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

  • M.G. Bloomfield
    Correspondence
    Corresponding author. Address: Department of Clinical Microbiology, University College London Hospital NHS Foundation Trust, 65 Whitfield Street, London W1T 4EU, UK. Tel.: +44 7403 568687; fax: +44 2034 778992.
    Affiliations
    Department of Clinical Microbiology, University College London Hospital NHS Foundation Trust, London, UK

    Department of Public Health and Primary Care, Institute of Public Health, The University of Cambridge, Cambridge, UK
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  • J.C. Sherwin
    Affiliations
    Department of Public Health and Primary Care, Institute of Public Health, The University of Cambridge, Cambridge, UK
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  • E. Gkrania-Klotsas
    Affiliations
    Department of Infectious Diseases, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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      Summary

      Background

      Clostridium difficile infection (CDI) is one of the most important healthcare-associated infections, causing considerable mortality. Numerous severity scores have been proposed to identify patients with CDI at risk of mortality, 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 mortality.

      Aim

      A systematic review of the published literature investigating clinically useful risk markers for mortality 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 cohort 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 mortality. 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 mortality.

      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 mortality 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.

      Keywords

      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.
      • Rupnik M.
      • Wilcox M.H.
      • Gerding D.N.
      Clostridium difficile infection: new developments in epidemiology and pathogenesis.
      Substantial rises in the reported incidence of CDI 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.
      • Kelly C.P.
      • LaMont J.T.
      Clostridium difficile – more difficult than ever.
      • Pépin J.
      • Valiquette L.
      • Alary M.-E.
      • et al.
      Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity.
      • Kuijper E.J.
      • Coignard B.
      • Tüll P.
      Emergence of Clostridium difficile-associated disease in North America and Europe.
      • Anonymous
      Rates of Clostridium difficile infection among hospitalised patients aged ≥65 years, by age group – National Hospital Discharge Survey, United States, 1996–2009.
      In addition to the rise in incidence, significant increases in severity of infection and mortality due to the disease have been observed.
      • Pépin J.
      • Valiquette L.
      • Alary M.-E.
      • et al.
      Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity.
      • Loo V.G.
      • Poirier L.
      • Miller M.A.
      • et al.
      A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality.
      A recent review of mortality due to CDI found pooled attributable mortality of 8.03% in studies reported since the year 2000, compared with 3.64% in those reported before 2000.
      • Karas J.A.
      • Enoch D.A.
      • Aliyu S.H.
      A review of mortality due to Clostridium difficile infection.
      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.
      • Zar F.A.
      • Bakkanagari S.R.
      • Moorthi K.M.L.S.T.
      • Davis M.B.
      A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity.
      • Gerding D.N.
      • Johnson S.
      Management of Clostridium difficile infection: thinking inside and outside the box.
      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 mortality 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.
      • Fujitani S.
      • George W.L.
      • Murthy A.R.
      Comparison of clinical severity score indices for Clostridium difficile infection.
      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 mortality. We aimed to systematically review the literature to identify previous studies investigating clinically useful markers of risk for mortality 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], ‘mortality’ [MeSH], ‘risk adjustment’ [MeSH], ‘severity of illness index’ [MeSH] and ‘severity’. The date of the final search was 13 September 2011. 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

      Studies fulfilling the following criteria were included: (1) those which investigated the relationship between demographic, clinical or laboratory markers and all-cause or disease-specific mortality; (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 cohort; (3) mean/median age of the cohort; (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 mortality was based on the number of studies demonstrating an association versus the number not—the size—of 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.
      • Valiquette L.
      • Pépin J.
      • Do X.V.
      • et al.
      Prediction of complicated Clostridium difficile infection by pleural effusion and increased wall thickness on computed tomography.
      • Umoh N.
      • Sucandy I.
      • Dancea H.
      • Choi L.
      • Esolen L.
      • Olson M.
      Predictors of fulminant colitis and mortality in patients with Clostridium difficile infection.
      Figure thumbnail gr1
      Figure 1Database search results for studies evaluating potential risk markers for mortality in Clostridium difficile infection (CDI).

      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 cohorts was 46.8–82.1 years, with more than half having a mean/median age of ≥65 years. There was a female predominance in most cohorts. Variations on all-cause and CDI-specific mortality were used as outcome measures, and several studies used composite outcomes. All-cause mortality was the most commonly used mortality metric, with only six studies using disease-specific mortality. The mortality experience of the cohorts 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.
      Table ICharacteristics of studies evaluating potential risk markers for mortality in CDI
      StudyYearCountryStudy designDiagnostic methodNMean/median age% FemaleOutcome variable used in analysisDeaths
      No. (%)As a % of total outcomes
      Bauer et al.
      • Bauer M.P.
      • Notermans D.W.
      • van Benthem B.H.B.
      • et al.
      Clostridium difficile infection in Europe: a hospital-based survey.
      201134 European countriesCohortEIA/CA/CC/PCR442715690-day CDI-related mortality40 (9%)100%
      Fujitani et al.
      • Fujitani S.
      • George W.L.
      • Murthy A.R.
      Comparison of clinical severity score indices for Clostridium difficile infection.
      2011USACohortEIA184704730-day CDI-related mortality, ICU admission, or surgery
      Manek et al.
      • Manek K.
      • Williams V.
      • Callery S.
      • Daneman N.
      Reducing the risk of severe complications among patients with Clostridium difficile infection.
      2011CanadaRetrospective cohortEIA305
      Included relapse episodes in their analysis, so was based on 365 episodes of CDI from 305 patients.
      7148Multiple
      Outcome included any of: all-cause mortality prior to completion of CDI treatment, ICU admission, perforation, megacolon, severe hypokalaemia or lower GI bleeding requiring transfusion.
      50 (16.4%)52%
      McGowan et al.
      • Mcgowan A.P.
      • Lalayiannis L.C.
      • Sarma J.B.
      • Marshall B.
      • Martin K.E.
      • Welfare M.R.
      Thirty-day mortality of Clostridium difficile infection in a UK National Health Service Foundation Trust between 2002 and 2008.
      2011UKRetrospective cohortEIA2571826430-day all-cause mortality834 (32.4%)100%
      Bhangu et al.
      • Bhangu A.
      • Czapran A.
      • Bhangu S.
      • Pillay D.
      Optimum timing of blood tests for monitoring patients with Clostridium difficile-associated diarrhea.
      2010UKRetrospective cohortEIA204816030-day all-cause mortality56 (27.5%)100%
      Bhangu et al.
      • Bhangu S.
      • Bhangu A.
      • Nightingale P.
      • Michael A.
      Mortality and risk stratification in patients with Clostridium difficile-associated diarrhoea.
      2010UKRetrospective cohortTA1588230-day all-cause in-hospital mortality60 (38.0%)100%
      Cadena et al.
      • Cadena J.
      • Thompson G.R.
      • Patterson J.E.
      • et al.
      Clinical predictors and risk factors for relapsing Clostridium difficile infection.
      2010USARetrospective cohortEIA12967590-day all-cause mortality38 (29.5%)100%
      Das et al.
      • Das R.
      • Feuerstadt P.
      • Brandt L.J.
      Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with Clostridium difficile-associated disease.
      2010USARetrospective cohortEIA1126655930-day all-cause mortality136 (12.1%)100%
      Dudukgian et al.
      • Dudukgian H.
      • Sie E.
      • Gonzalez-Ruiz C.
      • Etzioni D.A.
      • Kaiser A.M.
      C. difficile colitis – predictors of fatal outcome.
      2010USARetrospective cohortEIA/CS3985952All-cause mortality41 (10.3%)100%
      Naggie et al.
      • Naggie S.
      • Frederick J.
      • Pien B.C.
      • et al.
      Community-associated Clostridium difficile infection: experience of a veteran affairs medical center in southeastern USA.
      2010USARetrospective cohortEIA10860-day all-cause mortality15 (13.9%)100%
      Pant et al.
      • Pant C.
      • Madonia P.
      • Minocha A.
      • Manas K.
      • Jordan P.
      • Bass P.
      Laboratory markers as predictors of mortality in patients with Clostridium difficile infection.
      2010USARetrospective cohortEIA1845030-day all-cause mortality25 (13.6%)100%
      Southern et al.
      • Southern W.N.
      • Rahmani R.
      • Aroniadis O.
      • et al.
      Postoperative Clostridium difficile-associated diarrhea.
      2010USARetrospective cohortTA481686490-day all-cause mortality100%
      Wilson et al.
      • Wilson V.
      • Cheek L.
      • Satta G.
      • et al.
      Predictors of death after Clostridium difficile infection: a report on 128 strain-typed cases from a teaching hospital in the United Kingdom.
      2010UKCohortEIA + C
      Inclusion in cohort required positive EIA plus confirmatory culture.
      1285030-day all-cause mortality46 (35.9%)100%
      Gravel et al.
      • Gravel D.
      • Miller M.
      • Simor A.
      • et al.
      Health care-associated Clostridium difficile infection in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial Infection Surveillance Program study.
      2009CanadaCohortCA/TA/CS/PA1430704930-day CDI-related mortality, ICU admission, or colectomy82 (5.7%)79%
      Gujja et al.
      • Gujja D.
      • Friedenberg F.K.
      Predictors of serious complications due to Clostridium difficile infection.
      2009USARetrospective cohortEIA2006657CDI-related mortality or colectomy20 (10.0%)63%
      Henrich et al.
      • Henrich T.J.
      • Krakower D.
      • Bitton A.
      • Yokoe D.S.
      Clinical risk factors for severe Clostridium difficile-associated disease.
      2009USARetrospective cohortCA336644830-day CDI-related mortality, ICU admission, surgery or perforation21 (6.3%)51%
      Umoh et al.
      • Umoh N.
      • Sucandy I.
      • Dancea H.
      • Choi L.
      • Esolen L.
      • Olson M.
      Predictors of fulminant colitis and mortality in patients with Clostridium difficile infection.
      2009USARetrospective cohortTA1286552CDI-related mortality or colectomy18 (14%)78%
      Valiquette et al.
      • Valiquette L.
      • Pépin J.
      • Do X.V.
      • et al.
      Prediction of complicated Clostridium difficile infection by pleural effusion and increased wall thickness on computed tomography.
      2009CanadaRetrospective cohortCA165705530-day all-cause mortality, colectomy, perforation, megacolon or septic shock34 (20.6%)68%
      Hardt et al.
      • Hardt C.
      • Berns T.
      • Treder W.
      • Dumoulin F.-L.
      Univariate and multivariate analysis of risk factors for severe Clostridium difficile-associated diarrhoea: importance of co-morbidity and serum C-reactive protein.
      2008GermanyRetrospective cohortTA124765730-day all-cause mortality13 (10.5%)100%
      Labbe et al.
      • Labbe A.-C.
      • 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.
      2008CanadaRetrospective cohortCA23064–775230-day all-cause mortality55 (23.9%)100%
      Pepin et al.
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      2007CanadaRetrospective cohortCA/CS16165430-day all-cause mortality, colectomy, perforation, megacolon or septic shock170 (10.5%)77%
      Andrews et al.
      • Andrews C.N.
      • Raboud J.
      • Kassen B.O.
      • Enns R.
      Clostridium difficile-associated diarrhea: predictors of severity in patients presenting to the emergency department.
      2003CanadaRetrospective cohortEIA/CS1536365All-cause in-hospital mortality, ICU admission, colectomy, admission >14 days10 (6.5%)23%
      Morris et al.
      • Morris A.M.
      • Jobe B.A.
      • Stoney M.
      • Sheppard B.C.
      • Deveney C.W.
      • Deveney K.E.
      Clostridium difficile colitis: an increasingly aggressive iatrogenic disease?.
      2002USARetrospective cohortEIA157475190-day all-cause mortality24 (15.3%)100%
      Dharmarajan et al.
      • Dharmarajan T.
      • Sipalay M.
      • Shyamsundar R.
      • Norkus E.
      • Pitchumoni C.
      Co-morbidity, not age predicts adverse outcome in Clostridium difficile colitis.
      2000USARetrospective cohortEIA/CS1217762All-cause mortality27 (22.3%)100%
      Jobe et al.
      • Jobe B.A.
      • Grasley A.
      • Deveney K.E.
      • Deveney C.W.
      • Sheppard B.C.
      Clostridium difficile colitis: an increasing hospital-acquired illness.
      1995USARetrospective cohortCA2015232All-cause mortality7 (3.5%)100%
      Prendergast et al.
      • Prendergast T.M.
      • Marini C.P.
      • D'Angelo A.J.
      • Sher M.E.
      • Cohen J.R.
      Surgical patients with pseudomembranous colitis: factors affecting prognosis.
      1994USARetrospective cohortLA/TA2016357All-cause mortality16 (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 mortality is not specified in the table it reflects this not being specified as a criterion for mortality in the corresponding study. Unless otherwise stated, location of mortality 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 mortality prior to completion of CDI treatment, ICU admission, perforation, megacolon, severe hypokalaemia or lower GI bleeding requiring transfusion.
      c Inclusion in cohort required positive EIA plus confirmatory culture.

      Results of studies: clinical factors

      Results of the studies identified in the review are given in Table II, Table III. Six potential clinical risk markers had been evaluated by at least four studies. Pepin et al. reported results from two separate cohorts, one collected from 1991 to 2002 and one from 2003 to 2006; these were regarded as two distinct sets of results.
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      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 cohorts. 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.
      Table IIPotential clinical risk markers for mortality in CDI, evaluated by four or more studies
      Risk markerStudyNTiming of risk marker assessmentCut-off used to signify presence of risk markerOR (95% CI)
      WBC (×109/L)Gujja et al.
      • Gujja D.
      • Friedenberg F.K.
      Predictors of serious complications due to Clostridium difficile infection.
      200Initiation of CDI treatment>304.1 (1.3, 12.9)
      Fujitani et al.
      • Fujitani S.
      • George W.L.
      • Murthy A.R.
      Comparison of clinical severity score indices for Clostridium difficile infection.
      184At CDI diagnosis>204.4 (1.1, 17.7)
      Bhangu et al.
      • Bhangu A.
      • Czapran A.
      • Bhangu S.
      • Pillay D.
      Optimum timing of blood tests for monitoring patients with Clostridium difficile-associated diarrhea.
      204Peak within week of diagnosis>204.2 (1.9, 9.3)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Dudukgian et al.
      • Dudukgian H.
      • Sie E.
      • Gonzalez-Ruiz C.
      • Etzioni D.A.
      • Kaiser A.M.
      C. difficile colitis – predictors of fatal outcome.
      398Peak during CDI treatment>20
      Henrich et al.
      • Henrich T.J.
      • Krakower D.
      • Bitton A.
      • Yokoe D.S.
      Clinical risk factors for severe Clostridium difficile-associated disease.
      336Peak 4 days before to 2 days after diagnosis>202.8 (1.3, 6.0)
      Pepin et al. (1)
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      773Peak within week of diagnosis>203.7 (1.6, 8.2)
      Pepin et al. (2)
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      843Peak within week of diagnosis>205.5 (2.7, 11.1)
      Labbe et al.
      • Labbe A.-C.
      • 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.
      230Peak within week of diagnosis20–49.9 vs <203.7 (1.8, 7.6)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Manek et al.
      • Manek K.
      • Williams V.
      • Callery S.
      • Daneman N.
      Reducing the risk of severe complications among patients with Clostridium difficile infection.
      305Peak in 48 h after diagnosisPer unit increase1.0 (1.0, 1.1)
      Bhangu et al.
      • Bhangu S.
      • Bhangu A.
      • Nightingale P.
      • Michael A.
      Mortality and risk stratification in patients with Clostridium difficile-associated diarrhoea.
      158Peak in 72 h after diagnosisPer 10% increase1.1 (1.0, 1.2)
      Pant et al.
      • Pant C.
      • Madonia P.
      • Minocha A.
      • Manas K.
      • Jordan P.
      • Bass P.
      Laboratory markers as predictors of mortality in patients with Clostridium difficile infection.
      184At CDI diagnosis>202.0 (0.7, 6.0)
      Umoh et al.
      • Umoh N.
      • Sucandy I.
      • Dancea H.
      • Choi L.
      • Esolen L.
      • Olson M.
      Predictors of fulminant colitis and mortality in patients with Clostridium difficile infection.
      128>18
      Bauer et al.
      • Bauer M.P.
      • Notermans D.W.
      • van Benthem B.H.B.
      • et al.
      Clostridium difficile infection in Europe: a hospital-based survey.
      442Last level in week prior to diagnosis>151.5 (0.7, 3.4)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Wilson et al.
      • Wilson V.
      • Cheek L.
      • Satta G.
      • et al.
      Predictors of death after Clostridium difficile infection: a report on 128 strain-typed cases from a teaching hospital in the United Kingdom.
      128At CDI diagnosis>151.2 (0.5, 2.6)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Andrews et al.
      • Andrews C.N.
      • Raboud J.
      • Kassen B.O.
      • Enns R.
      Clostridium difficile-associated diarrhea: predictors of severity in patients presenting to the emergency department.
      153At CDI diagnosis>151.6 (0.8, 3.2)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Das et al.
      • Das R.
      • Feuerstadt P.
      • Brandt L.J.
      Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with Clostridium difficile-associated disease.
      1126Peak during admissionMean
      Prendergast et al.
      • Prendergast T.M.
      • Marini C.P.
      • D'Angelo A.J.
      • Sher M.E.
      • Cohen J.R.
      Surgical patients with pseudomembranous colitis: factors affecting prognosis.
      201Peak during admissionMeanP = 0.07
      Creatinine (μmol/L)Pant et al.
      • Pant C.
      • Madonia P.
      • Minocha A.
      • Manas K.
      • Jordan P.
      • Bass P.
      Laboratory markers as predictors of mortality in patients with Clostridium difficile infection.
      184At CDI diagnosis>2005.1 (1.8, 13.9)
      Pepin et al. (1)
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      773Peak within week of diagnosis>2004.2 (2.0, 8.8)
      Pepin et al. (2)
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      843Peak within week of diagnosis>2003.3 (1.8, 6.0)
      Henrich et al.
      • Henrich T.J.
      • Krakower D.
      • Bitton A.
      • Yokoe D.S.
      Clinical risk factors for severe Clostridium difficile-associated disease.
      336Peak 4 days before to 2 days after diagnosis>1772.5 (1.0, 5.9)
      Gujja et al.
      • Gujja D.
      • Friedenberg F.K.
      Predictors of serious complications due to Clostridium difficile infection.
      200Initiation of CDI treatment>50% rise from baseline
      Baseline defined as lowest creatinine level in first 24 h of admission.
      7.1 (3.1, 16.7)
      Labbe et al.
      • Labbe A.-C.
      • 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.
      230Peak within week of diagnosis>50% rise from baseline
      Baseline creatinine level definition not reported.
      6.5 (3.1, 13.7)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Dharmarajan et al.
      • Dharmarajan T.
      • Sipalay M.
      • Shyamsundar R.
      • Norkus E.
      • Pitchumoni C.
      Co-morbidity, not age predicts adverse outcome in Clostridium difficile colitis.
      121>133P = 0.11
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Wilson et al.
      • Wilson V.
      • Cheek L.
      • Satta G.
      • et al.
      Predictors of death after Clostridium difficile infection: a report on 128 strain-typed cases from a teaching hospital in the United Kingdom.
      128At CDI diagnosis>1001.7 (0.8, 3.5)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Bauer et al.
      • Bauer M.P.
      • Notermans D.W.
      • van Benthem B.H.B.
      • et al.
      Clostridium difficile infection in Europe: a hospital-based survey.
      442>50% rise from baseline
      Baseline creatinine level definition not reported.
      2.3 (0.6, 8.6)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Umoh et al.
      • Umoh N.
      • Sucandy I.
      • Dancea H.
      • Choi L.
      • Esolen L.
      • Olson M.
      Predictors of fulminant colitis and mortality in patients with Clostridium difficile infection.
      128Median1.2 (1.0, 1.4)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Manek et al.
      • Manek K.
      • Williams V.
      • Callery S.
      • Daneman N.
      Reducing the risk of severe complications among patients with Clostridium difficile infection.
      305Peak in 48 h after diagnosisMean
      Bhangu et al.
      • Bhangu A.
      • Czapran A.
      • Bhangu S.
      • Pillay D.
      Optimum timing of blood tests for monitoring patients with Clostridium difficile-associated diarrhea.
      204Peak within week of diagnosisMeanP = 0.18
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Das et al.
      • Das R.
      • Feuerstadt P.
      • Brandt L.J.
      Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with Clostridium difficile-associated disease.
      1126Peak during admissionMean
      Albumin (g/L)Dharmarajan et al.
      • Dharmarajan T.
      • Sipalay M.
      • Shyamsundar R.
      • Norkus E.
      • Pitchumoni C.
      Co-morbidity, not age predicts adverse outcome in Clostridium difficile colitis.
      121<35P < 0.05
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Fujitani et al.
      • Fujitani S.
      • George W.L.
      • Murthy A.R.
      Comparison of clinical severity score indices for Clostridium difficile infection.
      184At CDI diagnosis<3013.7 (1.3, 17.7)
      Wilson et al.
      • Wilson V.
      • Cheek L.
      • Satta G.
      • et al.
      Predictors of death after Clostridium difficile infection: a report on 128 strain-typed cases from a teaching hospital in the United Kingdom.
      128At CDI diagnosis<253.1 (1.3, 7.8)
      Henrich et al.
      • Henrich T.J.
      • Krakower D.
      • Bitton A.
      • Yokoe D.S.
      Clinical risk factors for severe Clostridium difficile-associated disease.
      336Peak 4 days before to 2 days after diagnosis<253.4 (1.6, 7.6)
      Bhangu et al.
      • Bhangu S.
      • Bhangu A.
      • Nightingale P.
      • Michael A.
      Mortality and risk stratification in patients with Clostridium difficile-associated diarrhoea.
      158Peak in 72 h after diagnosisPer unit increase0.9 (0.9, 1.0)
      Manek et al.
      • Manek K.
      • Williams V.
      • Callery S.
      • Daneman N.
      Reducing the risk of severe complications among patients with Clostridium difficile infection.
      305Peak in 48 h after diagnosisMeanP < 0.0001
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Bhangu et al.
      • Bhangu A.
      • Czapran A.
      • Bhangu S.
      • Pillay D.
      Optimum timing of blood tests for monitoring patients with Clostridium difficile-associated diarrhea.
      204Peak within week of diagnosisMeanP = 0.003
      Pant et al.
      • Pant C.
      • Madonia P.
      • Minocha A.
      • Manas K.
      • Jordan P.
      • Bass P.
      Laboratory markers as predictors of mortality in patients with Clostridium difficile infection.
      184At CDI diagnosis<201.6 (0.5, 4.6)
      Umoh et al.
      • Umoh N.
      • Sucandy I.
      • Dancea H.
      • Choi L.
      • Esolen L.
      • Olson M.
      Predictors of fulminant colitis and mortality in patients with Clostridium difficile infection.
      128Median
      Gujja et al.
      • Gujja D.
      • Friedenberg F.K.
      Predictors of serious complications due to Clostridium difficile infection.
      200Initiation of CDI treatmentMeanP = 0.45
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Prendergast et al.
      • Prendergast T.M.
      • Marini C.P.
      • D'Angelo A.J.
      • Sher M.E.
      • Cohen J.R.
      Surgical patients with pseudomembranous colitis: factors affecting prognosis.
      201At CDI diagnosisMeanP = 0.24
      TemperatureFujitani et al.
      • Fujitani S.
      • George W.L.
      • Murthy A.R.
      Comparison of clinical severity score indices for Clostridium difficile infection.
      184At CDI diagnosis>38.0 °C4.7 (1.1, 21.0)
      Bauer et al.
      • Bauer M.P.
      • Notermans D.W.
      • van Benthem B.H.B.
      • et al.
      Clostridium difficile infection in Europe: a hospital-based survey.
      442>38.5 °C1.3 (0.6, 2.8)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Dharmarajan et al.
      • Dharmarajan T.
      • Sipalay M.
      • Shyamsundar R.
      • Norkus E.
      • Pitchumoni C.
      Co-morbidity, not age predicts adverse outcome in Clostridium difficile colitis.
      121>38.3 °CP = 0.18
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Andrews et al.
      • Andrews C.N.
      • Raboud J.
      • Kassen B.O.
      • Enns R.
      Clostridium difficile-associated diarrhea: predictors of severity in patients presenting to the emergency department.
      153At CDI diagnosis>38.0 °C0.6 (0.3, 1.5)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Gujja et al.
      • Gujja D.
      • Friedenberg F.K.
      Predictors of serious complications due to Clostridium difficile infection.
      200Initiation of CDI treatmentMeanP = 0.82
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Prendergast et al.
      • Prendergast T.M.
      • Marini C.P.
      • D'Angelo A.J.
      • Sher M.E.
      • Cohen J.R.
      Surgical patients with pseudomembranous colitis: factors affecting prognosis.
      201Peak during admissionMeanP = 0.34
      Manek et al.
      • Manek K.
      • Williams V.
      • Callery S.
      • Daneman N.
      Reducing the risk of severe complications among patients with Clostridium difficile infection.
      305Peak in 48 h after diagnosisP = 0.63
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Pepin et al. (1)
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      773Peak within week of diagnosis
      Pepin et al. (2)
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      843Peak within

      week of diagnosis
      Hb/HctGujja et al.
      • Gujja D.
      • Friedenberg F.K.
      Predictors of serious complications due to Clostridium difficile infection.
      200Initiation of CDI treatment>100 g/L (Hb)1.1 (0.5, 2.6)
      Umoh et al.
      • Umoh N.
      • Sucandy I.
      • Dancea H.
      • Choi L.
      • Esolen L.
      • Olson M.
      Predictors of fulminant colitis and mortality in patients with Clostridium difficile infection.
      128<100 g/L (Hb)1.6 (0.7, 4.0)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Fujitani et al.
      • Fujitani S.
      • George W.L.
      • Murthy A.R.
      Comparison of clinical severity score indices for Clostridium difficile infection.
      184At CDI diagnosis>5% increase (Hct)
      Definition of 5% increase in haematocrit not reported.
      0.6 (0.2, 1.7)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Das et al.
      • Das R.
      • Feuerstadt P.
      • Brandt L.J.
      Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with Clostridium difficile-associated disease.
      1126Peak during admissionPer unit increase (Hct)1.0 (1.0, 1.0)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Andrews et al.
      • Andrews C.N.
      • Raboud J.
      • Kassen B.O.
      • Enns R.
      Clostridium difficile-associated diarrhea: predictors of severity in patients presenting to the emergency department.
      153At CDI diagnosisPer unit increase (Hb)1.0 (1.0, 1.0)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Prendergast et al.
      • Prendergast T.M.
      • Marini C.P.
      • D'Angelo A.J.
      • Sher M.E.
      • Cohen J.R.
      Surgical patients with pseudomembranous colitis: factors affecting prognosis.
      201Mean (Hct)P = 0.75
      Diarrhoea severityManek et al.
      • Manek K.
      • Williams V.
      • Callery S.
      • Daneman N.
      Reducing the risk of severe complications among patients with Clostridium difficile infection.
      305Peak in 48 h after diagnosisMean no. of stoolsP = 0.08
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Wilson et al.
      • Wilson V.
      • Cheek L.
      • Satta G.
      • et al.
      Predictors of death after Clostridium difficile infection: a report on 128 strain-typed cases from a teaching hospital in the United Kingdom.
      128At CDI diagnosis≥5 stools in first 24 h1.2 (0.5, 2.6)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Andrews et al.
      • Andrews C.N.
      • Raboud J.
      • Kassen B.O.
      • Enns R.
      Clostridium difficile-associated diarrhea: predictors of severity in patients presenting to the emergency department.
      153At CDI diagnosis1.0 (0.9, 1.1)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Prendergast et al.
      • Prendergast T.M.
      • Marini C.P.
      • D'Angelo A.J.
      • Sher M.E.
      • Cohen J.R.
      Surgical patients with pseudomembranous colitis: factors affecting prognosis.
      201P = 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 1991–2002 cohort, and Pepin et al. (2) refers to the 2003–2006 cohort. 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.
      Table IIIPotential demographic/comorbidity risk markers for mortality in CDI, evaluated by four or more studies
      Risk markerStudyNCut-off/definition used to signify presence of risk markerOR (95% CI)
      Age (years)McGowan et al.
      • Mcgowan A.P.
      • Lalayiannis L.C.
      • Sarma J.B.
      • Marshall B.
      • Martin K.E.
      • Welfare M.R.
      Thirty-day mortality of Clostridium difficile infection in a UK National Health Service Foundation Trust between 2002 and 2008.
      257160–79 vs <603.7 (2.2, 6.5)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      >80 vs <605.8 (3.4, 10.0)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      >80 vs 60–791.6 (1.3, 1.9)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Labbe et al.
      • Labbe A.-C.
      • 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.
      230>753.2 (1.3, 8.0)
      Henrich et al.
      • Henrich T.J.
      • Krakower D.
      • Bitton A.
      • Yokoe D.S.
      Clinical risk factors for severe Clostridium difficile-associated disease.
      336>703.4 (1.5, 7.6)
      Andrews et al.
      • Andrews C.N.
      • Raboud J.
      • Kassen B.O.
      • Enns R.
      Clostridium difficile-associated diarrhea: predictors of severity in patients presenting to the emergency department.
      153>703.1 (1.8, 8.6)
      Pepin et al.(1)
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      773>652.1 (1.1, 4.0)
      Bauer et al.
      • Bauer M.P.
      • Notermans D.W.
      • van Benthem B.H.B.
      • et al.
      Clostridium difficile infection in Europe: a hospital-based survey.
      442>653.3 (1.1, 9.8)
      Das et al.
      • Das R.
      • Feuerstadt P.
      • Brandt L.J.
      Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with Clostridium difficile-associated disease.
      1126Per year increase1.0 (1.0, 1.1)
      This is a hazard ratio, with 95% CI.
      ,
      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.
      Gravel et al.
      • Gravel D.
      • Miller M.
      • Simor A.
      • et al.
      Health care-associated Clostridium difficile infection in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial Infection Surveillance Program study.
      1430Per year increase1.0 (1.0, 1.0)
      This is a relative risk, with 95% CI.
      Bhangu et al.
      • Bhangu A.
      • Czapran A.
      • Bhangu S.
      • Pillay D.
      Optimum timing of blood tests for monitoring patients with Clostridium difficile-associated diarrhea.
      204MedianP < 0.001
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Pant et al.
      • Pant C.
      • Madonia P.
      • Minocha A.
      • Manas K.
      • Jordan P.
      • Bass P.
      Laboratory markers as predictors of mortality in patients with Clostridium difficile infection.
      184>750.6 (0.1, 3.0)
      Wilson et al.
      • Wilson V.
      • Cheek L.
      • Satta G.
      • et al.
      Predictors of death after Clostridium difficile infection: a report on 128 strain-typed cases from a teaching hospital in the United Kingdom.
      128>752.1 (0.9, 5.1)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Pepin et al. (2)
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      843>651.5 (0.8, 2.5)
      Bhangu et al.
      • Bhangu S.
      • Bhangu A.
      • Nightingale P.
      • Michael A.
      Mortality and risk stratification in patients with Clostridium difficile-associated diarrhoea.
      158Per year increase1.0 (1.0, 1.1)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Fujitani et al.
      • Fujitani S.
      • George W.L.
      • Murthy A.R.
      Comparison of clinical severity score indices for Clostridium difficile infection.
      184Mean
      Manek et al.
      • Manek K.
      • Williams V.
      • Callery S.
      • Daneman N.
      Reducing the risk of severe complications among patients with Clostridium difficile infection.
      305Mean
      Dudukgian et al.
      • Dudukgian H.
      • Sie E.
      • Gonzalez-Ruiz C.
      • Etzioni D.A.
      • Kaiser A.M.
      C. difficile colitis – predictors of fatal outcome.
      398MeanP = 0.097
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Gujja et al.
      • Gujja D.
      • Friedenberg F.K.
      Predictors of serious complications due to Clostridium difficile infection.
      200MeanP = 0.37
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Umoh et al.
      • Umoh N.
      • Sucandy I.
      • Dancea H.
      • Choi L.
      • Esolen L.
      • Olson M.
      Predictors of fulminant colitis and mortality in patients with Clostridium difficile infection.
      128Mean1.0 (1.0, 1.0)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Prendergast et al.
      • Prendergast T.M.
      • Marini C.P.
      • D'Angelo A.J.
      • Sher M.E.
      • Cohen J.R.
      Surgical patients with pseudomembranous colitis: factors affecting prognosis.
      201MeanP = 0.22
      SexFujitani et al.
      • Fujitani S.
      • George W.L.
      • Murthy A.R.
      Comparison of clinical severity score indices for Clostridium difficile infection.
      184Female0.8 (0.3, 2.1)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Manek et al.
      • Manek K.
      • Williams V.
      • Callery S.
      • Daneman N.
      Reducing the risk of severe complications among patients with Clostridium difficile infection.
      305FemaleP = 0.07
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Pant et al.
      • Pant C.
      • Madonia P.
      • Minocha A.
      • Manas K.
      • Jordan P.
      • Bass P.
      Laboratory markers as predictors of mortality in patients with Clostridium difficile infection.
      184Female0.5 (0.2, 1.3)
      Henrich et al.
      • Henrich T.J.
      • Krakower D.
      • Bitton A.
      • Yokoe D.S.
      Clinical risk factors for severe Clostridium difficile-associated disease.
      336Female0.9 (0.4, 2.0)
      Umoh et al.
      • Umoh N.
      • Sucandy I.
      • Dancea H.
      • Choi L.
      • Esolen L.
      • Olson M.
      Predictors of fulminant colitis and mortality in patients with Clostridium difficile infection.
      128Female1.0 (0.4, 2.4)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Andrews et al.
      • Andrews C.N.
      • Raboud J.
      • Kassen B.O.
      • Enns R.
      Clostridium difficile-associated diarrhea: predictors of severity in patients presenting to the emergency department.
      153Female0.9 (0.6, 1.3)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Wilson et al.
      • Wilson V.
      • Cheek L.
      • Satta G.
      • et al.
      Predictors of death after Clostridium difficile infection: a report on 128 strain-typed cases from a teaching hospital in the United Kingdom.
      128Male1.0 (0.5, 2.1)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Gujja et al.
      • Gujja D.
      • Friedenberg F.K.
      Predictors of serious complications due to Clostridium difficile infection.
      200Male1.0 (0.5, 2.2)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      ,
      This is a relative risk, with 95% CI.
      Labbe et al.
      • Labbe A.-C.
      • 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.
      230Male1.3 (0.7, 2.3)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Pepin et al. (1)
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      773Male
      Pepin et al. (2)
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      843Male1.4 (1.0, 2.1)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Bhangu et al.
      • Bhangu A.
      • Czapran A.
      • Bhangu S.
      • Pillay D.
      Optimum timing of blood tests for monitoring patients with Clostridium difficile-associated diarrhea.
      204N/AP = 0.87
      OR/P-value generated from univariate, rather than multivariate, analysis.
      McGowan et al.
      • Mcgowan A.P.
      • Lalayiannis L.C.
      • Sarma J.B.
      • Marshall B.
      • Martin K.E.
      • Welfare M.R.
      Thirty-day mortality of Clostridium difficile infection in a UK National Health Service Foundation Trust between 2002 and 2008.
      25711.1 (0.9, 1.3)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Dharmarajan et al.
      • Dharmarajan T.
      • Sipalay M.
      • Shyamsundar R.
      • Norkus E.
      • Pitchumoni C.
      Co-morbidity, not age predicts adverse outcome in Clostridium difficile colitis.
      121P = 0.55
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Hospital-acquired diseasePepin et al. (1)
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      773Inpatient for at least 1 night in 2 months prior to diagnosis2.8 (1.4, 5.8)
      Bauer et al.
      • Bauer M.P.
      • Notermans D.W.
      • van Benthem B.H.B.
      • et al.
      Clostridium difficile infection in Europe: a hospital-based survey.
      442Onset >48 h after admission or inpatient in prior 4 weeks4.9 (0.6, 40.0)
      Fujitani et al.
      • Fujitani S.
      • George W.L.
      • Murthy A.R.
      Comparison of clinical severity score indices for Clostridium difficile infection.
      1840.8 (0.3, 2.2)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Manek et al.
      • Manek K.
      • Williams V.
      • Callery S.
      • Daneman N.
      Reducing the risk of severe complications among patients with Clostridium difficile infection.
      305Onset >72 h after admission or in HCF in prior 8 weeksP = 0.67
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Naggie et al.
      • Naggie S.
      • Frederick J.
      • Pien B.C.
      • et al.
      Community-associated Clostridium difficile infection: experience of a veteran affairs medical center in southeastern USA.
      108Onset >72 h after admission or in HCF in prior 12 weeksP = 0.06
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Umoh et al.
      • Umoh N.
      • Sucandy I.
      • Dancea H.
      • Choi L.
      • Esolen L.
      • Olson M.
      Predictors of fulminant colitis and mortality in patients with Clostridium difficile infection.
      1281.7 (0.7, 4.1)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Pepin et al. (2)
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      843Inpatient for at least 1 night in 2 months prior to diagnosis2.1 (0.9, 4.8)
      Andrews et al.
      • Andrews C.N.
      • Raboud J.
      • Kassen B.O.
      • Enns R.
      Clostridium difficile-associated diarrhea: predictors of severity in patients presenting to the emergency department.
      153NH resident or hospitalized >24 h in prior 60 days1.4 (0.7, 2.9)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Charlson IndexLabbe et al.
      • Labbe A.-C.
      • 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.
      230≥7 points22.2 (2.3, 216.0)
      Das et al.
      • Das R.
      • Feuerstadt P.
      • Brandt L.J.
      Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with Clostridium difficile-associated disease.
      1126Per point increase1.1 (1.1, 1.1)
      This is a hazard ratio, with 95% CI.
      Umoh et al.
      • Umoh N.
      • Sucandy I.
      • Dancea H.
      • Choi L.
      • Esolen L.
      • Olson M.
      Predictors of fulminant colitis and mortality in patients with Clostridium difficile infection.
      1281.3 (1.0, 1.6)
      Cadena et al.
      • Cadena J.
      • Thompson G.R.
      • Patterson J.E.
      • et al.
      Clinical predictors and risk factors for relapsing Clostridium difficile infection.
      1291.2 (1.0, 1.5)
      ImmunocompromisePepin et al. (1)
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      773Multiple
      Defined as presence of human immunodeficiency virus (HIV), leukaemia, lymphoma, organ transplant, neutropenia, immunosuppressive drug use or systemic corticosteroids for >1 month.
      2.7 (1.5, 4.9)
      Pepin et al. (2)
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      843Multiple
      Defined as presence of human immunodeficiency virus (HIV), leukaemia, lymphoma, organ transplant, neutropenia, immunosuppressive drug use or systemic corticosteroids for >1 month.
      3.1 (1.8, 5.6)
      Dudukgian et al.
      • Dudukgian H.
      • Sie E.
      • Gonzalez-Ruiz C.
      • Etzioni D.A.
      • Kaiser A.M.
      C. difficile colitis – predictors of fatal outcome.
      398P = 0.56
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Wilson et al.
      • Wilson V.
      • Cheek L.
      • Satta G.
      • et al.
      Predictors of death after Clostridium difficile infection: a report on 128 strain-typed cases from a teaching hospital in the United Kingdom.
      1281.1 (0.4, 2.9)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Gujja et al.
      • Gujja D.
      • Friedenberg F.K.
      Predictors of serious complications due to Clostridium difficile infection.
      200Multiple
      Defined as presence of HIV, diabetes, transplant and on immunosuppressants, solid organ or haematological malignancy, haemodialysis, or corticosteroid use ≥10 mg.
      1.5 (0.7, 3.3)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      ,
      This is a relative risk, with 95% CI.
      Henrich et al.
      • Henrich T.J.
      • Krakower D.
      • Bitton A.
      • Yokoe D.S.
      Clinical risk factors for severe Clostridium difficile-associated disease.
      336Multiple
      Defined as presence of solid organ or haematopoietic stem cell transplant, immunoglobulin deficiencies, immunosuppressive drug use or severe autoimmune syndromes.
      0.4 (0.1, 2.0)
      Umoh et al.
      • Umoh N.
      • Sucandy I.
      • Dancea H.
      • Choi L.
      • Esolen L.
      • Olson M.
      Predictors of fulminant colitis and mortality in patients with Clostridium difficile infection.
      1281.7 (0.7, 4.0)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Labbe et al.
      • Labbe A.-C.
      • 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.
      230Multiple
      Defined as presence of HIV, leukaemia, lymphoma, chemotherapy in last two months, or renal or stem cell transplantation.
      0.6 (0.2, 1.7)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Morris et al.
      • Morris A.M.
      • Jobe B.A.
      • Stoney M.
      • Sheppard B.C.
      • Deveney C.W.
      • Deveney K.E.
      Clostridium difficile colitis: an increasingly aggressive iatrogenic disease?.
      157Multiple
      Defined as presence of HIV, on transplant medications or chemotherapy.
      P > 0.05
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Steroid useDas et al.
      • Das R.
      • Feuerstadt P.
      • Brandt L.J.
      Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with Clostridium difficile-associated disease.
      1126Any systemic use in 15 days prior to diagnosis2.1 (1.9, 2.3)
      This is a hazard ratio, with 95% CI.
      Dudukgian et al.
      • Dudukgian H.
      • Sie E.
      • Gonzalez-Ruiz C.
      • Etzioni D.A.
      • Kaiser A.M.
      C. difficile colitis – predictors of fatal outcome.
      398P < 0.05
      Prendergast et al.
      • Prendergast T.M.
      • Marini C.P.
      • D'Angelo A.J.
      • Sher M.E.
      • Cohen J.R.
      Surgical patients with pseudomembranous colitis: factors affecting prognosis.
      201P = 0.01
      Cadena et al.
      • Cadena J.
      • Thompson G.R.
      • Patterson J.E.
      • et al.
      Clinical predictors and risk factors for relapsing Clostridium difficile infection.
      129
      Henrich et al.
      • Henrich T.J.
      • Krakower D.
      • Bitton A.
      • Yokoe D.S.
      Clinical risk factors for severe Clostridium difficile-associated disease.
      336Any systemic use in 30 days prior to diagnosis1.1 (0.5, 2.7)
      Nasogastric tube usePepin et al. (1)
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      773Use in 2 months prior to diagnosis2.0 (1.0, 3.8)
      Fujitani et al.
      • Fujitani S.
      • George W.L.
      • Murthy A.R.
      Comparison of clinical severity score indices for Clostridium difficile infection.
      1841.1 (0.4, 3.3)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Manek et al.
      • Manek K.
      • Williams V.
      • Callery S.
      • Daneman N.
      Reducing the risk of severe complications among patients with Clostridium difficile infection.
      305P = 0.44
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Pepin et al. (2)
      • Pépin J.
      • Valiquette L.
      • Gagnon S.
      • Routhier S.
      • Brazeau I.
      Outcomes of Clostridium difficile-associated disease treated with metronidazole or vancomycin before and after the emergence of NAP1/027.
      843Use in 2 months prior to diagnosis1.5 (0.9, 2.6)
      Dharmarajan et al.
      • Dharmarajan T.
      • Sipalay M.
      • Shyamsundar R.
      • Norkus E.
      • Pitchumoni C.
      Co-morbidity, not age predicts adverse outcome in Clostridium difficile colitis.
      121P = 0.24
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Renal diseaseDudukgian et al.
      • Dudukgian H.
      • Sie E.
      • Gonzalez-Ruiz C.
      • Etzioni D.A.
      • Kaiser A.M.
      C. difficile colitis – predictors of fatal outcome.
      398P < 0.05
      Fujitani et al.
      • Fujitani S.
      • George W.L.
      • Murthy A.R.
      Comparison of clinical severity score indices for Clostridium difficile infection.
      1841.8 (0.6, 5.0)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Manek et al.
      • Manek K.
      • Williams V.
      • Callery S.
      • Daneman N.
      Reducing the risk of severe complications among patients with Clostridium difficile infection.
      305P = 0.22
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Wilson et al.
      • Wilson V.
      • Cheek L.
      • Satta G.
      • et al.
      Predictors of death after Clostridium difficile infection: a report on 128 strain-typed cases from a teaching hospital in the United Kingdom.
      1281.7 (0.8, 3.5)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Henrich et al.
      • Henrich T.J.
      • Krakower D.
      • Bitton A.
      • Yokoe D.S.
      Clinical risk factors for severe Clostridium difficile-associated disease.
      336Physician-documented diagnosis0.5 (0.8, 3.0)
      Morris et al.
      • Morris A.M.
      • Jobe B.A.
      • Stoney M.
      • Sheppard B.C.
      • Deveney C.W.
      • Deveney K.E.
      Clostridium difficile colitis: an increasingly aggressive iatrogenic disease?.
      157P > 0.05
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Prendergast et al.
      • Prendergast T.M.
      • Marini C.P.
      • D'Angelo A.J.
      • Sher M.E.
      • Cohen J.R.
      Surgical patients with pseudomembranous colitis: factors affecting prognosis.
      201P = 0.53
      DiabetesFujitani et al.
      • Fujitani S.
      • George W.L.
      • Murthy A.R.
      Comparison of clinical severity score indices for Clostridium difficile infection.
      1841.0 (0.4, 2.9)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Manek et al.
      • Manek K.
      • Williams V.
      • Callery S.
      • Daneman N.
      Reducing the risk of severe complications among patients with Clostridium difficile infection.
      305P = 0.44
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Dudukgian et al.
      • Dudukgian H.
      • Sie E.
      • Gonzalez-Ruiz C.
      • Etzioni D.A.
      • Kaiser A.M.
      C. difficile colitis – predictors of fatal outcome.
      398P = 0.14
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Wilson et al.
      • Wilson V.
      • Cheek L.
      • Satta G.
      • et al.
      Predictors of death after Clostridium difficile infection: a report on 128 strain-typed cases from a teaching hospital in the United Kingdom.
      1280.4 (0.1, 1.4)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Henrich et al.
      • Henrich T.J.
      • Krakower D.
      • Bitton A.
      • Yokoe D.S.
      Clinical risk factors for severe Clostridium difficile-associated disease.
      336Physician-documented diagnosisP = 1.0
      Morris et al.
      • Morris A.M.
      • Jobe B.A.
      • Stoney M.
      • Sheppard B.C.
      • Deveney C.W.
      • Deveney K.E.
      Clostridium difficile colitis: an increasingly aggressive iatrogenic disease?.
      157P > 0.05
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Dharmarajan et al.
      • Dharmarajan T.
      • Sipalay M.
      • Shyamsundar R.
      • Norkus E.
      • Pitchumoni C.
      Co-morbidity, not age predicts adverse outcome in Clostridium difficile colitis.
      121P = 0.62
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Prendergast et al.
      • Prendergast T.M.
      • Marini C.P.
      • D'Angelo A.J.
      • Sher M.E.
      • Cohen J.R.
      Surgical patients with pseudomembranous colitis: factors affecting prognosis.
      201P = 0.67
      CancerFujitani et al.
      • Fujitani S.
      • George W.L.
      • Murthy A.R.
      Comparison of clinical severity score indices for Clostridium difficile infection.
      1842.8 (1.1, 7.3)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Manek et al.
      • Manek K.
      • Williams V.
      • Callery S.
      • Daneman N.
      Reducing the risk of severe complications among patients with Clostridium difficile infection.
      305P = 0.96
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Dudukgian et al.
      • Dudukgian H.
      • Sie E.
      • Gonzalez-Ruiz C.
      • Etzioni D.A.
      • Kaiser A.M.
      C. difficile colitis – predictors of fatal outcome.
      398P = 0.25
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Wilson et al.
      • Wilson V.
      • Cheek L.
      • Satta G.
      • et al.
      Predictors of death after Clostridium difficile infection: a report on 128 strain-typed cases from a teaching hospital in the United Kingdom.
      1281.4 (0.6, 3.3)
      OR/P-value generated from univariate, rather than multivariate, analysis.
      Henrich et al.
      • Henrich T.J.
      • Krakower D.
      • Bitton A.
      • Yokoe D.S.
      Clinical risk factors for severe Clostridium difficile-associated disease.
      336Physician-documented diagnosis0.7 (0.3, 1.7)
      Prendergast et al.
      • Prendergast T.M.
      • Marini C.P.
      • D'Angelo A.J.
      • Sher M.E.
      • Cohen J.R.
      Surgical patients with pseudomembranous colitis: factors affecting prognosis.
      201P = 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 1991–2002 cohort, and Pepin et al. (2) refers to the 2003–2006 cohort. The ORs reported reflect the odds of the outcome (mortality 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.
      In 10 of 17 cohorts white blood cell count (WBC) was associated with outcome. Of the 10, seven used 20 × 109/L as the cut-off level. Studies not demonstrating an association tended to be smaller and use lower cut-offs. ORs in cohorts 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 cohorts. Studies showing an association with outcome tended to use a higher cut-off, most commonly 200 μmol/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 <25–35 g/L were most frequently used. Only one of nine cohorts evaluating temperature identified an association with outcome. Haemoglobin/haematocrit and 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 cohorts increasing age was associated with outcome, with three of these studies having >1000 participants. Age >65–75 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 cohorts 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.
      • Das R.
      • Feuerstadt P.
      • Brandt L.J.
      Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with Clostridium difficile-associated disease.
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • MacKenzie C.R.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      Pre-existing immunocompromise was associated with outcome in two of nine cohorts. 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 cohorts, 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 mortality 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 2009. We have identified a moderately large number of studies on this topic, with several factors found on multiple occasions to be significantly associated with mortality. The following parameters had the most evidence to support their use as markers of risk for mortality 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 >20 × 109/L; serum creatinine, possibly with a cut-off of >200 μmol/L; and serum albumin, most likely with a cut-off of <25–35 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.
      • Fujitani S.
      • George W.L.
      • Murthy A.R.
      Comparison of clinical severity score indices for Clostridium difficile infection.

      Risk markers

      Whereas age, WBC, serum creatinine and serum albumin each had a large number of cohorts demonstrating significant associations with outcome, each parameter had several studies in which no association was found. The negative studies tended 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.
      • Das R.
      • Feuerstadt P.
      • Brandt L.J.
      Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with Clostridium difficile-associated disease.
      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 low-risk 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.
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • MacKenzie C.R.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      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 mortality 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 hospital-acquired disease varied considerably between studies, again making it difficult to conclude based on this evidence that it is not associated with mortality. 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.
      • Crobach M.J.T.
      • Dekkers O.M.
      • Wilcox M.H.
      • Kuijper E.J.
      European Society of Clinical Microbiology and Infectious Diseases (ESCMID): data review and recommendations for diagnosing Clostridium difficile-infection (CDI).
      • Planche T.
      • Aghaizu A.
      • Holliman R.
      • et al.
      Diagnosis of Clostridium difficile infection by toxin detection kits: a systematic review.
      Consequently, many of these cohorts 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 cohorts, where inclusion in the cohort did not also require the presence of diarrhoea. Most studies used all-cause mortality as their endpoint, rather than CDI-specific mortality. As a result, the risk markers identified by these studies may have less relevance in aiding treatment decisions for CDI. However, it is understandable that most studies have used all-cause mortality, because death certification of CDI is known to be poor.
      • Mlangeni D.A.
      • Harris M.D.
      • Franklin L.
      • Hunt P.
      • Karas J.A.
      • Enoch D.A.
      Death certificates provide a poor estimation of attributable mortality due to Clostridium difficile when compared to a death review panel using defined criteria.
      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 mortality alone. Furthermore, given that 17 of 26 studies had mortality as their sole outcome variable, it seems likely that the potential risk markers identified in this review are applicable to the outcome of mortality. 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 mortality 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.
      • Kuijper E.J.
      • Coignard B.
      • Tüll P.
      Emergence of Clostridium difficile-associated disease in North America and Europe.
      • Loo V.G.
      • Poirier L.
      • Miller M.A.
      • et al.
      A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality.
      This may limit the generalizability of these studies to other countries and time periods, as the relationship between risk markers and mortality may differ in epidemic versus endemic CDI. However, it seems likely that these results would be broadly applicable to similar health systems in other developed countries, particularly since the studies in this review were performed in general hospital populations.

      Conflict of interest statement

      None declared.

      Funding sources

      None.

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