VEROCYTOTOXIN-PRODUCING ESCHERICHIA COLI INFECTION IN FAMILY
OF CHILDREN WITH HEMOLYTIC UREMIC SYNDROME
MARTA RIVAS1, LUIS E. VOYER2, MONICA TOUS1, MARIA F. DE MENA1,
LEARDINI1, RAQUEL WAINSZTEIN2, RAQUEL CALLEJO1. BEATRIZ QUADRI2,
CORTI2, VALERIA PRADO3
1 Instituto Nacional de Microbiología Carlos G. Malbrán y 2
Hospital General de Niños Pedro de Elizalde, Buenos Aires; 3
División Ciencias Médicas Oriente, Facultad de Medicina,
Universidad de Chile, Santiago, Chile
Key words: hemolytic uremic syndrome, family members,
hemolytic uremic syndrome (HUS) patients and ninety-five family
members were studied to determine the frequency of infection with
verocytotoxin-producing Escherichia coli (VTEC) in household
contacts using three diagnostic criteria: VTEC strains isolation
and characterization, detection of free fecal VT (FVT) and
VT-neutralizing antibodies (VT-NAbs). Gastrointestinal tract
symptoms occurred in one to six familiy members in 8 (23.5%) of
the index cases, the week before admission to hospital or
simultaneously. The control group consisted of 34 children with
acute gastroenteritis who did not develop HUS. Cumulative evidence
of VTEC infection was found in 13 (38.2%) of 34 HUS patients, in
30 (31.6%) of 95 family members and in 10 (29.4%) of 34 control
children. The serotypes of VTEC isolated were O157: H7 and O25:
H2. The prevalent VT type was VT2 in VTEC and FVT; and VT1 in
VT-NAbs. Both parents had the same infection rate by fecal toxin
or serological data (11.1% FVT, 32% VT-NAbs). These were higher
than those detected in siblings (6.2% FVT, 23.5% VT-NAbs) and
grandparents (0% FVT, 18% VT-NAbs). Of 16 patients without
evidence of infection, 3 had household contacts with FVT and 13
with VT-NAbs. Our results show the wide dissemination of VTEC in
the population of Argentina and that family members of HUS
patients are usually infected. Therefore, person-to-person
transmission may play an important role in the high incidence of
HUS in our country.
con Escherichia coli productor de verocitotoxina en convivientes
de niños con síndrome urémico hemolítico
Se estudiaron 34 pacientes con el sindrome urémico hemolítico
(SUH) y 95 convivientes para determinar la frecuencia de
infección con E. coli productor de verocitotoxina (VTEC),
utilizando distintos criterios diagnósticos. El grupo control
consistió en 34 niños con gastroenteritis aguda que no
desarrollaron SUH. Se obtuvieron muestras de materia fecal y suero
en el momento de internación del caso índice y 20 días
después. Los criterios diagnósticos utilizados fueron: a)
aislamiento de VTEC y su biotipificación, serotipificación y
caracterización de factores de virulencia; b) detección de
verocitotoxina libre en materia fecal (FVT); c) detección de
anticuerpos neutralizantes (NAbs) a-VT1 y a-VT2. Se aisló VTEC
O157:H7, biotipo D, VT2, susceptible a todos los antibióticos en
3/16 (18,7%) pacientes. En un paciente se detectaron 2 cepas VT2EC
de los serotipos O25: H2 y O157: H7. Se detectó FVT en 12/34
(35,3%) y VT-NAbs en 3/34 (8,8%) de los pacientes con SUH. El
23,5% de los casos tuvo de 1 a 6 convivientes con síntomas
gastrointestinales, la semana previa o simultáneamente. Los
hallazgos de laboratorio en los convivientes fueron los
siguientes: en 1/9 (11,1%) VT2EC, O157: H7, biotipo D; en 7/69
(10,1%) FVT y en 25/91 (27,5%) VT-NAbs. Ambos padres tuvieron la
misma tasa de infección (11.1% para FVT y 23.5% VT-NAbs) la cual
fue mayor que la determinada en hermanos (6.2% FVT y 23.5%
VT-NAbs) y abuelos (0% FVT y 18% VT-NAbs). Entre 16 pacientes sin
evidencias de infección, 3 presentaron convivientes con FVT y 13
con VT-NAbs. Diez (29,4%) de 34 niños del grupo control
presentaron evidencias de infección por VTEC.
Nuestros resultados muestran el carácter endémico de la
infección por VTEC, que los convivientes de los pacientes con SUH
están usualmente infectados y que la transmisión persona a
persona puede jugar un rol importante en la alta incidencia de la
enfermedad en nuestro país.
- Postal address: Dr. Marta Rivas, Instituto Nacional de
Microbiología Carlos G. Malbrán, Av.Vélez Sarsfield 563, 1281
Buenos Aires, Argentina.
Received: 4-X-1995 Accepted: 20-XII-1995
Infection by verocytotoxin-producing Escheri-chia coli (VTEC),
particularly strains of serotype O157: H7, can cause sporadic
cases and outbreaks of diarrhea, hemorrhagic colitis and hemolytic
uremic syndrome (HUS). Other E. coli serotypes (O5: NM; O26: H11;
O113: H21; O128: NM; O145: NM; among others) share a similar
pathogenic potential, and the group is called enterohemorrhagic E.
coli (EHEC).Although diarrhea usually resolves within a week,
5-10% of patients develop HUS, characterized by microan-giopathic
hemolytic anemia, thrombocytopenia and acute renal failure. The
case-fatality rate is 3-5%. Risk factors for developing HUS among
patients infected by E. coli O157: H7 include: age (children under
5 years and elderly people); weak or absent expression of P1 and
Pk antigens by red blood cells1, elevated leukocyte count, and use
of antimotility agents and antimicrobial therapy for diarrhea2.
Years before HUS emerged as an important pediatric disease in
North America, it was the major cause of acute renal failure in
infants in the cone of South America, being hyperendemic in
Argentina3 and endemic in Chile4.
The association between HUS and infection by VTEC, particularly
strains of serogroup O157, was first demonstrated in Canada in
1983-19855 and has been subsequently confirmed by numerous studies
conducted in different countries6, including Argentina7, 8.
Outbreaks of infection have been linked to the consumption of
contaminated water9 or foods of bovine origin, such as ground beef
and unpasteurized milk10, 11. Person-to-person transmission has
occurred among family members12, 14 in day care centers15, 16 and
in nursing homes17.
The aim of this study was to determine the frequency of infection
with VTEC in family members of children with HUS using several
- Material and Methods
Between January 1988 and December 1989 thirty-four patients with
HUS (19 males, 15 females; mean age 14.3 months ± 9.9 months)
were admitted to Hospital General de Niños "Pedro de
Elizalde" of Buenos Aires. Patients with HUS were defined as
previously healthy children who developed acute renal
insufficiency, thrombocytopenia and microangiopathic hemolytic
anemia, following an acute diarrheal prodromal illness. Bloody
diarrhea was observed in 91% of the HUS patients.
Ninety-five family members of children with HUS were enrolled in
this study. Family members were defined as persons who lived with
an HUS index case in the same house at least 5 hours daily.
Gastrointestinal tract symptons occurred in one to six household
contacts in 8 (23.5%) of the index cases, within the prior week or
simultaneously to admission to hospital of the HUS patient.
The control group consisted of thirty-four children with acute
gastroenteritis (19 males, 15 females, mean age 10.0 months ± 6.4
months), who did not develop HUS and who were admitted to the
hospital in the same period as the patient with HUS. Bloody
diarrhea was observed in 5.7% of the control cases.
Stool samples from HUS patients, their family members and control
children were collected for culture and for cytotoxin
determination after admission to hospital. Serum samples were
obtained on admission to the study and, when possible, 20 days
Three different diagnostic criteria were used to determine the
frequency of infection with VTEC:
a) VTEC strains isolation18, biotyping19, serotyping20 and
virulence factors characterization
- Ten lactose-fermenting colonies identified as E. coli were
selected from a primary MacConkey agar culture to detect non-O157
VTEC. Ten sorbitol-negative colonies from a Sorbitol-MacConkey
agar culture were picked to investigate O157 VTEC. Such isolates
were subcultured onto Trypticase Soy agar. Single colonies from
each subculture were inoculated into Penassay broth (Antibiotic
Medium N° 3, Difco Laboratories, Detroit) that was incubated
overnight at 37°C.
Bacterial supernatans and periplasmic cell extracts obtained by
polymyxin B sulfate treatment of bacterial pellets18 were assayed
for cytotoxic activity on Vero cells5.
E. coli virulence factors including cytotoxins, fimbrial adhesion
(EHEC factor), and attaching
and effacing factor (eae), were determined for all VTEC strains by
biotin-d-UTP labeled gene
probe under stringent conditions. Gene probes used were VT1 probe,
a BamH1 fragment of
1.1 - kbp cloned from the pJN37 -19 plasmid; VT2 probe, a
Smal-Pstl fragment of 0.84 - kbp cloned from the pNN110 - 18
plasmid; EHEC probe, a Hindlll fragment of 3.4 - kbp cloned from
the pCVD419 plasmid; eae probe, a Sall - Kpn1 fragment of 1 - kpb
cloned from pCVD43421.
Antibiotic susceptibility patterns were assayed by Kirby Bauer
method for ampicillin, carbenicillin, cephalotin, chloramphenicol,
streptomycin, gentamycin, nalidixic acid, colistin, and
tetracyclin22. E. coli strains were serotyped with specific
antisera for presence of different known O and H antigens by
b) Detection of specifically neutralizable free fecal VT (FVT)
- Equal volumes of the fecal specimen and PBS (0.01 M; pH 7.2)
were thoroughly mixed and then centrifuged. A bacteria - free
filtrate of the supernatant was assayed to VT activity. Cytotoxic
activity of fecal extracts was assayed on Vero cells (ATCC CCL81)
as previously described5. Specific toxin activity was evidenced by
neutralization test using VT1 and VT2 specific monoclonal
antibodies (MAb 13C4 and BC5BB12, respectively) provided by NA
Strockbine, Center for Infectious Diseases, Atlanta, Georgia, USA.
c) Serological test to detect VT-neutralizing antibodies (VT-NAbs)
was performed using 2
CD50 units of toxin preparations from reference E. coli strains
[C-984 (VT1); 1271-84 (VT2);
Fourfold or greater rises in titer were considered to indicate
The detection of VTEC, FVT and VT-NAbs in children with HUS,
in their family members and in control children with acute
gastroenteritis is shown in Tables 1, 2 and 3. VTEC O157: H7,
biotype D, VT2, susceptible to all the antibiotics tested was
found in 3 (18.7%) of 16 patients. Two VT2 - producing E. coli
belonging to serotypes O157: H7 and O25: H2 were isolated from one
VTEC O157: H7, biotype D, VT2, resistant to tetracyclin, was
detected in 1 (11,1%) of 9 family members (Table 1). VTEC strains
were not detected in the control group. There was no significant
difference (p>0.05) in the VTEC strains isolation between HUS
patients and their family members.
The long interval between onset of symptoms and stool collection
(9.8 days ± 6.9 days); and the antimicrobial therapy administered
to 76.5% of our HUS patients may have affected the VTEC strains
All O157: H7 E. coli strains were positive to VT2, fimbrial
adhesion and eae factors with DNA probes.
The O25: H2 E. coli strain produced VT2 as shown by cytotoxic and
neutralization assays on Vero cells and had a multiresistance
antibiotic pattern. This strain hybridized with the EHEC gene
probe but not with VT1, VT2 and eae gene probes.
FVT was detected in 12 (35.3%) of 34 patients; in 7 (10.1%) of 69
family members and in 1 (2.9%) of 34 control cases (Table 2).
Significant differences (p<0.01) were found in FVT detection
comparing HUS patients with their family members and with the
control group. FVT persists longer than VTEC strains in stool. In
one patient FVT was detected 33 days after onset of symptoms.
A fourfold or greater rise in VT-NAbs titer was found in 3 (8.8%)
of 34 patients. VT-NAbs were detected in 25 (27.5%) of 91 family
members; 7 with seroconversion to VT and 18 with ³ 1: 4 titers.
VT-NAbs were detected in 10 (52.6%) of 19 children of the control
group; 2 with seroconversion to VT and 8 with ³ 1: 4 titers
(Table 3). The prevalent VT type was VT2 in VTEC and FVT; and VT1
in VT-NAbs. These results are in agreement with previous reports
from several countries24, 27.
Both parents had the same infection rate according to fecal toxin
or serological data (11.1% FVT, 32% VT-NAbs), these were higher
than those detected in siblings (6.2% FVT, 23.5% VT-NAbs) and
grandparents (0% FVT, 18% VT-NAbs). Of 16 patients without
evidence of infection, 3 had family members with FVT and 13 with
VT-NAbs positive data. Different infection patterns in family
members of HUS patients in Argentina are shown in Figure 1.
Figure 1ª shows a child with FVT and seroconversion to VT and his
father with seroconversion to VT.
Figure 1b shows a girl with HUS and her mother with positive
results for FVT, VTEC and seroconversion to VT-NAbs.
Figure 1c shows a HUS patient without meeting any of the three
diagnostic criteria while her mother and brother presented
seroconversion to VT-NAbs and her father and grandmother, positive
serology to VT. This case shows the usefulness of evaluating
family members when it cannot be demonstrated VT - associated
illness in the index case. Figure 1d shows a HUS patient with
positive results for FVT and VTEC and his father with FVT.
Figure 1e shows a HUS patient without evidence of VT - associated
infection but her parents, siblings and grandmother presented
positive serology to VT indicating the prior exposition to VTEC of
the whole family.
Figure 1f represents a HUS patient with FVT, her mother who had
positive serology to VT and her father with seroconversion to VT.
Since Gasser's early description28, and due to a rise in the
incidence of HUS, several etiologic hypotheses have been
The association between VT - producing organisms and idiopathic
HUS, as demonstrated by Karmali et al.5 made etiologic diagnosis
possible. However, for this instance, multiple assays are
required: detection of FVT, isolation and characterization of VTEC
and serologic assays for presence and/or seroconversion to VT-NAbs
and to lipopolysaccharide (LPS) antibodies29.
HUS bears a prodromic period, ranging from 6 to 10 days and is
generally characterized by bloody diarrhea. E. coli O157: H7 is
easily isolated from feces in the first week after symptoms
appear; afterwards if becomes difficult to isolate15. DNA probes
to the VT genes, used to screen hundreds of E. coli colonies per
isolation plate, provide a sensitive way to detect the small
amount of organisms present late in infection30. Methods of
detecting FVT have the advantage of detecting cytotoxins produced
by any VTEC in the abscence of living organisms5, 31.
Cumulative evidence of VTEC infection was found in 13 (38.2%) of
34 HUS patients and in 30 (31.6%) of 95 family members using
microbiological and serological detection methods. However, 16/21
(76.2%) patients who met no diagnostic criteria had, at least, one
family member with evidence of infection.
Our work has demonstrated that the use of several diagnostic
criteria increases the possibility of establishing an association
between HUS and VTEC infection. In addition to this, evaluation
and analysis of family members of HUS patients are useful for an
accurate and early diagnosis, in order to determine the
appropriate therapy to prescribe. Evidence of VTEC infection could
be under-stimated because LPS serology was not performed in this
work. Further studies including investigation of serological
response to LPS are necessary to assess the real frequency of
O157:H7 infection in our country. The occurrence of most HUS cases
after a diarrheal prodrome, and the tendency for cases to occur in
clusters within communities and families led many researchers to
postulate several routes of transmission.
Outbreaks might be originated by simultaneous exposure of several
individuals to a common foodborne source. In sporadic cases there
might exist a primary infection, strongly associated with the
ingestion of contaminated food or water; secondary
person-to-person transmission may occur in small communities or
families. Familial outbreaks of HUS13, 14, and bloody diarrhea in
siblings of patients12 have been reported, even though they have
not been numerous.
A higher incidence of HUS has been reported in Canadá32 in
children who have a father who is either a physician or a lawyer,
attributed to their parent's habit of eating in fast-food
restaurants for reasons of professional duties. Besides, children
might acquire the infection in day care centers33 or
kindergartens. We have found a similar, and higher rate of
infection in parents than in siblings and grandparents.
Furthermore, Rowe et al34 have shown that patients with HUS were
more exposed to family or non-family contacts with gastroenteritis
than healthy controls, this implies that person-to-person
transmission could be an important factor in the development of
HUS in children. It has been demonstrated that 20% of Argentinean
healthy children belonging to the risk group have VT-NAbs8. Also
we found VT-neutralizing activity, without seroconversion, in
19.8% of the family members and in 42.1% of children with acute
gastroenteritis. These results confirm the wide dissemination of
VTEC in our country.
In conclusion, this report shows that VT2-producing E. coli
strains, mainly of serogroup O157, cause sporadic cases of HUS and
that family members are usually infected symptomatically or
asymptomatically with VTEC; therefore person-to-person
transmission might play an important role in the high incidence of
HUS in Argentina, with an annual rate of 7.8/100000 children under
5 years of age.
As VTEC has become an important emerging pathogen lately, the need
for systematic research must be stressed, in order to determine
its incidence as a diarrheal agent in patients and their family
members; surveillance in cattle should be performed as a way of
identifying reservoirs and routes of transmission to break the
epidemiologic chain. Laboratories must use Sorbitol-MacConkey agar
for the detection of VTEC O157 and determine if non-O157 strains
are VT producers by means of Enzyme Linked Immunosorbent Assay,
DNA probe hybridization; PCR techniques and/or specific
cytotoxicity assay in tissue cultures. Since therapy is limited
and only supportive, public heath efforts must be directed to the
prevention of infection and disease.
Acknowledgments: The technical assistance of Ana Garbini,
German Chillemi, Mónica Prieto and Fabian Pardon is acknowledged.
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- TABLE 1.- Detection of verocytotoxin-producing Escherichia coli
in children with Hemolytic
Uremic Sindrome (HUS) and their family members
Study N° with Type of VT Serotype Biotype Antibiotic
Population VTEC (%) Resistance Pattern
- HUS Patients
(n = 16) 3 (18.7)+ VT2 O157: H7 ++ D -
O25: H2++ Am-Cb-Cf-C-Gm-St
(n = 9) 1 (11.1)+ VT2 O157: H7 D Te
VTEC: Verocytotoxin-producing Escherichia coli; Am: Ampicillin;
Cb: Carbenicillin; Cf:
Cephalotin; C: Chloramphenicol; Gm: Gentamycin; St: Streptomycin;
Te: Tetracyclin. +: P>0.05 (Fisher's Exact Test).++: Two VT2 -
Producing Escherichia coli isolated from one patient.
- TABLE 2.- Detection of free fecal verocytotoxin (FVT) in
children with Hemolytic Uremic
Syndrome (HUS), in their family members and in control children
with acute gastroenteritis
Study N° with FVT Type of Verocytotoxin
Population (%) VT1 VT2 VT1-VT2
- HUS Patients 12 (35.3)*+ 2 10 0
(n = 34)
Family Members 7 (10.1)* 0 5 2
(n = 69)
Control Children 1 (2.9)+ 0 0 1
(n = 34)
- *+ P < 0.01 (c2 test with 2-tailed Yates's correction).
- TABLE 3.- Detection of Verocytotoxin neutralizing antibodies
(VT-NAbs) in children with
Hemolytic Uremic Syndrome (HUS) in their family members and in
control children with acute
Serological Data HUS Patients Family Members Control Children
(n = 34) (n = 91) (n = 19)
- Presence of VT-NAbs: Titer ³ 1: 4 against:
VT1 0 5 7
VT2 0 6 0
VT1 - VT2 0 7 1
0 (0.0%) 18 (19.8%) 8 (42.1%)
VT1 1 3 1
VT2 1 1 0
VT1 - VT2 1 3 1
3 (8.8%) 7 (7.7%) 2 (10.5%)
Total 3 (8.8%)*+ 25 (27.5%)* 10 (52.6%)+
- · P < 0.05 (c2 test with 2-tailed Yates's correction). + P
< 0.01 (Fisher's Exact Test).
- Fig. 1.- Evidence of infection with VT-producing Escherichia
coli in family members of six children with Hemolytic Uremic
Seroconversion Positive Serology