Risk factors for mortality in Clostridium difficile infection in the general hospital population: a systematic review

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1 Journal of Hospital Infection 82 (2012) 1e12 Available online at Journal of Hospital Infection journal homepage: Review Risk factors for in Clostridium difficile infection in the general hospital population: a systematic review M.G. Bloomfield a, b, *, J.C. Sherwin b, E. Gkrania-Klotsas c a Department of Clinical Microbiology, University College London Hospital NHS Foundation Trust, London, UK b Department of Public Health and Primary Care, Institute of Public Health, The University of Cambridge, Cambridge, UK c Department of Infectious Diseases, Addenbrooke s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK A R T I C L E I N F O S U M M A R Y Article history: Received 16 February 2012 Accepted 21 May 2012 Available online 22 June 2012 Keywords: Clostridium difficile Mortality Pseudomembranous colitis Severity Background: Clostridium difficile infection (CDI) is one of the most important healthcareassociated infections, causing considerable. Numerous severity scores have been proposed to identify patients with CDI at risk of, but a systematic review of the evidence upon which these are based has never been published. Such a review could permit future development of scores that better predict. Aim: A systematic review of the published literature investigating clinically useful risk markers for in CDI. Methods: We searched MEDLINE 1950 to present, Web of Science with conference proceedings 1899 to present and BIOSIS Citation Index 1969 to present using PubMed and Web of Knowledge. Potential risk markers that had been evaluated by at least four studies were extracted. Findings: Twenty-six studies, of 1617 initially identified, met inclusion criteria. The majority were retrospective studies, mostly based in the USA. Older age, higher white blood cell count (WBC), higher creatinine level, lower albumin levels and, to a lesser extent, corticosteroid use were most frequently associated with. Presence of fever, haemoglobin/haematocrit level, diarrhoea severity, presence of renal disease, diabetes, cancer, or nasogastric tube use did not appear to be associated with. Conclusion: Our results support the use of age, WBC, serum creatinine, serum albumin level and possibly pre-existing corticosteroid use as potentially useful risk markers for in CDI. Our results do not support the use of fever, haemoglobin/haematocrit, diarrhoea severity and several comorbidities as useful risk markers, raising questions about their inclusion in CDI severity scores. Ó 2012 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved. * Corresponding author. Address: Department of Clinical Microbiology, University College London Hospital NHS Foundation Trust, 65 Whitfield Street, London W1T 4EU, UK. Tel.: þ ; fax: þ address: maxim.bloomfield@cantab.net (M.G. Bloomfield). Introduction Clostridium difficile infection (CDI) is the most common form of hospital-acquired infectious diarrhoea, and represents one of the most important causes of healthcare-associated infection. 1 Substantial rises in the reported incidence of CDI /$ e see front matter Ó 2012 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

2 2 were seen in the early parts of this century across the USA, Canada, and Europe, and there is evidence suggesting that the incidence continues to rise among elderly patients in the USA. 2e5 In addition to the rise in incidence, significant increases in severity of infection and due to the disease have been observed. 3,6 A recent review of due to CDI found pooled attributable of 8.03% in studies reported since the year 2000, compared with 3.64% in those reported before Vancomycin has been shown to be superior to metronidazole in patients with severe CDI, and new therapies are on the horizon, which may offer advantages for patients with severe disease. 8,9 As such, the ability to accurately and promptly identify patients who are at risk of dying may permit intervention to reduce the substantial level of attributed to CDI. Numerous severity scores for CDI have been created for this purpose; however, to our knowledge, a systematic synthesis of the evidence upon which these scores are based has never been published. 10 Such a review would add additional objectivity to such scoring systems, and may permit future development of more accurate and evidence-based severity scores to identify patients at risk of. We aimed to systematically review the literature to identify previous studies investigating clinically useful markers of risk for in patients with CDI. Methods Search strategy The PubMed and Web of Knowledge databases were searched, which included MEDLINE 1950 to present, Web of Science with conference proceedings 1899 to present and BIOSIS Citation Index 1969 to present. Results were limited to publications in English, on research in humans, and published from 1978 onwards. Search terms included Clostridium difficile [MeSH], pseudomembranous colitis, pseudomembranous enterocolitis [MeSH], [MeSH], risk adjustment [MeSH], severity of illness index [MeSH] and severity. The date of the final search was 13 September A separate hand search of the bibliographies of articles identified in the primary search was undertaken to identify additional relevant studies. The search was performed independently by two authors (M.G.B. and J.C.S.). Any disagreements in article selection were resolved through discussion, and a third author (E.G.K.) was available to resolve disagreement. Inclusion criteria M.G. Bloomfield et al. / Journal of Hospital Infection 82 (2012) 1e12 Studies fulfilling the following criteria were included: (1) those which investigated the relationship between demographic, clinical or laboratory markers and all-cause or diseasespecific ; (2) risk markers that could be assessed early in the course of CDI, and assessments made before the onset of CDI-related complications; (3) CDI diagnosis was based on stool toxin assay, colonoscopy or sigmoidoscopy, or histopathological diagnosis; (4) hospital-based. All study types were eligible for inclusion. Conference or meeting abstracts were eligible for inclusion if they met the above criteria, there was no corresponding full text article available, and if they contained the following minimum data set: (1) number of participants; (2) number of deaths occurring in the ; (3) mean/median age of the ; (4) results of statistical tests to support conclusions. Exclusion criteria Studies were excluded if they had <100 participants, or if they were limited to one patient group, e.g. patients with inflammatory bowel disease, transplant patients, ICU patients. Data extraction and interpretation Data were extracted on to a pre-designed spreadsheet. Recorded study characteristics included year of publication, geographic location, study design, method of CDI diagnosis, risk markers assessed, timing of assessment, and primary outcome variable. Participant characteristics included total number, age, and sex. Study results included number of deaths, risk markers associated with outcome (with P < 0.05), risk markers not associated with outcome (P > 0.05), and magnitude of association. Results from multivariate analyses were favoured over results from univariate analyses. Risk markers from the included studies that could not be assessed early in the course of illness, e.g. ribotype, were not extracted. Risk markers that had been evaluated by at least four separate studies were included in the review. The judgement as to whether a parameter may be a useful risk marker for was based on the number of studies demonstrating an association versus the number notdthe sizedof those studies, and the magnitude of association. Results Search results Results of the database search are given in Figure 1. The initial search returned 1617 papers. Screening of titles and abstracts resulted in 1527 exclusions, leaving 90 articles to source in full text. Review of full text articles resulted in a further 65 exclusions. One additional relevant article was found in the hand search of bibliographies, leaving 26 papers in total for the review, including one conference abstract. 11,12 Included studies Characteristics of the studies identified by the literature search are given in Table I. Only two studies were performed outside of the USA, UK or Canada, with the USA accounting for the majority. Twenty-two of 26 studies based their analyses on retrospective data, mostly relying on medical and laboratory records, and administrative data. Most studies used enzyme immunoassays (EIAs) for CDI diagnosis. Cohort size varied from 108 to 2571 participants, with 17 of 26 studies having <250 participants. The mean/median age of s was 46.8e82.1 years, with more than half having a mean/median age of 65 years. There was a female predominance in most s. Variations on all-cause and CDI-specific were used as outcome measures, and several studies used composite outcomes. All-cause was the most commonly used metric, with only six studies using disease-specific

3 M.G. Bloomfield et al. / Journal of Hospital Infection 82 (2012) 1e12 3 Database search: PubMed: 512 articles Web of Knowledge: 1105 articles N = 1527 Articles excluded after screening of titles and abstracts according to inclusion/exclusion criteria 90 articles for review of full text N = 14 Fewer than 100 participants N = 13 Did not base diagnosis on toxin assay, endoscopy, or pathology, or did not state method of diagnosis N = 12 Did not examine individual risk markers or not an outcome N = 8 N = 5 N = 5 N = 4 N = 3 N = 1 Limited to patients with already complicated or fulminant disease Included patients without CDI Conference abstracts or letters not meeting the minimum data set Limited to one patient group Duplicates/based on same as other articles Risk markers not amenable to early assessment 25 articles + 1 article identified in review of full text bibliographies = 26 articles included in review Figure 1. Database search results for studies evaluating potential risk markers for in Clostridium difficile infection (CDI).. The experience of the s varied from 3.5% to 38.0%. In all except one of the studies using composite outcomes, deaths accounted for the majority of these endpoints. Results of studies: clinical factors Results of the studies identified in the review are given in Tables II and III. Six potential clinical risk markers had been evaluated by at least four studies. Pepin et al. reported results from two separate s, one collected from 1991 to 2002 and one from 2003 to 2006; these were regarded as two distinct sets of results. 13 The majority of potential clinical risk markers were assessed close to the time of CDI diagnosis. For many potential risk markers, various cut-off values were used to define risk groups in the different s. Most studies presented odds ratios (ORs) and 95% confidence intervals derived from logistic regression models, but some only reported P-values, particularly for parameters not associated with outcome. Most parameters that were associated with outcome were assessed in multivariate models, whereas a larger proportion of those not associated with outcome were excluded from analysis at the univariate stage. In 10 of 17 s white blood cell count (WBC) was associated with outcome. Of the 10, seven used /L as the cut-off level. Studies not demonstrating an association tended to be smaller and use lower cut-offs. ORs in s in which WBC was associated with outcome were often relatively large, the majority being 3.0. Serum creatinine level was associated with outcome in six of 13 s. Studies showing an association with outcome tended to use a higher cut-off, most commonly 200 mmol/l, and a rise in creatinine level of >50% from baseline was significant in two studies. ORs were again often relatively large, several being >4.0. Serum albumin level was significantly associated with outcome in seven studies. Cut-off levels of <25e35 g/l were most frequently used. Only one of nine s evaluating temperature identified an association with outcome. Haemoglobin/haematocrit and

4 Table I Characteristics of studies evaluating potential risk markers for in CDI Study Year Country Study design Diagnostic method N Mean/median age % Female Outcome variable used in analysis Deaths No. (%) As a % of total outcomes 40 (9%) 100% Bauer et al European countries Cohort EIA/CA/ CC/PCR day CDI-related Fujitani et al USA Cohort EIA day CDI-related e e, ICU admission, or surgery Manek et al Canada Retrospective EIA 305 a Multiple b 50 (16.4%) 52% McGowan et al UK Retrospective EIA day all-cause 834 (32.4%) 100% Bhangu et al UK Retrospective EIA day all-cause 56 (27.5%) 100% Bhangu et al UK Retrospective TA e 30-day all-cause 60 (38.0%) 100% in-hospital Cadena et al USA Retrospective EIA day all-cause 38 (29.5%) 100% Das et al USA Retrospective EIA day all-cause 136 (12.1%) 100% Dudukgian et al USA Retrospective EIA/CS All-cause 41 (10.3%) 100% Naggie et al USA Retrospective EIA 108 e e 60-day all-cause 15 (13.9%) 100% Pant et al USA Retrospective EIA 184 e day all-cause 25 (13.6%) 100% Southern et al USA Retrospective TA day all-cause e 100% Wilson et al UK Cohort EIA þ C c 128 e day all-cause 46 (35.9%) 100% Gravel et al Canada Cohort CA/TA/ day CDI-related 82 (5.7%) 79% CS/PA, ICU Gujja et al USA Retrospective Henrich et al USA Retrospective Umoh et al USA Retrospective admission, or colectomy EIA CDI-related or colectomy CA day CDI-related, ICU admission, surgery or perforation TA CDI-related or colectomy 20 (10.0%) 63% 21 (6.3%) 51% 18 (14%) 78% 4 M.G. Bloomfield et al. / Journal of Hospital Infection 82 (2012) 1e12

5 Valiquette et al Canada Retrospective Hardt et al Germany Retrospective Labbe et al Canada Retrospective Pepin et al Canada Retrospective Andrews et al Canada Retrospective Morris et al USA Retrospective Dharmarajan et al USA Retrospective Jobe et al USA Retrospective Prendergast et al USA Retrospective CA day all-cause, colectomy, perforation, megacolon or septic shock 34 (20.6%) 68% TA day all-cause 13 (10.5%) 100% CA e day all-cause 55 (23.9%) 100% CA/CS 1616 e day all-cause 170 (10.5%) 77%, colectomy, perforation, megacolon or septic shock EIA/CS All-cause in-hospital 10 (6.5%) 23%, ICU admission, colectomy, admission >14 days EIA day all-cause 24 (15.3%) 100% EIA/CS All-cause 27 (22.3%) 100% CA All-cause 7 (3.5%) 100% LA/TA All-cause 16 (8.0%) 100% CDI, Clostridium difficile infection; N, sample size; EIA, enzyme immunoassay; CA, cytotoxin assay; CC, cytotoxigenic culture; PCR, polymerase chain reaction; TA, toxin assay, but actual method not stated; CS, colonoscopy/sigmoidoscopy; C, culture; PA, pathological diagnosis; LA, latex agglutination. Where a time period for is not specified in the table it reflects this not being specified as a criterion for in the corresponding study. Unless otherwise stated, location of was not limited to in-hospital deaths. a Included relapse episodes in their analysis, so was based on 365 episodes of CDI from 305 patients. b Outcome included any of: all-cause prior to completion of CDI treatment, ICU admission, perforation, megacolon, severe hypokalaemia or lower GI bleeding requiring transfusion. c Inclusion in required positive EIA plus confirmatory culture. M.G. Bloomfield et al. / Journal of Hospital Infection 82 (2012) 1e12 5

6 6 M.G. Bloomfield et al. / Journal of Hospital Infection 82 (2012) 1e12 Table II Potential clinical risk markers for in CDI, evaluated by four or more studies Risk marker Study N Timing of risk marker assessment Cut-off used to signify OR (95% CI) presence of risk marker WBC (10 9 /L) Gujja et al. 27 * 200 Initiation of CDI treatment > (1.3, 12.9) Fujitani et al. 10 * 184 At CDI diagnosis > (1.1, 17.7) Bhangu et al. 17 * 204 Peak within week of diagnosis > (1.9, 9.3) a Dudukgian et al. 21 * 398 Peak during CDI treatment >20 e Henrich et al. 28 * 336 Peak 4 days before to 2 days > (1.3, 6.0) after diagnosis Pepin et al. (1) 13 * 773 Peak within week of diagnosis > (1.6, 8.2) Pepin et al. (2) 13 * 843 Peak within week of diagnosis > (2.7, 11.1) Labbe et al. 30 * 230 Peak within week of diagnosis 20e49.9 vs < (1.8, 7.6) a Manek et al. 15 * 305 Peak in 48 h after diagnosis Per unit increase 1.0 (1.0, 1.1) Bhangu et al. 18 * 158 Peak in 72 h after diagnosis Per 10% increase 1.1 (1.0, 1.2) Pant et al At CDI diagnosis > (0.7, 6.0) Umoh et al e >18 e Bauer et al Last level in week prior to diagnosis > (0.7, 3.4) a Wilson et al At CDI diagnosis > (0.5, 2.6) a Andrews et al At CDI diagnosis > (0.8, 3.2) a Das et al Peak during admission Mean e Prendergast et al Peak during admission Mean P ¼ 0.07 Creatinine (mmol/l) Pant et al. 23 * 184 At CDI diagnosis > (1.8, 13.9) Pepin et al. (1) 13 * 773 Peak within week of diagnosis > (2.0, 8.8) Pepin et al. (2) 13 * 843 Peak within week of diagnosis > (1.8, 6.0) Henrich et al. 28 * 336 Peak 4 days before to 2 days > (1.0, 5.9) after diagnosis Gujja et al. 27 * 200 Initiation of CDI treatment >50% rise from baseline b 7.1 (3.1, 16.7) Labbe et al. 30 * 230 Peak within week of diagnosis >50% rise from baseline c 6.5 (3.1, 13.7) a Dharmarajan et al e >133 P ¼ 0.11 a Wilson et al At CDI diagnosis > (0.8, 3.5) a Bauer et al e >50% rise from baseline c 2.3 (0.6, 8.6) a Umoh et al e Median 1.2 (1.0, 1.4) a Manek et al Peak in 48 h after diagnosis Mean e Bhangu et al Peak within week of diagnosis Mean P ¼ 0.18 a Das et al Peak during admission Mean e Albumin (g/l) Dharmarajan et al. 33 * 121 e <35 P < 0.05 a Fujitani et al. 10 * 184 At CDI diagnosis < (1.3, 17.7) Wilson et al. 25 * 128 At CDI diagnosis < (1.3, 7.8) Henrich et al. 28 * 336 Peak 4 days before to 2 days < (1.6, 7.6) after diagnosis Bhangu et al. 18 * 158 Peak in 72 h after diagnosis Per unit increase 0.9 (0.9, 1.0) Manek et al. 15 * 305 Peak in 48 h after diagnosis Mean P < a Bhangu et al. 17 * 204 Peak within week of diagnosis Mean P ¼ Pant et al At CDI diagnosis < (0.5, 4.6) Umoh et al e Median e Gujja et al Initiation of CDI treatment Mean P ¼ 0.45 a Prendergast et al At CDI diagnosis Mean P ¼ 0.24 Temperature Fujitani et al. 10 * 184 At CDI diagnosis >38.0 C 4.7 (1.1, 21.0) Bauer et al e >38.5 C 1.3 (0.6, 2.8) a Dharmarajan et al e >38.3 C P ¼ 0.18 a Andrews et al At CDI diagnosis >38.0 C 0.6 (0.3, 1.5) a Gujja et al Initiation of CDI treatment Mean P ¼ 0.82 a Prendergast et al Peak during admission Mean P ¼ 0.34 Manek et al Peak in 48 h after diagnosis e P ¼ 0.63 a Pepin et al. (1) Peak within week of diagnosis e e Pepin et al. (2) Peak within week of diagnosis e e

7 M.G. Bloomfield et al. / Journal of Hospital Infection 82 (2012) 1e12 7 Table II (continued) Risk marker Study N Timing of risk marker assessment Cut-off used to signify OR (95% CI) presence of risk marker Hb/Hct Gujja et al Initiation of CDI treatment >100 g/l (Hb) 1.1 (0.5, 2.6) Umoh et al e <100 g/l (Hb) 1.6 (0.7, 4.0) a Fujitani et al At CDI diagnosis >5% increase (Hct) d 0.6 (0.2, 1.7) a Das et al Peak during admission Per unit increase (Hct) 1.0 (1.0, 1.0) a Andrews et al At CDI diagnosis Per unit increase (Hb) 1.0 (1.0, 1.0) a Prendergast et al e Mean (Hct) P ¼ 0.75 Diarrhoea severity Manek et al Peak in 48 h after diagnosis Mean no. of stools P ¼ 0.08 a Wilson et al At CDI diagnosis 5 stools in first 24 h 1.2 (0.5, 2.6) a Andrews et al At CDI diagnosis e 1.0 (0.9, 1.1) a Prendergast et al e e P ¼ 0.49 CDI, Clostridium difficile infection; N, sample size; OR, odds ratio; CI, confidence interval; WBC, white blood cell count; Hb, haemoglobin; Hct, haematocrit. * Studies finding a significant association between risk marker and outcome. Pepin et al. (1) refers to the 1991e2002, and Pepin et al. (2) refers to the 2003e2006. The ORs reported reflect the odds of the outcome occurring in patients in which the risk marker is present. Where per unit/% increase is stated in the cut-off column, the corresponding OR reflects the increase in odds of outcome per unit/% change in the risk marker. Where Mean or Median is stated in the cut-off column, the corresponding study tested the difference in mean/median value of the risk marker between those experiencing the outcome and those not experiencing the outcome. ORs and 95% CIs have been rounded to one decimal place and P-values to two significant figures. Due to this, some of the 95% CIs reported as significant appear to include the null value of 1.0, whereas in their original form they did not. a OR/P-value generated from univariate, rather than multivariate, analysis. b Baseline defined as lowest creatinine level in first 24 h of admission. c Baseline creatinine level definition not reported. d Definition of 5% increase in haematocrit not reported. diarrhoea severity were assessed by six and four studies, respectively, and were not associated with outcome. Results of studies: demographic/comorbidity factors Ten different potential demographic or comorbidity risk markers had been evaluated by at least four studies (Table III). In nine of 19 s increasing age was associated with outcome, with three of these studies having >1000 participants. Age >65e75 years was the most common cut-off to be associated with outcome. Those not demonstrating an association were often smaller, and tended to compare mean age between survivors and non-survivors. Hospital-acquisition of disease was defined in a variety of ways, with one of eight s reporting an association with outcome. Three of four studies evaluating the Charlson Index identified a significant association, including the large study of Das et al. 20,36 Preexisting immunocompromise was associated with outcome in two of nine s. Corticosteroid use was assessed by five studies, with three finding an association with outcome, again including the study of Das et al., which was designed specifically to investigate steroid use and CDI outcome. Only one out of five and seven s, respectively, reported nasogastric tube use and pre-existing renal disease to be associated with outcome. Sex, diabetes, and cancer were not significantly associated with outcome. Discussion Summary of main results There has been considerable interest in potential risk markers for in CDI in recent years, reflected by the fact that more than two-thirds of the studies identified in this review have been published since We have identified a moderately large number of studies on this topic, with several factors found on multiple occasions to be significantly associated with. The following parameters had the most evidence to support their use as markers of risk for in CDI when assessed at or near the time of diagnosis: age, most likely with a cut-off between >65 and 75 years; WBC, with a cut-off of > /L; serum creatinine, possibly with a cut-off of >200 mmol/l; and serum albumin, most likely with a cut-off of <25e35 g/l. These parameters all have the potential to be useful components of a risk score, as they can be assessed cheaply, objectively and in a timely manner early in the course of CDI. Of the lesser-studied parameters, corticosteroid use and Charlson Index appeared to show some promise as potential risk markers. By contrast, temperature, haemoglobin level/haematocrit, sex, severity of diarrhoea, hospital-acquired disease, presence of renal disease, diabetes, cancer and nasogastric tube use did not appear to be associated with outcome in patients with CDI. Several of these parameters, along with others such as abdominal tenderness and radiological findings, have been incorporated into various severity scores for CDI; however, we have found little evidence to support their use, raising questions about the ongoing inclusion of these parameters in established CDI severity scores. 10 Risk markers Whereas age, WBC, serum creatinine and serum albumin each had a large number of s demonstrating significant associations with outcome, each parameter had several studies in which no association was found. The negative studies tended

8 8 M.G. Bloomfield et al. / Journal of Hospital Infection 82 (2012) 1e12 Table III Potential demographic/comorbidity risk markers for in CDI, evaluated by four or more studies Risk marker Study N Cut-off/definition used OR (95% CI) to signify presence of risk marker Age (years) McGowan et al. 16 * e79 vs < (2.2, 6.5) a >80 vs < (3.4, 10.0) a >80 vs 60e (1.3, 1.9) a Labbe et al. 30 * 230 > (1.3, 8.0) Henrich et al. 28 * 336 > (1.5, 7.6) Andrews et al. 31 * 153 > (1.8, 8.6) Pepin et al.(1) 13 * 773 > (1.1, 4.0) Bauer et al. 14 * 442 > (1.1, 9.8) Das et al. 20 * 1126 Per year increase 1.0 (1.0, 1.1) b,c Gravel et al. 26 * 1430 Per year increase 1.0 (1.0, 1.0) d Bhangu et al. 17 * 204 Median P < a Pant et al > (0.1, 3.0) Wilson et al > (0.9, 5.1) a Pepin et al. (2) > (0.8, 2.5) Bhangu et al Per year increase 1.0 (1.0, 1.1) a Fujitani et al Mean e Manek et al Mean e Dudukgian et al Mean P ¼ a Gujja et al Mean P ¼ 0.37 a Umoh et al Mean 1.0 (1.0, 1.0) a Prendergast et al Mean P ¼ 0.22 Sex Fujitani et al Female 0.8 (0.3, 2.1) a Manek et al Female P ¼ 0.07 a Pant et al Female 0.5 (0.2, 1.3) Henrich et al Female 0.9 (0.4, 2.0) Umoh et al Female 1.0 (0.4, 2.4) a Andrews et al Female 0.9 (0.6, 1.3) a Wilson et al Male 1.0 (0.5, 2.1) a Gujja et al Male 1.0 (0.5, 2.2) a,d Labbe et al Male 1.3 (0.7, 2.3) a Pepin et al. (1) Male e Pepin et al. (2) Male 1.4 (1.0, 2.1) a Bhangu et al N/A P ¼ 0.87 a McGowan et al e 1.1 (0.9, 1.3) a Dharmarajan et al e P ¼ 0.55 a Hospital-acquired disease Pepin et al. (1) 13 * 773 Inpatient for at least 2.8 (1.4, 5.8) 1 night in 2 months prior to diagnosis Bauer et al Onset >48 h after 4.9 (0.6, 40.0) admission or inpatient in prior 4 weeks Fujitani et al e 0.8 (0.3, 2.2) a Manek et al Onset >72 h after P ¼ 0.67 a admission or in HCF in prior 8 weeks Naggie et al Onset >72 h after admission or P ¼ 0.06 a in HCF in prior 12 weeks Umoh et al e 1.7 (0.7, 4.1) a Pepin et al. (2) Inpatient for at least 1 night in 2.1 (0.9, 4.8) 2 months prior to diagnosis Andrews et al NH resident or hospitalized >24 h in prior 60 days 1.4 (0.7, 2.9) a

9 M.G. Bloomfield et al. / Journal of Hospital Infection 82 (2012) 1e12 9 Table III (continued) Risk marker Study N Cut-off/definition used to signify presence of risk marker OR (95% CI) Charlson Index Labbe et al. 30 * points 22.2 (2.3, 216.0) Das et al. 20 * 1126 Per point increase 1.1 (1.1, 1.1) b Umoh et al. 12 * 128 e 1.3 (1.0, 1.6) Cadena et al e 1.2 (1.0, 1.5) Immunocompromise Pepin et al. (1) 13 * 773 Multiple e 2.7 (1.5, 4.9) Pepin et al. (2) 13 * 843 Multiple e 3.1 (1.8, 5.6) Dudukgian et al e P ¼ 0.56 a Wilson et al e 1.1 (0.4, 2.9) a Gujja et al Multiple f 1.5 (0.7, 3.3) a,d Henrich et al Multiple g 0.4 (0.1, 2.0) Umoh et al e 1.7 (0.7, 4.0) a Labbe et al Multiple h 0.6 (0.2, 1.7) a Morris et al Multiple i P > 0.05 a Steroid use Das et al. 20 * 1126 Any systemic use in 15 days 2.1 (1.9, 2.3) b prior to diagnosis Dudukgian et al. 21 * 398 e P < 0.05 Prendergast et al. 35 * 201 e P ¼ 0.01 Cadena et al e e Henrich et al Any systemic use in 30 days prior to diagnosis 1.1 (0.5, 2.7) Nasogastric tube use Pepin et al. (1) 13 * 773 Use in 2 months prior 2.0 (1.0, 3.8) to diagnosis Fujitani et al e 1.1 (0.4, 3.3) a Manek et al e P ¼ 0.44 a Pepin et al. (2) Use in 2 months prior 1.5 (0.9, 2.6) to diagnosis Dharmarajan et al e P ¼ 0.24 a Renal disease Dudukgian et al. 21 * 398 e P < 0.05 Fujitani et al e 1.8 (0.6, 5.0) a Manek et al e P ¼ 0.22 a Wilson et al e 1.7 (0.8, 3.5) a Henrich et al Physician-documented 0.5 (0.8, 3.0) diagnosis Morris et al e P > 0.05 a Prendergast et al e P ¼ 0.53 Diabetes Fujitani et al e 1.0 (0.4, 2.9) a Manek et al e P ¼ 0.44 a Dudukgian et al e P ¼ 0.14 a Wilson et al e 0.4 (0.1, 1.4) a Henrich et al Physician-documented P ¼ 1.0 diagnosis Morris et al e P > 0.05 a Dharmarajan et al e P ¼ 0.62 a Prendergast et al e P ¼ 0.67 (continued on next page)

10 10 M.G. Bloomfield et al. / Journal of Hospital Infection 82 (2012) 1e12 Table III (continued) Risk marker Study N Cut-off/definition used to signify presence of risk marker OR (95% CI) Cancer Fujitani et al e 2.8 (1.1, 7.3) a Manek et al e P ¼ 0.96 a Dudukgian et al e P ¼ 0.25 a Wilson et al e 1.4 (0.6, 3.3) a Henrich et al Physician-documented 0.7 (0.3, 1.7) diagnosis Prendergast et al e P ¼ 0.70 CDI, Clostridium difficile infection; N, sample size; OR, odds ratio; CI, confidence interval; HCF, healthcare facility; NH, nursing home. Pepin et al. (1) refers to the 1991e2002, and Pepin et al. (2) refers to the 2003e2006. The ORs reported reflect the odds of the outcome ( or composite score) occurring in patients in which the risk marker is present. Where per year/point increase is stated in the cut-off column, the corresponding OR reflects the increase in odds of outcome per year/point change in the risk marker. Where Mean or Median is stated in the cut-off column, the corresponding study tested the difference in mean/median value of the risk marker between those experiencing the outcome and those not experiencing the outcome. * Studies finding a significant association between risk marker and outcome. ORs and 95% CIs have been rounded to one decimal place and P-values to two significant figures. Due to this, some of the 95% CIs reported as significant appear to include the null value of 1.0, whereas in their original form they did not. a OR/P-value generated from univariate, rather than multivariate, analysis. b This is a hazard ratio, with 95% CI. c The original ORs for Das et al. and Gravel et al. were 1.04 (1.03, 1.05) and 1.02 (1.01, 1.04), respectively. d This is a relative risk, with 95% CI. e Defined as presence of human immunodeficiency virus (HIV), leukaemia, lymphoma, organ transplant, neutropenia, immunosuppressive drug use or systemic corticosteroids for >1 month. f Defined as presence of HIV, diabetes, transplant and on immunosuppressants, solid organ or haematological malignancy, haemodialysis, or corticosteroid use 10 mg. g Defined as presence of solid organ or haematopoietic stem cell transplant, immunoglobulin deficiencies, immunosuppressive drug use or severe autoimmune syndromes. h Defined as presence of HIV, leukaemia, lymphoma, chemotherapy in last two months, or renal or stem cell transplantation. i Defined as presence of HIV, on transplant medications or chemotherapy. to be smaller in size, so may have lacked power to detect an association. The major exception to this was the study of Das et al., in which WBC and serum creatinine were not associated with outcome. 20 However, Das et al. used the patient s highest WBC and creatinine levels during their entire admission, rather than the level at or around the time of diagnosis, which may have reduced the applicability of the results in this context. Negative studies for WBC, creatinine and albumin also tended to use lower cut-off levels, suggesting that these levels may be less useful for discriminating between high- and lowrisk patients. Charlson Index was consistently associated with outcome, but was designed to quantify comorbidity for research purposes rather than in clinical practice, and involves calculating a score based on 19 comorbidities, so would be unlikely to be useful clinically as part of a risk score for patients with CDI. 36 Negative findings for several of the potential risk markers may have been affected by study methodologies. Type II error relating to small sample size and low power may mean that associations between risk markers and were missed. Severity of diarrhoea is likely to be difficult to assess from retrospective record review, which may in part explain the lack of association seen. The definition of hospitalacquired disease varied considerably between studies, again making it difficult to conclude based on this evidence that it is not associated with. Similarly, whereas several of the negative studies examining immunocompromise may have lacked sufficient power, it is difficult to draw conclusions regarding its usefulness as a risk marker given the heterogeneity in the definitions of immunocompromise used. Quality of the evidence The studies identified in this review have several potential limitations. The majority of studies were retrospective, with investigators relying on routinely collected data. As a result, due to limited available data, many analyses were only able to examine a select few potential risk markers. This also affected reporting of comorbidities, which were extracted directly from records, without prospective diagnostic criteria. A minority of studies reported significant associations based on univariate analyses, and therefore will not have accounted for the effect of one risk marker on another in their models. Most studies employed single stage stool testing procedures, often using an EIA, without confirmatory testing. EIAs have been criticized both for poor sensitivity and specificity when used as a sole means of diagnosis, with the latter resulting in false-positive results. 37,38 Consequently, many of these s are likely to be contaminated with patients without true CDI. This may have been particularly problematic in the retrospective studies that used laboratory records of toxin-positive patients to assemble their s, where inclusion in the did not also require the presence of diarrhoea. Most studies used all-cause as their endpoint, rather than CDI-specific. As a result, the risk markers identified by these

11 studies may have less relevance in aiding treatment decisions for CDI. However, it is understandable that most studies have used all-cause, because death certification of CDI is known to be poor. 39 Although several studies employed composite endpoints in their analyses, deaths accounted for the majority of outcomes in most of these studies. It is therefore likely that their results are still relevant with respect to the outcome of alone. Furthermore, given that 17 of 26 studies had as their sole outcome variable, it seems likely that the potential risk markers identified in this review are applicable to the outcome of. We did not objectively score studies for methodological quality, but our strict inclusion and exclusion criteria will have selected for studies with more robust methodologies. The baseline characteristics we extracted from studies also permitted an assessment of the quality of included studies with respect to study design, inclusion criteria, size and outcome measure. As such, we believe the overall quality of the majority of studies presented in this review to be acceptable. Potential limitations of the review process There was marked variability between studies in how risk markers were assessed, which cut-offs were used and how associations were reported. As a result a formal meta-analysis of results was impossible. Pooled statistics for each risk marker would have permitted objective interpretation of the evidence at hand, rather than the more subjective, narrative approach we were required to take, and also would have mitigated problems relating to individual studies lacking power. The inability to meta-analyse also meant that it was impossible to formally test for publication bias with funnel plots or other tests. It seems likely that publication bias has affected the results of this review, given the large number of small studies reporting significant associations, but it is difficult to determine the likely magnitude of this effect. We attempted to reduce the impact of publication bias by applying a comprehensive search strategy, and by excluding studies with <100 participants. External validity Observed relationships between risk markers and may have been influenced by local CDI epidemiology, particularly given the problems experienced in the USA, UK and Canada with the virulent NAP1/B1/027 strain of C. difficile at the times many of the studies in this review were conducted. 4,6 This may limit the generalizability of these studies to other countries and time periods, as the relationship between risk markers and may differ in epidemic versus endemic CDI. 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