Enteroaggregative Escherichia coli:

An Emerging Pathogen in Children

David B. Huang, MD*, and Herbert L. DuPont, MD*,,,
Enteroaggregative Escherichia coli (EAEC) is an emerging pathogen that causes enteric
and food-borne infectious diseases. Children throughout the world appear to be susceptible to EAEC infection. EAEC pathogenesis involves the following three stages: 1)
adherence to the intestinal mucosa; 2) increased production and deposition of a mucus
biofilm; and 3) mucosal toxicity due to inflammation and cytokine release. The HEp-2
cell adherent assay allows identification of EAECs characteristic aggregative or
stacked brick adherence pattern. Antimicrobial treatment of children who develop an
EAEC infection should be individually based. All children with EAEC diarrhea should
receive adequate oral fluid hydration. For children who have persistent diarrhea and
severe dehydrating illness despite having received adequate oral rehydration, antimicrobials may be initiated. Azithromycin and rifaximin have been shown to shorten the
course of EAEC diarrhea in adults and probably represent the recommended antimicrobials of choice for children with severe or persistent illness. The objective of this
review is to increase awareness of this important emerging pathogen and to discuss the
epidemiology, pathogenesis, and pathogen and host factors associated with EAEC
infection in children.
Semin Pediatr Infect Dis 15:266-271 2004 Elsevier Inc. All rights reserved.

iarrheagenic Escherichia coli are a major worldwide

cause of illness in children. As a group, diarrheagenic
E. coli are the most common cause of bacterial pediatric
diarrhea in developing regions. This group of E. coli has
been classified loosely into five major categories based on
clinical associations, serotyping, phenotypic assays, and
the presence of virulence genes. These groups are enterotoxigenic E. coli (ETEC), enteroinvasive E. coli (EIEC), enterohemorrhagic E. coli (EHEC), enteropathogenic E. coli
(EPEC), and enteroaggregative E. coli (EAEC). EAEC is the
most recently recognized cause of diarrhea worldwide. It
is characterized by its diffuse adherence pattern, in contrast to the localized pattern of EPEC, in infected humanepithelial cells (HEp-2).1-3

*Department of Medicine, Baylor College of Medicine, Houston, TX.

University of Texas at Houston School of Public Health, Houston, TX.
University of Texas at Houston Medical School, Houston, TX.
St Lukes Episcopal Hospital, Houston, TX.
Our research support comes from the VTEU Enteric Challenge Studies,
NO1-AI-25465 and Public Health Service grant DK 56338, which funds
the Texas Gulf Coast Digestive Diseases Center.
Address reprint requests to Herbert L. DuPont, MD, St Lukes Episcopal
Hospital, 6720 Bertner Ave, MC1-164, Houston, TX 77030. E-mail:
hdupont@sleh.com

266

1045-1870/04/$-see frontmatter 2004 Elsevier Inc. All rights reserved.

doi:10.1053/j.spid.2004.07.008

Epidemiology
EAEC is gaining recognition rapidly in both developed countries and industrialized nations, including the United
States.1-4 EAEC is thought to be a cause of enteric and foodborne infectious diseases. Viable EAEC can be isolated in as
many as 66 percent of tabletop Mexican sauces served in
Guadalajara, Mexico, compared with 0 percent in Houston,
Texas, restaurants.5 EAEC is able to survive in bottled mineral and spring water at common storage temperatures. The
survival levels of EAEC were significantly higher (P 0.01)
at 23C and 10C compared with 4C; survival levels also
were significantly higher (P 0.01) in mineral water than in
spring water at 4C and 10C.6
In some regions of the world, EAEC has been shown to be
the most common cause of pediatric diarrhea. In a prospective study in Switzerland, EAEC was the bacterial pathogen
most commonly identified in the stool specimens of children
younger than the age of 16 years. This pathogen was found in
12 percent of children with diarrhea and was associated
mainly with a history of recent travel outside Switzerland.7 In
other areas of the world, especially developing regions, EAEC
is the second most common cause of acute travelers diarrhea,
surpassed by only ETEC.
EAEC is an important agent of acute and persistent diar-

Enteroaggregative Escherichia coli

267

Figure 1 HEp-2 cell assay for enteroaggregative E. coli (EAEC). EAEC has a characteristic aggregative pattern of
adherence on the surface of the human epithelial tissue culture (HEp-2) cells, which includes prominent clustering of
bacteria to cells and glass coverslip described as a stacked-brick configuration (Giemsa stain, 1000). Kindly provided
by PC Okhuysen and L Carlin.

rhea in many populations all over the world.8-10 These populations include children from both the developing and the
developed nations. EAEC accounts for 8 to 32 percent of
acute diarrhea cases in infants and young children depending
on the region of the world.11-16 Many of the initial epidemiologic reports implicated EAEC as a cause of persistent
(14 days) diarrhea, accounting for 20 to 30 percent of
cases.13,14,17-22 The largest outbreak of EAEC diarrhea was
described in Japan, where a total of 2697 of 6636 schoolchildren (attack rate of 40.6%) from 16 different schools became
ill after consuming contaminated school lunches.23 The total
number of persistent diarrhea cases, however, was not reported for this outbreak.
The exact epidemiologic characteristics of transmission of
EAEC are still undefined. In a limited number of adults, a
high inoculum dose is needed to produce disease. One volunteer study showed that oral ingestion of 1010 cfu of EAEC
elicited diarrhea.24 The infectious dose in children is unknown. Risk factors for the development of EAEC infection
are similar to those of other diarrheagenic E. coli, which include improper food refrigeration, contamination of foods,
and poor hygiene.5 Advanced human immunodeficiency virus (HIV) infection also is a risk factor. Before the development and availability of protease inhibitors, 10 to 44 percent
of adult HIV-infected patients with diarrhea had EAEC infection.25-28 The incidence and prevalence of diarrhea caused by
EAEC in children with HIV is not known, although studies in
Zambia have suggested they may play a role.25 Because current diagnostic reagents are largely research tools, we have
limited data on the importance of this pathogen worldwide.

More studies and better diagnostic tools are needed to allow

for a better understanding of the true epidemiology of EAEC
in children.

Microbial Pathogenesis
The study of EAEC pathogenesis has been limited because of
heterogeneity of strains. EAEC is associated with diarrhea in
some children, but in others, EAEC strains appear to cause
subclinical infection or intestinal colonization.29 The current
model of EAEC pathogenesis includes the following three
stages: 1) adherence to the intestinal mucosa by an aggregative adherence fimbrae (AAF) or other organism adherence
factor10; 2) increased production of mucus by the bacteria
and intestinal cell that encrusts EAEC on the surface of enterocytes30,31; and 3) an inflammatory response with cytokine
release that can cause mucosal toxicity and intestinal secretion.32-36
Figure 1 shows the first stage of EAEC pathogenesis, which
includes aggregative adherence (AA) to the intestinal mucosa
in a stacked-brick configuration.10 Table 1 lists the virulence
factors reported to be important in the adherence of EAEC to
the intestinal mucosa. Aggregative adherence fimbriae I
(AAF/I) and AAF/II are the structural subunits of the AAF10
and are encoded by two genes on the pAA plasmid, aggA and
aafA, respectively. AAF/I confers the aggregative phenotype
and human erythrocyte hemagglutination, and AAF/II is involved in intestinal mucosal adherence. Other adherence factors important to the adhesion process include membraneassociated proteins (MAPs)37 and a recently recognized 58

D.B. Huang and H.L. DuPont

268
Table 1 Virulence Properties/Enterotoxins of Enteroaggregative E. coli (EAEC)
References
Aggregative adherence fimbriae AAF/I
and AAF/II
Dispersin
EAEC flagellin
Membrane-associated proteins (MAPs)
Outer membrane protein
Plasmid encoded toxins (Pet)
EAEC heat-stable enterotoxin 1 (EAST1)
Virulence factors with similarity with
E. coli pathogens and Shigella
enterotoxins (ShET1 and ShET2)
E. coli alpha hemolysin (hly gene)
Cytolethal distending toxin (cdt gene)
Protein for Yersiniabactin biosynthesis
(irp2 gene)
Cryptic open reading frame (shf gene)

70
71
49
37
38
39,40
43,44
72,73

72,73
72,73
72,73
74

kDa plasmid-encoded outer membrane protein, called aggregative protein 58 (Ap58). Ap58 is thought to be associated
with the adherence capabilities and hemagglutination of animal cells.38
The second stage of EAEC pathogenesis involves production of a mucus layer, probably from both bacteria and the
intestinal mucosa. EAEC adherence to intestinal mucosa
stimulates mucus secretion in both in vivo and in vitro studies.39 The thick mucus-containing biofilm then encrusts and
embeds the EAEC on the surface of enterocytes.30,31 This
mucus-EAEC-containing biofilm may explain the clinical
features of EAEC diarrhea, which include mucoid stools,
malnutrition, and persistent colonization with prolonged diarrhea.40,41
The final stage of EAEC pathogenesis is an inflammatory response with cytokine release that can cause mucosal toxicity and
intestinal secretion.32-36 Studies have shown that EAEC causes
destruction of enterocytes at both the tips and the sides of intestinal villi.32,39 The two best-studied toxins are plasmid-encoded
toxin (Pet) and heat-stable enterotoxin 1 (EAST1). Pet, an autotransporter protein, induces enterotoxic and cytotoxic effects
that contribute to mucosal intestinal toxicity, including dilation
of crypt openings, rounding and exfoliation of colonic enterocytes, widening of intercrypt crevices, and loss of apical mucus
from goblet cells.40 EAST1, a toxin encoded by the gene astA,42
has been shown to induce diarrhea in both humans and animals
by stimulating the particulate form of guanylate cyclase through
the STa guanylin receptor.43,44
Intestinal inflammatory markers, interleukin-1 (IL-1),
IL-8, interferon- (INF-), lactoferrin (60% of isolates), fecal
leukocytes (29% of isolates), and occult blood (31% of isolates), are released in response to EAEC infection.36,45,46 Individuals who develop EAEC diarrhea excrete higher levels of
fecal IL-8 in their stools compared with those with asymptomatic EAEC infections.36 IL-8 is a chemokine that recruits
neutrophils to the epithelial mucosa, causing epithelial destruction and fluid secretion.47,48 The factors involved with

IL-8 excretion include EAEC flagellin (the major structural

protein of EAEC flagella),49 other virulence genes, and specific host genetic variants.50 Flagellin is a potent trigger of the
innate immune responses in human epithelial cell lines because it induces an inflammatory response mediated through
toll-like receptors (TLRs), specifically TLR5. TLRs recognize
microbial particles and activate immune cells against the
source of these microbial particles. The presence of specific
virulence genes in EAEC appears to be associated with increased levels of fecal cytokines.5 The inflammatory responses to EAEC infection may vary by geographic location.36 Likely, additional, currently unidentified virulence
properties of EAEC strains account for the heterogeneity and
varying clinical overlap among EAEC infections.
The intestinal localization of EAEC infection is being investigated. Endoscopic specimens of EAEC infection from
healthy children show that EAEC can bind to jejunal, ileal,
and colonic epithelium.51 In other studies in adult volunteers, infection with EAEC strain 042 was found to be recovered from duodenal aspirates.24 These results suggest that the
affinity of EAEC for segments of the intestinal tract is heterogeneous and that both the small bowel and colon are susceptible to EAEC.

Clinical Features and

Natural History of Infection
Children with EAEC infection may develop acute watery diarrhea with or without passage of blood and mucus, abdominal pain, nausea, vomiting, borborygmi, and low-grade fever. Perhaps most importantly, EAEC has been shown to be a
major cause of a persistent diarrhea (14 days) in children.52-54 The incubation period of EAEC infection is 8 to 18
hours. In our studies, asymptomatic infections with EAEC
occur in adult travelers, and the rate likely increases with the
length of time within an endemic region.55 These findings
may be similar in infants and young children reared in endemic areas with EAEC. The presence or absence of illness
during infection with EAEC is due to a combination of the
variability of virulence of EAEC strains, dose of ingested bacteria, and host factors.35,50 Among individuals who develop
symptomatic infection, those homozygous for a single nucleotide polymorphism (SNP) in the IL-8 promoter region 251
AA produce higher levels of fecal IL-8 (odds ratio [OR],
208.51; 95% confidence interval [CI], 28.5-1525.36) compared with those who were heterozygous for the gene.50 The
AA 251 SNP may explain in part the variable clinical presentations seen with EAEC infection.

Diagnosis
In the HEp-2 cell adherent assay, EAEC, unlike other E. coli,
produce a characteristic aggregative or stacked brick adherence pattern. This assay has some limitations, including the
difficulty of screening large numbers of colonies from stool
samples, labor and time intensity, and the potential of cross
contamination of tissue culture cells.56-58 Use of the HEp-2

Enteroaggregative Escherichia coli

cell adherent assay has been limited to research facilities. A
formalin-fixed HEp-2 cell assay increases the availability of
the HEp-2 cells and decreases the risk of contamination; this
assay has a sensitivity of 92 to 98 percent with a specificity of
100 percent.57 However, it has not been validated prospectively.
Other available molecular diagnostic tools for detecting
EAEC include DNA probes based on a 1.0-kb DNA fragmentlabeled PCVD432 from the 60-MDa plasmid of the EAEC
strain 17-256,59-61 and a polymerase chain reaction (PCR) assay with a primer pair complementary to the PCVD432 sequence.23,62-64 These tests have a sensitivity of 15 to 89 percent and a specificity of 96 to 99 percent compared with the
HEp-2 cell assay. The variable sensitivity likely is due to the
false assumption that the DNA sequences targeted correspond to a conserved virulence factor.59

Treatment
The empiric treatment of EAEC infection is based on the
antimicrobial susceptibility in that region. In many different
geographic regions, EAEC has a moderate to high level of
resistance to ampicillin, tetracycline, trimethoprim-sulfamethoxazole, and chloramphenicol. The antimicrobials with
the greatest activity against EAEC include fluorquinolones,
azithromycin, rifaximin, amoxicillin/clavulanic acid, and nalidixic acid.65-67
For children with diarrhea, the recommended treatment is
oral rehydration therapy. Antimicrobial therapy usually is
not recommended except in the more severe cases. Antimicrobials may be useful in reducing associated enteric symptoms, including watery diarrhea and/or dysentery (passage of
bloody stools) or fever (37.8C) in the more severe cases of
illness and in the management of persistent diarrhea. In these
cases, based on data obtained from studies in adults, azithromycin 10 mg/kg for day 1 and then 5 mg/kg/day on days 2
and 3 as needed may be appropriate. Alternatives to azithromycin include a parenterally administered third-generation
cephalosporin68 or a pediatric suspension of rifaximin (ie,
100 mg qid for 3 days). Rifaximin is a promising new poorly
absorbed antimicrobial that is likely to become widely used
for non-invasive bacterial causes of diarrhea.69

Conclusion
EAEC is an important emerging pathogen in children, especially in the developing world. Greater recognition of EAEC
infection likely will occur with the development of better
diagnostic tools, which likely will yield identification of epidemiologic patterns of illness and the development of new
treatment recommendations. Rifaximin has recently been
shown to treat EAEC diarrhea successfully in adults.75

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