacement of ongoing losses during the first 4-6 hr should be carried out using an appropriate oral rehydration solution. Once a patient is rehydrated, an orally administered maintenance solution should be used (see Table 481). Home remedies including decarbonated soda beverages, fruit juices, Jell-O, Kool-Aid, and tea are not suitable for use because they have inappropriately high osmolalities owing to excessive carbohydrate concentrations, which may exacerbate diarrhea; low sodium concentrations, which may cause hyponatremia; and inappropriate carbohydrate to sodium ratios. Once rehydration is complete, food should be reintroduced while the oral electrolyte solution is continued to replace ongoing losses from stools and for maintenance. Breast-feeding of infants should be resumed as soon as possible. Older children should be re-fed as soon as they can tolerate feeding. Foods with complex carbohydrates (e.g., rice, wheat, potatoes, bread, and cereals), lean meats, yogurt, fruits, and vegetables are better tolerated. Fatty foods or foods high in simple sugars (including juices and carbonated sodas) should be avoided. ANTIDIARRHEAL COMPOUNDS.

These agents are classified by their mechanism of action, which includes alteration of intestinal motility, adsorption of fluid or toxins, alteration of intestinal microflora, and alteration of fluid and electrolyte secretion. Antidiarrheal compounds generally are not recommended for use in children with diarrhea because of their minimal benefit and potential for side effects. Prevention. Patients who are hospitalized should be placed under contact precautions, including handwashing before and after patient contact, gowns when soiling is likely, and gloves when touching contaminated material. Patients and their families should be educated about the mode of acquisition of enteropathogens and methods to decrease transmission. Patients who attend childcare centers should be excluded from the center or cared for in a separate area until diarrhea has subsided. Cases of diarrhea caused by C. botulinum, E. coli O157:H7, Salmonella, Shigella, V. cholerae, Cryptosporidium, and Cyclospora are nationally notifiable diseases and should be reported to personnel at the local health department. Other enteric pathogens associated with outbreaks (e.g., in childcare centers) or food borne or water borne disease also should be reported. Vaccines are available to prevent or modify infection by Salmonella typhi (see Chapter 181). A rotavirus vaccine was briefly available in the United States but has been removed from the market because of the association with intussusception. Other vaccines to prevent rotavirus infection are in clinical trials. Acute Food Borne and Water Borne Disease. Food borne and water borne disease is a major cause of morbidity and mortality in all developed countries, including the United States. Changes in food production, flaws in inspection systems, rapid international distribution of food, alterations in dietary habits, and lack of recognition of methods of prevention magnify these problems. Food borne illness in the United States is estimated to cause millions of cases of gastroenteritis yearly, which results in thousands of deaths and is associated with billions of dollars in medical costs and lost productivity. The diagnosis of a food borne or water borne illness should be considered when two or more persons who have ingested common food or water develop a similar acute illness that usually is characterized by nausea, emesis, diarrhea, or neurologic symptoms. Pathogenesis and severity of bacterial disease depend on whether organisms have preformed toxins (e.g., Staphylococcus aureus, Bacillus cereus), produce toxins, or are invasive and whether they replicate in food. The severity of disease due to viral, parasitic, and chemical causes depends on the amount inoculated into the food or water, whereas bacteria have the potential to replicate in food once introduced. The epidemiology of outbreaks often suggests specific etiologic agents. Determination of the incubation period and the specific clinical syndrome often leads to the correct diagnosis. Confirmation is established by specific laboratory testing of food, stool, or emesis. As a general

rule, when outbreaks are grouped by incubation period of illness, those occurring in less than 1 hr are associated with chemical poisoning, toxins from fish or shellfish, or preformed toxins of S. aureus or B. cereus. Enterotoxin-producing bacteria, invasive bacteria, calicivirus, and some forms of mushroom poisoning have longer incubation periods. CLINICAL SYNDROMES. Table 321-4. Clinical Manifestations, Incubation Periods, and Major Causes of Foodborne Diseaset Clinical ManifestationsIncubation Periods (hr)Main Causative Agents Gastrointestinal tract Vomiting<1Chemical Vomiting and diarrhea1-6Bacillus cereus and Staphylococcus aureus preformed toxins Watery diarrhea, abdominal cramps8-72Many organisms including Salmonella Bloody diarrhea15Many organisms including Salmonella Neurologic0-6Fish, shellfish, monosodium glutamate 0-24Mushrooms 18-24Clostridium botulinum SystemicVariedListeria monocytogenes Brucella Trichinella Toxoplasma gondii Vibrio vulnificus Hepatitis A

Several clinical syndromes follow ingestion of contaminated food or water, including nausea and vomiting within 6 hr; paresthesia within 6 hr; neurologic and gastrointestinal tract symptoms within 2 hr; abdominal cramps and watery diarrhea within 16-48 hr; fever, abdominal cramps, and diarrhea within 8-72 hr; abdominal cramps and bloody diarrhea without fever within 72-120 hr; neurologic signs and symptoms within 6-24 hr; and nausea, vomiting, and paralysis within 1848 hr (Table 321-4). page 1275 page 1276

Short incubation periods with vomiting as the major sign are associated with toxins that produce direct gastric irritation, such as heavy metals, or with preformed toxins of B. cereus or S. aureus; B. cereus also produces an enterotoxin. Paresthesias after a brief incubation period are suggestive of scombroid (histamine) fish poisoning, paralytic or neurotoxic shellfish poisoning, Chinese restaurant syndrome (monosodium glutamate poisoning), niacin poisoning, or ciguatera fish poisoning. The early-onset syndrome associated with ingestion of toxic mushrooms ranges from gastroenteritis to neurologic symptoms that include parasympathetic hyperactivity, confusion, visual disturbances, and hallucinations to hepatic or hepatorenal failure, which occurs after a 6-24 hr incubation period. Watery diarrhea and abdominal cramps after an 8-16 hr incubation period are associated with enterotoxin-producing Clostridium perfringens and B. cereus. Abdominal cramps and watery diarrhea after a 16-48 hr incubation period can be associated with calicivirus, several enterotoxinproducing bacteria, Cryptosporidium, and Cyclospora. Several organisms including Salmonella, Shigella, C. jejuni, Y. enterocolitica, enteroinvasive E. coli, and V. parahaemolyticus are associated with diarrhea that may contain fecal leukocytes, abdominal cramps, and fever, although these organisms can cause watery diarrhea without fever. Bloody diarrhea and abdominal cramps after a 72-120 hr incubation period are associated with Shiga toxin-producing E. coli, such as E. coli O157:H7. Hemolytic-uremic syndrome (see Chapter 510) is a sequela of infection with Shiga toxin-producing E. coli. The combination of gastrointestinal tract symptoms followed by blurred vision, dry mouth, dysarthria, diplopia, or descending paralysis suggests Clostridium botulinum. Therapy for most persons with food borne disease is supportive, because the majority of these illnesses are self-limited. Exceptions are botulism, paralytic shellfish poisoning, and long-acting mushroom poisoning, all of which may be fatal in previously healthy persons. If a food borne or water borne outbreak is suspected, public health officials should be notified. American Academy of Pediatrics, Subcommittee on Acute Gastroenteritis: Practice parameter: The management of acute gastroenteritis in young children. Pediatrics 1996;97:424-35.