AIM: To investigate risk factors for severe clostridium difficile associated diarrhoea (CDAD) in hospitalized patients.

METHODS: We analysed risk factors for severe CDAD (associated with systemic signs of hypovolemia) in 124 hospitalized patients by retrospective chart review.

RESULTS: Severe CDAD was present in 27 patients (22%). Statistical analysis showed a significant association with a higher 30-d mortality (33% vs 4%, P < 0.001) and a higher proportion of longer hospital stay exceeding 14 d (74% vs 52%, P = 0.048). Charlson co-morbidity score (OR 1.29 for 1 point increment, P < 0.05) and serum C-reactive protein at diagnosis (OR 1.15 for 10 mg/L increment, P < 0.001) were independent predictors of severe CDAD.

CONCLUSION: Patients with a severe level of co-morbidity and high serum C-reactive protein levels at the time of diagnosis should receive particular attention.

Clostridium difficile associated diarrhoea (CDAD) is the most common cause of healthcare-associated diarrhoea and results in a wide spectrum of disease severity ranging from asymptomatic carriage to life-threatening enterocolitis and death[1–5]. Recently, a new epidemic strain producing higher levels of toxin has emerged in Canada and the US[5–8] as well as in some European countries which results in CDAD with higher morbidity and mortality[9–13]. Many studies have investigated risk factors for infection with Clostridium difficile (C. difficile) and subsequent development of CDAD. Thus, advanced age, severe comorbidity[14], hospitalisation[15], antibiotic exposure, immunosuppressive therapy[1617] and treatment with motility influencing or acid-suppressive drugs have all been reported as risk factors for CDAD[18–21]. In contrast, less is known about risk factors associated with a severe course of CDAD in hospitalized patients.

We conducted a retrospective analysis of CDAD in hospitalized patients to identify possible risk factors for a severe clinical course. Our institution is a community hospital treating approximately 19 000 in-patients per year. Using a computer-based search, we identified 186 positive stool tests for C. difficile toxin B from 142 patients who fulfilled the case definition for CDAD between October 2003 and August 2006. After chart review 18 cases were excluded: 5 patients had multiple admissions and only the first admission was included, 5 patients were younger than 18 years and in 8 patients data were incomplete, leaving 124 patients for further analysis. We recorded patient age, sex, nursing home residency, comorbidity to calculate the Charlson comorbidity score[2223] previous and concomitant medication (systemic antibiotic treatment within 6 wk preceding diagnosis, continuation of the initial antibiotic therapy after diagnosis of CDAD, use of opioids or laxatives), predisposing medical or surgical procedures (endoscopy, percutaneous gastrostomy, nasogastric tubes, chemotherapy or radiotherapy) as well as vital signs (heart rate, blood pressure and body temperature) and laboratory parameters (white blood cells, C-reactive protein, sodium, potassium, creatinine) at the time of diagnosis. In addition, we recorded the length of hospital stay, the period until beginning therapy for CDAD after the onset of diarrhoea, whether a specific antibiotic therapy for CDAD was instituted or not and the 30-d mortality after initial diagnosis of CDAD.

Patients with more than three loose stools per day on more than two consecutive days with a positive stool test for C. difficile toxin were diagnosed as CDAD[1624]. Hospital-acquired CDAD was assumed if the onset of diarrhoea was > 72 h after hospital admission or if there had been a hospital admission for CDAD within the previous 6 wk. Severe CDAD was defined as profuse diarrhoea associated with a positive shock index (heart rate bpm/systolic blood pressure mmHg >1.5) at initial diagnosis[10]. All other patients were classified as non-severe CDAD.

Comparisons between the two groups of severe and non-severe CDAD were performed by Student t test for normally distributed data, proportions were analysed by χ² or F test as appropriate. A two-sided error level of P < 0.05 was considered statistically significant. Variables significantly associated with severe CDAD in univariate analysis together with risk factors reported in the literature were entered into a multivariate analysis. Statistical analysis was computed with SPSS version 14.0 (SPSS, Inc., Chicago, IL, USA).

The major findings in this retrospective analysis were a 22% rate of severe CDAD significantly associated with relatively high 30-d mortality (33% vs 4%, P <0.001) and a higher proportion of a hospital stay exceeding 14 d (74% vs 52%, P <0.05). In addition, comorbidity assessed by the Charlson comorbidity score (P <0.05) and serum C-reactive protein at the time of diagnosis (P <0.001) were identified as independent risk factors for severe CDAD in multivariate analysis.

The rate of severe CDAD and associated 30-d mortality in this study are relatively high. Infection with the recently emerging strain BI/NAP1 associated with severe courses of CDAD[28–11] is an unlikely explanation, since this strain had not been documented in Germany at the time of our retrospective analysis[25]. Therefore the most likely explanation are advanced age (median 76 years) and high comorbidity (median Charlson score of 4) of our cohort. The observed association of disease severity with comorbidity assessed by the Charlson comorbidity score is in line with reports on an association of severe CDAD with cognitive impairment[16], number of chronically affected organ systems[26], cardiac disease, malignancy, chronic obstructive pulmonary disease, pre-existing renal failure and other severe disease[2728]. Our data support the hypothesis that comorbidity is an important risk factor for severe CDAD and the Charlson comorbidity score, which includes most of these conditions, might be a useful tool to identify patients at particular risk for severe CDAD. We also identified serum levels of C-reactive protein as independently associated with severe CDAD. In fact, serum C-reactive protein was a far better predictor of severe CDAD than white blood cell count, which has been described by others[2829]. Thus, at the median Charlson comorbidity score of our cohort (4 points) a C-reactive protein level of 250 mg/L at diagnosis predicted a higher than 50% probability for severe CDAD. Perhaps more sensitive markers of inflammation such as procalcitonin might be even more useful in the evaluation of disease severity.

Other known risk factors for CDAD[21830] might also be relevant for severe CDAD. In line with these data we found comedication with laxatives, opioids and acid-suppressive therapy associated with severe CDAD in univariate analysis although these risk factors could not be confirmed in multivariate analysis. In contrast, a variety of other putative risk factors for severe CDAD could not be confirmed. Thus, we did not detect an association of severe CDAD with increased age[2730], which is probably due to the already advanced median age of our cohort. Moreover, prolonged antibiotic use per se, continuation of the antibiotic therapy after the diagnosis of CDAD, gastrointestinal procedures or surgery, which have all been reported as risk factors for C. difficile colonisation and CDAD[217] were not associated with severe disease in this study.

In conclusion, comorbidity and serum levels of serum C-reactive protein were identified as predictors of severe CDAD. Patients with strong comorbidity and high serum C-reactive protein levels at the time of diagnosis should be treated with particular attention.