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Prognostic factors for severe and recurrent Clostridioides difficile infection: a systematic review

  • Author Footnotes
    † Tessel M. van Rossen and Rogier E. Ooijevaar contributed equally and should be considered first authors.
    Tessel M. van Rossen
    Correspondence
    Corresponding author. Tessel M. van Rossen, Amsterdam UMC locatie VUmc, PK 2X132, De Boelelaan 1117, Amsterdam, the Netherlands.
    Footnotes
    † Tessel M. van Rossen and Rogier E. Ooijevaar contributed equally and should be considered first authors.
    Affiliations
    Amsterdam UMC, VU University Medical Center, Medical Microbiology & Infection Control, Amsterdam Infection & Immunity, Amsterdam, the Netherlands
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  • Author Footnotes
    † Tessel M. van Rossen and Rogier E. Ooijevaar contributed equally and should be considered first authors.
    Rogier E. Ooijevaar
    Correspondence
    Corresponding author. Rogier E. Ooijevaar, Amsterdam UMC locatie VUmc, PK 2X132, De Boelelaan 1117, Amsterdam, the Netherlands.
    Footnotes
    † Tessel M. van Rossen and Rogier E. Ooijevaar contributed equally and should be considered first authors.
    Affiliations
    Amsterdam UMC, VU University Medical Center, Gastroenterology & Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
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  • Christina M.J.E. Vandenbroucke-Grauls
    Affiliations
    Amsterdam UMC, VU University Medical Center, Medical Microbiology & Infection Control, Amsterdam Infection & Immunity, Amsterdam, the Netherlands

    Aarhus University, Clinical Epidemiology, Aarhus, Denmark
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  • Olaf M. Dekkers
    Affiliations
    Leiden University Medical Center, Clinical Epidemiology, Leiden, the Netherlands
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  • Ed J. Kuijper
    Affiliations
    Leiden University Medical Center, Center for Infectious Diseases, Medical Microbiology, Leiden, the Netherlands
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  • Josbert J. Keller
    Affiliations
    Haaglanden Medical Center, Gastroenterology & Hepatology, The Hague, the Netherlands

    Leiden University Medical Center, Gastroenterology & Hepatology, Leiden, the Netherlands
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  • Joffrey van Prehn
    Affiliations
    Leiden University Medical Center, Center for Infectious Diseases, Medical Microbiology, Leiden, the Netherlands
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  • Author Footnotes
    † Tessel M. van Rossen and Rogier E. Ooijevaar contributed equally and should be considered first authors.
Open AccessPublished:October 13, 2021DOI:https://doi.org/10.1016/j.cmi.2021.09.026

      Abstract

      Objectives

      Clostridioides difficile infection (CDI), its subsequent recurrences (rCDIs), and severe CDI (sCDI) provide a significant burden for both patients and the healthcare system. Identifying patients diagnosed with initial CDI who are at increased risk of developing sCDI/rCDI could lead to more cost-effective therapeutic choices. In this systematic review we aimed to identify clinical prognostic factors associated with an increased risk of developing sCDI or rCDI.

      Methods

      PubMed, Embase, Emcare, Web of Science and COCHRANE Library databases were searched from database inception through March, 2021. The study eligibility criteria were cohort and case–control studies. Participants were patients ≥18 years old diagnosed with CDI, in which clinical or laboratory factors were analysed to predict sCDI/rCDI. Risk of bias was assessed by using the Quality in Prognostic Research (QUIPS) tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool modified for prognostic studies. Study selection was performed by two independent reviewers. Overview tables of prognostic factors were constructed to assess the number of studies and the respective effect direction and statistical significance of an association.

      Results

      136 studies were included for final analysis. Greater age and the presence of multiple comorbidities were prognostic factors for sCDI. Identified risk factors for rCDI were greater age, healthcare-associated CDI, prior hospitalization, proton pump inhibitors (PPIs) started during or after CDI diagnosis, and previous rCDI.

      Conclusions

      Prognostic factors for sCDI and rCDI could aid clinicians to make treatment decisions based on risk stratification. We suggest that future studies use standardized definitions for sCDI/rCDI and systematically collect and report the risk factors assessed in this review, to allow for meaningful meta-analysis of risk factors using data of high-quality trials.

      Keywords

      Introduction

      Clostridioides difficile infection (CDI), its subsequent recurrences (rCDIs), and severe CDI (sCDI) are a significant burden for both patients and the healthcare system [
      • Lessa F.C.
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      • Bamberg W.M.
      • Beldavs Z.G.
      • Dumyati G.K.
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      Burden of Clostridium difficile infection in the United States.
      ]. Antibiotic treatment with oral vancomycin and fidaxomicin is the cornerstone of CDI treatment [
      • McDonald L.C.
      • Gerding D.N.
      • Johnson S.
      • Bakken J.S.
      • Carroll K.C.
      • Coffin S.E.
      • et al.
      Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the infectious diseases society of America (IDSA) and society for healthcare epidemiology of America (SHEA).
      ,
      • Debast S.B.
      • Bauer M.P.
      • Kuijper E.J.
      European society of clinical Microbiology and infectious diseases. European society of clinical Microbiology and infectious diseases: update of the treatment guidance document for Clostridium difficile infection.
      ,
      • Ooijevaar R.E.
      • van Beurden Y.H.
      • Terveer E.M.
      • Goorhuis A.
      • Bauer M.P.
      • Keller J.J.
      • et al.
      Update of treatment algorithms for Clostridium difficile infection.
      ]. Fidaxomicin reduces the number of recurrences compared to vancomycin [
      • Beinortas T.
      • Burr N.E.
      • Wilcox M.H.
      • Subramanian V.
      Comparative efficacy of treatments for Clostridium difficile infection: a systematic review and network meta-analysis.
      ]. Bezlotoxumab, a monoclonal anti-toxin B antibody, can be added to oral anti-CDI antibiotic therapy and reduces the number or recurrences in patients at high risk for recurrence [
      • Wilcox M.H.
      • Gerding D.N.
      • Poxton I.R.
      • Kelly C.
      • Nathan R.
      • Birch T.
      • et al.
      Bezlotoxumab for prevention of recurrent Clostridium difficile infection.
      ]. Faecal microbiota transplantation (FMT) is a highly efficacious ancillary treatment for multiple rCDIs, and can lower the mortality risk and disease burden of sCDI [
      • Ianiro G.
      • Masucci L.
      • Quaranta G.
      • Simonelli C.
      • Rizzatti G.
      • Lopetuso L.
      • et al.
      Randomized clinical trial: single-infusion Fmt versus multiple-infusion Fmt for the treatment of severe C. difficile infection.
      ,
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      • Fuentes S.
      • Zoetendal E.G.
      • de Vos W.M.
      • et al.
      Duodenal infusion of donor feces for recurrent Clostridium difficile.
      ].
      The acquisition costs of fidaxomicin, bezlotoxumab and FMT are higher compared to those of vancomycin, which may limit their widespread application. To this end the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) 2021 update on the treatment guidance for C. difficile infection suggests applying a risk stratification strategy in case of economic restraints [
      • van Prehn E.R.J.
      • Vogelzang E.H.
      • Bouza E.
      • Hristea A.
      • Guery B.
      • Krutova M.
      • et al.
      European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults.
      ]. Identifying patients at risk, however, is challenging. Several prediction models have been developed [
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      • Marrodan T.
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      Nosocomial Infection Study. Prediction of recurrent Clostridium difficile infection at the bedside: the GEIH-CDI score.
      ,
      • D'Agostino R.B.
      • Collins S.H.
      • Pencina K.M.
      • Kean Y.
      • Gorbach S.
      Risk estimation for recurrent Clostridium difficile infection based on clinical factors.
      ,
      • Zilberberg M.D.
      • Reske K.
      • Olsen M.
      • Yan Y.
      • Dubberke E.R.
      Development and validation of a recurrent Clostridium difficile risk-prediction model.
      ,
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      • Rodriguez V.
      • Ferrer C.
      • Bartolome R.
      • et al.
      First recurrence of Clostridium difficile infection: clinical relevance, risk factors, and prognosis.
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      • et al.
      Derivation and validation of a Clostridium difficile infection recurrence prediction rule in a national cohort of veterans.
      ,
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      • Khatchatourian L.
      • Nowak M.A.
      Development of a bedside scoring system for predicting a first recurrence of Clostridium difficile-associated diarrhea.
      ,
      • Hebert C.
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      Electronic health record-based detection of risk factors for Clostridium difficile infection relapse.
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      A prediction model for Clostridium difficile recurrence.
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      • et al.
      Prospective derivation and validation of a clinical prediction rule for recurrent Clostridium difficile infection.
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      Prediction tools for unfavourable outcomes in Clostridium difficile infection: a systematic review.
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      • Arora V.
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      • Dupont H.L.
      • Garey K.W.
      High Horn's index score predicts poor outcomes in patients with Clostridium difficile infection.
      ,
      • Bhangu S.
      • Bhangu A.
      • Nightingale P.
      • Michael A.
      Mortality and risk stratification in patients with Clostridium difficile-associated diarrhoea.
      ,
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      • Titball R.W.
      • Bhangu A.
      • et al.
      Derivation and validation of a simple, accurate and robust prediction rule for risk of mortality in patients with Clostridium difficile infection.
      ,
      • Drew R.J.
      • Boyle B.
      RUWA scoring system: a novel predictive tool for the identification of patients at high risk for complications from Clostridium difficile infection.
      ,
      • Hensgens M.P.
      • Dekkers O.M.
      • Goorhuis A.
      • LeCessie S.
      • Kuijper E.J.
      Predicting a complicated course of Clostridium difficile infection at the bedside.
      ,
      • Lungulescu O.A.
      • Cao W.
      • Gatskevich E.
      • Tlhabano L.
      • Stratidis J.G.
      CSI: a severity index for Clostridium difficile infection at the time of admission.
      ,
      • Na X.
      • Martin A.J.
      • Sethi S.
      • Kyne L.
      • Garey K.W.
      • Flores S.W.
      • et al.
      A multi-center prospective derivation and validation of a clinical prediction tool for severe Clostridium difficile infection.
      ,
      • Rubin M.S.
      • Bodenstein L.E.
      • Kent K.C.
      Severe Clostridium difficile colitis.
      ,
      • Valiquette L.
      • Pépin J.
      • Do X.V.
      • Nault V.
      • Beaulieu A.A.
      • Bédard J.
      • et al.
      Prediction of complicated Clostridium difficile infection by pleural effusion and increased wall thickness on computed tomography.
      ,
      • Velazquez-Gomez I.
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      • Gutierrez-Nuñez J.J.
      • Gonzalez G.
      • Saavedra S.
      A severity score index for Clostridium difficile infection.
      ,
      • Welfare M.R.
      • Lalayiannis L.C.
      • Martin K.E.
      • Corbett S.
      • Marshall B.
      • Sarma J.B.
      Co-morbidities as predictors of mortality in Clostridium difficile infection and derivation of the ARC predictive score.
      ,
      • Zilberberg M.D.
      • Shorr A.F.
      • Micek S.T.
      • Doherty J.A.
      • Kollef M.H.
      Clostridium difficile-associated disease and mortality among the elderly critically ill.
      ], yet none has been widely adopted in clinical practice. Here, we aim to identify clinical prognostic factors associated with an increased risk of developing sCDI or rCDI.

      Methods

      This systematic review was performed in the context of the ESCMID 2021 update of the CDI treatment guidance in adults. Preliminary results have been presented to the expert panel of the guideline committee of the European Study Group on C. difficile (ESGCD). As the review of prognostic factors for sCDI/rCDI yielded interesting findings that merited further discussion, it was decided to incorporate these results in a separate manuscript to allow in-depth discussion of results and methodology. The review is conducted according to the recommendations by the Cochrane Prognosis Methods Group following the structure of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • Boutron I.
      • Hoffmann T.C.
      • Mulrow C.D.
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      ,
      • Hayden J.A.
      • van der Windt D.A.
      • Cartwright J.L.
      • Cote P.
      • Bombardier C.
      Assessing bias in studies of prognostic factors.
      ,
      • Huguet A.
      • Hayden J.A.
      • Stinson J.
      • McGrath P.J.
      • Chambers C.T.
      • Tougas M.E.
      • et al.
      Judging the quality of evidence in reviews of prognostic factor research: adapting the GRADE framework.
      ].

       Data sources

      Two searches were performed to identify risk factors for (a) sCDI and (b) rCDI. The search terms and strategy were constructed by a trained librarian (see Supplementary Material). PubMed, Embase, Emcare, Web of Science and COCHRANE Library databases were searched on 4th October 2019 and updated on 13th March 2021. Meeting abstracts were not considered. The search was not limited by year of publication. References of key papers were assessed for relevant papers.

       Study eligibility criteria

      Study eligibility was assessed in a two-step selection process. Two independent reviewers (TvR and RO) screened titles and abstracts for potentially eligible articles; discrepancies were resolved by consensus. Full-text articles were retrieved for eligibility; data extraction and risk of bias assessment of included studies was performed by two researchers (TvR and RO).
      Inclusion criteria were prospective and retrospective cohort and case–control studies including patients ≥18 years, diagnosed with CDI, and providing an analysis of clinical or laboratory data to predict severe/recurrent CDI.
      Exclusion criteria were studies in specific patient populations with a distinct medical condition other than CDI (e.g. a study population comprises only haemodialysis patients, since these results are not generalizable to the average C. difficile patient), and small studies (<30 patients with severe/recurrent CDI), since these increase the risk of false-positive results, risk overestimation of the magnitude of associations, and do not allow adjustment for important confounders. However, studies that assessed a particular medical condition as a prognostic factor and compared this to a control group of patients without the condition were included, as were laboratory values that were studied as prognostic factors but which are not part of the regular work-up in CDI (e.g. specific cytokine assays). Variables that are part of the definition of sCDI (e.g. leukocytosis) were excluded as prognostic factors for sCDI to avoid circularity.
      Studies on prognostic factors with conflicting results in univariate and multivariable analyses were scrutinized by weighing the results by the quality of evidence per study.
      Outcomes of interest were:
      • 1.
        Severe CDI:
        • (a)
          ESCMID 2014/2021 definition: an episode of CDI with (one or more specific signs and symptoms of) severe colitis or a complicated course of disease, with significant systemic toxin effects and shock, resulting in need for ICU admission, colectomy or death [
          • Debast S.B.
          • Bauer M.P.
          • Kuijper E.J.
          European society of clinical Microbiology and infectious diseases. European society of clinical Microbiology and infectious diseases: update of the treatment guidance document for Clostridium difficile infection.
          ,
          • Bauer M.P.
          • Kuijper E.J.
          • van Dissel J.T.
          European society of clinical Microbiology and infectious diseases (ESCMID): treatment guidance document for Clostridium difficile infection (CDI).
          ,
          • van Prehn E.R.J.
          • Vogelzang E.H.
          • Bouza E.
          • Hristea A.
          • Guery B.
          • Krutova M.
          • et al.
          European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults.
          ]; or
        • (b)
          Infectious Diseases Society of America (IDSA)/Society for Healthcare Epidemiology of America (SHEA) definition: an episode of CDI with a white blood cell count of ≥15 × 109 cells/mL or a serum creatinine level >1.5 mg/dL or increase of ≥50% from baseline [
          • McDonald L.C.
          • Gerding D.N.
          • Johnson S.
          • Bakken J.S.
          • Carroll K.C.
          • Coffin S.E.
          • et al.
          Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the infectious diseases society of America (IDSA) and society for healthcare epidemiology of America (SHEA).
          ]; or
        • (c)
          Any other author-constructed definition of severe/complicated/fulminant/fatal CDI.
      • 2.
        Recurrent CDI: recurrence is a new episode of CDI within 2–12 weeks after a previous episode, provided the symptoms of the previous episode resolved after completion of initial treatment [
        • Surawicz C.M.
        • Brandt L.J.
        • Binion D.G.
        • Ananthakrishnan A.N.
        • Curry S.R.
        • Gilligan P.H.
        • et al.
        Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.
        ,
        • Kuijper E.J.
        • Coignard B.
        • Tull P.
        ESCMID study group for C. difficile, EU member states, European Centre for disease prevention and control. Emergence of Clostridium difficile-associated disease in North America and Europe.
        ].

       Assessment of risk of bias

      Risk of bias was assessed with the Quality in Prognostic Research (QUIPS) tool [
      • Hayden J.A.
      • van der Windt D.A.
      • Cartwright J.L.
      • Cote P.
      • Bombardier C.
      Assessing bias in studies of prognostic factors.
      ], which is recommended by the Cochrane Prognosis Methods Group. The QUIPS tool appraises six domains: (a) study participation, (b) study attrition, (c) prognostic factor measurement, (d) outcome measurement, (e) study confounding and (f) statistical analysis and reporting. The overall risk of bias per study is scored as low, moderate, or high.

       Quality assessment and data synthesis

      The quality of evidence per study was assessed by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool, modified for prognostic studies (Supplementary Material Fig. S1) [
      • Huguet A.
      • Hayden J.A.
      • Stinson J.
      • McGrath P.J.
      • Chambers C.T.
      • Tougas M.E.
      • et al.
      Judging the quality of evidence in reviews of prognostic factor research: adapting the GRADE framework.
      ]. This tool is recommended by the Cochrane Prognosis Methods Group and consists of eight domains. The starting point for the quality of evidence is based on the phase of investigation. The quality can be up- or down-graded according to seven other domains. The QUIPS score is included in the second domain (‘Study limitations/risk of bias’) of the GRADE tool. The outcome of this assessment is the quality of evidence per study, which can be very low (+), low (++), moderate (+++) or high (++++).
      Overview tables of prognostic factors were constructed to assess the number of studies and the respective direction of association—i.e. positive, negative, or no association—based on effect estimates, 95%CI intervals and p values, stratified by univariate and multivariate analyses. ‘Vote counting based on the direction of effect’ was performed to assess the direction of effect regardless of statistical significance and to overcome some limitations of underpowered studies [
      ]. Similar prognostic factors (e.g. coronary artery disease and myocardial infarction) were combined into one factor for a more compact overview. No formal meta-analyses were performed since the definitions of the outcomes of interest (sCDI/rCDI), as well as the definitions of the prognostic factors used in the studies included in this review were highly heterogeneous, and due to incompletely reported effect estimates and different effect measures used across studies.

      Results

      The search for prognostic factors for sCDI yielded 1242 references; 126 studies were assessed in more detail, and 76 were included for analysis [
      • Bhangu S.
      • Bhangu A.
      • Nightingale P.
      • Michael A.
      Mortality and risk stratification in patients with Clostridium difficile-associated diarrhoea.
      ,
      • Lungulescu O.A.
      • Cao W.
      • Gatskevich E.
      • Tlhabano L.
      • Stratidis J.G.
      CSI: a severity index for Clostridium difficile infection at the time of admission.
      ,
      • Na X.
      • Martin A.J.
      • Sethi S.
      • Kyne L.
      • Garey K.W.
      • Flores S.W.
      • et al.
      A multi-center prospective derivation and validation of a clinical prediction tool for severe Clostridium difficile infection.
      ,
      • Welfare M.R.
      • Lalayiannis L.C.
      • Martin K.E.
      • Corbett S.
      • Marshall B.
      • Sarma J.B.
      Co-morbidities as predictors of mortality in Clostridium difficile infection and derivation of the ARC predictive score.
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      • Durando P.
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      Increasing incidence of Clostridium difficile infections: results from a 5-year retrospective study in a large teaching hospital in the Italian region with the oldest population.
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      • Gainer V.
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      Predictors of severe outcomes associated with Clostridium difficile infection in patients with inflammatory bowel disease.
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      • Andrews C.N.
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      Clostridium difficile-associated diarrhea: predictors of severity in patients presenting to the emergency department.
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      • Archbald-Pannone L.R.
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      • Warren C.A.
      Delirium and other clinical factors with Clostridium difficile infection that predict mortality in hospitalized patients.
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      • Atamna A.
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      The effect of statins on the outcome of Clostridium difficile infection in hospitalized patients.
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      • Barker A.K.
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      • Cook C.H.
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      Impact of the NAP-1 strain on disease severity, mortality, and recurrence of healthcare-associated Clostridium difficile infection.
      ,
      • Berry C.E.
      • Davies K.A.
      • Owens D.W.
      • Wilcox M.H.
      Is there a relationship between the presence of the binary toxin genes in Clostridium difficile strains and the severity of C. difficile infection (CDI)?.
      ,
      • Boone J.H.
      • Archbald-Pannone L.R.
      • Wickham K.N.
      • Carman R.J.
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      Ribotype 027 Clostridium difficile infections with measurable stool toxin have increased lactoferrin and are associated with a higher mortality.
      ,
      • Caupenne A.
      • Ingrand P.
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      • lohessy P.C.
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      ,
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      An observational cohort study of Clostridium difficile ribotype 027 and recurrent infection.
      ,
      • Rodriguez-Pardo D.
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      Barcelona Clostridium difficile Study, epidemiology of Clostridium difficile infection and risk factors for unfavorable clinical outcomes: results of a hospital-based study in Barcelona, Spain.
      ,
      • Rotramel A.
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      • Messaris E.
      • Berg A.
      • Stewart D.B.
      PPI therapy and albumin are better predictors of recurrent Clostridium difficile colitis than choice of antibiotics.
      ,
      • van Beurden Y.H.
      • Nezami S.
      • Mulder C.J.J.
      • Vandenbroucke-Grauls C.
      Host factors are more important in predicting recurrent Clostridium difficile infection than ribotype and use of antibiotics.
      ,
      • Zilberberg M.D.
      • Reske K.
      • Olsen M.
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      • Dubberke E.R.
      Risk factors for recurrent Clostridium difficile infection (CDI) hospitalization among hospitalized patients with an initial CDI episode: a retrospective cohort study.
      ] as were seven studies from cross-references [
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      Clostridium difficile infection in Europe: a hospital-based survey.
      ,
      • Cadena J.
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      • et al.
      Clinical predictors and risk factors for relapsing Clostridium difficile infection.
      ,
      • Shakov R.
      • Salazar R.S.
      • Kagunye S.K.
      • Baddoura W.J.
      • DeBari V.A.
      Diabetes mellitus as a risk factor for recurrence of Clostridium difficile infection in the acute care hospital setting.
      ,
      • Fekety R.
      • McFarland L.V.
      • Surawicz C.M.
      • Greenberg R.N.
      • Elmer G.W.
      • Mulligan M.E.
      Recurrent Clostridium difficile diarrhea: characteristics of and risk factors for patients enrolled in a prospective, randomized, double-blinded trial.
      ,
      • Ryu H.S.
      • Kim Y.S.
      • Seo G.S.
      • Lee Y.M.
      • Choi S.C.
      Risk factors for recurrent Clostridium difficile infection.
      ,
      • Golan Y.
      • DuPont H.L.
      • Aldomiro F.
      • Jensen E.H.
      • Hanson M.E.
      • Dorr M.B.
      Renal impairment, C. difficile recurrence, and the differential effect of bezlotoxumab: a post hoc analysis of pooled data from 2 randomized clinical trials.
      ,
      • Weiss K.
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      • Gorbach S.L.
      Effects of proton pump inhibitors and histamine-2 receptor antagonists on response to fidaxomicin or vancomycin in patients with Clostridium difficile-associated diarrhoea.
      ]. This resulted in 43 studies for final analysis (Fig. 1). Additionally, data of the pivotal RCTs on fidaxomicin and bezlotoxumab were used to support findings [
      • Wilcox M.H.
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      • Poxton I.R.
      • Kelly C.
      • Nathan R.
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      Bezlotoxumab for prevention of recurrent Clostridium difficile infection.
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      • Miller M.A.
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      ,
      • Louie T.J.
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      ,
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      Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial.
      ].
      Fig. 1
      Fig. 1Flow diagram of the process of selection of studies on prognostic factors for severe/recurrent Clostridioides difficile infection (CDI).

       Prognostic factors for severe CDI

      The overall quality of evidence ranged from very low to moderate, mainly due to the retrospective nature and small sample size of most studies. The prognostic factors studied in five or more articles are shown in Table 1. An overview of all included studies is provided in Supplementary Material Table S1.
      Table 1Potential prognostic factors for severe Clostridioides difficile infection (CDI)
      Table thumbnail fx1
      Age was the most studied prognostic factor, and was investigated in 53 of 88 included studies [
      • Bhangu S.
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      • Michael A.
      Mortality and risk stratification in patients with Clostridium difficile-associated diarrhoea.
      ,
      • Lungulescu O.A.
      • Cao W.
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      • Stratidis J.G.
      CSI: a severity index for Clostridium difficile infection at the time of admission.
      ,
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      • Kyne L.
      • Garey K.W.
      • Flores S.W.
      • et al.
      A multi-center prospective derivation and validation of a clinical prediction tool for severe Clostridium difficile infection.
      ,
      • Welfare M.R.
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      • Sarma J.B.
      Co-morbidities as predictors of mortality in Clostridium difficile infection and derivation of the ARC predictive score.
      ,
      • Alicino C.
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      • Durando P.
      • Bellina D.
      • Paganino C.
      • Del Bono V.
      • et al.
      Increasing incidence of Clostridium difficile infections: results from a 5-year retrospective study in a large teaching hospital in the Italian region with the oldest population.
      ,
      • Ananthakrishnan A.N.
      • Guzman-Perez R.
      • Gainer V.
      • Cai T.
      • Churchill S.
      • Kohane I.
      • et al.
      Predictors of severe outcomes associated with Clostridium difficile infection in patients with inflammatory bowel disease.
      ,
      • Andrews C.N.
      • Raboud J.
      • Kassen B.O.
      • Enns R.
      Clostridium difficile-associated diarrhea: predictors of severity in patients presenting to the emergency department.
      ,
      • Archbald-Pannone L.R.
      • McMurry T.L.
      • Guerrant R.L.
      • Warren C.A.
      Delirium and other clinical factors with Clostridium difficile infection that predict mortality in hospitalized patients.
      ,
      • Atamna A.
      • Yahav D.
      • Eliakim-Raz N.
      • Goldberg E.
      • Ben-Zvi H.
      • Barsheshet A.
      • et al.
      The effect of statins on the outcome of Clostridium difficile infection in hospitalized patients.
      ,
      • Bauer K.A.
      • Johnston J.E.W.
      • Wenzler E.
      • Goff D.A.
      • Cook C.H.
      • Balada-Llasat J.M.
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      Impact of the NAP-1 strain on disease severity, mortality, and recurrence of healthcare-associated Clostridium difficile infection.
      ,
      • Boone J.H.
      • Archbald-Pannone L.R.
      • Wickham K.N.
      • Carman R.J.
      • Guerrant R.L.
      • Franck C.T.
      • et al.
      Ribotype 027 Clostridium difficile infections with measurable stool toxin have increased lactoferrin and are associated with a higher mortality.
      ,
      • Caupenne A.
      • Ingrand P.
      • Ingrand I.
      • Forestier E.
      • Roubaud-Baudron C.
      • Gavazzi G.
      • et al.
      Acute Clostridioides difficile infection in hospitalized persons aged 75 and older: 30-day prognosis and risk factors for mortality.
      ,
      • Charilaou P.
      • Devani K.
      • John F.
      • Kanna S.
      • Ahlawat S.
      • Young M.
      • et al.
      Acute kidney injury impact on inpatient mortality in Clostridium difficile infection: a national propensity-matched study.
      ,
      • Chintanaboina J.
      • Navabi S.
      • Suchniak-Mussari K.
      • Stern B.
      • Bedi S.
      • Lehman E.B.
      • et al.
      Predictors of 30-day mortality in hospitalized patients with Clostridium difficile infection.
      ,
      • 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.
      ,
      • Dudukgian H.
      • Sie E.
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      Difficile colitis—predictors of fatal outcome.
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      External validation of Velazquez–Gomez severity score index and ATLAS scores and the identification of risk factors associated with mortality in Clostridium difficile infections.
      ,
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      Appendectomy and risk of Clostridium difficile recurrence.
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      Clostridium difficile associated risk of death score (CARDS): a novel severity score to predict mortality among hospitalised patients with C. difficile infection.
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      Epidemiology, outcomes, and predictors of mortality in hospitalized adults with Clostridium difficile infection.
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      • Cook H.
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      Development and validation of a prediction model for mortality and adverse outcomes among patients with peripheral eosinopenia on admission for Clostridium difficile infection.
      ,
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      ,
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      Poor functional status as a risk factor for severe Clostridium difficile infection in hospitalized older adults.
      ,
      • Rao K.
      • Micic D.
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      • Winters S.
      • Kiel M.J.
      • Walk S.T.
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      Clostridium difficile ribotype 027: relationship to age, detectability of toxins A or B in stool with rapid testing, severe infection, and mortality.
      ,
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      ,
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      NAP1 strain type predicts outcomes from Clostridium difficile infection.
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      Clinical factors associated with development of severe-complicated Clostridium difficile infection.
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      Epidemiological factors influencing the development of relapsing and severe Clostridium difficile infection.
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      Clostridium difficile ribotype does not predict severe infection.
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      ,
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      ]. Fifty-one studies performed a univariate analysis and 40 studies (also) a multivariable analysis; 37/51 studies reported higher age as a risk factor for sCDI in univariate analysis, and 26/40 studies in multivariable analysis (overall moderate quality of evidence).
      Thirty-two studies assessed the presence of multiple comorbidities as risk factor for sCDI [
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      A multi-center prospective derivation and validation of a clinical prediction tool for severe Clostridium difficile infection.
      ,
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      Increasing incidence of Clostridium difficile infections: results from a 5-year retrospective study in a large teaching hospital in the Italian region with the oldest population.
      ,
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      Predictors of severe outcomes associated with Clostridium difficile infection in patients with inflammatory bowel disease.
      ,
      • Andrews C.N.
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      • Enns R.
      Clostridium difficile-associated diarrhea: predictors of severity in patients presenting to the emergency department.
      ,
      • Archbald-Pannone L.R.
      • McMurry T.L.
      • Guerrant R.L.
      • Warren C.A.
      Delirium and other clinical factors with Clostridium difficile infection that predict mortality in hospitalized patients.
      ,
      • Atamna A.
      • Yahav D.
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      The effect of statins on the outcome of Clostridium difficile infection in hospitalized patients.
      ,
      • Boone J.H.
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      • Wickham K.N.
      • Carman R.J.
      • Guerrant R.L.
      • Franck C.T.
      • et al.
      Ribotype 027 Clostridium difficile infections with measurable stool toxin have increased lactoferrin and are associated with a higher mortality.
      ,
      • Caupenne A.
      • Ingrand P.
      • Ingrand I.
      • Forestier E.
      • Roubaud-Baudron C.
      • Gavazzi G.
      • et al.
      Acute Clostridioides difficile infection in hospitalized persons aged 75 and older: 30-day prognosis and risk factors for mortality.
      ,
      • Charilaou P.
      • Devani K.
      • John F.
      • Kanna S.
      • Ahlawat S.
      • Young M.
      • et al.
      Acute kidney injury impact on inpatient mortality in Clostridium difficile infection: a national propensity-matched study.
      ,
      • Chintanaboina J.
      • Navabi S.
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      • Stern B.
      • Bedi S.
      • Lehman E.B.
      • et al.
      Predictors of 30-day mortality in hospitalized patients with Clostridium difficile infection.
      ,
      • 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.
      ,
      • Kassam Z.
      • Cribb Fabersunne C.
      • Smith M.B.
      • Alm E.J.
      • Kaplan G.G.
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      Clostridium difficile associated risk of death score (CARDS): a novel severity score to predict mortality among hospitalised patients with C. difficile infection.
      ,
      • Khanna S.
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      Epidemiology, outcomes, and predictors of mortality in hospitalized adults with Clostridium difficile infection.
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      • Cook H.
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      ,
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      • Ring C.
      • et al.
      Poor functional status as a risk factor for severe Clostridium difficile infection in hospitalized older adults.
      ,
      • Rao K.
      • Micic D.
      • Natarajan M.
      • Winters S.
      • Kiel M.J.
      • Walk S.T.
      • et al.
      Clostridium difficile ribotype 027: relationship to age, detectability of toxins A or B in stool with rapid testing, severe infection, and mortality.
      ,
      • See I.
      • Mu Y.
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      NAP1 strain type predicts outcomes from Clostridium difficile infection.
      ,
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      Clinical factors associated with development of severe-complicated Clostridium difficile infection.
      ,
      • Starzengruber P.
      • Segagni Lusignani L.
      • Wrba T.
      • Mitteregger D.
      • Indra A.
      • Graninger W.
      • et al.
      Severe Clostridium difficile infection: incidence and risk factors at a tertiary care university hospital in Vienna, Austria.
      ,
      • Tschudin-Sutter S.
      • Braissant O.
      • Erb S.
      • Stranden A.
      • Bonkat G.
      • Frei R.
      • et al.
      Growth patterns of Clostridium difficile—correlations with strains, binary toxin and disease severity: a prospective cohort study.
      ,
      • van der Wilden G.M.
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      • Subramanian M.
      • Schipper I.B.
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      Fulminant Clostridium difficile colitis: prospective development of a risk scoring system.
      ,
      • Vojtilova L.
      • Freibergerova M.
      • Jurankova J.
      • Bortlicek Z.
      • Husa P.
      Epidemiological factors influencing the development of relapsing and severe Clostridium difficile infection.
      ,
      • Walk S.T.
      • Micic D.
      • Jain R.
      • Lo E.S.
      • Trivedi I.
      • Liu E.W.
      • et al.
      Clostridium difficile ribotype does not predict severe infection.
      ,
      • Wilson V.
      • Cheek L.
      • Satta G.
      • Walker-Bone K.
      • Cubbon M.
      • Citron D.
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      Predictors of death after Clostridium difficile infection: a report on 128 strain-typed cases from a teaching hospital in the United Kingdom.
      ,
      • Xu Q.
      • Chen Y.
      • Gu S.
      • Lv T.
      • Zheng B.
      • Shen P.
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      Hospital-acquired Clostridium difficile infection in Mainland China: a seven-year (2009–2016) retrospective study in a large university hospital.
      ,
      • Khanna S.
      • Aronson S.L.
      • Kammer P.P.
      • Baddour L.M.
      • Pardi D.S.
      Gastric acid suppression and outcomes in Clostridium difficile infection: a population-based study.
      ,
      • Nagayoshi Y.
      • Yamamoto K.
      • Sato S.
      • Suyama N.
      • Izumikawa T.
      • Izumikawa K.
      • et al.
      Clinical significance of a positive Clostridioides difficile glutamate dehydrogenase test on the outcomes of hospitalized older patients.
      ,
      • Tay H.L.
      • Chow A.
      • Ng T.M.
      • Lye D.C.
      Risk factors and treatment outcomes of severe Clostridioides difficile infection in Singapore.
      ,
      • Origuen J.
      • Orellana M.A.
      • Fernandez-Ruiz M.
      • Corbella L.
      • San Juan R.
      • Ruiz-Ruigomez M.
      • et al.
      Toxin B PCR amplification cycle threshold adds little to clinical variables for predicting outcomes in Clostridium difficile infection: a retrospective cohort study.
      ]; 20/30 studies found an association between the presence of multiple comorbidities and sCDI in univariate analysis and 11/22 studies in multivariable analysis (moderate quality of evidence).
      For both higher age and the presence of multiple comorbidities a dose effect was observed: the higher the age or the more concurrent the disorders, the higher the risk of severe disease. No specific medical condition was associated with sCDI, although a positive effect direction (regardless of statistical significance) was observed for cardiovascular, pulmonary, neurological, infectious, renal and hepatic comorbidity and for malignancy.
      For clinical decision-making, a specific cut-off value for age and number of comorbidities would be convenient. However, in many studies age was used as a continuous variable (31/53 studies) or varying cut-off values are used. The majority of studies found a higher risk for sCDI in patients older than 65–70 years. For comorbidity, different established or self-constructed comorbidity scores were reported, most frequently the Charlson comorbidity index (CCI) [
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • MacKenzie C.R.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      ]. Again, most studies used CCI as a continuous variable. Of the studies that identified more comorbidities as a risk factor for sCDI, only three used a cut-off value: one study reported a higher risk in patients with a CCI of ≥3, and two found a higher risk in patients with ≥2 comorbidities [
      • Starzengruber P.
      • Segagni Lusignani L.
      • Wrba T.
      • Mitteregger D.
      • Indra A.
      • Graninger W.
      • et al.
      Severe Clostridium difficile infection: incidence and risk factors at a tertiary care university hospital in Vienna, Austria.
      ,
      • Vojtilova L.
      • Freibergerova M.
      • Jurankova J.
      • Bortlicek Z.
      • Husa P.
      Epidemiological factors influencing the development of relapsing and severe Clostridium difficile infection.
      ,
      • Wilson V.
      • Cheek L.
      • Satta G.
      • Walker-Bone K.
      • Cubbon M.
      • Citron D.
      • et al.
      Predictors of death after Clostridium difficile infection: a report on 128 strain-typed cases from a teaching hospital in the United Kingdom.
      ]. Thus, no statement can be made on the association between exact numbers of comorbidities and severe CDI.
      Twenty articles studied the association between the presence of NAP1/RT027 strain and sCDI [
      • Bauer K.A.
      • Johnston J.E.W.
      • Wenzler E.
      • Goff D.A.
      • Cook C.H.
      • Balada-Llasat J.M.
      • et al.
      Impact of the NAP-1 strain on disease severity, mortality, and recurrence of healthcare-associated Clostridium difficile infection.
      ,
      • Berry C.E.
      • Davies K.A.
      • Owens D.W.
      • Wilcox M.H.
      Is there a relationship between the presence of the binary toxin genes in Clostridium difficile strains and the severity of C. difficile infection (CDI)?.
      ,
      • Boone J.H.
      • Archbald-Pannone L.R.
      • Wickham K.N.
      • Carman R.J.
      • Guerrant R.L.
      • Franck C.T.
      • et al.
      Ribotype 027 Clostridium difficile infections with measurable stool toxin have increased lactoferrin and are associated with a higher mortality.
      ,
      • Fountain E.M.
      • Moses M.C.
      • Park L.P.
      • Woods C.W.
      • Arepally G.M.
      Thrombocytopenia in hospitalized patients with severe Clostridium difficile infection.
      ,
      • Hubert B.
      • Loo V.G.
      • Bourgault A.M.
      • Poirier L.
      • Dascal A.
      • Fortin E.
      • et al.
      A portrait of the geographic dissemination of the Clostridium difficile North American pulsed-field type 1 strain and the epidemiology of C. difficile-associated disease in Quebec.
      ,
      • Huttunen R.
      • Vuento R.
      • Syrjanen J.
      • Tissari P.
      • Aittoniemi J.
      Case fatality associated with a hypervirulent strain in patients with culture-positive Clostridium difficile infection: a retrospective population-based study.
      ,
      • Mascart G.
      • Delmee M.
      • Van Broeck J.
      • Cytryn E.
      • Karmali R.
      • Cherifi S.
      Impact of ribotype 027 on Clostridium difficile infection in a geriatric department.
      ,
      • Miller M.
      • Gravel D.
      • Mulvey M.
      • Taylor G.
      • Boyd D.
      • Simor A.
      • et al.
      Health care-associated Clostridium difficile infection in Canada: patient age and infecting strain type are highly predictive of severe outcome and mortality.
      ,
      • Rao K.
      • Micic D.
      • Natarajan M.
      • Winters S.
      • Kiel M.J.
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      • et al.
      Clostridium difficile ribotype 027: relationship to age, detectability of toxins A or B in stool with rapid testing, severe infection, and mortality.
      ,
      • Scardina T.
      • Labuszewski L.
      • Pacheco S.M.
      • Adams W.
      • Schreckenberger P.
      • Johnson S.
      Clostridium difficile infection (CDI) severity and outcome among patients infected with the NAP1/BI/027 strain in a non-epidemic setting.
      ,
      • See I.
      • Mu Y.
      • Cohen J.
      • Beldavs Z.G.
      • Winston L.G.
      • Dumyati G.
      • et al.
      NAP1 strain type predicts outcomes from Clostridium difficile infection.
      ,
      • Starzengruber P.
      • Segagni Lusignani L.
      • Wrba T.
      • Mitteregger D.
      • Indra A.
      • Graninger W.
      • et al.
      Severe Clostridium difficile infection: incidence and risk factors at a tertiary care university hospital in Vienna, Austria.
      ,
      • Tamez-Torres K.M.
      • Torres-Gonzalez P.
      • Leal-Vega F.
      • Garcia-Alderete A.
      • Lopez Garcia N.I.
      • Mendoza-Aguilar R.
      • et al.
      Impact of Clostridium difficile infection caused by the NAP1/RT027 strain on severity and recurrence during an outbreak and transition to endemicity in a Mexican tertiary care center.
      ,
      • Tschudin-Sutter S.
      • Braissant O.
      • Erb S.
      • Stranden A.
      • Bonkat G.
      • Frei R.
      • et al.
      Growth patterns of Clostridium difficile—correlations with strains, binary toxin and disease severity: a prospective cohort study.
      ,
      • Walk S.T.
      • Micic D.
      • Jain R.
      • Lo E.S.
      • Trivedi I.
      • Liu E.W.
      • et al.
      Clostridium difficile ribotype does not predict severe infection.
      ,
      • Wilson V.
      • Cheek L.
      • Satta G.
      • Walker-Bone K.
      • Cubbon M.
      • Citron D.
      • et al.
      Predictors of death after Clostridium difficile infection: a report on 128 strain-typed cases from a teaching hospital in the United Kingdom.
      ,
      • Menon A.
      • Perry D.A.
      • Motyka J.
      • Weiner S.
      • Standke A.
      • Penkevich A.
      • et al.
      Changes in the association between diagnostic testing method, PCR ribotype, and clinical outcomes from Clostridioides difficile infection: one Institution's experience.
      ,
      • Korac M.
      • Rupnik M.
      • Nikolic N.
      • Jovanovic M.
      • Tosic T.
      • Malinic J.
      • et al.
      Clostridioides difficile ribotype distribution in a large teaching hospital in Serbia.
      ,
      • Mani N.S.
      • Lynch J.B.
      • Fang F.C.
      • Chan J.D.
      Risk factors for BI/NAP1/027 Clostridioides difficile infections and clinical outcomes compared with non-NAP1 strains.
      ,
      • Bauer M.P.
      • Notermans D.W.
      • van Benthem B.H.
      • Brazier J.S.
      • Wilcox H.
      • Rupnik M.
      • et al.
      Clostridium difficile infection in Europe: a hospital-based survey.
      ]; 9/19 studies reported a higher risk of sCDI in patients with the NAP1/027 strain in univariate analysis, and 7/10 in multivariate analysis. One study found that the NAP1/027 strain was more prevalent in patients with mild disease compared to patients with sCDI [
      • Bauer K.A.
      • Johnston J.E.W.
      • Wenzler E.
      • Goff D.A.
      • Cook C.H.
      • Balada-Llasat J.M.
      • et al.
      Impact of the NAP-1 strain on disease severity, mortality, and recurrence of healthcare-associated Clostridium difficile infection.
      ].
      Furthermore, seven studies assessed C. difficile binary toxin as a risk factor for sCDI [
      • Berry C.E.
      • Davies K.A.
      • Owens D.W.
      • Wilcox M.H.
      Is there a relationship between the presence of the binary toxin genes in Clostridium difficile strains and the severity of C. difficile infection (CDI)?.
      ,
      • Reigadas E.
      • Alcala L.
      • Marin M.
      • Martin A.
      • Iglesias C.
      • Bouza E.
      Role of binary toxin in the outcome of Clostridium difficile infection in a non-027 ribotype setting.
      ,
      • Tschudin-Sutter S.
      • Braissant O.
      • Erb S.
      • Stranden A.
      • Bonkat G.
      • Frei R.
      • et al.
      Growth patterns of Clostridium difficile—correlations with strains, binary toxin and disease severity: a prospective cohort study.
      ,
      • Walk S.T.
      • Micic D.
      • Jain R.
      • Lo E.S.
      • Trivedi I.
      • Liu E.W.
      • et al.
      Clostridium difficile ribotype does not predict severe infection.
      ,
      • Origuen J.
      • Orellana M.A.
      • Fernandez-Ruiz M.
      • Corbella L.
      • San Juan R.
      • Ruiz-Ruigomez M.
      • et al.
      Toxin B PCR amplification cycle threshold adds little to clinical variables for predicting outcomes in Clostridium difficile infection: a retrospective cohort study.
      ,
      • Lopez-Cardenas S.
      • Torres-Martos E.
      • Mora-Delgado J.
      • Sanchez-Calvo J.M.
      • Santos-Pena M.
      • Zapata Lopez A.
      • et al.
      The prognostic value of toxin B and binary toxin in Clostridioides difficile infection.
      ,
      • Carlson T.J.
      • Endres B.T.
      • Le Pham J.
      • Gonzales-Luna A.J.
      • Alnezary F.S.
      • Nebo K.
      • et al.
      Eosinopenia and binary toxin increase mortality in hospitalized patients with Clostridioides difficile infection.
      ]. Of these, three identified C. difficile binary toxin as a risk factor for sCDI in univariate analysis, and only 1/1 study in multivariate analysis. The overall quality of evidence of these studies was low. We scrutinized the separate studies on the presence of NAP1/RT027 strain and/or binary toxin by weighing the results by the quality of evidence per study, but this did not alter the conclusion. However, when we considered the direction of effect regardless of statistical significance, we observed a positive effect direction for both NAP1/RT027 strain and binary toxin.
      Another interesting finding was that the majority of studies did not find an association between the use of proton pump inhibitors (PPIs), H2 receptor antagonists or antibiotics and the occurrence of sCDI in univariate and multivariate analyses. Also for these factors we found a positive effect direction. However, the quality of evidence was low.
      In conclusion, only the factors higher age (>65–70 years old) and the presence of multiple comorbidities were consistently associated with sCDI (Table 3).
      Table 2Potential prognostic factors for recurrent Clostridioides difficile infection (CDI)
      Table thumbnail fx2
      Table 3Summary of findings
      Prognostic factorQuality of evidence
      Severe CDI
       Higher age (>65–70 years old)Moderate
       Presence of multiple comorbiditiesModerate
      Recurrent CDI
       Higher age (>65–70 years old)Moderate
       Previous recurrence of CDI (<3 months)Moderate
       Healthcare-associated CDILow
       Prior hospitalization (<3 months)Low
       Proton pump inhibitors started during/after CDI diagnosisLow
      CDI, Clostridioides difficile infection.

       Prognostic factors for recurrent CDI

      The overall quality of evidence for the prognosis of rCDI was low to moderate (Table 2). Most of the studies were retrospective, with a high to moderate risk of bias. An overview of all included studies is provided in Supplementary Material Table S2.
      Higher age (≥65 years old) is the most studied factor and was investigated in 35/43 included studies [
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      Nosocomial Infection Study. Prediction of recurrent Clostridium difficile infection at the bedside: the GEIH-CDI score.
      ,
      • D'Agostino R.B.
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      • Kean Y.
      • Gorbach S.
      Risk estimation for recurrent Clostridium difficile infection based on clinical factors.
      ,
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      ,
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      Derivation and validation of a Clostridium difficile infection recurrence prediction rule in a national cohort of veterans.
      ,
      • Viswesh V.
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      • Nowak M.A.
      Development of a bedside scoring system for predicting a first recurrence of Clostridium difficile-associated diarrhea.
      ,
      • Hebert C.
      • Du H.
      • Peterson L.R.
      • Robicsek A.
      Electronic health record-based detection of risk factors for Clostridium difficile infection relapse.
      ,
      • Fujii L.
      • Fasolino J.
      • Crowell M.D.
      • Dibaise J.K.
      Appendectomy and risk of Clostridium difficile recurrence.
      ,
      • Khanna S.
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      • Kammer P.P.
      • Baddour L.M.
      • Pardi D.S.
      Gastric acid suppression and outcomes in Clostridium difficile infection: a population-based study.
      ,
      • Bauer M.P.
      • Notermans D.W.
      • van Benthem B.H.
      • Brazier J.S.
      • Wilcox H.
      • Rupnik M.
      • et al.
      Clostridium difficile infection in Europe: a hospital-based survey.
      ,
      • Origuen J.
      • Orellana M.A.
      • Fernandez-Ruiz M.
      • Corbella L.
      • San Juan R.
      • Ruiz-Ruigomez M.
      • et al.
      Toxin B PCR amplification cycle threshold adds little to clinical variables for predicting outcomes in Clostridium difficile infection: a retrospective cohort study.
      ,
      • Abdelfatah M.
      • Nayfe R.
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      • Enriquez K.
      • Ali E.
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      • et al.
      Factors predicting recurrence of Clostridium difficile infection (CDI) in hospitalized patients: retrospective Study of more than 2000 patients.
      ,
      • Appaneal H.J.
      • Caffrey A.R.
      • Beganovic M.
      • Avramovic S.
      • LaPlante K.L.
      Predictors of Clostridioides difficile recurrence across a national cohort of veterans in outpatient, acute, and long-term care settings.
      ,
      • Carpenter B.P.
      • Hennessey E.K.
      • Bryant A.M.
      • Khoury J.A.
      • Crannage A.J.
      Identification of factors impacting recurrent Clostridium difficile infection and development of a risk evaluation tool.
      ,
      • Dharbhamulla N.
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      • Gaughan J.
      • Roy S.
      Risk factors associated with recurrent Clostridium difficile infection.
      ,
      • Eyre D.W.
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      ,
      • Freedberg D.E.
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      Proton pump inhibitors and risk for recurrent Clostridium difficile infection among inpatients.
      ,
      • Im G.Y.
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      ,
      • Kimura T.
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      Characterization and risk factors for recurrence of Clostridioides (Clostridium) difficile infection in Japan: a nationwide real-world analysis using a large hospital-based administrative dataset.
      ,
      • Lavergne V.
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      • Su S.H.
      Lymphopenia as a novel marker of Clostridium difficile infection recurrence.
      ,
      • Louie T.J.
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      ,
      • Lupse M.
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      Predictors of first recurrence in Clostridium difficile-associated disease. A study of 306 patients hospitalized in a Romanian tertiary referral center.
      ,
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      ,
      • McDonald E.G.
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      Continuous proton pump inhibitor therapy and the associated risk of recurrent Clostridium difficile infection.
      ,
      • McFarland L.V.
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      • Elmer G.W.
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      Recurrent Clostridium difficile disease: epidemiology and clinical characteristics.
      ,
      • Na'amnih W.
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      • Carmeli Y.
      Risk factors for recurrent Clostridium difficile infection in a tertiary hospital in Israel.
      ,
      • Pepin J.
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      • Valiquette L.
      • Raiche E.
      • Ruel J.
      • Fulop K.
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      Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada.
      ,
      • Rao K.
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      ,
      • Rodriguez-Pardo D.
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      Barcelona Clostridium difficile Study, epidemiology of Clostridium difficile infection and risk factors for unfavorable clinical outcomes: results of a hospital-based study in Barcelona, Spain.
      ,
      • Rotramel A.
      • Poritz L.S.
      • Messaris E.
      • Berg A.
      • Stewart D.B.
      PPI therapy and albumin are better predictors of recurrent Clostridium difficile colitis than choice of antibiotics.
      ,
      • van Beurden Y.H.
      • Nezami S.
      • Mulder C.J.J.
      • Vandenbroucke-Grauls C.
      Host factors are more important in predicting recurrent Clostridium difficile infection than ribotype and use of antibiotics.
      ,
      • Zilberberg M.D.
      • Reske K.
      • Olsen M.
      • Yan Y.
      • Dubberke E.R.
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      • Echevarria K.
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      ,
      • Shakov R.
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      • Kagunye S.K.
      • Baddoura W.J.
      • DeBari V.A.
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      ,
      • Fekety R.
      • McFarland L.V.
      • Surawicz C.M.
      • Greenberg R.N.
      • Elmer G.W.
      • Mulligan M.E.
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      ,
      • Ryu H.S.
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      • Choi S.C.
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      ], 15/30 studies identified higher age as a risk factor for rCDI in univariate analysis, and 16/31 studies in multivariable analysis. Moreover, higher age was the only factor for which we found a moderate to large effect size and a dose-dependent effect.
      Eight studies assessed whether a previous CDI recurrence in the preceding 3 months was a risk factor for subsequent rCDI, and showed inconsistent results [
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      • Martinez C.
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      • Shaw E.
      • Marrodan T.
      • et al.
      Nosocomial Infection Study. Prediction of recurrent Clostridium difficile infection at the bedside: the GEIH-CDI score.
      ,
      • D'Agostino R.B.
      • Collins S.H.
      • Pencina K.M.
      • Kean Y.
      • Gorbach S.
      Risk estimation for recurrent Clostridium difficile infection based on clinical factors.
      ,
      • Hebert C.
      • Du H.
      • Peterson L.R.
      • Robicsek A.
      Electronic health record-based detection of risk factors for Clostridium difficile infection relapse.
      ,
      • Bauer M.P.
      • Notermans D.W.
      • van Benthem B.H.
      • Brazier J.S.
      • Wilcox H.
      • Rupnik M.
      • et al.
      Clostridium difficile infection in Europe: a hospital-based survey.
      ,
      • Carpenter B.P.
      • Hennessey E.K.
      • Bryant A.M.
      • Khoury J.A.
      • Crannage A.J.
      Identification of factors impacting recurrent Clostridium difficile infection and development of a risk evaluation tool.
      ,
      • Kimura T.
      • Snijder R.
      • Sugitani T.
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      ,
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      ,