Risk Factors for Recurrence, Complications and Mortality in Clostridium difficile Infection: A Systematic Review

Complications and Mortality in Clostridium difficile Infection: A Systematic Review. PLoS ONE 9(6): e98400. doi:10.1371/journal.pone.0098400 Risk Factors for Recurrence, Complications and Mortality in Clostridium difficile Infection: A Systematic Review Claire Nour Abou Chakra 0 Jacques Pepin 0 Stephanie Sirard 0 Louis Valiquette 0 Daniel Paredes-Sabja, Universidad Andres Bello, Chile 0 Department of Microbiology and Infectious Diseases, Universite de Sherbrooke , Sherbrooke, Quebec , Canada Background: Clostridium difficile infection (CDI) can lead to complications, recurrence, and death. Numerous studies have assessed risk factors for these unfavourable outcomes, but systematic reviews or meta-analyses published so far were limited in scope or in quality. Methods: A systematic review was completed according to PRISMA guidelines. An electronic search in five databases was performed. Studies published until October 2013 were included if risk factors for at least one CDI outcome were assessed with multivariate analyses. Results: 68 studies were included: 24 assessed risk factors for recurrence, 18 for complicated CDI, 8 for treatment failure, and 30 for mortality. Most studies accounted for mortality in the definition of complicated CDI. Important variables were inconsistently reported, such as previous episodes and use of antibiotics. Substantial heterogeneity and methodological limitations were noted, mainly in the sample size, the definition of the outcomes and periods of follow-up, precluding a meta-analysis. Older age, use of antibiotics after diagnosis, use of proton pump inhibitors, and strain type were the most frequent risk factors for recurrence. Older age, leucocytosis, renal failure and co-morbidities were frequent risk factors for complicated CDI. When considered alone, mortality was associated with age, co-morbidities, hypo-albuminemia, leucocytosis, acute renal failure, and infection with ribotype 027. Conclusion: Laboratory parameters currently used in European and American guidelines to define patients at risk of a complicated CDI are adequate. Strategies for the management of CDI should be tailored according to the age of the patient, biological markers of severity, and underlying co-morbidities. - Highly associated with exposure to antibiotics, Clostridium difficile infection (CDI) causes 20 to 30% of antibiotic-associated diarrhea and is the most common cause of nosocomial diarrhoea [14]. The risk of CDI increases up to 6-fold during antibiotic therapy and in the subsequent month [5,6]. In the early 2000s, a renewed interest in CDI followed the emergence of a hypervirulent strain (NAP1/BI/027) associated with frequent recurrences and higher severity [7,8]. Several novel treatments of CDI are being studied, some of which have been associated with a lower risk of recurrence [911]. Identifying clinical parameters or host-related factors associated with adverse outcomes would improve the management of CDI in the early stage of the disease. In a previous systematic review [12], we showed that several studies used empirically-defined risk factors for the derivation of clinical prediction rules for unfavourable outcomes of CDI, while others used univariate comparisons between CDI and non-CDI groups. Few clinical variables remained significant in multivariate analyses. Risk factors for unfavourable outcomes of CDI have been studied before and after the emergence of NAP1/BI/027. To our knowledge, only one systematic review with a meta-analysis, published in 2008, has addressed risk factors for recurrence with a search limited to PubMed [13]. More recently, a systematic review of risk factors for mortality pooled results of univariate and multivariate analyses of hospital-based studies [14]. Two other reviews that ascertained CDI-related mortality were performed but specific risk factors were not reported [15,16]. Consequently, we performed a systematic review of all publications that identified risk factors for recurrence, treatment failure, complications and/or mortality in patients diagnosed with CDI. Search strategy and selection criteria A systematic review was performed according to PRISMA guidelines [17] (Checklist S1) using an electronic search of all studies published from January 1978 until October 2013. The search was limited to human studies and used the following online libraries and databases: MEDLINE, PubMed, Cochrane Library for evidence based-medicine, Embase and Web of Science (Text S1). The final electronic search was performed on 21 October 2013. Publications from all sources were merged into one file and duplicates were removed. A first screening of titles and abstracts followed by a full-text review were performed. In addition, the reference lists of identified studies were searched manually. We included studies that: i) targeted C. difficile as the main pathogen; ii) measured at least one relevant outcome: severity, complications, mortality, treatment failure and/or recurrence; iii) identified risk factors for the main outcome(s) using risk assessment measures such as odds ratios (OR), relative risks or ratios (RR) and hazard ratios (HR). Any complication, fulminant colitis, ICU admission, shock, and/or death (when used as part of a composite outcome) were grouped under complicated CDI. We excluded all studies that used only univariate comparisons of groups, aimed to develop a risk stratification tool or a predictive model [12], and those conducted exclusively in children, in populations with selected pathologies or undergoing particular procedures (e.g. organ transplants, CT-scans, or endoscopies). Data extraction Two reviewers (CAC and SS) extracted the following data into a standardized matrix: year of publication, location, year of diagnosis, type of tests for the laboratory diagnosis of CDI, definition and frequency of the outcome(s) of interest, study design, duration of follow-up, population and comparison groups, sample size, statistical analyses, number of variables and number of events per variable (EPV) in the final model, and main results in relation with the objectives of the review. Correspondences requesting clarifications were sent to authors in case of missing or incomplete data (n = 9). Studies that assessed two or more outcomes were allocated to each category of outcomes. Results from included studies were plotted using GraphPad Prism 6.01 (GraphPad Software, San Diego, CA). Due to the small number of studies assessing common risk factors for defined outcomes, ORs, RRs and HRs with their confidence intervals (CI) are reported in the same forest plots. Some factors such as multi-organ failure or other severe medical status immediately preceding mortality were considered too closely related to death in the pathogenic pathway and were therefore not considered as risk factors in this review. Risk of bias assessment A quality control process was performed on 10% of the first screening of abstracts (LV), as we (...truncated)