ArticlesUnderdiagnosis of Clostridium difficile across Europe: the European, multicentre, prospective, biannual, point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea (EUCLID)
Introduction
Clostridium difficile is the major infective cause of nosocomial diarrhoea in developed countries. Rapid and accurate diagnosis is important to optimise patients' care and infection prevention.1 An increase has been recorded in the measured incidence of C difficile infection in countries with surveillance programmes, and a striking shift in epidemiology has been noted over the past decade.2, 3, 4 In Europe, C difficile is the most commonly reported pathogen associated with hospital-associated gastrointestinal disease,5 whereas in the USA it was the most commonly reported health-care associated microorganism in a survey of 183 hospitals in 2010.6
In the most recent European epidemiological survey of C difficile infection (2008), the incidence in 97 hospitals across 29 countries varied widely (range 0·0–36·3 per 10 000 patient bed-days per hospital; weighted mean 4·1).7 The reasons for this large variation are unclear. Predisposing factors to C difficile infection, including increasing age, comorbidities, and use of broad-spectrum antibiotics, might be similar across Europe, although exposure to different C difficile strains probably varies.1, 8 Notably, a more than 40-fold variation in testing frequency for C difficile infection was recorded across European countries, and a correlation between testing rate and reported infection rate was identified.7 Suboptimum case ascertainment, either because of inadequate laboratory diagnosis or absence of clinical suspicion, means that the true burden of C difficile infection is unclear.9, 10, 11, 12 In a point-prevalence study done in Spain, 66% of patients with C difficile infection on one day were undiagnosed or misdiagnosed because of either a lack of clinical suspicion (47%) or insufficient laboratory testing (19%).9 Optimum laboratory diagnosis of C difficile infection depends on testing relevant patients at the correct time with suitable tests. Importantly, detection of C difficile toxin in patients' faecal samples, compared with identification of toxigenic C difficile (strains that either produce toxin in vitro or have toxin genes present), correlates with disease severity and mortality.12, 13 To improve the suboptimum sensitivity of commercially available toxin detection assays, two-stage laboratory diagnosis, including a sensitive C difficile screening test followed by a C difficile toxin assay, is recommended.1, 12 Nevertheless, a questionnaire-based study in 125 European laboratories in 2010 showed wide variation in use of C difficile infection diagnostic methods, with a quarter still using one assay.14 Notably, however, such data do not ascertain the true extent of missed C difficile infection diagnoses.
We aimed to investigate the underdiagnosis of C difficile infection in hospitals in 20 European countries by asking participating hospitals to forward inpatients' diarrhoeal faecal samples to a national coordinating laboratory for C difficile infection testing by the study reference method, irrespective of whether microbiology tests had been requested or done locally, on 2 days—one day in winter (December, 2012, or January, 2013) and one day in the summer (July, 2013, or August, 2013). Participating hospitals were also asked to complete a study questionnaire about C difficile infection testing.
Section snippets
Study design
We did a European, multicentre, prospective, biannual, point-prevalence study of C difficile infection in patients admitted with diarrhoea (the EUCLID study). Our study followed the design of a previous point-prevalence study done in Spain.9 We coordinated the EUCLID study from the European coordinating laboratory in Leeds, UK. We included 20 countries from Europe and selected a national coordinating laboratory for every country. National coordinators selected participating hospitals to cover
Role of the funding source
The EUCLID study was initiated and wholly supported financially by Astellas Pharmaceuticals Europe. The funder contributed to study design but did not contribute to data collection, data analysis, data interpretation, or writing of the report. Astellas Pharma Europe reviewed the report before submission, in line with the terms of the funding agreement. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication.
Results
The EUCLID study took place between December, 2012, and August, 2013, and used data obtained between September, 2011, and August, 2013. 482 participating hospitals from 20 European countries were included in the study (94·3% of the target number of hospitals). 3923 faecal samples were submitted on one sampling day during the winter testing period (December, 2012, or January, 2013) and 3389 samples were submitted on one sampling day in the summer period (July, 2013, or August, 2013). 15 samples
Discussion
Findings of the EUCLID study show that C difficile infection is underdiagnosed across Europe, driven mainly by an absence of clinical suspicion and, hence, no local testing for C difficile infection. Underdiagnosis was compounded by misdiagnosis related to suboptimum methods. On one day across Europe, a mean of 74 inpatients with C difficile infection were not tested for C difficile infection by their hospital; on average a further 34 patients had a false-negative result at the local hospital (
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