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Journal of Clinical Microbiology, July 1998, p. 2076-2080, Vol. 36, No. 7
0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Survey of Incidence of Clostridium
difficile Infection in Canadian Hospitals and Diagnostic
Approaches
Michelle J.
Alfa,1,2,*
Tim
Du,1 and
Gabi
Beda2
Department of Medical Microbiology,
University of Manitoba,1 and
St.
Boniface General Hospital,2 Winnipeg,
Manitoba, Canada
Received 26 September 1997/Returned for modification 19 November
1997/Accepted 8 April 1998
 |
ABSTRACT |
A questionnaire relating to Clostridium difficile
disease incidence and diagnostic practices was sent to 380 Canadian
hospitals (all with >50 beds). The national questionnaire response
rate was 63%. In-house testing was performed in 17.6, 61.5, and 74.2% of the hospitals with <300, 300 to 500, and >500 beds, respectively. The average test positivity rates were 17.2, 15.3, and 13.2% for hospitals with <300, 300 to 500, and >500 beds, respectively. The
average disease incidences were 23.5, 30.8, and 40.3 cases per 100,000 patient days in the hospitals with <300, 300 to 500, and >500 beds,
respectively. In the 81 hospitals where in-house testing was performed,
cytotoxin testing utilizing tissue culture was most common (44.4%),
followed by enzyme-linked immunosorbent assay (38.3%), culture for
toxigenic C. difficile (32.1%), and latex agglutination
(13.6%). The clinical criteria for C. difficile testing
were variable, with 85% of hospitals indicating that a test was done
automatically if ordered by a doctor. Our results show that C. difficile-associated diarrhea is a major problem in hospitals
with 
200 beds. Despite a lower disease incidence in smaller
hospitals, there was a higher diagnostic test positivity rate. This may
reflect the preference of smaller hospitals for culture and latex
agglutination tests.
| |
TEXT |
Clostridium difficile is
an opportunistic, gram-positive anaerobe whose pathogenicity is
associated with the production of two exotoxins: toxin A (enterotoxin)
and toxin B (cytotoxin) (42). Toxin A is a potent
enterotoxin with cytotoxic activity. When injected into rabbit ileal
loops, toxin A is capable of inducing epithelial damage, hemorrhage,
and fluid secretion (32, 42). Toxin B, although incapable of
mucosal damage, is a 1,000-fold more potent cytotoxin than toxin A. Picogram quantities of toxin B are sufficient to cause cell rounding
(10, 16). Toxigenic strains of C. difficile are
known to cause various clinical symptoms, ranging from asymptomatic
colonization to life-threatening pseudomembranous colitis
(3). Asymptomatic colonization is found in ~3 to 4% of
healthy adults (25) but in as many as 15 to 75% of neonates (30, 39).
Nosocomial acquisition and transmission of C. difficile have
been well documented (19, 25, 28, 33, 41). Outbreaks of
C. difficile-associated diarrhea (CAD) have occurred on
geriatric wards (6), orthopedic wards (34),
medical wards (26), surgical wards (43), and
long-term care facilities (5). The incidence rate of
nosocomial CAD may vary with hospital populations and is influenced by
the presence of predisposing factors, such as increased patient age,
type and duration of antimicrobial therapy, severity of underlying
illness(es), and length of hospital stay (1, 5, 8, 31). As
the most frequently isolated nosocomial gastrointestinal pathogen,
C. difficile is believed to be the leading cause of
infectious nosocomial diarrhea, accounting for 20 to 45% of all cases
(21, 24, 33). Despite the prevalence of the disease, the
mechanism(s) of nosocomial acquisition or transmission is still not
fully understood. The environment (28, 36), cross-infection
between patients (11, 23), and carriage by hospital
employees have all been cited as plausible sources of infection.
In the United States, nosocomial infections affect over 4 million
patients annually (9, 22). Aside from the morbidity and
mortality rates associated with nosocomial infections, there is also a
significant financial drain on the health care system. One study
modestly estimated the cost of treating a single CAD infection to be in
excess of £4,000 (44). Although C. difficile is
a significant nosocomial pathogen, little documentation is available to
reflect disease prevalence or the diagnostic testing methods employed
by Canadian hospitals.
The study described here was undertaken to assess current testing
methods and testing criteria for C. difficile, as well as to
survey CAD incidence rates across Canada. Data collected in the survey
was intended to help hospitals compare their CAD incidence rates and
diagnostic standards of practice with those of other, similar-size
institutions.
Participants.
A questionnaire requesting information on
hospital size (number of beds), hospital type, disease incidence, and
diagnostic test methods was distributed in 1995 to 380 hospitals and
provincial laboratories across Canada. Participants were instructed to
complete the questionnaire by using their most recent 12 consecutive
months of data. Statistical analysis was done by using Graphpad InStat (Graphpad Program Software, San Diego, Calif.). A follow-up telephone call was made 1.5 months after distribution of the questionnaire to
optimize compliance and to validate the data. Those laboratories which
participated in the survey were sent a summary report of collated data
from all of the other Canadian hospitals surveyed. Private laboratories
were not included in the survey.
Classification of hospitals.
Survey participants were asked to
classify their hospitals based on the following categories: tertiary
care, hospital with an intensive care unit and affiliation with medical
teaching; general medicine, hospital with an intensive care unit but no affiliation with medical teaching; community medicine, hospital with no
intensive care unit and no affiliation with medical teaching; geriatric, hospital providing primary care for the elderly; other, any
institution which does not fit into any of the other four categories.
In our tertiary care hospital (a teaching hospital with approximately
700 beds in 1994), the CAD incidence rate was 40.5/100,000 patient days
in 1994. Review of the overall isolation statistics for 1996 showed
that CAD was a significant cause, accounting for about 44% of the 126 patients who were subjected to some form of isolation precautions
(Table 1). Patient morbidity and
mortality and increased costs associated with controlling this
infection further support the value of determining national data on CAD as a nosocomial disease.
Completed questionnaires were received from 238 of the 380 institutions
surveyed (63% response rate). Because there was a
telephone follow-up,
we feel that the survey was an accurate representation
of
C. difficile testing and disease incidence across Canada.
Stratification of data based on hospital size suggested that smaller
hospitals (<300 beds) sent most of their stool specimens
off site for
diagnostic testing (Fig.
1). In-house
testing was
performed in 17.6, 61.5, and 74.2% of the hospitals with
<300,
300 to 500, and >500 beds, respectively. There was a general
trend
for larger hospitals to submit more specimens for
C. difficile testing (Fig.
1). Despite some diversity in the number
of specimens
submitted each year for testing, the diagnostic test
positivity
rate was greatest in smaller hospitals. The average test
positivity
rates were 17.2, 15.3, and 13.2% for hospitals with <300,
300
to 500, and >500 beds, respectively. The average test positivity
rate was greatest for hospitals having 100 to 199 beds (18.6%)
and
least for hospitals having 500 to 599 beds (10.3%) (Fig.
1).
Since
many hospitals sent their specimens to provincial laboratories,
two
provincial laboratories were sent surveys to obtain information
on
diagnostic test methods. These centers processed an average
of 2,879 specimens per year, with a test positivity rate of 20.4%
(data not
shown).
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FIG. 1.
Specimen processing and test positivity rates stratified
according to hospital size (number of beds). A total of 81 hospitals
performed in-house testing. Some hospitals referred specimens out for
diagnostic testing. Data on the volume of specimens processed and test
positivity rates was not provided by all hospitals.
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|
Analysis of data based on patient populations also showed evidence of
diversity in test positivity rates. Hospitals classified
under tertiary
care, community, and general medicine had average
test positivity rates
of about 15%. Geriatric medicine and other
types of centers had lower
test positivity rates. Furthermore,
the incidence of CAD per 100,000 patient days or per 1,000 patient
admissions was highest in tertiary
care hospitals, followed by
general medicine hospitals, community
hospitals, geriatric hospitals,
and other centers. A similar
correlation between hospital size
and disease incidence was also seen
when data was stratified based
on hospital size (Fig.
2).
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FIG. 2.
C. difficile-associated diarrhea rates. Data
is stratified according to hospital size (number of beds). C. difficile-associated diarrhea rates are expressed as the number of
cases per 100,000 patient days and per 1,000 patient admissions.
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|
The provincial CAD incidence rates across Canada, for all hospitals
with
200 beds, is shown in Fig.
3. With
the exception
of Nova Scotia, which had very few hospitals reporting
incidence
data, Ontario and Alberta seemed to have the highest CAD
incidence
rates.
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FIG. 3.
National C. difficile disease incidence
rates. Asterisks indicate that data on disease incidence from hospitals
having fewer than 200 beds were excluded. Data on disease incidence was
not available for Newfoundland. Data on disease incidence per 100,000 patient days was not available for Saskatchewan. The numbers above the
bars are the numbers of respondents.
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|
Of the 81 centers which performed in-house testing, the most commonly
employed diagnostic test method for CAD was cytotoxin
testing using
tissue culture (44.4%), followed by enzyme-linked
immunosorbent assay
(ELISA) (38.3%). Culture of
C. difficile was
performed by
26 (32.1%) of the 81 hospitals doing in-house testing.
Although
culture was utilized by a large percentage of the hospitals,
only eight
(9.9%) centers used it as the sole method. Subsequent
verification of
toxin production was also performed by five of
these eight centers
employing culture. Latex agglutination was
utilized by 11 (13.6%) of
the 81 hospitals surveyed. Of the 11
hospitals utilizing this method,
only 4 (4.9% of the 81 hospitals)
used it as the sole method of
testing.
Stratification of testing methods based on hospital size showed that
smaller hospitals (<300 beds) tended to use easier and
more readily
available methods, such as culture, ELISA, and latex
agglutination
(Table
2). Interestingly, 3 (7.5%) of 40 hospitals
that had between 300 and 500 beds used latex agglutination as
the sole method of diagnostic testing. When methods were stratified
based on hospital type, it was apparent that general medicine
hospitals
(100- to 200-bed median) used ELISA the most, followed
by the cytotoxin
test (Fig.
4). In tertiary care hospitals
(400-
to 500-bed median), cytotoxin testing was the preferred method,
followed by ELISA (Fig.
4).
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FIG. 4.
C. difficile testing methods for tertiary
care versus general medicine hospitals. Responses were obtained from 43 tertiary care hospitals and 31 general medicine hospitals.
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|
The criteria for
C. difficile testing were also assessed at
the different institutions surveyed. A summary of the questions
asked
is provided in Table
3. Data from the
survey showed a great
diversity in the approaches taken by hospitals
regarding the clinical
criteria that had to be met before a
C. difficile diagnostic test
was performed. Of the institutions which
responded, 85% said the
assay was done automatically if ordered by a
doctor.
Hospital-acquired infections are important concerns for many health
care institutions and contribute significantly to patient
morbidity and
mortality, as well as to the costs associated with
prolonged patient
stays and care. Despite some geographical variation,
diarrhea is
considered to account for 1 to 14% of all nosocomial
infections
throughout the world (
24,
45). Surveillance data
from one
Turkish hospital indicated that nosocomial diarrhea was
ranked fifth
and comprised about 7% of all nosocomial infections
according to
Centers for Disease Control 1988 criteria (
17).
Furthermore,
in this hospital,
C. difficile was responsible for
22.2% of
the nosocomial diarrhea cases that occurred within a
general medicine
ward (
40). There is good evidence that routine
enteric
cultures should not be done for patients hospitalized
for 3 or more
days (
18). Our data indicated that 29% of the
hospitals
surveyed have not yet adopted this practice (Table
3).
Disease severity and patient suffering can be reduced if proper
treatment and intervention strategies are made available.
These factors
are influenced by rapid, reliable, and accurate
diagnosis of CAD. The
currently available diagnostic tests include
colonoscopy, tissue
culture cytotoxin assay, stool culture for
toxigenic
C. difficile, latex agglutination, counterimmunoelectrophoresis,
ELISA, and molecular diagnostics such PCR (
35). Results from
our survey indicate that for diagnostic testing, cytotoxin testing
and
ELISA predominate, followed by culture for toxigenic
C. difficile and latex agglutination.
Despite the technical nature of the "gold standard" (
35)
tissue culture cytotoxin assay, this was the most prevalent method
used
for the diagnosis of CAD, with 44.4% of in-house testing
facilities
employing the assay. In larger institutions, such as
tertiary care
hospitals, cytotoxin testing use was at 58%. Test
rapidity (2.5 to
3.5 h) and ease of performance due to automation
likely account
for the ELISA being the second most common (38.3%)
in-house diagnostic
test. Several investigators (
2,
7,
12,
13,
15,
35) have
found ELISA sensitivity to approach or
equal that of cytotoxin assays
(87 to 98%). Although culturing
is considered to be the most sensitive
assay for
C. difficile (
35), a subsequent
cytotoxin assay must be performed to determine
if the isolate is
toxigenic, making the procedure very time consuming
and labor
intensive. The advantage of the culturing method is
that the organism
is available for epidemiological typing, which
may be beneficial when
outbreaks occur. In our survey, culturing
was prevalent, with 32.1% of
the hospitals that did in-house testing
employing the technique;
however, only eight (9.9%) centers employed
it as a stand-alone test.
Five of these eight centers also performed
subsequent cytotoxin assays
to confirm that the organisms were
toxigenic. The latex agglutination
test, although rapid and easy
to perform, is not recommended as a sole
diagnostic test, since
it is not specific for toxigenic
C. difficile and frequently results
in false-positive reactions
(
27,
29). Our survey indicated
that most hospitals are aware
of this, as only four (4.9%) centers
used it as the sole method of
testing. When we performed a telephone
follow-up, we found that
subsequent to receiving our survey summary
report (1 year later), all
of the centers using latex agglutination
as the sole test method had
switched over to ELISA technology.
Similarly, the centers previously
employing culture as the stand-alone
test now employ cytotoxin assays
and ELISA.
Asymptomatic carriage of toxigenic strains of
C. difficile
makes it critical that diagnostic testing be done only for symptomatic
patients. Data from Table
3 indicates that most centers do not
use
stringent criteria when accepting stools submitted for CAD
testing.
Testing of stool from patients without clinical indications
of CAD is
not only an unnecessary cost but may also complicate
patient care if
unnecessary antibiotic treatment is given. Testing
for CAD should be
based not on length of hospitalization but,
rather, on the presence of
clinically significant diarrhea (
29)
(e.g., four or more
bowel movements per day for 3 or more days)
with a history of
antibiotic therapy or the presence of acute
abdominal syndrome with
little or no diarrhea (
20). Communication
of these criteria
to clinicians who order tests for CAD is important.
In our study, 54 (30%) of 182 respondents said they received stool
samples for
cytotoxin testing on patients less than 1 year old.
Although there are
rare instances in which toxin B in children
less than 1 year old is
significant (
38), up to 50% of neonates
may be colonized
with toxigenic strains without clinical symptoms
(
4,
14,
18). It is important that laboratory workers performing
tests on
children less that 1 year old be sure that the clinicians
ordering this
test are aware of the high rate of asymptomatic
carriage within the
neonatal population. It has been reported
that 35% of patients with
cystic fibrosis can also be asymptomatic
carriers of toxigenic
C. difficile (
37).
The results of our survey indicated higher test positivity rates in
smaller hospitals. Since smaller hospitals were more likely
to use
easier and more readily available methods, such as latex
agglutination,
culturing, and ELISA, higher test positivity rates
may have been
reflective of false-positive reactions, particularly
for the latex
agglutination test. Variations in test positivity
rates may also have
been influenced by the number of repeat specimens
taken from an
individual patient or by stool samples taken from
patients without
clinically significant diarrhea. Data from the
survey showed a higher
disease incidence in larger hospitals.
Since severe underlying
illnesses are predisposing factors for
CAD, larger centers with larger
critically ill patient populations
should be expected to have higher
disease incidence rates.
In summary,
C. difficile is an important nosocomial pathogen
in Canada, with a national average CAD incidence of 36.18/100,000
patient days or 3.06/1,000 admissions in hospitals with
200 beds.
Diversity in test positivity rates may have been influenced by
testing
criteria or choice of testing method. The use of latex
agglutination as
a sole diagnostic test is not recommended. Implementation
of
standardized clinical criteria for
C. difficile testing
should
be considered, as it would increase the reliability and accuracy
of diagnosis.
| |
ACKNOWLEDGMENTS |
The assistance of Nancy Olson in data collection and the
translation of the questionnaire into French by Pat DeGagne are
acknowledged.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Microbiology,
St. Boniface General Hospital, 409 Tache Ave., Winnipeg, MB R2H 2A6, Canada. Phone: (204) 237-2105. Fax: (204) 237-6065. E-mail:
malfa{at}cc.umanitoba.ca.
| |
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Journal of Clinical Microbiology, July 1998, p. 2076-2080, Vol. 36, No. 7
0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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