A Multi-Center Prospective Derivation and Validation of a Clinical Prediction Tool for Severe Clostridium difficile Infection

April A Multi-Center Prospective Derivation and Validation of a Clinical Prediction Tool for Severe Clostridium difficile Infection Xi Na 0 1 Alan J. Martin 0 1 Saurabh Sethi 0 1 Lorraine Kyne 0 1 Kevin W. Garey 0 1 Sarah W. Flores 0 1 Mary Hu 0 1 Dhara N. Shah 0 1 Kelsey Shields 0 1 Daniel A. Leffler 0 1 Ciarn P. Kelly 0 1 0 1 Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School , Boston , Massachusetts, United States of America, 2 Department of Medicine for the Older Person, Mater Misericordiae University Hospital and University College Dublin , Dublin, Ireland , 3 University of Houston College of Pharmacy , Houston, Texas , United States of America 1 Academic Editor: Abhishek Deshpande, Cleveland Clinic , UNITED STATES Background and Aims Prediction of severe clinical outcomes in Clostridium difficile infection (CDI) is important to inform management decisions for optimum patient care. Currently, treatment recommendations for CDI vary based on disease severity but validated methods to predict severe disease are lacking. The aim of the study was to derive and validate a clinical prediction tool for severe outcomes in CDI. - Funding: This work was funded in part by the following grants: NIH Awards DK-07760 (XN) and AI95256 (CPK), Merck Investigator Studies Program (CPK and KWG), and Health Research Board Ireland CSA 2007/4 (LK and AJM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. A cohort totaling 638 patients with CDI was prospectively studied at three tertiary care clinical sites (Boston, Dublin and Houston). The clinical prediction rule (CPR) was developed by multivariate logistic regression analysis using the Boston cohort and the performance of this model was then evaluated in the combined Houston and Dublin cohorts. The CPR included the following three binary variables: age 65 years, peak serum creatinine 2 mg/dL and peak peripheral blood leukocyte count of 20,000 cells/L. The Clostridium difficile severity score (CDSS) correctly classified 76.5% (95% CI: 70.87-81.31) and 72.5% (95% CI: 67.52-76.91) of patients in the derivation and validation cohorts, respectively. In the validation cohort, CDSS scores of 0, 1, 2 or 3 were associated with severe clinical outcomes of CDI in 4.7%, 13.8%, 33.3% and 40.0% of cases respectively. We prospectively derived and validated a clinical prediction rule for severe CDI that is simple, reliable and accurate and can be used to identify high-risk patients most likely to benefit from measures to prevent complications of CDI. Competing Interests: The funding sources do not alter the authors adherence to all PLOS ONE policies on sharing data and materials. Clostridium difficile is a gram-positive anaerobic bacterium that is an important human pathogen causing antibiotic associated diarrhea and pseudomembranous colitis [1, 2]. C. difficile infection (CDI) is highly prevalent in hospitals and nursing homes where patients frequently receive antibiotics and is now a leading cause of hospital-associated infection [1]. The overall incidence of CDI has increased dramatically in the United States, Canada and parts of Europe in recent years [1, 35]. Disease severity has also increased with increasingly virulent strains of C. difficile leading to markedly increased case fatality rates [6]. Nosocomial CDI has been estimated to more than quadruple the cost of otherwise matched hospitalizations, totaling up to $3 billion/year in hospital costs in the United States [79] The clinical outcomes of CDI range from symptomless carriage, to mild diarrhea, to fulminant pseudomembranous colitis and death [1, 10]. Several factors appear to influence the clinical outcome of CDI including the virulence of the infecting strain, the general health of the host and the host immune response [6, 1113]. There are recent data to indicate that oral vancomycin is superior to metronidazole for treatment of severe CDI [14]. Hence, recent guidelines recommend using oral vancomycin as first-line therapy in patients presenting with severe CDI [1, 15]. These guidelines also acknowledge the need for prospectively validated severity scores for CDI as presented in this study. Thus, it is important to establish clinical prediction tools for severe clinical outcomes in CDI in order to inform early patient management decisions, to improve quality of care to patients suffering from CDI and to facilitate the development and implementation of new interventions to improve clinical outcomes in severe disease. The goal of this study was to develop and validate a simple, easy to apply, clinical prediction rule that could be used at the time of CDI diagnosis to identify patients at high risk for adverse outcomes of the disease. Materials and Methods Patient Populations and Definitions CDI was defined as diarrhea, coupled with a positive stool assay for Clostridium difficile toxin A or toxin B (evaluated in all cases by enzyme-immunoassay) and not attributed other causes. Diarrhea was defined as a change in bowel habit with 3 or more unformed bowel movements per day for at least 2 days. The primary outcome of interest was severe CDI which was defined as a case of CDI leading to any one of the following outcomes: death attributable to CDI or with CDI as a contributing factor; intensive care unit (ICU) admission attributable to CDI or with CDI as a contributing factor; toxic megacolon or colectomy attributable to CDI. The relatedness of ICU admission or death to CDI was determined by chart review performed by two independent physician investigators. In the case of discordant determinations a third physician provided the deciding judgment. All of the severe outcomes evaluated occurred during the same hospital admission when CDI was diagnosed. Our rationale was that severe complications of an acute CDI were likely to occur quite quickly whereas negative outcomes that transpired days or weeks after hospital discharge were unlikely to be related to the index CDI. Patients with CDI were studied at three sites: i) Beth Israel Deaconess Medical Center (BIDMC), Boston, Massachusetts, ii) Mater Misericordiae University Hospital and St Vincents University Hospital, Dublin, Ireland and iii) Baylor St. Lukes Medical Center, Houston, Texas. The data consisted of clinical information and clinical outcomes data for all patients. The study was approved by the Committee on Clinical Investigations at BIDMC in Boston (local protocol number 2010P-000302), the Committee for the Protection of Research Subjects at the University of Houston (local protocol number CPHS 1310101), and the Mater Misericordiae University Hospital Ethics Committee (local protocol number 1/378/856). The data presented in this paper from the Houston and Boston sites used information available from patient medical records and as such the protocols at these sites were approved by their (...truncated)