These are described in detail in the Methods section.
ReviewDiagnosis of Clostridium difficile infection by toxin detection kits: a systematic review
Introduction
Clostridium difficile-associated diarrhoea (CDAD) is life threatening, with an attributable mortality of 6–15%.1 CDAD has become more common and may also be increasing in severity.2 There is an urgent need to control the spread of this infection in hospitals, where it frequently afflicts the most vulnerable patients who receive antibiotic therapies for complicated infections. Public concern about C difficile has increased in recent years, and in the UK, national reporting of CDAD is mandatory,3, 4 with a commitment to reduce prevalence of C difficile infections being part of government policy.5 A proportion of funding to acute health-care trusts in England and Wales is dependent on reductions in the number of reported C difficile cases according to a standard formula.6
Accurate diagnosis of CDAD is crucial in the management of individual patients, in controlling its spread, and in the generation of reliable surveillance data; such data allow reliable tracking of the infection, comparisons between institutions, and assessment of the efficacy of interventions. Intrinsic test limitations can undermine these aims in various ways. Tests of limited sensitivity will obviously miss some patients, who may then receive suboptimum care and be ineffectively isolated, thus leading to further cases of CDAD. The consequences of limitations in specificity are perhaps less well appreciated: less specific tests will generate more false-positive cases in patients, who may subsequently have necessary antibiotics curtailed, and receive unnecessary treatment for CDAD. Such patients might then be nursed in wards or bays with genuine cases, putting them at increased risk of CDAD. Limitations in either sensitivity or specificity may undermine the reliability of surveillance data and their conclusions. An understanding of the performance characteristics of the tests in use should help to inform professionals involved in the management of CDAD, both in terms of patient care and public-health policy.
Since the identification of toxin-producing C difficile as a cause of antibiotic-associated diarrhoea in the 1970s, several diagnostic methods have been used to detect infection. Most tests rely on detection of C difficile toxin (CDT) A with or without CDT B. The reference method for the detection of C difficile is cytotoxicity of stool in cell culture that may be neutralised by antisera.7, 8 This test takes 2–3 days to complete. Some researchers recommend the additional culture of stool for C difficile with confirmation of toxin production, because this may improve sensitivity.1, 9
Over the past two decades, more rapid detection methods have been developed for the detection of CDT, although early tests detected CDT A only. However, after the recognition that some isolates only produce CDT B, combined assays were introduced, and most currently available commercial assays detect both toxins. Other detection methods for C difficile, such as PCR,10, 11 or detection of the presence of glutamate dehydrogenase,11, 12, 13 are also available. Current UK guidance recommends that laboratories should test specimens by either an enzyme immunoassay (EIA) that detects both CDT A and B, or by a neutralised cell cytotoxicity assay.14 New guidance in the UK is currently under consultation, but testing strategies have not changed.15 The current EIAs used for surveillance in the UK are thought to provide satisfactory sensitivity and specificity, provided that an assay that detects both CDT A and B is used.14 However, no review of performance characteristics of these tests has been done, although the performance characteristics of assays in general has been extensively reviewed elsewhere.16
We assessed the value and limitations of several widely used commercially available kits for diagnosis of CDAD (for CDT A and B) in the UK, with particular respect to the diagnosis of nosocomial disease. This analysis was designed to compare the sensitivity and specificity of these immunoassays.
Section snippets
Performance characteristics of tests
The properties of a test independent of the prevalence of a condition are its sensitivity (true positives/[true positives+false negatives]) and specificity (true negatives/[true negatives+false positives]). Because the chance of misidentifying negative cases as false positives increases with a decline in specificity, it is often useful to consider false positivity (1–specificity). For example, a test with a specificity of 97% (false positivity of 3%) will wrongly identify 30 false-positive
Results
The results of the two searches (articles and abstracts) are summarised in figure 2. Some of the included studies compared more than one assay with a reference standard, giving a total of 28 comparisons of toxin detection kits with reference standards. Summaries of the studies included are shown in table 1.
No significant difference in sensitivity or specificity was attributable to the reference method used in the study (sensitivity p=0·45, specificity p=0·36), and therefore studies were
Discussion
Because there was heterogeneity in sensitivity and specificity of data in these studies, we are unable to provide mean estimates for sensitivity and specificity. Nevertheless, reasons for this heterogeneity are of interest and could include geographic variation either in patient populations or in C difficile isolates that give rise to observed differences in assessment of diagnostic performance of these assays. There may also be differences in the laboratory processing of samples during these
Search strategy and selection criteria
References (41)
- et al.
Performance of TechLab C. DIFF QUIK CHEK and TechLab C. DIFFICILE TOX A/B II for the detection of Clostridium difficile in stool samples
Diagn Microbiol Infect Dis
(2007) - et al.
The diagnostic odds ratio: a single indicator of test performance
J Clin Epidemiol
(2003) - et al.
A European survey of diagnostic methods and testing protocols for Clostridium difficile
Clin Microbiol Infect
(2003) - et al.
The diagnosis of Clostridium difficile-associated diarrhea: comparison of Triage C difficile panel, EIA for Tox A/B and cytotoxin assays
Diagn Microbiol Infect Dis
(2002) - et al.
Clinical recognition and diagnosis of Clostridium difficile infection
Clin Infect Dis
(2008) - et al.
Measures to control and prevent Clostridium difficile infection
Clin Infect Dis
(2008) Changes to the mandatory healthcare associated infection surveillance system for Clostridium difficile infection (CDI) from 1st January 2008 [PL CMO (2008)1]
Mandatory surveillance of orthopaedic surgical site infection and C difficile associated diarrhoea
Hansard daily report. Clostridium difficile. Statement by the Secretary of State for Health (Alan Johnson), 15 Oct 2007, column 557
The standard NHS contract for acute hospital services (2007) [schedule 3, part 1, para 9]
Clinical practice. Antibiotic-associated diarrhea
N Engl J Med
Clostridium difficile-associated diarrhea in adults
CMAJ
Selective and differential medium for isolation of Clostridium difficile
J Clin Microbiol
Evaluation of real-time PCR and conventional diagnostic methods for the detection of Clostridium difficile-associated diarrhoea in a prospective multicentre study
J Med Microbiol
Multiplex PCR targeting tpi (triose phosphate isomerase), tcdA (toxin A), and tcdB (toxin B) genes for toxigenic culture of Clostridium difficile
J Clin Microbiol
Performance of the TechLab C DIFF CHEK-60 enzyme immunoassay (EIA) in combination with the C difficile Tox A/B II EIA kit, the Triage C difficile panel immunoassay, and a cytotoxin assay for diagnosis of Clostridium difficile-associated diarrhea
J Clin Microbiol
Report to the Department of Health
Clostridium difficile infection: how to deal with the problem—a board to ward approach
Diagnostic tests. 1: sensitivity and specificity
BMJ
Cochrane handbook for systematic reviews of interventions 4.2.6 [updated September, 2006]
Cited by (289)
One-day prevalence of asymptomatic carriage of toxigenic and non-toxigenic Clostridioides difficile in 10 French hospitals
2022, Journal of Hospital InfectionJapanese Clinical Practice Guidelines for Management of Clostridioides (Clostridium) difficile infection
2022, Journal of Infection and ChemotherapyCurrent challenges and advancements towards discovery and resistance of antibiotics
2022, Journal of Molecular StructureAcute Onset Rectal Prolapse with a Pseudomembranous Covering
2019, Journal of Pediatrics