Predictors of serious complications due to Clostridium difficile infection

Alimentary Pharmacology & Therapeutics Predictors of serious complications due to Clostridium difficile infection D. GUJJA* & F. K. FRIEDENBERG *Department of Medicine, Abington Memorial Hospital, Abington, PA, USA, and The Gastroenterology Section, Temple University School of Medicine, Philadelphia, PA, USA Correspondence to: Dr F. K. Friedenberg, Temple University Hospital, 8th Floor, Parkinson Pavilion, 3401 N. Broad Street, Philadelphia, PA 19140, USA. E-mail: frank.friedenberg@temple.edu Publication data Submitted 22 October 2008 First decision 13 November 2008 Resubmitted 3 December 2008 Accepted 3 December 2008 Epub Accepted Article 10 December 2008 SUMMARY Background Identifying individuals with severe Clostridium difficile infection (CDI) at risk for major complications has become an important objective. Presence of clinical variables that predict complications from CDI would have the potential to strongly influence management. Aim To determine which clinical variables predict complications from CDI. Methods Cross-sectional study of all individuals admitted to Temple University Hospital between 12 1 03 and 7 1 08 with the primary discharge diagnosis of CDI were eligible. Only patients experiencing their first episode of CDI were included. Abstracted data included demographic, physiological, laboratory, radiological, endoscopic, pharmacy and outcome data. Response was categorized as none, partial or complete. Complications attributed to CDI were defined as colon resection or death. Results Overall 32 of 200 patients (16%) experienced a complication due to CDI including death (n = 20) and colectomy (n = 12). White blood cell count above 30,000 cells mm 3 (OR = 4.06; 95% CI, 1.28 12.87) and a rise in the creatinine to over 50% above baseline (OR = 7.13; 95% CI, 3.05 16.68) predicted a complication. AROC for percent rise in serum creatinine was 0.73 (95% CI: 0.64 0.85) and 0.62 (95% CI: 0.58 0.80) for white blood cell count. Conclusions Severe white blood cell count elevation and a rise in the creatinine to over 50% above baseline are important independent predictors of serious adverse events due to CDI. These patients likely would benefit from more intensive care and early surgical consultation. 635 doi:10.1111/j.1365-2036.2008.03914.x

636 D. GUJJA and F. K. FRIEDENBERG INTRODUCTION Over the past 10 years, there has been an increase in the incidence of Clostridium difficile infection (CDI) in North America. 1, 2 Of more concern have been reports primarily from North America and Western Europe of an increased incidence of complications due to CDI including colectomy and death. 2 4 The risk of complicated CDI has, in part, been explained by the re-emergence of the BI NAP1 027 strain of C. difficile. This strain has been demonstrated to elaborate high levels of toxin A and B. 5 It proliferates particularly in hospitals which overutilize fluoroquinolone antibiotics; however other factors, including a breakdown in infection control measures, have contributed to its proliferation. 6 At present, a majority of states in the US have had at least one hospital report of an outbreak due to the BI NAP1 027 strain. 7 As a consequence of the changing epidemiology of CDI, identifying individuals with CDI at risk for a serious complication such as death or colectomy has become an important objective. Several non-validated risk scoring systems have been developed to categorize patients into two or three strata such as mild, moderate and severe. These scoring systems have notable shortcomings including high complexity and subjective variables. More importantly, the majority of severe cases in these scales do not progress to a serious complication and, on occasion, initially mild-moderate cases progress to severe sequelae. The purpose of this study was to re-examine this issue in the hope of simplifying and clarifying which clinical variables predict serious adverse events due to CDI. Knowledge of these clinical variables could strongly influence management of patients with CDI. MATERIALS AND METHODS All individuals admitted to Temple University Hospital between 12 1 03 and 7 1 08 with the primary discharge diagnosis of CDI (ICD-9: 008.45) were eligible for inclusion in this study. 8 To be included, the CDI had to be the patient s first bout and not a recurrence. The Temple University IRB approved the study protocol. From the electronic medical record, we abstracted demographic (age, gender, race), physiological (temperature, body mass index), laboratory (complete blood count, liver function tests, albumin, creatinine), radiological (CT scan), endoscopic (flexible sigmoidoscopy or colonoscopy), pharmacy [use of metronidazole and or vancomycin (Vancocin Ò, ViroPharma Incorporated, Exton, PA, USA)] and outcome data (resolution, complication, etc.). All data were from the time a decision was made to initiate therapy for CDI except for baseline creatinine. Baseline creatinine was the lowest creatinine value recorded for the patient within the first 24 h of admission. The primary endpoint, defined as a serious adverse event from CDI, included the composite endpoint of colon resection or death. Death from an unrelated cause (e.g. pneumonia) was not considered a complication. Although not our primary objective, we assessed response to treatment in uncomplicated cases. Response to therapy was categorized as complete (resolution of nausea, abdominal pain, and 2 bowel movements day), partial (improvement, but failure to achieve complete resolution) and none (no appreciable response to therapy). CT scan findings were recorded as severe if ascites, toxic megacolon, thumbprinting or peri-colonic fat stranding were present. 9 Length of the treatment observation period included the time from commencement of CDI therapy until discharge. Patients were labelled as immunocompromised if any of the following was present: diabetes, status-post organ transplant on immunosuppressant therapy, solid or haematological malignancy, end-stage renal disease requiring haemodialysis, HIV and corticosteroid use 10 mg. Patients were included only if the stool toxin EIA (Wampole C. difficile Tox A B II, TechLab, Blacksburg, VA, USA) was positive. Rare patients with other types of colitis (e.g. CMV) occurring simultaneously were excluded. Statistical analysis The primary dependent variable for analysis was complication status (complication from CDI vs. no CDI). In univariate analysis, continuous variables were compared using unpaired t-tests and proportions with Pearson s chi-squared test. Those variables with a P value 0.05 from univariate analysis served as predictor (independent) variables in a subsequent logistic regression model. The regression model served to determine adjusted odds for predictors of complications from CDI. For significant predictor variables from the logistic model, an area under the receiver operator curve (AROC) was generated to model their predictive capability.

SERIOUS COMPLICATIONS DUE TO CLOSTRIDIUM DIFFICILE 637 RESULTS A total of 274 individual patient charts were screened and 200 met criteria to be included for analysis (Figure 1). Follow-up inpatient data were available for a median of 10 days (IQR 5-19 days) after the initiation of therapy and were utilized to determine response and the development of a complication. Overall, 100 patients (50%) had a complete response to therapy and 68 (34%) had a partial response. Thirty two patients (16%) experienced a complication due to CDI including either death (n = 20) or colectomy (n = 12). Ten of the patients who died had colon surgery (partial or subtotal colectomy) prior to death. These patients were only counted once - as a death. Several (n = 9) of the patients were diagnosed with a megacolon by plain radiograph or CT scan prior to their complication. Patients who experienced a complication had a significantly greater rise in serum creatinine from baseline to time of CDI diagnosis (Table 1). At the time of diagnosis, they also had a higher white blood cell count and haemoglobin. There were no differences in age, race, gender, albumin, liver enzymes, temperature, or body mass index. Surprisingly, immune status was unrelated to complications (P = 0.36). Fewer than half of the patients (n = 80) underwent a CT scan; however, severe findings on the study were closely associated with the occurrence of a complication (P = 0.003). Only 25 patients (12.5%) had an endoscopic exam and the presence of pseudomembranes approached significance (P = 0.053). For the logistic regression model, white blood cell count, % rise in serum creatinine and haemoglobin were chosen as predictor variables from the univariate analysis. CT scan and endoscopic result were not included due to the high frequency of missing data points. A white blood cell count >30 000 cells mm 3 had an adjusted odds ratio for the presence of a complication of 4.06 (95% CI, 1.28 12.87) using a count <15 000 cells mm 3 as the reference (Table 2). In fact, 11 27 (40.7%) of patients with a leucocytosis >30 000 cells mm 3 developed a CDI complication. A rise in the serum creatinine by >50% was also independently associated (AOR = 7.13; 95% CI, 3.05 16.68) with a complication of CDI. Haemoglobin did not prove to be independently associated with CDI complications. Predictive value of creatinine and white blood cell count for CDI Of 12 patients who had both an elevation of creatinine above baseline by >50% and white blood cell count >30 000 cells mm 3, 7 (58%) experienced a serious CDI complication. There were 61 patients who had neither a rise in the creatinine nor white cell count above these thresholds and 57 (93.4%) did not have a complication. Separate AROC curves were generated using rise in serum creatinine >50% and white blood cell count > 30,000 cells mm 3 as the predictor variables and presence of a complication as the state variable. The AROC for percent rise in serum creatinine was 0.73 (95% CI: 0.64 0.85) and it was 0.62 (95% CI: 0.58 0.80) for white blood cell count. This means that for a hypothetical pair of patients with CDI, assuming one patient had a complication and the other did not, a > 50% rise in serum creatinine or white blood cell Charts coded with 1 diagnosis of C. difficile infection (n = 274) Excluded (n = 74) C. difficile not documented (n = 64) Relapse case (n = 7) Pediatric patient (n = 2) CMV colitis co-infection (n = 1) Final study group (n = 200) Figure 1. Flow diagram of patients included in the study. Complete response (n = 100) Complication (n = 32) Death (n = 20) Colectomy (n = 12) Partial response (n = 68)

638 D. GUJJA and F. K. FRIEDENBERG Table 1. Characteristics of 200 in-patients diagnosed with first episode of Clostridium difficile infection stratified by complication status Complication* n = 32 mean (s.d.) No complication n = 168 mean (s.d.) 95% Confidence interval of difference P Value Age (year) 68.8 (12.9) 65.9 (17.2) )9.2 3.4 0.37 Creatinine increase (%) 106.7 (132.9) 27.4 (70.2) 30.3 128.2 0.002 Temperature ( F) 99.5 (2.2) 99.4 (1.9) )0.82 0.65 0.82 WBC (10 3 ll) 27.3 (19.9) 16.7 (9.6) 3.3 17.9 0.006 Albumin (g dl) 2.1 (0.7) 2.3 (1.5) )0.33 0.75 0.45 ALT (U L) 51.7 (50.6) 34.0 (38.0) )36.8 1.5 0.07 Total bilirubin (mg dl) 0.92 (0.53) 0.83 (0.76) )0.37 0.19 0.54 Haemoglobin (gm dl) 10.9 (2.0) 10.2 (1.8) 0.1 1.5 0.02 Body mass index (kg m 2 ) 29.5 (9.4) 26.7 (10.3) )6.9 1.2 0.17 n (%) n (%) Risk estimate (95% CI) P Value Gender 0.98 Female 18 (15.9) 95 (84.1) Male 14 (16.1) 73 (83.9) 1.01 (0.47 2.17) Race 0.83 White 11 (18.5) 48 (81.4) Black 17 (17.0) 83 (83.0) Hispanic 3 (11.5) 23 (88.5) Immune status 0.36 Immunosuppressed ()) 10 (13.0) 67 (87) Immunosuppressed (+) 22 (17.9) 101 (82.1) 1.46 (0.65 3.28) Pseudomembranes 0.053 No 0 (0) 4 (100) Yes 11 (52.4) 10 (47.6) 2.1 (1.0 3.3) Severe CT findings 0.003 No 2 (5.0) 38 (95.0) Yes 12 (30.0) 28 (70.0) 8.1 (1.7 39.3) * Complication defined as colectomy or death directly attributable to C. difficile infection. Increase calculated as creatinine at time of treatment minus baseline creatinine. Table 2. Results of logistic regression analysis using complication status as the dependent variable CDI complication Yes, n No, n Unadjusted odds ratio Adjusted odds ratio 95% confidence interval of adjusted odds ratio P Value WBC Count (10 3 ll) <15 000 9 88 1.00(referent) 1.00(referent) 15 000 30 000 12 85 1.44 0.93 0.34 2.60 0.71 >30 000 11 27 6.04 4.06 1.28 12.87 0.02 Creatinine rise (%) <50 12 152 1.00(referent) 1.00(referent) >50 20 48 8.33 7.13 3.05 16.68 <0.001 Haemoglobin (g dl) <10 15 104 1.00(referent) 1.00(referent) >10 17 96 1.31 1.09 0.46 2.60 0.83

SERIOUS COMPLICATIONS DUE TO CLOSTRIDIUM DIFFICILE 639 count >30 000 cells mm 3 would be able to predict correctly which of the pair would develop a complication 73% and 62% of the time respectively (chance = 50%). Use of antibiotics All 200 patients received antibiotic therapy after the diagnosis of CDI. Either intravenous or oral metronidazole was used for treatment in all 200 patients. A total of 64 patients received oral vancomycin 125 500 mg orally at some point during therapy. Of these, 15 (23.4%) experienced a complication. Eleven of 37 (29.7%) patients in whom vancomycin was added to therapy after perceived failure of metronidazole monotherapy experienced a complication. A similar proportion of individuals (3 of 10 or 30%) experienced a complication when vancomycin was started as initial co-therapy with metronidazole. However, only 1 17 (5.9%) who discontinued metronidazole and switched to vancomycin had a CDI complication. DISCUSSION The purpose of this retrospective analysis was to clarify which clinical variables predicted a complication in-patients experiencing their first episode of CDI (CDI). In all, 32 out of 200 patients with a primary discharge diagnosis of CDI over a 4.5 year period experienced a complication as a direct consequence of their CDI. An elevation of the white blood cell count above 30 000 cells mm 3 (OR = 4.06; 95% CI, 1.28 12.87) and a rise in the creatinine to > 50% above baseline (OR = 7.13; 95% CI, 3.05 16.68) predicted a complication. The presence of severe findings on CT scan was strongly associated with a complication on univariate analysis, but was not included in the regression model as fewer than half the patients underwent this diagnostic study. Unlike Ramaswamy et al., we did not find serum albumin to be predictive of mortality. 10 Our results further refine the group of patients with CDI who may benefit from more intense monitoring during their disease course. In our study group, 11 27 (40.7%) patients with a white blood cell count >30 000 cells mm 3 and 20 48 (41.7%) with a rise in the creatinine to >50% above baseline experienced a serious complication. Patients with an elevation above threshold for both laboratory values had a CDI complication rate of 58.3%. Intensified management may take the form of intensive care unit or unit step-down placement and early surgical consultation. Whether vancomycin therapy should be started from the onset of CDI is not answered by this paper and should be the focus of a prospective trial. In our study, vancomycin was selected for use in a particularly ill subgroup and was either added to metronidazole therapy or begun afterwards due to perceived metronidazole failure. Overall, 15 of 64 patients (23.4%) that were prescribed vancomycin experienced a complication vs. 12.5% of patients not receiving this therapy. Adding vancomycin to metronidazole at the beginning of CDI treatment or during the disease course was associated with a complication rate of approximately 30%. Discontinuing metronidazole and switching to vancomycin was associated with a much lower rate (5.9%). We do not believe vancomycin increases the risk of a complication from CDI, nor do we believe it inhibits the efficacy of metronidazole. However, a prospective trial would clarify these issues. Overall, 93.4% of patients with both laboratory values below the threshold for white blood cell count and creatinine did not experience a CDI complication. This knowledge could influence resource utilization and discharge planning if verified. Our study has several important strengths. Principle among them is that we used a highly relevant, completely objective composite endpoint (colectomy or death). We did not include toxic megacolon as an endpoint because it is a subjective diagnosis based on radiographic and clinical data (especially when there is only segmental colonic dilation). We studied a homogeneous population in which all patients had a first-episode diagnosis of CDI, verified by a positive EIA toxin assay. It was the primary diagnosis on discharge for all patients and dominated their inpatient clinical course. An additional strength is that variables used in the final predictive model (white blood cell count and creatinine) are readily available and do not require specialized testing such as endoscopy. We specifically avoided subjective predictive variables used in other models such as alteration in mental status 11 and severity of abdominal pain. 12, 13 We also did not include bowel movement frequency as this is highly unreliable even in the research setting and of no practical value in-patients with incontinence (common in elderly, ill CDI patients). 11 We avoided the use of blood pressure as this can vary widely on a daily basis. ICU placement was not considered a predictor variable or endpoint because of the widely disparate use and availability of ICU care around the world.

640 D. GUJJA and F. K. FRIEDENBERG A weakness of our study is that the retrospective study design did not allow for control of management which ultimately could have impacted on the occurrence of complicated outcomes. For example, we did not use a standardized protocol to govern management decisions such as use of anti-diarrhoeals and use of nasogastric decompression for ileus or vomiting. An additional weakness is that we were not able to identify individuals potentially infected with the BI NAP1 027 strain. Our data, we believe, simplify risk stratification in CDI. Two recent, as yet unpublished abstracts highlight how confusing this area has been. Fujitani 14 attempted to validate two complex severity scales for their ability to predict complicated outcomes as defined by Loo et al. (colectomy, death, or ICU care due to CDI). 15 Both the University of Pittsburgh Medical Center (versions 1 and 2) severity scales 12 and the Rubin scale 13 (Table 3) demonstrated poor positive predictive value (34 46%), but excellent negative predictive value (>95%). Amongst several shortcomings of this abstract were that complications were rare (19 of 184 or 10.3%) and, even more importantly, were not specified. It appears that a majority (15 of 19) of patients were defined as complicated by virtue of placement in the ICU due to CDI. A second recent abstract by Luz and others was a validation study comparing the Rubin 13 and Belmares Scales 16 (Table 3) with adverse outcomes in 78 patients. 17 Limitations of this study are that only two deaths occurred and the scales had drastically different rates of categorizing patients as severe. Overall, 9.9% and 35.9% of CDI cases were categorized as severe using the Rubin and Belmares scales respectively. A final limitation is that the scales were unable to predict the need for colectomy. Table 3. Proposed severity scoring systems to predict complications from Clostridium difficile infection Variable Rubin (ref 13) Belmares (ref 16) UPMC Version 1 (ref 12) UPMC Version 2 (ref 12) Age (>90 years) Fever Ileus distention Systolic blood pressure <100 mmhg WBC count (cells mm 3 ) >25 000 or <1500 (1)* <15 000 (0) 15 000 30 000 (1) <30 000 (2) >20 000 or <1500 (1) >20 000 or <1500 (1) Abnormal CT findings 1 finding (1) 2 findings (2) à Abdominal pain Abdominal tenderness Clindamycin use Anti-diarrhoeal use Depressed mental status Renal insufficiency COPD Albumin (mg dl) <3 (1) <3 or ascites or pneumatosis coli (1) Haemoconcentration >5% HCT increase (1) Immunosuppression Medication Point Criteria for Severe CDI 5 2 5 (or ileus or pancolitis on CT) 2 CDI, C. difficile infection; UPMC, University of Pittsburgh Medical Center. * Numbers in parenthesis are points received for finding. For UPMC version 1, pancolitis or wall thickening or ascites or Pneumatosis coli. UPMC version 1 also referred to as the C. difficile Severity and Prognosis Score (CDSPS). à For UPMC version 2: wall thickening and ascites by CT or ileus.

SERIOUS COMPLICATIONS DUE TO CLOSTRIDIUM DIFFICILE 641 There have been five publications which have studied risk factors for severe CDI, but did not develop predictive scales. 11, 18 21 Andrews et al. used the combined endpoints of Loo et al. with the addition of hospital stay > 14 days to categorize severe disease. 18 They found that predictors of severe disease included age > 70 years, comorbid organ system involvement and classification as a recurrent CDI case. Kyne et al. defined severe disease by diarrhoea duration ( 10 days) and presence of abdominal pain, distention, toxic megacolon or pseudomembranes. 11 Risk factors for severe disease were cognitive impairment and an endoscopy before disease onset. Dubberke and others developed a grading scale in allogenic stem cell transplant recipients based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3. 19 Patients with hypo- or hyperthermia, diarrhoea output > 1001 ml, and grade 3 or higher colitis were considered to have severe CDI. These patients experienced acute renal failure and blood stream infections due to enteric organisms at a higher rate than those with lower grades of colitis. Kenneally et al. found that septic shock, ICU care and increasing APACHE II scores predicted 30 day mortality in-patients with CDI. 20 Finally, Moshkowitz and others found that a white blood cell count above 20 000 cells mm 3, albumin <2.5 g dl and NGT feeding predicted mortality in a group of 72 elderly patients with pseudomembranous colitis. 21 A separate, but related issue has been the development of severity scales to predict response to CDI treatment, not outcome. Zar, in a study comparing metronidazole and vancomycin, utilized age ( 60), fever ( 38.3 C), albumin ( 2.5 mg dl), WBC ( 15 000 cells mm 3 ), ICU care and presence of pseudomembranes on endoscopy to categorize severity. 22 In the Phase III trial of an anionic polymer that binds toxins A and B (Tolevamer, Genzyme, Cambridge, MA, USA), bowel movements per day, severity of abdominal pain and white blood cell count elevation were used to categorize patients. 23 In both studies, vancomycin showed superiority in-patients with severe disease. Recently, based on these studies, the Infectious Disease Society of America has recommended utilizing a WBC >15 000 cells mm 3 or rise in the baseline creatinine >50% as criteria for beginning CDI treatment with vancomycin. 24 In conclusion, in our study group, an elevation of the white blood cell count above 30 000 cells mm 3 and a rise in the creatinine to >50% above baseline were strong predictors of serious adverse events inpatients experiencing their first episode of CDI. These variables, if validated, could be used alone or incorporated with other variables into a new severity scale. On the basis of our univariate analysis, we also believe that, when feasible, a CT scan should be performed. This result could clarify even further the risk for a CDI complication. If validated, our data have the potential to alter management in that a low threshold for more intensive hospital care and surgical consultation should be considered in-patients at high risk for complicated CDI. The mortality rate of over 60% in our patients with a complication suggests that patients destined to do poorly are being recognized too late or are treated with inadequate aggression. ACKNOWLEDGEMENTS The authors wish to thank the assistance of Mr Stephen Young in compiling the list of patients included in this manuscript. Declaration of personal and funding interests: Dr Friedenberg has received funding for research from, and has served as a speaker and advisory board member for, ViroPharma, Inc. REFERENCES 1 Redelings MD, Sorvillo F, Mascola L. Increase in Clostridium difficile-related mortality rates, United States, 1999-2004. Emerg Infect Dis 2007; 13: 1417 9. 2 Zilberberg MD, Shorr AF, Kollef MH. Increase in adult Clostridium difficilerelated hospitalizations and case-fatality rate, united states, 2000-2005. Emerg Infect Dis 2008; 14: 929 31. 3 Office for National Statistics. Deaths involving Clostridium difficle: England and wales, 1999 and 2001-06. Health Stat Q 2008 Spring: 52 6. 4 Labbe AC, Poirier L, Maccannell D, et al. Clostridium difficile infections in a Canadian tertiary care hospital before and during a regional epidemic associated with the BI NAP1 027 strain. Antimicrob Agents Chemother 2008; 52: 3180 7. 5 Warny M, Pepin J, Fang A, et al. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 2005; 366: 1079 84. 6 Muto CA, Pokrywka M, Shutt K, et al. A large outbreak of Clostridium difficileassociated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased

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