Acute infectious gastroenteritis (AGE) is one of the most common illnesses treated by pediatricians and family practitioners. It is characterized by diarrhea and may include symptoms of nausea, vomiting, abdominal pain, and fever; occasional cases may present only with these latter complaints. Diagnosis usually is simple. Careful physical examination and a few well-chosen laboratory tests done in the physician's office will lead to appropriate therapy in most cases.
CAUSES OF AGE
* Viruses. Viral agents account for 70 to 80 percent of AGE. Rotavirus is the most important cause of AGE in childhood,' and although epidemics occur in winter, sporadic cases are diagnosed throughout the year. Rotavirus infection can be diagnosed by demonstrating the virus through immune electron microscopy of the stool, by serologìe methods using complement fixation titers, or by stool examination using the enzyme-linked immunoabsorbent assay (ELISA). Methods of diagnosis of rotavirus infection are now available commercially. The ability to make a specific diagnosis of rotavirus will help predict the course of the illness, and will reassure the parents and the physician. Other viruses, including Adeno, Coxsackie, and ECHO viruses have been implicated as causes of AGE.
For viruses to interfere with intestinal function, the agents must attach to and damage or destroy the absorptive cells and the intestinal crypt cells.2'3 Infection causes a decreased absorptive surface area, and decreased specific activity of the disaccharidases, peptides and Upases of the absorptive cells. The persistence of partially digested, osmotically active food particles within the lumen causes a net movement of fluid from the small bowel tissues into the lumen, resulting in diarrhea. In most instances, the decrease in absorptive capacity is accompanied by a compensatory acceleration in the growth and differentiation of new enterocytes within the crypts, so that recovery of normal structure and function occurs within three to six days. Infrequently, a viral infection may cause severe mucosal injury, and recovery of absorptive ability may take a prolonged period of time. Therapeutic formulas administered continuously or intermittently, or parenteral nutrition, may be required in those with the severest injury. Viral AGE is not associated with colitis.
* Bacteria. Bacterial pathogens are identified in 10 to 20 percent of AGE. The common bacterial pathogens in this country cause AGE by direct invasion of colonie and/ or small intestinal mucosa. Campylobacter fetus subspecies jejuni,4 Shigella, Salmonella, E. coli and Yersinia enterocolitica* are the causes of bacterial gastroenteritis. All are associated with stools containing polymorphonuclear leukocytes and microscopic or gross blood. Campylobacter and Shigella are the most common in the toddler. E. coli is frequently associated with travel, and is the most important cause of "tourista." E. coli is also a cause of epidemic diarrheal illness in nurseries.
Although only certain serotypes of E. coli were once felt to be pathogens, newer data have proven this concept incorrect. The virulence of E, coli is not related to serotype, and routine serotyping in children with AGE is unnecessary. Serotyping can be helpful in, incriminating a specific organism responsible for outbreaks of diarrhea in nurseries, and in other situations when culstering of diarrhea cases occurs. For public health reasons, it is important to recognize the presence of an epidemic of E. coli AGE, although treatment for affected individuals is not altered by knowledge of the serotype involved.
Diarrhea and colitis following the use of antibiotics is caused by a toxin produced by the bacterium Clostridiwn diffìcile? This bacterium, which may be a component of normal fecal flora, overgrows in the presence of antibiotics. The diagnosis of antibiotic-associated colitis requires: 1) a patient with clinical evidence of colitis; 2) growth of C. diffìcile from stool samples obtained from the patient; 3) cytotoxicity of cell-free fecal extracts in tissue cultures; and 4) neutralization of the cytotoxic effect by C Bordelli antitoxin. Antibiotic-associated colitis may present as AGE at any time up to two months after discontinuing the antimicrobial agents. Although initially labelled "pseudomembranous colitis," antibioticassociated colitis can present with a spectrum of symptomatology ranging from fever and abdominal pain with only slight changes in stool frequency and consistency to either frank bloody or watery purulent diarrhea. With the exception of antituberculous agents, urinary antiseptics and parenterally-administered aminogiycosides, all antibacterial agents are capable of inciting C. diffìcile colitis. In children presenting with symptoms of AGE who have a history of antibiotic ingestion within the preceeding two months, it is important to consider antibiotic-associated colitis, because a specific therapy, oral vancomycin, is available,
Campy lobacter, Shigelia, Salmonella, E, coli and Clostrìdium diffìcile cause AGE by destroying the colonie mucosa, either directly by invasion or by toxins. This results in a decrease in absorption of water and electrolytes from the colon, and a loss of blood and plasma throughout the injured area. Increased stool frequency is, in part, due to the inflammation within the sigmoid colon and rectum which causes pain and spasm when the lumen is distended with gas or feces.
In contrast to bacteria which produce symptoms by direct invasion, a number of bacteria produce enterotoxins which cause net small intestinal fluid and electrolyte secretion without affecting the bowel morphology.7 Vibrio cholera and its toxin has been most extensively studied and is the best example of this kind of bacteria. Cholera toxin binds to the membranes of enterocytes, activating adenylate cyclase and increasing cellular cyclic AMP. These intracellular events are associated with an increase in chloride outflux from the enterocytes, with the resultant net water and electrolyte secretion from the intestine. True cholera outbreaks are almost unheard of in this country; however, in recent years a number of gram-negative bacilli have been identified which produce acute diarrheal illness mediated by toxins. Like cholera toxin, these toxins also bind to villus epithelium and cause a secretory diarrhea. E. coli, Klebsietta, Cilrobacler, Salmonella, and Aeromonas species have produced secretory diarrhea mediated by an enterotoxin. (E. coli and Salmonella are, therefore, capable of causing AGE by direct invasion of colonie mucosa, production of a small bowel toxin, or through both mechanisms simultaneously.)
* Parasites. Two parasitic infections may present as AGE. Amoebiasis is endemic in areas of the united States with a tropical climate. Amoebiasis causes abdominal pain and diarrhea, and is difficult to differentiate on clinical grounds from bacterial colitis or idiopathic ulcerative colitis. Fortunately, large motile trophozoites of Entamoeba histolytica, containing freshly ingested red blood cells, can frequently be found by examining brushings of the rectal mucosa or fresh stools. Amoeba invade the colonie mucosa and submucosa, producing characteristic flask-shaped ulcerations.
Giardia lamblia, a flagellated protozoan, is a cause of outbreaks of AGE in day-care centers, in travelers to endemic areas and even in individuals who have not travelled outside of their local communities. The protozoan invades and/or attaches itself to absorptive cells in the upper small bowel and damages the villi, resulting in malabsorption. Giardiasis usually presents with a prodrome of anorexia, borborygmi and abdominal pain before the onset of diarrhea. Diarrhea may be intermittent and, if diagnosis is not established, may persist for weeks or months. Children with chronic giardiasis, because of the malnutrition and characteristic habits they develop, may be mistaken to have celiac sprue. The diagnosis of giardiasis may be elusive, because the organism is not present in stool samples in more than half of the patients. The diagnosis can be made most accurately (90 percent of the time) by obtaining a duodenal aspirate, peroral duodenal biopsy, or using the Enterotest® string to obtain a sample of duodenal fluid.
EVALUATION OF THE CHILD WITH AGE
The two chief things the pediatrician or family practitioner must do in assessing youngsters with AGE are: 1) determine the state of hydration; 2) determine the source of diarrhea. A careful physical examination is mandatory to assure that symptoms are not a systemic manifestation of a local infection, such as otitis media or urinary tract infection.
* Estimation of the state of hydration. The younger the child, the more susceptible he/she is to rapid dehydration; infants, therefore, must be re-evaluated with a greater frequency than older children. The clinical criteria for determining the degree of dehydration are listed in Table 1 . Under optimal circumstances, it is useful to observe children under two years of age for a period of two to four hours. This period of time can be used to obtain a urine specimen to check the specific gravity and to rule out a urinary tract infection (which can present as diarrheal illness with fever), to assess the infant's ability to ingest liquids without vomiting, and to complete an assessment of a fresh stool sample.
* The stool examination. The stool examination is the single most important initial step in assessing the category of diarrheal illness (Table 2). A stool sample should be obtained by doing a rectal examination if a fresh one is not present in the infant's diaper. Stool should be observed for color, consistency, odor and for the presence or absence of mucus and blood. A stool which has a sweet, yeasty or acidic odor suggests carbohydrate malabsorption typical of the osmotic diarrhea of viral enteritis. Stool with a purulent odor suggests colitis. Stool p H should be determined only if the stool is watery, using pH indicator paper with a range from 4.5 to 8.0. Except in the first month of life, when stools may normally have a pH as low as 5.0, a pH less than 6.0 suggests carbohydrate malabsorption. If the stool is liquid, it can be recovered from the diaper by several methods: The examiner dons plastic gloves and wrings out the diaper directly over a basin, recovering the drops by aspirating them into a syringe or Pasteur pipette. (It is important to be sure the stool is not mixed with urine); an alternative method, useful when the diarrhea is less copious, is to tear away the top layer of diaper which holds the solid portion of stool, and collect a few wet underlayers of diaper material. Place these absorbent pieces into a syringe, replace the plunger, and squeeze the drops of liquid stool into a test tube for analysis. The use of Clinitest® tablets to estimate malabsorption of carbohydrate is semi-quanti tati ve and reproduceable. If the patient has been on a diet with glucose or lactose as the major carbohydrate source, then six drops of stool water are mixed with 12 drops of tap water and a Clinitest tablet is added. The final color indicates the presence or absence of carbohydrate malabsorption. If the patient's diet contains sucrose, a non-reducing sugar, as the principal carbohydrate source (e.g. soy formulas), then the test must be modified by adding six drops of stool water to 1 2 drops of 1 N HCl and then heating the suspension to boiling for 30 seconds to hydrolyze the sucrose to glucose and fructose. Then, after cooling the suspension of stool, add the Clinitest tablet. Malabsorption of carbohydrates occurs when there has been damage to the small bowel mucosa, but not with a secretory diarrhea such as produced by cholera or E, coli enterotoxin. Occult blood assessed by Hemoccult® or the guaiac reagent indicates a break in the mucosa! integrity of the gastrointestinal tract and is most common in colitic infections. To look for the presence of polymorphonuclear leukocytes (PMNs), methylene blue or Wright's stain should be done: A pin-head amount of mucus or solid material is placed on top of a glass slide. Two drops of methylene blue are added and mixed with stool. A cover slip is added, and the wet mount is then reviewed. The presence of PMNs indicates an active inflammatory process, most typical of the invasive bacterial pathogens such as Campylobacter, Shigella, Salmonella, and E. coli.
* Laboratory tests. A stool culture should be obtained for diagnostic purposes if hospitalizaron is contemplated and there are PMNs in the stool, but is not helpful in the immediate management of the patient. In patients who have fever to 390C, appear toxic, or are in shock, blood cultures should be drawn. The total and differential white blood cell counts are generally of little use, but in a patient judged clinically to be dehydrated 5 percent or more, it is important to assess the serum electrolytes and acid-base status. If the ELISA test is available it would be useful to confirm a diagnosis of AGE, but would not necessarily alter treatment.
CLINICAL FEATURES OF DEHYDRATION
MANAGEMENT OF AGE
Most patients with AGE are managed successfully as outpatients. The goals of fluid and electrolyte therapy both for in- and out-patients are to replace body losses and to provide the requirements for maintenance in continuing loss. Criteria for hospital admission and intravenous replacement therapy are given in Table 3. (Intravenous fluid and electrolyte therapy is discussed at length in standard pediatric texts, and will not be discussed here.)
Orai rehydration protocols have come under close scrutiny in the past few years, when a world-wide program examining the efficacy of oral electrolyte solutions in AGE was sponsored by the World Health Organization (results briefly reviewed by Finberg8). Oral rehydration results in more stool volume than does intravenous therapy; as long as the net fluid balance is positive, this need not be disconcerting. The ideal oral rehydration solution contains glucose or sucrose potassium to fulfill body requirements. The coupled absorption of sodium and glucose at the intestinal brush border facilitates free water absorption by the phenomenon of solvent drag, so the ideal oral solution provides a balance of sugar and salt. It is important to remember that sodium and potassium losses are dependent on stool volume. There is progressive increase in the concentration of sodium with increasing stool volume, so that sodium losses are most impressive when diarrhea is severe. When profuse diarrhea persists during oral rehydration, the patient should undergo a re-evaluation, including physical examination, body weight, serum electrolytes, and urin specific gravity.
EXAMINATION OF FRESH STOOL TO DETERMINE CATEGORY OF ILLNESS
Two of the commercially available solutions, Pedialyte® and Lytren®, provide basal sodium and potassium requirements; they still are not ideal, however, since they do not contain extra electrolytes to make up for deficits and ongoing excess losses. Hydralyte®, a powder that requires mixing, provides a large amount of sodium appropriate for electrolyte maintenance and replacement during a severe diarrhea! illness such as cholera, or a severe episode of AGE. Carbonated beverages, apple juice, rice water and tea do not supply adequate sodium, and may result in hyponatremia. It is prudent to avoid the use of home recipes for oral rehydration solutions because of the frequency of mixing errors resulting in hypernatremia (Table 4).
Children who are not vomiting can be encouraged to drink volumes of a rehydration solution until satisfied. Children who are vomiting but who do not appear severely dehydrated can be offered small volumes- 1 5 ml for infants, 30 ml for toddlers and older children - every 20 to 30 minutes. Gastric distention will be minimized, and vomiting is less likely to occur. Children should not be forced to drink, but fluids must be offered regularly and frequently during the first 24 to 48 hours of oral rehydration. Milk and milk formula feedings are omitted for several reasons: 1) A period of transient laclase deficiency is the rule during viral AGE, and the unabsorbed lactose in the intestinal lumen results in osmotic forces pulling water into the lumen and thereby increasing stool output; 2) The fat in the milk delays gastric emptying, resulting in slower fluid absorption and in gastric distention which may predispose to vomiting; 3) Milk may result in thick, irritating pharyngeal mucous secretions predisposing the infant to episodes of emesis. Breast feeding may be continued during a diarrheal illness unless there is clear evidence of lactose malabsorption.
In mild to moderate AGE, the patient improves after 24 to 48 hours of therapy, so that a more nutritious diet can be initiated. Recovery from diarrheal symptoms depends not only on the resolution of the infection, but also on prompt and appropriate nutritional support aimed at providing calories adequate for rebuilding the damaged absorptive surface.
In infants who demonstrate improvement in symptoms after 24 to 48 hours of oral rehydration therapy, it is judicious to attempt refeeding with diluted formula (1:1 formula:water). Refeeding is more often successful if the carbohydrate source is sucrose or glucose oligosaccharide rather than lactose.9 If the illness has been mild, a half-strength lactose-containing formula may be restarted to avoid a series of formula changes. As formula feedings are advanced, (he stool volume and frequency should be estimated. If an exacerbation of diarrhea occurs, the infant's status must be re-evaluated, including an assessment of sugar malabsorption in the stools. If the dilute formula is tolerated, changes in strength may be made over consecutive 24-hour periods.
CRITERIA FOR THE USE OF HOSPITAL ADMISSION AND INTRAVENOUS THERAPY IN AGE
In toddlers and older children recovering from AGE, clear fluids can be supplemented with solid foods high in starch and sugars (except lactose), and low in fats. The traditional BRAT diet (bananas, rice, apples and toast) fits such a description. (Perhaps one reason for the popularity of the BRAT diet- other than the attraction to the acronym - is that raw apples and bananas contain pectin, a nondigestible starch, that can absorb fluid and give form to watery stool.) If the high carbohydrate diet is successful, and diarrhea does not persist, the child may resume a normal diet for age, with the exclusion of milk. Because lactose absorption is the last function to return to normal after small bowel mucosal injury, milk should be restarted three to five days after recovery begins.
* Medication. Specific antimicrobial therapy may be indicated for patients with bacterial AGE after identification of the organism and its antibiotic sensitivities. In cases of AGE due to Shigeiia, antibiotics reduce the duration of symptoms and eradicate the organism from the stools. Most Shigeiia species are resistant to sulfonamide alone, and there is growing resistance to ampicillin; the treatment of choice is now trimethoprim 1 0 mg and sulfamethoxazole 50 mg/ kg/ day, divided into two equal doses, for five days. Campyhbacter infections should be treated with erythromycin 50 mg/kg/day, divided into four equal doses, for ten days. In the uncommon instance of a Campyhbacter organism that is resistant to erythromycin, aminoglycosides are effective. In contrast to the success of antibiotics in the treatment of AGE caused by Shigellaand Campyhbacter, there is no good evidence that antibiotic treatment affects the course of AGE due to invasive E. coli or Yersinia. Finally, simple AGE due to Salmonella should not be treated with antibiotics because antibiotics prolong the infectious state and may convert a localized infection to a more systemic one. Severe Salmonella infections, such as typhoid fever and bacteremic states, should be treated with intravenous chloramphenicol 100 mg/kg/day divided into four doses, or ampicillin 200 mg/kg/day divided into four doses.
The preferred treatment for giardiasis in children is quinacrine hydrochloride 7 mg/kg/day (300 mg/day maximum) divided into three equal doses. Equally effective is meironidazole 20 mg/kg/day (750 mg/day maximum) divided into four doses, for ten days. Amoebic colitis is treated with metronidazole 50 mg/kg/day (750 mg/day maximum) divided into three daily doses, for ten days followed by diiodohydroxyquin 40 mg/kg/day (650 mg/day maximum) divided into thirds, for 21 days.
Medications which have been used for symptomatic relief of AGE in adults include absorbent agents, agents which alter intestinal motility, and antiemetics. None of these agents are indicated for children with AGE.
Kaopectate®, psyllium, aluminum hydroxide, and cholestyramine, by their presence within the intestinal lumen, add form to otherwise formless, watery stool. The use of these agents does not result in altering the pathophysiology or cause of the illness. These medications have no serious side effects, but an infant derives more benefit from ingesting a rehydration solution.
Agents that slow propagated peristalsis- natural and synthetic opiates and anticholinergics - have significant side effects which preclude their use in young children. Rarely, the use of such medication is associated with the onset of toxic megacolon. Intestinal motility patterns are abnormal in AGE, but as a consequence of the primary process rather than an etiology.
ELECTROLYTE COMPOSITION OF COMMON REHYDRATION SOLUTIONS
Antiemetics are not indicated for young children with AGE because they may mask more severe underlying disease. Most children who vomit will do so for 24 hours or less; small, frequent, clear liquid feedings seem effective in reducing emesis. Intractable vomiting may reflect a more serious disturbance such as bowel obstruction, and requires admission for diagnostic workup and intravenous fluid therpy. It is not clear that antiemetics have efficacy during infancy, and the side effects associated with phenothiazine-related antiemetics - sedation, and less commonly, occulogyric crisis - contraindicate their use. If a patient vomits for more than 24 hours despite use of oral electrolyte hydrating solutions, serum electrolytes should be checked and the patient re-examined.
COMPLICATIONS OF AGE
* Acute. The potential gastrointestinal complications common to bacterial and amoebic colitis include hemorrhage, perforation, rectal prolapse, and intussusception. Bacterial pathogens occasionally produce respiratory disease, including pneumonia, and infrequently are associated with severe systemic illness. Specific pathogens are responsible for unique complications. For example, Shigella may release a neurotoxin resulting in aseptic meningitis or encephalitis, and amoebae may produce a mass lesion known as amoebo'ma.
* Chronic. In the first three years of life, the most common cause of chronic (duration more than two weeks) diarrheal illness is malabsorption following severe viral AGE. I0 In a susceptible infant, viral AGE may result in marked destruction of the intestinal villi. Malabsorption of all nutrients occurs because the absorptive surface area of the small intestine is drastically reduced. Regeneration of the villus structure does not occur because of restricted dietary intake, poor nutritional reserve, and severity of mucosal injury. Diarrhea, malabsorption, and failure to thrive will persist until treatment is initiated. Treatment may include an elemental or pre-digested formula administered by continuous drip through a nasogastric feeding tube, central or peripheral parenteral nutrition, or a combination of these modalities.
Although AGE has been managed by physicians daily for centuries, enormous strides have been made in just the past ten years- previously unrecognized pathogens have been identified; cellular pathophysiology elucidated; new therapies applied; and old and new therapeutic ideas tested in sound scientific fashion.
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CLINICAL FEATURES OF DEHYDRATION
EXAMINATION OF FRESH STOOL TO DETERMINE CATEGORY OF ILLNESS
CRITERIA FOR THE USE OF HOSPITAL ADMISSION AND INTRAVENOUS THERAPY IN AGE
ELECTROLYTE COMPOSITION OF COMMON REHYDRATION SOLUTIONS