CDAD is an infection of great clinical importance in hospitalised patients the incidence of which has increased markedly over the past 10 years4
). In our hospital, the number of patients with C difficile
infection increased from 29 in 1993 to 210 in 1995. A retrospective analysis of the case notes of 110 patients in 1995 showed that the first stool test for C difficile
cytotoxin was negative in a significant minority of patients (17%), leading to a significant delay (8.2 (6.6) days) before the second diagnostic stool sample allowed appropriate treatment and infection control measures to be undertaken.14
It is well recognised that the sensitivity of neither the stool cytotoxicity test nor the ELISA tests is 100%.12,13,18
As endoscopic examination can reveal characteristic appearances of pseudomembranous colitis, our aim was to prospectively investigate the role of flexible sigmoidoscopy, at the bedside, in the diagnosis and management of CDAD. Flexible, rather than rigid, sigmoidoscopy was used because rectal sparing can occur in some patients with pseudomembranous colitis19
(which was confirmed in 10.7% of patients in our study). In order to determine the role of flexible sigmoidoscopy, it was felt that a “head to head” comparison with the stool cytotoxin test would be appropriate because, to our knowledge, such a prospective study has not been previously performed. Of a total of 136 patients with CDAD, in 73 (53.7%) the diagnosis had already been made (and treatment initiated) following a positive stool test for C difficile
cytotoxin (prior to our seeing the patient). Review of the notes and results of these patients showed that in 36%, the first stool test for C difficile
cytotoxin had been negative and the diagnosis of CDAD was not established until a second stool sample (sent by the team looking after the patient) was sent a mean 13.1 (2.3) days after the first. Following diagnosis of CDAD, these patients were subsequently followed up by us until resolution of diarrhoea.
A total of 179 patients with persistent diarrhoea of unknown cause entered that part of the study in which flexible sigmoidoscopy was compared with the stool C difficile
cytotoxin test. Sixty three patients in this group were considered to have CDAD, with flexible sigmoidoscopy showing pseudomembranes in 56. In those with pseudomembranous colitis, the stool C difficile
cytotoxin test (performed at the same time as sigmoidoscopy) was negative in 29 (52%). A previous stool C difficile
cytotoxin test was also negative in a significant proportion of the latter group (16; 55.2% of those in whom the stool C difficile
cytotoxin test was negative at the time of sigmoidoscopy). This raises the possibility that pseudomembranous colitis in these patients was due to another enteric pathogen and not toxigenic C difficile
We believe that pseudomembranous colitis in our patients was due to toxigenic C difficile
for the following reasons. All of these patients responded to oral vancomycin and/or metronidazole over a period of time that was similar to those with pseudomembranous colitis and a positive C difficile
cytotoxin test. Moreover, in nine patients (with a negative stool C difficile
cytotoxin test) in whom a frozen aliquot of stool sample (taken at the same time as sigmoidoscopy) was available, toxigenic C difficile
was isolated during anaerobic culture. Enterotoxigenic C perfringens
can cause antibiotic associated diarrhoea (which can respond to metronidazole) but to our knowledge this infection has not been reported to cause pseudomembranous colitis.21,22
The reasons for negative stool C difficile cytotoxin tests in many of the CDAD patients in our study are unknown. For the sigmoidoscopy arm of the study, stool samples were collected and sent to the enteric laboratory on the same day as the endoscopic examination. Although there was no delay in sending these stool samples, it is conceivable that toxin degradation may occur rapidly in some samples because of the presence of proteases derived from other bacteria. Another possibility is that other components in stool samples (which may also be derived from bacteria) may interfere with the bioassay by binding to the toxins. Further studies are required to address these possibilities.
As stool C difficile
cytotoxicity assays and ELISAs for toxins A and B are known to be negative in a proportion of patients with CDAD, it has been suggested that either stool culture for toxigenic C difficile
and toxin detection should be performed at the same time on all stool specimens23
or toxigenic culture performed on those with a negative stool toxin assay.18
The former strategy would allow more cases of CDAD to be diagnosed but would impose a significant burden on the laboratory services, particularly as cultured C difficile
would have to be confirmed to be toxigenic (by demonstration of toxin secretion or the presence of their genes), and a positive result would not be a significant addition in those patients with a positive stool toxin assay. Toxigenic culture in patients with a negative stool toxin assay would require either an aliquot of the original stool sample to be stored or another sample collected for anaerobic culture. Moreover, anaerobic culture and identification of toxigenic C difficile
would take some time, during which the patient may deteriorate and continue to pose a risk of transmission of infection to neighbouring patients. Our study has shown that flexible sigmoidoscopy is superior to stool C difficile
cytotoxin test in a subgroup of patients with C difficile
associated pseudomembranous colitis. Because of the characteristic appearance of pseudomembranous colitis, flexible sigmoidoscopy would allow a rapid diagnosis in patients with a negative stool toxin assay, enabling treatment and infection control measures to be initiated, particularly as transmission of infection has been shown to occur in hospital.24–26
Endoscopy would also allow an assessment of the severity of the colitis in these patients, thereby facilitating subsequent management.
As shown in table 3, many of the hospitalised patients with persistent diarrhoea and a negative C difficile
toxin assay will not have CDAD but other conditions such as ulcerative colitis, Crohn’s disease, ischaemic colitis, or infectious enterocolitis. As the endoscopic appearances in many of these conditions are characteristic, together with the facility to take biopsies for histology and stool samples for further microbiological studies, flexible sigmoidoscopy could be of considerable benefit in the management of hospitalised patients with diarrhoea. However, because it is non-invasive and more cost effective, we agree with the recommendation that examination of a stool sample for C difficile
toxins should be the initial investigation of choice in a hospitalised patient with diarrhoea.27
In the presence of continuing diarrhoea and a negative stool test for C difficile
toxins (and other enteric pathogens), we recommend flexible sigmoidoscopy as it will enable a rapid diagnosis in those patients with pseudomembranous colitis who need treatment the most. Our study has shown that flexible sigmoidoscopy is well tolerated in these patients and can be undertaken by the bedside with the advantage of minimising the risk of transmission of the disease by transportation to the endoscopy unit.
Our study suggests that in the absence of pseudomembranes at sigmoidoscopy, specific treatment (apart from discontinuation of the offending antibiotics) may not be necessary but further studies are required to determine whether endoscopic findings are superior to clinical features in making such decisions about management. As none of the small number of CDAD patients without pseudomembranes at sigmoidoscopy relapsed during the study, it is possible that pseudomembranous colitis increases the risk of subsequent relapse. However, the difference in our study was not statistically significant and further work is required. If the presence of pseudomembranes is shown to be associated with the risk of relapse, such patients could be selected for studies to investigate therapeutic agents that may reduce this risk.
A significant proportion (28%) of our patients with CDAD developed their disease in the community (in their own homes in over half of these patients) following administration of antibiotics. The majority of these patients had been hospital inpatients over the preceding 12 months, raising the possibility that colonisation with toxigenic C difficile
, without significant symptoms, occurred during such an admission. Asymptomatic acquisition of toxigenic C difficile
following admission to hospital has been reported.24,28
If this were the case, growth of toxigenic C difficile
could occur following antibiotic induced disruption of the normal bowel flora and would suggest the cautious use of antibiotics in community elderly patients who have had recent hospital admissions.