ETIOLOGY AND PATHOGENESIS.
Five classes of E. coli are recognized as agents associated with pediatric gastroenteritis. Because E. coli organisms are normal fecal flora, demonstration of virulence characteristics is the only way by which the diarrheagenic E. coli can be defined. The mechanism by which E. coli produces diarrhea typically involves adherence of organisms to a glycoprotein or glycolipid receptor, followed by production of some noxious substance that injures gut cells or disturbs gut function. The genes for virulence properties and for antibiotic resistance are often carried on transferable plasmids or bacteriophages. The current classification is summarized here; the classification changes as new virulence genes are cloned and sequenced.
Enterotoxigenic E. coli (ETEC). These E. coli serogroups produce a heat-labile enterotoxin (LT) and/or a heat-stable enterotoxin (ST). LT, a large molecule consisting of five receptor-binding subunits and one enzymatically active subunit, is structurally, functionally, and immunologically related to cholera toxin produced by Vibrio cholerae. ST is a small molecule (18–19 amino acids) not related to LT or cholera toxin, although it is related to an enterotoxin produced by some strains of Yersinia enterocolitica. These toxins do not injure or kill cells; rather, they disturb cyclic nucleotide–regulated fluid and electrolyte absorption. ST stimulates guanylate cyclase, resulting in increased cyclic GMP, but LT (like cholera toxin) stimulates adenylate cyclase, resulting in increased cyclic AMP. The ETEC typically also possess fimbria or colonization factor antigens (CFAs) that allow them to adhere tightly to intestinal epithelium, thereby efficiently colonizing and delivering toxin to the epithelium. Several CFAs have been recognized as important in effecting the adherence of ETEC to gut mucosal cells. These CFAs are called CFA I, CFA II, CFA III, CFA IV, CS7, CS17, 2230, 8786, PCF 09, PCF 0166, PCF 0148, and PCF 0159. After colonization of intestinal epithelium, the ETEC release ST or LT. The genes for both colonization factors and enterotoxins are typically encoded on the same plasmid. Of the more than 170 E. coli serogroups only a relatively small number typically are ETEC; these serogroups (06, 08, 015, 020, 025, 027, 063, 078, 080, 085, 0115, 0128ac [but not subgroups 0128ab or 0128ad], 0139, 0148, 0153, 0159, and 0167) are generally different from those found in the other diarrhea-associated E. coli.
Enteroinvasive E. coli (EIEC). These E. coli serogroups behave like shigellae in their capacity to invade gut epithelium and produce a dysentery-like illness. The EIEC adhere to and invade gut epithelium. This Shigella-like behavior occurs because these E. coli possess a large virulence plasmid closely related to the plasmid that endows Shigella with its invasiveness (see Chapter 183). As with Shigella, a small group of polypeptides encoded on these plasmids is critical to the invasion of intestinal epithelium. Invasion of epithelium causes cell death and a brisk inflammatory response (clinically recognizable as colitis). The bacterial product that kills intestinal cells is not known. EIEC encompass a small number of serogroups (028ac, 029, 0124, 0136, 0143, 0144, 0152, 0164, 0167, and some untypable strains). These serogroups have lipopolysaccharide (LPS) antigens related to Shigella LPS, and, like shigellae, the organisms are nonmotile (they lack H or flagellar antigens) and are usually nonlactose fermenters.
Enteropathogenic E. coli (EPEC). These diarrheagenic E. coli belong to serogroups (O antigen or lipopolysaccharide antigen) that have been associated with outbreaks of infantile gastroenteritis but do not produce conventional enterotoxins or invade epithelial cells. Low levels of invasion are observed in some assay systems. However, organisms within these serogroups also have been isolated from well individuals. The EPEC adhere to the intestinal mucosa in a distinctive way. This pattern of adherence, seen on transmission electron microscopy, has been called "close attaching and effacing" adherence or "pedestal-forming" adherence. The lesion consists of loss of microvilli with adherence of bacteria to the epithelial cells, which form a cup or pedestal in which the bacteria can be seen. Chronic inflammation with flattened villi may also be seen on small bowel biopsy of affected children. EPEC cause localized or diffuse adherence based on HEp-2 cell assays. EPEC with localized adherence attach loosely to the microvilli of the epithelial cell through ropelike structures called bundle-forming pili, which are encoded on a plasmid (EAF plasmid), followed by attachment to the epithelial cell through the action of the eae gene (E. coli attaching-effacing). Attachment results in increased intracellular calcium concentration and dense polymerization of actin at the site of attachment. How these cytoskeletal changes cause diarrhea is not clear. EPEC, which are diffusely adherent in the HEp-2 cell assay system, produce an adhesin involved in diffuse adherence (AIDA-I), which has homology to a S. flexneri protein associated with intercellular spread (VirG). Some serogroups are associated with localized adherence and are EAF probe positive (055, 086, 0111, 0119, 0125, 0126, 0127, 0128ab, and 0142) whereas others are nonadherent or diffusely adherent to HEp-2 cells and are usually EAF probe negative (018, 044, 0112, and 0114).
Enterohemorrhagic E. coli (EHEC). These E. coli serogroups produce one or more toxins that kill mammalian cells. They have also been called enterocytotoxic E. coli, Shiga-like toxin–producing E. coli (SLT-EC), and verotoxin-producing E. coli (VTEC). Two major toxins are produced by EHEC. One is essentially identical to shigatoxin, the protein synthesis–inhibiting exotoxin of Shigella dysenteriae serotype 1. The second is more distantly related to shigatoxin (only 55% amino acid homology). The first toxin is called SLT-I (VT-1) and the second SLT-II (VT-2). Multiple variants of these toxins probably exist. Some EHEC produce only SLT-I, others only SLT-II, but most EHEC produce both toxins. These toxins kill cells by cleaving an adenine residue from ribosomal RNA at the site where elongation factor 1–dependent attachment of aminoacyl t-RNA occurs; the result is protein synthesis inhibition and cell death. EHEC adhere to intestinal cells and produce attaching-effacing lesions that resemble, on electron microscopy, those seen with EPEC, although they are more restricted in their distribution (being found primarily in the colon) compared with EPEC (which infest the entire intestine). The protein product of the eae gene of EHEC is closely related but not identical to intimin, the product of the eae gene of EPEC, and to invasin, produced by Yersinia pseudotuberculosis. The most common serotypes are E. coli 0157:H7 and E. coli 026:H11, although a number of other serotypes have also been described. E. coli 026:H11 was formerly considered an EPEC.
Enteroaggregative E. coli (EAggEC). These E. coli serogroups have the ability to adhere to HEp-2 cells in tissue culture. They are also referred to as autoagglutinating and enteroadherent-aggregative E. coli. It is likely that this group will be further subdivided, and some of these organisms will be shown to be nonpathogens. EAggEC attach to HEp-2 cells and colonic epithelial cells by plasmid-encoded aggregative adherence fimbriae (AAF/I). These organisms do not possess the eae genes or produce attaching-effacing lesions. A 4.1-kD heat-stable toxin EAST 1, related to the heat-stable toxin of ETEC, is encoded on a plasmid. A second toxin is a 120-kD heat-labile protein related to the pore-forming cytolytic toxin family, which contains the Bordetella pertussis adenylate cyclase hemolysin. This heat-labile toxin increases intracellular levels of calcium. The role of these toxins in EAggEC pathogenesis is unknown. EAggEC appear to colonize the colon.
EPIDEMIOLOGY.
In the developing world, the various diarrheagenic serogroups of E. coli cause frequent infections in the first few years of life. They occur with increased frequency during the warm months in temperate climates and during rainy season months in tropical climates. Most E. coli strains (except EHEC and perhaps some EPEC) require a large inoculum of organisms to induce disease; person-to-person spread is atypical, but foodborne or waterborne illness is common. Infection is most likely when food-handling or sewage-disposal practices are suboptimal. Although infection occurs in children in the United States
PATHOLOGY.
ETEC cause little or no structural alterations in the gut mucosa. EIEC cause colonic lesions like those of bacillary dysentery; ulcerations, hemorrhage, and infiltration of polymorphonuclear leukocytes with mucosal and submucosal edema are typical. EPEC are associated with blunting of villi, inflammatory changes and sloughing of superficial mucosal cells on light microscopy, and attaching and effacing changes on transmission electron microscopy; these lesions are found from the duodenum through the colon. EHEC affect the colon most severely. These organisms cause edema, fibrin deposits, hemorrhage in the submucosa, mucosal ulceration, neutrophil infiltration, and microvascular thrombi. Some of these effects may result from a synergistic action of the Shiga-like toxin and the lipid A portion of the LPS. The pathology of EAggEC consists of secretory diarrhea caused by heat-stable or heat-labile toxins.
CLINICAL MANIFESTATIONS.
As might be expected from the different mechanisms of disease production, the clinical features of E. coli–associated diarrhea vary from group to group. ETEC are a major cause of dehydrating infantile diarrhea in the developing world. The typical signs and symptoms include explosive watery diarrhea, abdominal pain, nausea, vomiting, and little or no fever. Resolution usually occurs in a matter of days. These infections have an untoward effect on infant nutritional status.
EIEC cause an illness that is indistinguishable from classic bacillary dysentery. Fever, systemic toxicity, crampy abdominal pain, tenesmus, and urgency with water or bloody diarrhea are characteristic.
EPEC usually are isolated from infants and children in the first few years of life who have a nonbloody diarrhea with mucus; fever may occur. Unlike ETEC, EIEC, or EHEC, these organisms often cause a prolonged diarrheal disease.
EHEC may cause a nondescript diarrheal illness or an illness characterized by abdominal pain with diarrhea that is initially watery but within a few days becomes grossly bloody (hemorrhagic colitis). Although this pattern resembles that of shigellosis or EIEC disease, it differs in that fever is an uncommon manifestation. The major risk with EHEC is that approximately 10% of symptomatic infections are complicated by development of hemolytic-uremic syndrome.
EAggEC cause significant fluid loss with dehydration, but vomiting and grossly bloody stools are relatively infrequent. These organisms, like the EPEC, are often associated with prolonged diarrhea.
COMPLICATIONS.
The major complications are those related to dehydration and electrolyte loss. Some complications are related to specific pathogens. EPEC and EAEC are likely to cause persistent diarrhea. Infection with EHEC is frequently associated with the hemolytic-uremic syndrome.
DIAGNOSIS.
The clinical features of illness are seldom distinctive enough to allow confident diagnosis, and routine laboratory studies are of very limited value. Diagnosis currently depends heavily on laboratory studies that are not readily available to the practitioner. Routine stool cultures from which E. coli organisms are isolated are interpreted as showing "normal flora." Biochemical criteria (e.g., fermentation patterns) are of minimal value. EHEC serotype O157:H7 is suggested by failure of a suspect colony to ferment sorbitol on MacConkey sorbitol medium; latex agglutination confirms that the organism contains O157 LPS. The other EHEC cannot be detected in routine hospital laboratories, although it is likely that assays based on toxin detection will become available. Culture of duodenal fluid may be helpful in the diagnosis of EPEC because of their tendency to colonize the small intestine. This study is generally indicated only in the child with chronic diarrhea.
Other laboratory data are at best nonspecific indicators of etiology. Fecal leukocyte examination of the stool is usually positive with the EIEC but negative with all other diarrheagenic E. coli. Blood counts, especially with EIEC and EHEC, often show an elevated leukocyte count with a left shift. Electrolyte changes are nonspecific, reflecting only fluid loss.
The traditional methods of identification of these organisms require animal or tissue culture models that are unacceptably cumbersome and expensive for routine use by hospital laboratories. Some of these organisms, especially the EPEC, could theoretically be defined serologically. However, the frequency of cross reactions, the unavailability of suitable reagents, and the infrequency with which the serogroup alone is adequate to define a pathogen make these methods unsuitable. DNA probes for genes encoding the various virulence traits hold the greatest promise for the future; they are currently appropriate only in the research laboratory setting. Probes have been developed for ETEC, EIEC, EPEC, EAggEC, and EHEC.
Suspected organisms should be forwarded to reference or research laboratories for definitive evaluation. Such efforts are seldom necessary, but they may be critical for correct diagnosis of the child with severe or life-threatening complications or for the occasional outbreak investigation.
TREATMENT.
The cornerstone of proper management is related to fluid and electrolyte therapy. In general, this therapy should include oral replacement and maintenance with rehydrating solutions such as those specified by the World Health Organization. Early refeeding with breast milk or dilute formula should be encouraged as soon as dehydration is corrected. Prolonged withholding of feeding frequently leads to chronic diarrhea and malnutrition.
Specific antimicrobial therapy of diarrheagenic E. coli is problematic because of the difficulty of making an accurate diagnosis of these pathogens and the unpredictability of antibiotic susceptibilities. ETEC respond to antimicrobial agents such as trimethoprim-sulfamethoxazole (TMP-SMX) when the E. coli strains are susceptible. However, other than for a child recently returning from travel to the developing world, empirical treatment of severe watery diarrhea with antibiotics is seldom appropriate. Although treatment of EPEC infection with TMP-SMX (6.4 mg/kg/24 hr of the trimethoprim component in four divided doses intravenously or orally for 5 days) is effective in speeding resolution, the lack of a rapid diagnostic test makes treatment decisions difficult. EIEC infections are usually treated prior to the availability of culture results because the clinician typically suspects shigellosis and begins empirical therapy. If the organisms are susceptible, TMP-SMX is an appropriate choice. The EHEC represent a particularly difficult therapeutic dilemma. The data suggest that antibiotic treatment, particularly with sulfa-containing regimens, may increase the risk of hemolytic-uremic syndrome; however, the lack of prospective controlled trials makes these observations questionable. It is too early to assess the usefulness of antibiotics in the treatment of EAEC.
Antibiotic resistance is often encoded on the same plasmids that carry virulence properties and continues to make rational decisions about antibiotic therapy difficult. Because emergence of resistance to widely used regimens is typical, new antimicrobial agents must continue to be evaluated.
Prophylactic antibiotic therapy, although effective in adult travelers, has not been studied in children and is not generally recommended. Public health measures, including sewage disposal and food-handling practices, have made pathogens that require large inocula to produce illness relatively uncommon in industrialized countries. Foodborne outbreaks of EHEC are a problem for which no adequate solution has been found. During the occasional hospital outbreak of EPEC disease, attention to enteric isolation precautions and cohorting may be critical.
PREVENTION.
In the developing world, prevention of disease caused by diarrheogenic E. coli is probably best done by maintaining prolonged breast-feeding, paying careful attention to personal hygiene, and following proper food- and water-handling procedures. Children traveling to these places can be best protected by paying careful attention to diet, in particular consuming only processed water, bottled beverages, breads, fruit juices, fruits that can be peeled, or foods that are served steaming hot.
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