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Risk factors for Clostridioides difficile infection in children: a systematic review and meta-analysis

  • Author Footnotes
    † These authors contributed equally to this work and share first authorship.
    N. Dong
    Footnotes
    † These authors contributed equally to this work and share first authorship.
    Affiliations
    Provincial Centre for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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  • Author Footnotes
    † These authors contributed equally to this work and share first authorship.
    Z.R. Li
    Footnotes
    † These authors contributed equally to this work and share first authorship.
    Affiliations
    Provincial Centre for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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  • P. Qin
    Affiliations
    Provincial Centre for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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  • C.X. Qiang
    Affiliations
    Provincial Centre for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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  • J. Yang
    Affiliations
    Provincial Centre for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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  • Y.N. Niu
    Affiliations
    Provincial Centre for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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  • X.R. Niu
    Affiliations
    Provincial Centre for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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  • X.X. Liu
    Affiliations
    Provincial Centre for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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  • W.G. Wang
    Affiliations
    Provincial Centre for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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  • B.J. Wen
    Affiliations
    Provincial Centre for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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  • Z.R. Ouyang
    Affiliations
    Provincial Centre for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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  • Y.L. Zhang
    Affiliations
    Provincial Centre for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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  • M. Zhao
    Affiliations
    Provincial Centre for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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  • J.Y.R. Li
    Affiliations
    Provincial Centre for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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  • J.H. Zhao
    Correspondence
    Corresponding author. Address: No. 215 Heping West Road, Shijiazhuang, Hebei Province, China. Tel.: +86311 66002711.
    Affiliations
    Provincial Centre for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

    Department of Clinical Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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  • Author Footnotes
    † These authors contributed equally to this work and share first authorship.
Open AccessPublished:September 12, 2022DOI:https://doi.org/10.1016/j.jhin.2022.09.004

      Summary

      Background

      Clostridioides difficile is considered an urgent threat to human health by the US Centers for Disease Control and Prevention. In recent years, C. difficile has been reported increasingly as a cause of gastrointestinal disease in children, and the prevalence of hospital-acquired C. difficile infection and community-acquired CDI in children is increasing.

      Aim

      To perform a systematic review and meta-analysis of risk factors for CDI in children.

      Methods

      MEDLINE/PubMed, EMBASE, Web of Science, Scopus, OVID, China National Knowledge Infrastructure, Wanfang (Chinese), SinoMed (Chinese) and Weipu (Chinese) were searched from inception to 12th January 2022. Observational studies (cohort, case–control and cross-sectional) on CDI in children were included in the analysis. Data were pooled using a fixed or random-effects model, and odds ratios (OR) were calculated.

      Findings

      In total, 25 observational studies were included in the analysis. Prior antibiotic exposure [OR 1.93, 95% confidence interval (CI) 1.25–2.97], prolonged hospitalization (OR 14.68, 95% CI 13.24–16.28), history of hospitalization (OR 3.67, 95% CI 1.91–7.06), gastric acid suppressants (OR 1.96, 95% CI 1.41–2.73), male gender (OR 1.18, 95% CI 1.05–1.32), neoplastic disease (OR 3.40, 95% CI, 2.85–4.07), immunodeficiency (OR 4.18, 95% CI 3.25–5.37), solid organ transplantation (OR 4.56, 95% CI 3.95–5.27) and enteral feeding (OR 2.21, 95% CI 1.05–4.62) were associated with increased risk of CDI.

      Conclusion

      This systematic review and meta-analysis provides further evidence for the susceptibility factors of CDI to improve clinicians' awareness of CDI, and prevent C. difficile-associated diarrhoea in children.

      Keywords

      Introduction

      Clostridioides difficile, a Gram-positive spore-forming anaerobic bacterium, is considered an ‘urgent threat’ to human health by the US Centers for Disease Control and Prevention [
      • Abt M.C.
      • McKenney P.T.
      • Pamer E.G.
      Clostridium difficile colitis: pathogenesis and host defence.
      ]. Over the past two decades, C. difficile has caused outbreaks of hospital-acquired infection in many parts of the world, with clinical symptoms ranging from self-limiting diarrhoea to pseudomembranous colitis, toxic megacolon, septic shock, colon perforation, multi-organ failure and death [
      • Smits W.K.
      • Lyras D.
      • Lacy D.B.
      • Wilcox M.H.
      • Kuijper E.J.
      Clostridium difficile infection.
      ]. It is estimated that C. difficile infection (CDI) is responsible for over 500,000 enteric infections, 29,000 deaths and over $4.8 billion in healthcare costs each year in the USA [
      • Heimann S.M.
      • Cruz A.M.
      • Mellinghof S.
      • Vehreschild M.
      Economic burden and cost-effective management of Clostridium difficile infections.
      ]. Furthermore, based on the 2016–2017 point prevalence survey of the European Centre for Disease Prevention and Control, it is estimated that 189,526 cases of CDI are reported annually in acute care hospitals, resulting in considerable morbidity and mortality [
      • Suetens C.
      • Latour K.
      • Karki T.
      • Ricchizzi E.
      • Kinross P.
      • Moro M.L.
      • et al.
      Prevalence of healthcare-associated infections, estimated incidence and composite antimicrobial resistance index in acute care hospitals and long-term care facilities: results from two European point prevalence surveys, 2016 to 2017.
      ,
      • Kwon J.H.
      • Olsen M.A.
      • Dubberke E.R.
      The morbidity, mortality, and costs associated with Clostridium difficile infection.
      ]. Although the incidence of hospital-acquired CDI (HA-CDI) in the USA has decreased moderately in recent years, the rates of community-acquired CDI (CA-CDI) have remained largely unchanged or even increased slightly [
      • Turner N.A.
      • Grambow S.C.
      • Woods C.W.
      • Fowler V.J.
      • Moehring R.W.
      • Anderson D.J.
      • et al.
      Epidemiologic trends in Clostridioides difficile infections in a regional community hospital network.
      ,
      • Guh A.Y.
      • Mu Y.
      • Winston L.G.
      • Johnston H.
      • Olson D.
      • Farley M.M.
      • et al.
      Trends in U.S. burden of Clostridioides difficile infection and outcomes.
      ].
      CDI has been studied extensively in adults, and traditional risk factors include history of antibiotic use, old age, comorbidities, disease severity and hospitalization [
      • Loo V.G.
      • Bourgault A.M.
      • Poirier L.
      • Lamothe F.
      • Michaud S.
      • Turgeon N.
      • et al.
      Host and pathogen factors for Clostridium difficile infection and colonization.
      ,
      • Al-Tureihi F.I.
      • Hassoun A.
      • Wolf-Klein G.
      • Isenberg H.
      Albumin, length of stay, and proton pump inhibitors: key factors in Clostridium difficile-associated disease in nursing home patients.
      ]. However, despite being isolated initially from infants, little is known about CDI in children. In recent years, C. difficile has caused gastrointestinal diseases in children, and is more prevalent in children with diarrhoea than in children with rotavirus or Cryptosporidium infection [
      • Plants-Paris K.
      • Bishoff D.
      • Oyaro M.O.
      • Mwinyi B.
      • Chappell C.
      • Kituyi A.
      • et al.
      Prevalence of Clostridium difficile infections among Kenyan children with diarrhea.
      ]. In addition, the prevalence rates of HA-CDI and CA-CDI in children are increasing [
      • Deshpande A.
      • Pant C.
      • Anderson M.P.
      • Donskey C.J.
      • Sferra T.J.
      Clostridium difficile infection in the hospitalized pediatric population: increasing trend in disease incidence.
      ,
      • Kim J.
      • Smathers S.A.
      • Prasad P.
      • Leckerman K.H.
      • Coffin S.
      • Zaoutis T.
      Epidemiological features of Clostridium difficile-associated disease among inpatients at children’s hospitals in the United States, 2001–2006.
      ,
      • Nylund C.M.
      • Goudie A.
      • Garza J.M.
      • Fairbrother G.
      • Cohen M.B.
      Clostridium difficile infection in hospitalized children in the United States.
      ]. Although several systematic reviews and meta-analyses have shown that antibiotic therapy and the use of proton pump inhibitors (PPIs) increase the risk of CDI in paediatric inpatients, few studies have evaluated other risk factors for CDI in children [
      • Anjewierden S.
      • Han Z.
      • Foster C.B.
      • Pant C.
      • Deshpande A.
      Risk factors for Clostridium difficile infection in pediatric inpatients: a meta-analysis and systematic review.
      ,
      • Oshima T.
      • Wu L.
      • Li M.
      • Fukui H.
      • Watari J.
      • Miwa H.
      Magnitude and direction of the association between Clostridium difficile infection and proton pump inhibitors in adults and pediatric patients: a systematic review and meta-analysis.
      ]. To this end, this study systematically retrieved and summarized relevant studies in order to assess the risk factors for CDI in children comprehensively.

      Methods

      This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (Table S1, see online supplementary material) [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ]. The protocol of this systematic review and meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42022339371).

      Eligibility criteria

      The inclusion criteria were: (i) observational studies (cohort, case–control and cross-sectional) on primary CDI in children (age ≤18 years); (ii) studies with sufficient data to estimate the odds ratio (OR), relative risk (RR) or hazard ratio (HR) and 95% confidence interval (CI); (iii) studies that evaluated more than one risk factor for CDI, including, but not limited to, pharmacological agents [e.g. antibiotics, PPIs, H2 receptor antagonists (H2RAs)], age, gender, comorbidities, history of hospitalization, history of CDI, and other clinical risk factors; and (iv) no restrictions on study setting (inpatient or outpatient). Studies with recurrent CDI or asymptomatic colonization in children were excluded, as were reviews, case reports, non-human trials, letters, conference abstracts and comments.

      Data sources and search strategy

      A comprehensive search of MEDLINE/PubMed, EMBASE, Web of Science, Scopus, OVID, China National Knowledge Infrastructure, Wanfang (Chinese), SinoMed (Chinese), and Weipu (Chinese) from inception to 12th January 2022 was conducted, using the following medical subject headings: ‘child’, ‘children’, ‘Clostridioides difficile infection’, ‘C. difficile infection’, ‘CDI’, ‘Clostridium difficile infection’, ‘Clostridium difficile associated infection’, ‘CDAD’ combined with ‘risk factors’, ‘risk’, ‘predictor’ and ‘relative risk.’ The search strategy is shown in the online supplementary material.

      Study selection and data extraction

      Titles, abstracts and full texts were screened independently by two investigators to assess suitability for inclusion in the final review according to the criteria defined above. Data were extracted for each study, including study setting and design, patient demographics, year of publication, country where the study was undertaken, methods used to diagnose CDI, and identified risk factors for CDI. For all studies, adjusted data were extracted where possible to calculate the OR. Disagreements in data extraction were resolved by consensus.

      Outcomes assessment

      This systematic review and meta-analysis focused on assessing risk factors associated with CDI in children. In the included studies, CDI was defined by symptoms (usually diarrhoea), a stool test positive for C. difficile toxins, the detection of toxigenic C. difficile, colonoscopy, or histopathological findings revealing pseudomembranous colitis. HA-CDI was defined as symptom onset within ≥48 h after hospital admission and <4 weeks after hospital discharge. CA-CDI was defined as disease in the community, symptom onset within <48 h of hospitalization in children without previous hospitalization, or symptom onset >12 weeks after hospital discharge. In addition, some studies defined CDI cases as patients with an International Classification of Diseases, Ninth Revision (ICD-9) diagnostic code of 008.45, which is considered the only code devoted to CDI, and it has been validated previously as an accurate determinant of actual disease.

      Quality assessment

      The quality of the observational studies (including cross-sectional, cohort and case–control) was assessed independently by two investigators using the Newcastle–Ottawa Scale (NOS). The NOS comprises three domains: selection (four questions), comparability (two questions), and outcome (cohort studies) or exposure (case–control studies) (three questions). The NOS assigns a maximum of four points for selection, two points for comparability (the study controlled for age or other confounding factors) and three points for exposure or outcome. Studies with a cumulative score >7 were considered to be high quality; scores of 5–7 and <5 were considered to indicate moderate quality and low quality, respectively. Any disagreements or discrepancies were resolved by consensus.

      Statistical analysis

      Statistical analysis was performed using STATA Version 14.0 (using the packages ‘metan,’ ‘metafunnel,’ ‘metaninf’ and ‘metabias’) to calculate the pooled effect size of studies that reported OR and 95% CI in multi-variate analyses. Considering the low disease frequency and prevalence of CDI in this population, any RR and HR with similar values were combined into the OR. The pooled OR and 95% CI was used to describe the relationship between various risk factors and CDI.
      Heterogeneity was assessed by Cochran Q test and I2 statistics. Significant heterogeneity was defined as P<0.10 or I2>75%, and moderate and low heterogeneity was defined as I2 of 51–75% and <50%, respectively [
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ]. A random-effects model was used when I2>50% or P<0.10. Otherwise, a fixed-effects model was applied. Potential causes of heterogeneity with stratification were explored by clinical and methodological features of the studies. This stratification included duration of antibiotic exposure, type of gastric acid suppressant (PPI or H2RA), study setting, study design, and CDI diagnostic assays. Secondary analyses considered the risk associated with cephalosporin subclasses. Given that seven and six meta-analyses were performed to assess the significance of prior antibiotic exposure and gastric acid suppressants, the Bonferroni corrected significance levels were 0.007 (=0.05/7) and 0.008 (=0.05/6), which provides a stringent approach for preventing false-positive findings. In contrast, for the analysis of publication bias and heterogeneity, an uncorrected significance level of 0.05 was used to ensure that any of these potential problems with the findings could be detected. Publication bias was assessed by generating funnel plots, and tested used Egger's asymmetry test.

      Results

      Characteristics and quality of studies

      The search retrieved 4340 studies, of which 70 were selected for full-text review after screening by title and abstract. Forty-five studies were excluded (Figure 1). Twenty-five studies were included in the analysis [
      • Nylund C.M.
      • Goudie A.
      • Garza J.M.
      • Fairbrother G.
      • Cohen M.B.
      Clostridium difficile infection in hospitalized children in the United States.
      ,
      • Miranda-Katz M.
      • Parmar D.
      • Dang R.
      • Alabaster A.
      • Greenhow T.L.
      Epidemiology and risk factors for community associated Clostridioides difficile in children.
      ,
      • Zhao C.
      • Guo S.
      • Jia X.
      • Xu X.
      Distribution and risk factor analysis for Clostridium difficile-associated diarrhea among hospitalized children over one year of age.
      ,
      • Mayer E.F.
      • Maron G.
      • Dallas R.H.
      • Ferrolino J.
      • Tang L.
      • Sun Y.
      • et al.
      A multicenter study to define the epidemiology and outcomes of Clostridioides difficile infection in pediatric hematopoietic cell and solid organ transplant recipients.
      ,
      • Weng M.K.
      • Adkins S.H.
      • Bamberg W.
      • Farley M.M.
      • Espinosa C.C.
      • Wilson L.
      • et al.
      Risk factors for community-associated Clostridioides difficile infection in young children.
      ,
      • Khalil A.
      • Hendaus M.A.
      • Elmagboul E.
      • Mohamed A.
      • Deshmukh A.
      • Elmasoudi A.
      Incidence of Clostridium difficile infection and associated risk factors among hospitalized children in Qatar.
      ,
      • Migriauli I.
      • Meunargia V.
      • Chkhaidze I.
      • Sabakhtarishvili G.
      • Gujabidze K.
      • Butsashvili M.
      • et al.
      Factors affecting development of Clostridium difficile infection in hospitalized pediatric patients in the country Georgia.
      ,
      • Adams D.J.
      • Eberly M.D.
      • Rajnik M.
      • Nylund C.M.
      Risk factors for community-associated Clostridium difficile infection in children.
      ,
      • Daida A.
      • Yoshihara H.
      • Inai I.
      • Hasegawa D.
      • Ishida Y.
      • Urayama K.Y.
      • et al.
      Risk factors for hospital-acquired Clostridium difficile infection among pediatric patients with cancer.
      ,
      • Crews J.D.
      • Anderson L.R.
      • Waller D.K.
      • Swartz M.D.
      • DuPont H.L.
      • Starke J.R.
      Risk factors for community-associated Clostridium difficile-associated diarrhea in children.
      ,
      • Santiago B.
      • Guerra L.
      • García-Morín M.
      • González E.
      • Gonzálvez A.
      • Izquierdo G.
      • et al.
      [Clostridium difficile isolation in children hospitalized with diarrhea].
      ,
      • de Blank P.
      • Zaoutis T.
      • Fisher B.
      • Troxel A.
      • Kim J.
      • Aplenc R.
      Trends in Clostridium difficile infection and risk factors for hospital acquisition of Clostridium difficile among children with cancer.
      ,
      • Guo S.
      • Xu X.W.
      • Dong F.
      [Risk factors of Clostridium difficile-associated diarrhea in children].
      ,
      • Turco R.
      • Martinelli M.
      • Miele E.
      • Roscetto E.
      • Del P.M.
      • Greco L.
      • et al.
      Proton pump inhibitors as a risk factor for paediatric Clostridium difficile infection.
      ,
      • Tai E.
      • Richardson L.C.
      • Townsend J.
      • Howard E.
      • McDonald C.
      Clostridium difficile infection among children with cancer.
      ,
      • Samady W.
      • Bush R.
      • Pong A.
      • Andrews A.
      • Fisher E.S.
      Predictors of Clostridium difficile infections in hospitalized children.
      ,
      • Sathyendran V.
      • McAuliffe G.N.
      • Swager T.
      • Freeman J.T.
      • Taylor S.L.
      • Roberts S.A.
      Clostridium difficile as a cause of healthcare-associated diarrhoea among children in Auckland, New Zealand: clinical and molecular epidemiology.
      ,
      • Banaszkiewicz A.
      • Kowalska-Duplaga K.
      • Pytrus T.
      • Pituch H.
      • Gawrońska A.
      • Radzikowski A.
      Clostridium difficile infection in newly diagnosed pediatric patients with inflammatory bowel disease: prevalence and risk factors.
      ,
      • Brown K.E.
      • Knoderer C.A.
      • Nichols K.R.
      • Crumby A.S.
      Acid-suppressing agents and risk for Clostridium difficile infection in pediatric patients.
      ,
      • Freedberg D.E.
      • Lamousé-Smith E.S.
      • Lightdale J.R.
      • Jin Z.
      • Yang Y.X.
      • Abrams J.A.
      Use of acid suppression medication is associated with risk for C. difficile infection in infants and children: a population-based study.
      ,
      • Predrag S.
      • Branislava K.
      • Nikola S.
      • Niko R.
      • Zorica S.R.
      • Stanković-Đorđević D.
      Community-acquired Clostridium difficile infection in Serbian pediatric population.
      ,
      • Karaaslan A.
      • Soysal A.
      • Yakut N.
      • Akkoç G.
      • Demir S.O.
      • Atıcı S.
      • et al.
      Hospital acquired Clostridium difficile infection in pediatric wards: a retrospective case–control study.
      ,
      • Jimenez J.
      • Drees M.
      • Loveridge-Lenza B.
      • Eppes S.
      • DelRosario F.
      Exposure to gastric acid-suppression therapy is associated with health care- and community-associated Clostridium difficile infection in children.
      ,
      • Sandora T.J.
      • Fung M.
      • Flaherty K.
      • Helsing L.
      • Scanlon P.
      • Potter-Bynoe G.
      • et al.
      Epidemiology and risk factors for Clostridium difficile infection in children.
      ,
      • Li Y.
      Analysis of risk factors for possible foodborne transmission of Clostridium difficile infection.
      ], and their characteristics are shown in Table I.
      Figure 1
      Figure 1Flowchart of study selection according to PRISMA guidelines. CDI, Clostridioides difficile infection.
      Table ICharacteristics of studies included in the meta-analysis
      StudyYearStudy locationStudy periodStudy designRoute of acquisitionSettingSample size (N)Age range (years)Diagnostic test
      Miranda-Katz et al. [
      • Miranda-Katz M.
      • Parmar D.
      • Dang R.
      • Alabaster A.
      • Greenhow T.L.
      Epidemiology and risk factors for community associated Clostridioides difficile in children.
      ]
      2020USAJanuary 2012–December 2016Case–controlCA-CDIInpatients and outpatients8981–17EIA, PCR (Toxin A/B); GDH
      Zhao et al. [
      • Zhao C.
      • Guo S.
      • Jia X.
      • Xu X.
      Distribution and risk factor analysis for Clostridium difficile-associated diarrhea among hospitalized children over one year of age.
      ]
      2020ChinaJanuary 2011–January 2014Retrospective cohort-Inpatients1971–15.6PCR (Toxin A/B)
      Mayer et al. [
      • Mayer E.F.
      • Maron G.
      • Dallas R.H.
      • Ferrolino J.
      • Tang L.
      • Sun Y.
      • et al.
      A multicenter study to define the epidemiology and outcomes of Clostridioides difficile infection in pediatric hematopoietic cell and solid organ transplant recipients.
      ]
      2020USAJanuary 2010–June 2013Nested case–control-Inpatients25860–18EIA, PCR (Toxin A/B)
      Weng et al. [
      • Weng M.K.
      • Adkins S.H.
      • Bamberg W.
      • Farley M.M.
      • Espinosa C.C.
      • Wilson L.
      • et al.
      Risk factors for community-associated Clostridioides difficile infection in young children.
      ]
      2019USAOctober 2014–February 2016Case–controlCA-CDIOutpatients1361–5EIA, PCR (Toxin A/B)
      Khalil et al. [
      • Khalil A.
      • Hendaus M.A.
      • Elmagboul E.
      • Mohamed A.
      • Deshmukh A.
      • Elmasoudi A.
      Incidence of Clostridium difficile infection and associated risk factors among hospitalized children in Qatar.
      ]
      2019QatarJanuary 2015–December 2015Retrospective cohortHA-CDIInpatients2002–14RT-PCR (Toxin A/B)
      Migriauli et al. [
      • Migriauli I.
      • Meunargia V.
      • Chkhaidze I.
      • Sabakhtarishvili G.
      • Gujabidze K.
      • Butsashvili M.
      • et al.
      Factors affecting development of Clostridium difficile infection in hospitalized pediatric patients in the country Georgia.
      ]
      2018USAMay 2016–December 2017Cross-sectional-Inpatients2200–18EIA, PCR (Toxin A/B)
      Adams et al. [
      • Adams D.J.
      • Eberly M.D.
      • Rajnik M.
      • Nylund C.M.
      Risk factors for community-associated Clostridium difficile infection in children.
      ]
      2017USA2001–2013Case–controlCA-CDIInpatients53241–18ICD-9 Code (008.45)
      Daida et al. [
      • Daida A.
      • Yoshihara H.
      • Inai I.
      • Hasegawa D.
      • Ishida Y.
      • Urayama K.Y.
      • et al.
      Risk factors for hospital-acquired Clostridium difficile infection among pediatric patients with cancer.
      ]
      2017JapanJuly 2003–September 2012Case–controlHA-CDIInpatients1450–19EIA (Toxin A/B)
      Crews et al. [
      • Crews J.D.
      • Anderson L.R.
      • Waller D.K.
      • Swartz M.D.
      • DuPont H.L.
      • Starke J.R.
      Risk factors for community-associated Clostridium difficile-associated diarrhea in children.
      ]
      2015USAJanuary 2012–June 2013Case–controlCA-CDIInpatients and outpatients2071–18RT-PCR (Toxin A/B)
      Santiago et al. [
      • Santiago B.
      • Guerra L.
      • García-Morín M.
      • González E.
      • Gonzálvez A.
      • Izquierdo G.
      • et al.
      [Clostridium difficile isolation in children hospitalized with diarrhea].
      ]
      2015SpainSeptember 2010–October 2011Retrospective cohort-Inpatients2500–15Culture; PCR (Toxin A/B)
      De Blank et al. [
      • de Blank P.
      • Zaoutis T.
      • Fisher B.
      • Troxel A.
      • Kim J.
      • Aplenc R.
      Trends in Clostridium difficile infection and risk factors for hospital acquisition of Clostridium difficile among children with cancer.
      ]
      2013USA1999–2011Retrospective cohortHA-CDIInpatients33,0951–18ICD-9 Code (008.45)
      Guo et al. [
      • Guo S.
      • Xu X.W.
      • Dong F.
      [Risk factors of Clostridium difficile-associated diarrhea in children].
      ]
      2012ChinaDecember 2010–March 2011CohortHA-CDIInpatients1980–18PCR (Toxin A/B)
      TURCO et al. [
      • Turco R.
      • Martinelli M.
      • Miele E.
      • Roscetto E.
      • Del P.M.
      • Greco L.
      • et al.
      Proton pump inhibitors as a risk factor for paediatric Clostridium difficile infection.
      ]
      2010ItalyJune 2005–July 2009Case–control-Inpatients1361–18EIA (Toxin A/B)
      Tai et al. [
      • Tai E.
      • Richardson L.C.
      • Townsend J.
      • Howard E.
      • McDonald C.
      Clostridium difficile infection among children with cancer.
      ]
      2010USA2000, 2003, 2006Retrospective cohort-Inpatients297,4610–18-
      Samady et al. [
      • Samady W.
      • Bush R.
      • Pong A.
      • Andrews A.
      • Fisher E.S.
      Predictors of Clostridium difficile infections in hospitalized children.
      ]
      2014USAJune 2008–May 2010Case–controlCA-CDI and HA-CDIInpatients4081–18EIA (Toxin A/B)
      Sathyendran et al. [
      • Sathyendran V.
      • McAuliffe G.N.
      • Swager T.
      • Freeman J.T.
      • Taylor S.L.
      • Roberts S.A.
      Clostridium difficile as a cause of healthcare-associated diarrhoea among children in Auckland, New Zealand: clinical and molecular epidemiology.
      ]
      2014New ZealandNovember 2011–June 2012Cross-sectionalCA-CDI and HA-CDIInpatients3200–15EIA, PCR (Toxin A/B); GDH
      Banaszkiewicz et al. [
      • Banaszkiewicz A.
      • Kowalska-Duplaga K.
      • Pytrus T.
      • Pituch H.
      • Gawrońska A.
      • Radzikowski A.
      Clostridium difficile infection in newly diagnosed pediatric patients with inflammatory bowel disease: prevalence and risk factors.
      ]
      2011Poland2007–2010Retrospective cohort-Inpatients1340–18EIA (Toxin A/B)
      Nylund et al. [
      • Nylund C.M.
      • Goudie A.
      • Garza J.M.
      • Fairbrother G.
      • Cohen M.B.
      Clostridium difficile infection in hospitalized children in the United States.
      ]
      2011USA1997, 2000, 2003, and 2006Retrospective cohort-Inpatients10,495,7281–17ICD-9 Code (008.45)
      Brown et al. [
      • Brown K.E.
      • Knoderer C.A.
      • Nichols K.R.
      • Crumby A.S.
      Acid-suppressing agents and risk for Clostridium difficile infection in pediatric patients.
      ]
      2015USAJune 2008–June 2012Case–control-Inpatients4581–17RT-qPCR (Toxin B)
      Freedberg et al. [
      • Freedberg D.E.
      • Lamousé-Smith E.S.
      • Lightdale J.R.
      • Jin Z.
      • Yang Y.X.
      • Abrams J.A.
      Use of acid suppression medication is associated with risk for C. difficile infection in infants and children: a population-based study.
      ]
      2015USA1995–2014Nested case–control-Inpatients38500–17THIN Code
      Predrag et al. [
      • Predrag S.
      • Branislava K.
      • Nikola S.
      • Niko R.
      • Zorica S.R.
      • Stanković-Đorđević D.
      Community-acquired Clostridium difficile infection in Serbian pediatric population.
      ]
      2018SerbiaJanuary 2012–May 2017Prospective case–controlCA-CDIOutpatients and community1891–12ELISA, RT-PCR (Toxin A/B)
      Karaaslan et al. [
      • Karaaslan A.
      • Soysal A.
      • Yakut N.
      • Akkoç G.
      • Demir S.O.
      • Atıcı S.
      • et al.
      Hospital acquired Clostridium difficile infection in pediatric wards: a retrospective case–control study.
      ]
      2016TurkeyJanuary 2012–December 2014Case–controlHA-CDIInpatients9860–18EIA (Toxin A/B)
      Jimenez et al. [
      • Jimenez J.
      • Drees M.
      • Loveridge-Lenza B.
      • Eppes S.
      • DelRosario F.
      Exposure to gastric acid-suppression therapy is associated with health care- and community-associated Clostridium difficile infection in children.
      ]
      2015USAJanuary 2005–December 2010Case–controlCA-CDI and HA-CDIInpatients and outpatients4141–18EIA (Toxin A/B)
      Sandora et al. [
      • Sandora T.J.
      • Fung M.
      • Flaherty K.
      • Helsing L.
      • Scanlon P.
      • Potter-Bynoe G.
      • et al.
      Epidemiology and risk factors for Clostridium difficile infection in children.
      ]
      2011USAJanuary and August 2008Nested case–controlCA-CDI and HA-CDIInpatients and outpatients3331–18Toxin A/B tests
      Li et al. [
      • Li Y.
      Analysis of risk factors for possible foodborne transmission of Clostridium difficile infection.
      ]
      2015ChinaJune 2013–November 2013CohortCA-CDI and HA-CDIInpatients2090–14RT-PCR (Toxin A/B)
      HA-CDI, hospital-acquired Clostridioides difficile infection; CA-CDI, community-acquired Clostridioides difficile infection; PCR, polymerase chain reaction; GDH, glutamate dehydrogenase; EIA, enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay; RT-PCR, real-time PCR; qPCR, quantitative polymerase chain reaction; ICD-9, International Classification of Diseases, Ninth Revision; THIN, Health Improvement Network.
      HA-CDI, hospital-acquired Clostridioides difficile infection; CA-CDI, community-acquired Clostridioides difficile infection; PCR, polymerase chain reaction; GDH, glutamate dehydrogenase; EIA, enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay; RT-PCR, real-time PCR; qPCR, quantitative polymerase chain reaction; ICD-9, International Classification of Diseases, Ninth Revision; THIN, Health Improvement Network.
      The studies were published from 2010 to 2020, and evaluated 10,844,084 participants, of whom 31,225 had CDI. Of the 25 included studies, nine were cohort studies [
      • Nylund C.M.
      • Goudie A.
      • Garza J.M.
      • Fairbrother G.
      • Cohen M.B.
      Clostridium difficile infection in hospitalized children in the United States.
      ,
      • Zhao C.
      • Guo S.
      • Jia X.
      • Xu X.
      Distribution and risk factor analysis for Clostridium difficile-associated diarrhea among hospitalized children over one year of age.
      ,-
      • Khalil A.
      • Hendaus M.A.
      • Elmagboul E.
      • Mohamed A.
      • Deshmukh A.
      • Elmasoudi A.
      Incidence of Clostridium difficile infection and associated risk factors among hospitalized children in Qatar.
      ,
      • Santiago B.
      • Guerra L.
      • García-Morín M.
      • González E.
      • Gonzálvez A.
      • Izquierdo G.
      • et al.
      [Clostridium difficile isolation in children hospitalized with diarrhea].
      ,
      • de Blank P.
      • Zaoutis T.
      • Fisher B.
      • Troxel A.
      • Kim J.
      • Aplenc R.
      Trends in Clostridium difficile infection and risk factors for hospital acquisition of Clostridium difficile among children with cancer.
      ,
      • Guo S.
      • Xu X.W.
      • Dong F.
      [Risk factors of Clostridium difficile-associated diarrhea in children].
      ,
      • Tai E.
      • Richardson L.C.
      • Townsend J.
      • Howard E.
      • McDonald C.
      Clostridium difficile infection among children with cancer.
      ,
      • Banaszkiewicz A.
      • Kowalska-Duplaga K.
      • Pytrus T.
      • Pituch H.
      • Gawrońska A.
      • Radzikowski A.
      Clostridium difficile infection in newly diagnosed pediatric patients with inflammatory bowel disease: prevalence and risk factors.
      ,
      • Li Y.
      Analysis of risk factors for possible foodborne transmission of Clostridium difficile infection.
      ], 14 were case–control studies [
      • Miranda-Katz M.
      • Parmar D.
      • Dang R.
      • Alabaster A.
      • Greenhow T.L.
      Epidemiology and risk factors for community associated Clostridioides difficile in children.
      ,
      • Mayer E.F.
      • Maron G.
      • Dallas R.H.
      • Ferrolino J.
      • Tang L.
      • Sun Y.
      • et al.
      A multicenter study to define the epidemiology and outcomes of Clostridioides difficile infection in pediatric hematopoietic cell and solid organ transplant recipients.
      ,
      • Weng M.K.
      • Adkins S.H.
      • Bamberg W.
      • Farley M.M.
      • Espinosa C.C.
      • Wilson L.
      • et al.
      Risk factors for community-associated Clostridioides difficile infection in young children.
      ,-
      • Adams D.J.
      • Eberly M.D.
      • Rajnik M.
      • Nylund C.M.
      Risk factors for community-associated Clostridium difficile infection in children.
      ,
      • Daida A.
      • Yoshihara H.
      • Inai I.
      • Hasegawa D.
      • Ishida Y.
      • Urayama K.Y.
      • et al.
      Risk factors for hospital-acquired Clostridium difficile infection among pediatric patients with cancer.
      ,
      • Crews J.D.
      • Anderson L.R.
      • Waller D.K.
      • Swartz M.D.
      • DuPont H.L.
      • Starke J.R.
      Risk factors for community-associated Clostridium difficile-associated diarrhea in children.
      ,
      • Turco R.
      • Martinelli M.
      • Miele E.
      • Roscetto E.
      • Del P.M.
      • Greco L.
      • et al.
      Proton pump inhibitors as a risk factor for paediatric Clostridium difficile infection.
      ,
      • Samady W.
      • Bush R.
      • Pong A.
      • Andrews A.
      • Fisher E.S.
      Predictors of Clostridium difficile infections in hospitalized children.
      ,
      • Brown K.E.
      • Knoderer C.A.
      • Nichols K.R.
      • Crumby A.S.
      Acid-suppressing agents and risk for Clostridium difficile infection in pediatric patients.
      ,
      • Freedberg D.E.
      • Lamousé-Smith E.S.
      • Lightdale J.R.
      • Jin Z.
      • Yang Y.X.
      • Abrams J.A.
      Use of acid suppression medication is associated with risk for C. difficile infection in infants and children: a population-based study.
      ,
      • Predrag S.
      • Branislava K.
      • Nikola S.
      • Niko R.
      • Zorica S.R.
      • Stanković-Đorđević D.
      Community-acquired Clostridium difficile infection in Serbian pediatric population.
      ,
      • Karaaslan A.
      • Soysal A.
      • Yakut N.
      • Akkoç G.
      • Demir S.O.
      • Atıcı S.
      • et al.
      Hospital acquired Clostridium difficile infection in pediatric wards: a retrospective case–control study.
      ,
      • Jimenez J.
      • Drees M.
      • Loveridge-Lenza B.
      • Eppes S.
      • DelRosario F.
      Exposure to gastric acid-suppression therapy is associated with health care- and community-associated Clostridium difficile infection in children.
      ,
      • Sandora T.J.
      • Fung M.
      • Flaherty K.
      • Helsing L.
      • Scanlon P.
      • Potter-Bynoe G.
      • et al.
      Epidemiology and risk factors for Clostridium difficile infection in children.
      ] and two were cross-sectional studies [
      • Migriauli I.
      • Meunargia V.
      • Chkhaidze I.
      • Sabakhtarishvili G.
      • Gujabidze K.
      • Butsashvili M.
      • et al.
      Factors affecting development of Clostridium difficile infection in hospitalized pediatric patients in the country Georgia.
      ,
      • Sathyendran V.
      • McAuliffe G.N.
      • Swager T.
      • Freeman J.T.
      • Taylor S.L.
      • Roberts S.A.
      Clostridium difficile as a cause of healthcare-associated diarrhoea among children in Auckland, New Zealand: clinical and molecular epidemiology.
      ]. Most studies (19/25) [
      • Miranda-Katz M.
      • Parmar D.
      • Dang R.
      • Alabaster A.
      • Greenhow T.L.
      Epidemiology and risk factors for community associated Clostridioides difficile in children.
      ,
      • Zhao C.
      • Guo S.
      • Jia X.
      • Xu X.
      Distribution and risk factor analysis for Clostridium difficile-associated diarrhea among hospitalized children over one year of age.
      ,
      • Mayer E.F.
      • Maron G.
      • Dallas R.H.
      • Ferrolino J.
      • Tang L.
      • Sun Y.
      • et al.
      A multicenter study to define the epidemiology and outcomes of Clostridioides difficile infection in pediatric hematopoietic cell and solid organ transplant recipients.
      ,
      • Weng M.K.
      • Adkins S.H.
      • Bamberg W.
      • Farley M.M.
      • Espinosa C.C.
      • Wilson L.
      • et al.
      Risk factors for community-associated Clostridioides difficile infection in young children.
      ,
      • Khalil A.
      • Hendaus M.A.
      • Elmagboul E.
      • Mohamed A.
      • Deshmukh A.
      • Elmasoudi A.
      Incidence of Clostridium difficile infection and associated risk factors among hospitalized children in Qatar.
      ,
      • Migriauli I.
      • Meunargia V.
      • Chkhaidze I.
      • Sabakhtarishvili G.
      • Gujabidze K.
      • Butsashvili M.
      • et al.
      Factors affecting development of Clostridium difficile infection in hospitalized pediatric patients in the country Georgia.
      ,
      • Daida A.
      • Yoshihara H.
      • Inai I.
      • Hasegawa D.
      • Ishida Y.
      • Urayama K.Y.
      • et al.
      Risk factors for hospital-acquired Clostridium difficile infection among pediatric patients with cancer.
      ,
      • Crews J.D.
      • Anderson L.R.
      • Waller D.K.
      • Swartz M.D.
      • DuPont H.L.
      • Starke J.R.
      Risk factors for community-associated Clostridium difficile-associated diarrhea in children.
      ,
      • Santiago B.
      • Guerra L.
      • García-Morín M.
      • González E.
      • Gonzálvez A.
      • Izquierdo G.
      • et al.
      [Clostridium difficile isolation in children hospitalized with diarrhea].
      ,
      • Guo S.
      • Xu X.W.
      • Dong F.
      [Risk factors of Clostridium difficile-associated diarrhea in children].
      ,
      • Turco R.
      • Martinelli M.
      • Miele E.
      • Roscetto E.
      • Del P.M.
      • Greco L.
      • et al.
      Proton pump inhibitors as a risk factor for paediatric Clostridium difficile infection.
      ,-
      • Samady W.
      • Bush R.
      • Pong A.
      • Andrews A.
      • Fisher E.S.
      Predictors of Clostridium difficile infections in hospitalized children.
      ,
      • Sathyendran V.
      • McAuliffe G.N.
      • Swager T.
      • Freeman J.T.
      • Taylor S.L.
      • Roberts S.A.
      Clostridium difficile as a cause of healthcare-associated diarrhoea among children in Auckland, New Zealand: clinical and molecular epidemiology.
      ,
      • Banaszkiewicz A.
      • Kowalska-Duplaga K.
      • Pytrus T.
      • Pituch H.
      • Gawrońska A.
      • Radzikowski A.
      Clostridium difficile infection in newly diagnosed pediatric patients with inflammatory bowel disease: prevalence and risk factors.
      ,
      • Brown K.E.
      • Knoderer C.A.
      • Nichols K.R.
      • Crumby A.S.
      Acid-suppressing agents and risk for Clostridium difficile infection in pediatric patients.
      ,
      • Predrag S.
      • Branislava K.
      • Nikola S.
      • Niko R.
      • Zorica S.R.
      • Stanković-Đorđević D.
      Community-acquired Clostridium difficile infection in Serbian pediatric population.
      ,
      • Karaaslan A.
      • Soysal A.
      • Yakut N.
      • Akkoç G.
      • Demir S.O.
      • Atıcı S.
      • et al.
      Hospital acquired Clostridium difficile infection in pediatric wards: a retrospective case–control study.
      ,
      • Jimenez J.
      • Drees M.
      • Loveridge-Lenza B.
      • Eppes S.
      • DelRosario F.
      Exposure to gastric acid-suppression therapy is associated with health care- and community-associated Clostridium difficile infection in children.
      ,
      • Li Y.
      Analysis of risk factors for possible foodborne transmission of Clostridium difficile infection.
      ] used enzyme immunoassays or nucleic acid amplification assays to detect C. difficile toxins, four studies [
      • Nylund C.M.
      • Goudie A.
      • Garza J.M.
      • Fairbrother G.
      • Cohen M.B.
      Clostridium difficile infection in hospitalized children in the United States.
      ,
      • Adams D.J.
      • Eberly M.D.
      • Rajnik M.
      • Nylund C.M.
      Risk factors for community-associated Clostridium difficile infection in children.
      ,
      • de Blank P.
      • Zaoutis T.
      • Fisher B.
      • Troxel A.
      • Kim J.
      • Aplenc R.
      Trends in Clostridium difficile infection and risk factors for hospital acquisition of Clostridium difficile among children with cancer.
      ,
      • Freedberg D.E.
      • Lamousé-Smith E.S.
      • Lightdale J.R.
      • Jin Z.
      • Yang Y.X.
      • Abrams J.A.
      Use of acid suppression medication is associated with risk for C. difficile infection in infants and children: a population-based study.
      ] used ICD-9 or other billing codes to screen CDI patients, and the remaining studies did not mention the testing method. The studies were conducted in China, the USA, Japan, Spain, Italy, New Zealand and other European countries. Seventeen studies [
      • Nylund C.M.
      • Goudie A.
      • Garza J.M.
      • Fairbrother G.
      • Cohen M.B.
      Clostridium difficile infection in hospitalized children in the United States.
      ,
      • Miranda-Katz M.
      • Parmar D.
      • Dang R.
      • Alabaster A.
      • Greenhow T.L.
      Epidemiology and risk factors for community associated Clostridioides difficile in children.
      ,
      • Zhao C.
      • Guo S.
      • Jia X.
      • Xu X.
      Distribution and risk factor analysis for Clostridium difficile-associated diarrhea among hospitalized children over one year of age.
      ,
      • Khalil A.
      • Hendaus M.A.
      • Elmagboul E.
      • Mohamed A.
      • Deshmukh A.
      • Elmasoudi A.
      Incidence of Clostridium difficile infection and associated risk factors among hospitalized children in Qatar.
      ,
      • Adams D.J.
      • Eberly M.D.
      • Rajnik M.
      • Nylund C.M.
      Risk factors for community-associated Clostridium difficile infection in children.
      ,
      • Daida A.
      • Yoshihara H.
      • Inai I.
      • Hasegawa D.
      • Ishida Y.
      • Urayama K.Y.
      • et al.
      Risk factors for hospital-acquired Clostridium difficile infection among pediatric patients with cancer.
      ,
      • Santiago B.
      • Guerra L.
      • García-Morín M.
      • González E.
      • Gonzálvez A.
      • Izquierdo G.
      • et al.
      [Clostridium difficile isolation in children hospitalized with diarrhea].
      ,
      • de Blank P.
      • Zaoutis T.
      • Fisher B.
      • Troxel A.
      • Kim J.
      • Aplenc R.
      Trends in Clostridium difficile infection and risk factors for hospital acquisition of Clostridium difficile among children with cancer.
      ,
      • Turco R.
      • Martinelli M.
      • Miele E.
      • Roscetto E.
      • Del P.M.
      • Greco L.
      • et al.
      Proton pump inhibitors as a risk factor for paediatric Clostridium difficile infection.
      ,
      • Samady W.
      • Bush R.
      • Pong A.
      • Andrews A.
      • Fisher E.S.
      Predictors of Clostridium difficile infections in hospitalized children.
      ,
      • Sathyendran V.
      • McAuliffe G.N.
      • Swager T.
      • Freeman J.T.
      • Taylor S.L.
      • Roberts S.A.
      Clostridium difficile as a cause of healthcare-associated diarrhoea among children in Auckland, New Zealand: clinical and molecular epidemiology.
      ,
      • Freedberg D.E.
      • Lamousé-Smith E.S.
      • Lightdale J.R.
      • Jin Z.
      • Yang Y.X.
      • Abrams J.A.
      Use of acid suppression medication is associated with risk for C. difficile infection in infants and children: a population-based study.
      ,
      • Predrag S.
      • Branislava K.
      • Nikola S.
      • Niko R.
      • Zorica S.R.
      • Stanković-Đorđević D.
      Community-acquired Clostridium difficile infection in Serbian pediatric population.
      ,
      • Karaaslan A.
      • Soysal A.
      • Yakut N.
      • Akkoç G.
      • Demir S.O.
      • Atıcı S.
      • et al.
      Hospital acquired Clostridium difficile infection in pediatric wards: a retrospective case–control study.
      ,
      • Jimenez J.
      • Drees M.
      • Loveridge-Lenza B.
      • Eppes S.
      • DelRosario F.
      Exposure to gastric acid-suppression therapy is associated with health care- and community-associated Clostridium difficile infection in children.
      ,
      • Sandora T.J.
      • Fung M.
      • Flaherty K.
      • Helsing L.
      • Scanlon P.
      • Potter-Bynoe G.
      • et al.
      Epidemiology and risk factors for Clostridium difficile infection in children.
      ,
      • Li Y.
      Analysis of risk factors for possible foodborne transmission of Clostridium difficile infection.
      ] were of high quality and eight studies [
      • Mayer E.F.
      • Maron G.
      • Dallas R.H.
      • Ferrolino J.
      • Tang L.
      • Sun Y.
      • et al.
      A multicenter study to define the epidemiology and outcomes of Clostridioides difficile infection in pediatric hematopoietic cell and solid organ transplant recipients.
      ,
      • Weng M.K.
      • Adkins S.H.
      • Bamberg W.
      • Farley M.M.
      • Espinosa C.C.
      • Wilson L.
      • et al.
      Risk factors for community-associated Clostridioides difficile infection in young children.
      ,
      • Migriauli I.
      • Meunargia V.
      • Chkhaidze I.
      • Sabakhtarishvili G.
      • Gujabidze K.
      • Butsashvili M.
      • et al.
      Factors affecting development of Clostridium difficile infection in hospitalized pediatric patients in the country Georgia.
      ,
      • Crews J.D.
      • Anderson L.R.
      • Waller D.K.
      • Swartz M.D.
      • DuPont H.L.
      • Starke J.R.
      Risk factors for community-associated Clostridium difficile-associated diarrhea in children.
      ,
      • Guo S.
      • Xu X.W.
      • Dong F.
      [Risk factors of Clostridium difficile-associated diarrhea in children].
      ,
      • Tai E.
      • Richardson L.C.
      • Townsend J.
      • Howard E.
      • McDonald C.
      Clostridium difficile infection among children with cancer.
      ,
      • Banaszkiewicz A.
      • Kowalska-Duplaga K.
      • Pytrus T.
      • Pituch H.
      • Gawrońska A.
      • Radzikowski A.
      Clostridium difficile infection in newly diagnosed pediatric patients with inflammatory bowel disease: prevalence and risk factors.
      ,
      • Brown K.E.
      • Knoderer C.A.
      • Nichols K.R.
      • Crumby A.S.
      Acid-suppressing agents and risk for Clostridium difficile infection in pediatric patients.
      ] were of moderate quality. Assessment of methodological quality is presented in Tables S2 and S3 (see online supplementary material).

      Analysis of risk factors for CDI

      Prior antibiotic exposure

      Patients with prior antibiotic exposure had a significantly higher risk of developing CDI than patients without antibiotic exposure (OR 1.93, 95% CI 1.25–2.97; P<0.001) (Figure S1, see online supplementary material). However, there was high heterogeneity among these studies (I2=92.2%).
      Meta-analysis of different classes of antibiotics showed that the risk of CDI was greatest with clindamycin (OR 13.92, 95% CI 2.84–68.26; P=0.001), followed by cephalosporins (OR 2.26, 95% CI 1.45–3.50; P<0.001) and amoxicillin-clavulanate (OR 1.93, 95% CI 1.20–3.12; P=0.007), and was lower for fluoroquinolones (OR 3.10, 95% CI 0.12–82.15; P=0.499) and penicillin (OR 0.42, 95% CI 0.03–5.14; P=0.498) (Figure S2, see online supplementary material). Furthermore, stratification by cephalosporin subclass revealed that third-generation cephalosporins (OR 3.83, 95% CI 1.32–11.12; P=0.014) had higher risk of CDI compared with first- (OR 2.11, 95% CI 1.35–3.30; P=0.001) and fourth-generation cephalosporins (OR 2.33, 95% CI 1.84–2.94; P<0.001). However, heterogeneity persisted, especially for third-generation cephalosporins (I2=94.5%) (Figure S3, see online supplementary material).
      Given the significant heterogeneity in the meta-analyses of all included studies, subgroup analyses were performed to better understand the heterogeneity. The duration of antibiotic exposure varied between the studies (4–12 weeks), with lower heterogeneity when subgroup analysis was performed on studies with antibiotic exposure in the preceding 12 weeks (OR 2.12, 95% CI 1.64–2.76; P<0.001; I2=49.2%); this significant effect persisted after Bonferroni's correction was applied (Figure S4, see online supplementary material). Subgroup analysis based on study design, separating case–control and cross-sectional studies, showed that neither case–control study results (OR 1.70, 95% CI 0.99–2.93; P=0.054; I2=89.5%) nor cross-sectional study results (OR 1.89, 95% CI 0.60–5.93; P=0.277; I2=80.0%) were significant (Figure S5, see online supplementary material). Meta-analysis based on CDI diagnostic assays revealed increased risk of CDI among studies that used C. difficile toxin assays to detect CDI, with high heterogeneity between studies (OR 1.90, 95% CI 1.12–3.22; P=0.017; I2=91.6%), but this significant effect disappeared after Bonferroni's correction was applied (Figure S6, see online supplementary material). In addition, the study population was the most common source of heterogeneity. Subgroup analyses of the studies with patients from the inpatient setting only revealed increased risk of CDI after antibiotic use (OR 2.43; 95% CI 1.43–4.14; P=0.001; I2=91.3%); this association remained significant after Bonferroni's correction was applied (Figure S7, see online supplementary material).

      Prolonged hospitalization

      Three cohort studies [
      • Zhao C.
      • Guo S.
      • Jia X.
      • Xu X.
      Distribution and risk factor analysis for Clostridium difficile-associated diarrhea among hospitalized children over one year of age.
      ,
      • Khalil A.
      • Hendaus M.A.
      • Elmagboul E.
      • Mohamed A.
      • Deshmukh A.
      • Elmasoudi A.
      Incidence of Clostridium difficile infection and associated risk factors among hospitalized children in Qatar.
      ,
      • Tai E.
      • Richardson L.C.
      • Townsend J.
      • Howard E.
      • McDonald C.
      Clostridium difficile infection among children with cancer.
      ] evaluated prolonged hospitalization as a risk factor for CDI. A meta-analysis of these studies using a fixed-effects model showed that patients with prolonged hospitalization had a significantly increased risk of CDI (OR 14.68, 95% CI 13.24–16.28; P<0.001). There was low heterogeneity among studies (I2=27.8%) (Figure S8, see online supplementary material).

      History of hospitalization

      The meta-analysis of three case–control studies [
      • Samady W.
      • Bush R.
      • Pong A.
      • Andrews A.
      • Fisher E.S.
      Predictors of Clostridium difficile infections in hospitalized children.
      ,
      • Freedberg D.E.
      • Lamousé-Smith E.S.
      • Lightdale J.R.
      • Jin Z.
      • Yang Y.X.
      • Abrams J.A.
      Use of acid suppression medication is associated with risk for C. difficile infection in infants and children: a population-based study.
      ,
      • Karaaslan A.
      • Soysal A.
      • Yakut N.
      • Akkoç G.
      • Demir S.O.
      • Atıcı S.
      • et al.
      Hospital acquired Clostridium difficile infection in pediatric wards: a retrospective case–control study.
      ] using a random-effects model demonstrated that patients with a history of hospitalization had a significantly increased risk of CDI compared with patients without a history of hospitalization (OR 3.67, 95% CI 1.91–7.06; P<0.001). There was moderate heterogeneity across the included studies (I2=58.7%) (Figure S9, see online supplementary material).

      Gastric acid suppressants

      The meta-analysis using a random-effects model demonstrated that patients receiving gastric acid suppressants had increased risk of developing CDI (OR 1.96, 95% CI 1.41–2.73; P<0.001). There was significant heterogeneity among the studies, with an I2 value of 85.5% (Figure S10, see online supplementary material).
      Several studies included patients who received PPIs or H2RAs alone. This review separated studies using PPIs or H2RAs alone. Meta-analysis revealed increased risk of CDI with PPI use (OR 2.01, 95% CI 1.40–2.89; P<0.001; I2=79.9%), but not with H2RA use (OR 2.15, 95% CI 0.72–6.42; P=0.171; I2=85.2%) (Figure S11, see online supplementary material).
      Subgroup analyses based on study design showed increased risk of CDI among patients receiving gastric acid suppressants in case–control studies (OR 2.78, 95% CI 1.68–4.62; P<0.001; I2=82.0%), but not in cohort studies (OR 1.01; 95% CI 0.53–1.91; P=0.980) (Figure S12, see online supplementary material). Subgroup analysis on the basis of the diagnostic assay used for CDI revealed increased risk of CDI among studies that used C. difficile toxin assay (OR 1.80, 95% CI 1.29–2.50; P<0.001; I2=65.8%) and ICD-9 or other billing codes (OR 2.45, 95% CI 1.19–5.07; P=0.016; I2=92.1%) to detect CDI (Figure S13, see online supplementary material). These significant effects (except for studies that used ICD-9 or other codes to detect CDI) persisted after Bonferroni's correction for multiple comparisons was applied.

      Gender

      Four studies reported data on gender as a risk factor for CDI [
      • Nylund C.M.
      • Goudie A.
      • Garza J.M.
      • Fairbrother G.
      • Cohen M.B.
      Clostridium difficile infection in hospitalized children in the United States.
      ,
      • Mayer E.F.
      • Maron G.
      • Dallas R.H.
      • Ferrolino J.
      • Tang L.
      • Sun Y.
      • et al.
      A multicenter study to define the epidemiology and outcomes of Clostridioides difficile infection in pediatric hematopoietic cell and solid organ transplant recipients.
      ,
      • de Blank P.
      • Zaoutis T.
      • Fisher B.
      • Troxel A.
      • Kim J.
      • Aplenc R.
      Trends in Clostridium difficile infection and risk factors for hospital acquisition of Clostridium difficile among children with cancer.
      ,
      • Tai E.
      • Richardson L.C.
      • Townsend J.
      • Howard E.
      • McDonald C.
      Clostridium difficile infection among children with cancer.
      ]. Meta-analysis of the four included studies showed a significantly increased risk of CDI associated with male gender (OR 1.18, 95% CI 1.05–1.32; P=0.005). There was moderate heterogeneity between these studies (I2=69.0%) (Figure S14, see online supplementary material).

      Comorbidities

      Meta-analysis of comorbidities revealed that neoplastic disease (OR 3.40, 95% CI 2.85–4.07; P<0.001), immunodeficiency (OR 4.18; 95% CI 3.25–5.37; P<0.001), solid organ transplantation (OR 4.56, 95% CI 3.95–5.27; P<0.001) and enteral feeding (OR 2.21, 95% CI 1.05–4.62; P=0.036) were associated with increased risk of CDI, but inflammatory bowel disease (OR 3.54, 95% CI 0.36–35.10; P=0.280) and cardiac disease (OR 2.00, 95% CI 0.68–5.87; P=0.206) were not associated with increased risk of CDI. There was significant heterogeneity in enteral feeding (I2=76.1%) (Figure S15, see online supplementary material).

      Other risk factors

      The meta-analysis did not include other risk factors associated with CDI in children, including age, chemotherapy, race, immunosuppressive agents, white blood cell count and history of CDI, because each factor was only evaluated in a single study (Table S4, see online supplementary material).

      Publication bias

      Most of the risk factors in this study were evaluated by fewer than 10 studies. Thus, the results of antibiotic exposure and gastric acid suppressants alone were interpreted. Funnel plots and Egger's test showed little evidence of publication bias in studies on antibiotic exposure (except for gastric acid suppressants). Sensitivity analysis showed that the pooled effect of all risk factors did not change significantly after excluding any particular study, indicating that the results are stable and reliable (Figures S16–19 and Table S5, see online supplementary material).

      Discussion

      The present study analysed the association between various risk factors and CDI comprehensively and systematically. Antibiotic exposure, prolonged hospitalization, history of hospitalization, gastric acid suppressants, male gender and underlying comorbidities were associated with increased risk of CDI in children (Table II).
      Table IISummary of meta-regression analysis
      ExposureNo. of studiesOR95% CIHeterogeneity, I2, %P-valueModel
      Antibiotics101.931.25–2.9792.2<0.0001RAM
      Amoxicillin-clavulanate21.931.20–3.120.00.459FEM
      Cephalosporins112.261.45–3.5087.8<0.0001RAM
      Clindamycin313.922.84–68.2679.60.007RAM
      Fluoroquinolones23.100.12–82.1596.7<0.0001RAM
      Penicillin20.420.03–5.1495.4<0.0001RAM
      Prolonged hospitalization314.6813.24–16.2827.80.250FEM
      History of hospitalization33.671.91–7.0658.70.064RAM
      Gastric acid suppressants111.961.41–2.7385.5<0.0001RAM
      PPI72.011.40–2.8979.9<0.0001RAM
      H2RA42.150.72–6.4285.2<0.0001RAM
      Male gender41.181.05–1.3269.00.022RAM
      Comorbidities
      Inflammatory bowel disease23.540.36–35.1099.9<0.0001RAM
      Solid organ transplant24.563.95–5.270.00.402FEM
      Neoplastic disease43.402.85–4.0769.80.019RAM
      Cardiac disease22.000.68–5.8762.50.103RAM
      Immunodeficiency24.183.25–5.370.00.491FEM
      Enteral feeding52.211.05–4.6276.10.002RAM
      OR, odds ratio; CI, confidence interval; RAM, random-effects model; FEM, fixed-effects model; PPI, proton pump inhibitor; H2RA, H2 receptor antagonist.
      Exposure to antibiotics during childhood is an important determinant of long-term health, and antibiotic therapy can lead to CDI by changing the composition of the commensal gut microbiota, resulting in loss of microbiota diversity and colonization resistance, facilitating the proliferation of C. difficile [
      • Lynn M.A.
      • Eden G.
      • Ryan F.J.
      • Bensalem J.
      • Wang X.
      • Blake S.J.
      • et al.
      The composition of the gut microbiota following early-life antibiotic exposure affects host health and longevity in later life.
      ,
      • Reyman M.
      • van Houten M.A.
      • van Baarle D.
      • Bosch A.
      • Man W.H.
      • Chu M.
      • et al.
      Impact of delivery mode-associated gut microbiota dynamics on health in the first year of life.
      ,
      • Vasilescu I.M.
      • Chifiriuc M.C.
      • Pircalabioru G.G.
      • Filip R.
      • Bolocan A.
      • Lazar V.
      • et al.
      Gut dysbiosis and Clostridioides difficile infection in neonates and adults.
      ]. These disruptions can persist and predispose to CDI for weeks to months after the interruption of antibiotic therapy [
      • Kuntz J.L.
      • Chrischilles E.A.
      • Pendergast J.F.
      • Herwaldt L.A.
      • Polgreen P.M.
      Incidence of and risk factors for community-associated Clostridium difficile infection: a nested case–control study.
      ]. The present review found that antibiotic exposure increased the risk of CDI significantly (OR 1.93). When subgroup analysis was performed by study setting, antibiotic use was shown to increase the risk of CDI in inpatients (OR 2.43). Similarly, Anjewierden et al. [
      • Anjewierden S.
      • Han Z.
      • Foster C.B.
      • Pant C.
      • Deshpande A.
      Risk factors for Clostridium difficile infection in pediatric inpatients: a meta-analysis and systematic review.
      ] found that the risk of CDI increased 2- to 3-fold in paediatric inpatients exposed to antibiotics. However, high heterogeneity was still detected, which may be related to patient characteristics and the duration and dose of antibiotic therapy. In addition, this review found that the risk of CDI remained significantly increased within 12 weeks after cessation of antibiotic therapy (OR 2.12), which is consistent with the study by Hensgens et al. [
      • Hensgens M.P.
      • Goorhuis A.
      • Dekkers O.M.
      • Kuijper E.J.
      Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics.
      ]. In particular, Hensgens et al. found that the highest risk of CDI was during the first month after the interruption of antibiotic therapy, with more than 6-fold increased risk of CDI. However, in the present meta-analysis, only one study reported that the risk of CDI increased in the first month after the cessation of antibiotic therapy (OR 3.1); as such, the association of this period with risk of CDI could not be assessed by pooled effects. Nonetheless, these results were sufficient to suggest that the disruption of the gut microbiota by antibiotics is long term, and the risk of CDI is higher within 12 weeks of the cessation of antibiotic therapy.
      Appropriate antibiotic use is critical for proper treatment and effective prevention of bacterial infections. The severe disruption of gut microbiota by clindamycin, fluoroquinolones and cephalosporins, and the low susceptibility of C. difficile to these classes of antibiotics, have been associated with high risk of CDI [
      • Owens R.J.
      • Donskey C.J.
      • Gaynes R.P.
      • Loo V.G.
      • Muto C.A.
      Antimicrobial-associated risk factors for Clostridium difficile infection.
      ,
      • Brown K.A.
      • Langford B.
      • Schwartz K.L.
      • Diong C.
      • Garber G.
      • Daneman N.
      Antibiotic prescribing choices and their comparative C. difficile infection risks: a longitudinal case–cohort study.
      ]. Previous meta-analyses showed that cephalosporins and clindamycin (broad-spectrum antibiotics) were more strongly associated with HA-CDI, whereas clindamycin, cephalosporins and quinolones were more strongly linked with CA-CDI [
      • Slimings C.
      • Riley T.V.
      Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis.
      ,
      • Deshpande A.
      • Pasupuleti V.
      • Thota P.
      • Pant C.
      • Rolston D.D.
      • Sferra T.J.
      • et al.
      Community-associated Clostridium difficile infection and antibiotics: a meta-analysis.
      ,
      • Brown K.A.
      • Khanafer N.
      • Daneman N.
      • Fisman D.N.
      Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection.
      ]. In the present meta-analysis, overall antibiotic use was associated with a two-fold increased risk of CDI in children, but significant differences in risk associated with different antimicrobial classes were also detected, with clindamycin and cephalosporins (especially third-generation cephalosporins) associated with the greatest increase in risk. Although the primary meta-analysis showed a non-significant result, fluoroquinolones still need attention. Recent studies in the USA have revealed significant positive associations between the use of total, third- and fourth-generation cephalosporins, and fluoroquinolones and hospital-onset Clostridioides difficile infection (HO-CDI) rates. HO-CDI rates decreased when cephalosporins and fluoroquinolones were targeted to reduce use [
      • Kazakova S.V.
      • Baggs J.
      • Yi S.H.
      • Reddy S.C.
      • Hatfield K.M.
      • Guh A.Y.
      • et al.
      Associations of facility-level antibiotic use and hospital-onset Clostridioides difficile infection in US acute-care hospitals.
      ]. For other classes of antibiotics included in the assessment, such as non-steroidal anti-inflammatory drugs, tetracycline, macrolides and aminoglycosides, which significantly increased the risk of CDI, the present authors were unable to pool the data due to insufficient numbers of studies (Table S4, see online supplementary material). These results demonstrate that while antibiotics are necessary for treating bacterial infections, clinicians should be aware that these drugs may predispose children to CDI. Therefore, measures to optimize the appropriate use of these drugs in children are warranted.
      The traditional risk factors for CDI include antibiotic therapy, hospitalization and older age (>65 years) [
      • Seekatz A.M.
      • Young V.B.
      Clostridium difficile and the microbiota.
      ]. In the present meta-analysis, prolonged hospitalization (OR 14.68) was associated with higher risk of CDI compared with previous hospitalization (OR 3.67). Human gut microbiota protects against colonization by C. difficile [
      • Britton R.A.
      • Young V.B.
      Role of the intestinal microbiota in resistance to colonization by Clostridium difficile.
      ]. Changes in the gut microbiota caused by hospitalization or antibiotic exposure can increase susceptibility to CDI [
      • Sorbara M.T.
      • Pamer E.G.
      Interbacterial mechanisms of colonization resistance and the strategies pathogens use to overcome them.
      ]. On the other hand, long-term hospitalization increases the risk of hospital-associated infections, including those caused by contact with patients with CDI [
      • Morinville V.
      • McDonald J.
      Clostridium difficile-associated diarrhea in 200 Canadian children.
      ]. Thus, isolation measures, hypochlorite-based disinfectants for environmental disinfection, and routine cleaning with germicidal bleach in paediatric wards with high rates of hospital-acquired infections can reduce the incidence of CDI.
      PPIs and H2RAs are the most effective and prescribed medications for acid-related upper gastrointestinal diseases in outpatient and inpatient settings. C. difficile spores are acid-tolerant; thus, acid suppression is unlikely to impact spore survival directly. The increased risk of CDI may be mediated by the effect of pH changes on the diversity of the gut microbiota [
      • Jackson M.A.
      • Goodrich J.K.
      • Maxan M.E.
      • Freedberg D.E.
      • Abrams J.A.
      • Poole A.C.
      • et al.
      Proton pump inhibitors alter the composition of the gut microbiota.
      ]. Although gastric acid suppression increases the risk of CDI, the risk was not significant after controlling for age, hospital stay, antibiotic exposure and comorbidities [
      • Faleck D.M.
      • Salmasian H.
      • Furuya E.Y.
      • Larson E.L.
      • Abrams J.A.
      • Freedberg D.E.
      Proton pump inhibitors do not increase risk for Clostridium difficile infection in the intensive care unit.
      ,
      • 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.
      ]. Nonetheless, the US Food and Drug Administration has reported that PPIs increase the risk of CDI. In this meta-analysis, the odds of CDI development following PPI therapy (OR 2.01) were similar to those after antibiotic therapy. However, there was significant heterogeneity between these studies. In addition, subgroup analyses based on the use of gastric acid suppressants (PPIs and H2RAs), case selection and study design did not identify sources of heterogeneity, possibly due to potential confounders, including comorbidities or concomitant antibiotic use. A meta-analysis of paediatric inpatients found that PPIs increased the risk of CDI 1.33-fold, and the discrepancy in the results may be due to differences in the study populations [
      • Anjewierden S.
      • Han Z.
      • Foster C.B.
      • Pant C.
      • Deshpande A.
      Risk factors for Clostridium difficile infection in pediatric inpatients: a meta-analysis and systematic review.
      ]. Notwithstanding, both studies demonstrated a direct association between acid-suppressive therapy and CDI. However, more research is needed to identify the most effective acid-suppressive therapy for patients with CDI or at risk of CDI.
      Previous studies have found that the existence of underlying comorbidities is associated with poor prognosis in patients with CDI, including gastrointestinal diseases such as inflammatory bowel disease and liver cirrhosis, as well as congestive heart disease, chronic pulmonary disease and renal failure [
      • Goodhand J.R.
      • Alazawi W.
      • Rampton D.S.
      Systematic review: Clostridium difficile and inflammatory bowel disease.
      ,
      • Liu Y.
      • Chen M.
      Clostridioides difficile infection in liver cirrhosis: a concise review.
      ,
      • Medaglia A.A.
      • Buffa S.
      • Gioe C.
      • Bonura S.
      • Rubino R.
      • Iaria C.
      • et al.
      An emergent infectious disease: Clostridioides difficile infection hospitalizations, 10-year trend in Sicily.
      ]. Chemotherapy for neoplastic diseases (malignancies or cancers) is another risk factor for CDI, mediated in part by the antibiotic activity of chemotherapeutic agents, but may also be associated with the immunosuppressive effects of neutropenia [
      • Mutch S.O.
      Decreasing hospital-acquired Clostridioides difficile in patients with cancer.
      ]. Among the comorbidities examined in this meta-analysis, neoplastic disease, immunodeficiency, solid organ transplantation and enteral feeding were associated with increased risk of CDI. Evidence suggests that C. difficile is the most common recognized cause of bacterial diarrhoea in patients infected with human immunodeficiency virus who are at increased risk for CDI due to immunosuppression, antibiotics or exposure to healthcare facilities [
      • Sanchez T.H.
      • Brooks J.T.
      • Sullivan P.S.
      • Juhasz M.
      • Mintz E.
      • Dworkin M.S.
      • et al.
      Bacterial diarrhea in persons with HIV infection, United States, 1992–2002.
      ]. On the other hand, enteral feeding increased the risk of CDI 2.21-fold, which might be related to the contamination of healthcare workers' hands with C. difficile spores, bacterial contamination in enteral feeding systems, or increased colonic pH due to lack of fibre in enteral formulas [
      • Bliss D.Z.
      • Johnson S.
      • Savik K.
      • Clabots C.R.
      • Willard K.
      • Gerding D.N.
      Acquisition of Clostridium difficile and Clostridium difficile-associated diarrhea in hospitalized patients receiving tube feeding.
      ,
      • Thurn J.
      • Crossley K.
      • Gerdts A.
      • Maki M.
      • Johnson J.
      Enteral hyperalimentation as a source of nosocomial infection.
      ]. Hence, clinicians should pay more attention to high-risk groups with the above-mentioned comorbidities to minimize the incidence of CDI.
      Notably, early life is a critical period in which the gut microbiota impacts health status [
      • Robertson R.C.
      • Manges A.R.
      • Finlay B.B.
      • Prendergast A.J.
      The human microbiome and child growth – first 1000 days and beyond.
      ,
      • Derrien M.
      • Alvarez A.S.
      • de Vos W.M.
      The gut microbiota in the first decade of life.
      ]. The gut of children aged <12 months appears to be resistant to the effects of C. difficile toxins A and B, and rarely develops infections. Potential mechanisms for disease resistance in neonates include the absence of toxin receptors, downstream signalling pathways in the immature intestinal mucosa, and protective factors in breast milk and gut microbiota [
      • Jangi S.
      • Lamont J.T.
      Asymptomatic colonization by Clostridium difficile in infants: implications for disease in later life.
      ]. However, the protective effect was reduced significantly after 12–24 months of life, when the gut microbiota was unstable and less resilient to changes than the adult gut microbiota. The ecosystem develops in alpha diversity until around 3–5 years of age, where stable adult-like microbiomes have been established [
      • Jangi S.
      • Lamont J.T.
      Asymptomatic colonization by Clostridium difficile in infants: implications for disease in later life.
      ,
      • Lozupone C.A.
      • Stombaugh J.I.
      • Gordon J.I.
      • Jansson J.K.
      • Knight R.
      Diversity, stability and resilience of the human gut microbiota.
      ,
      • Rodriguez J.M.
      • Murphy K.
      • Stanton C.
      • Ross R.P.
      • Kober O.I.
      • Juge N.
      • et al.
      The composition of the gut microbiota throughout life, with an emphasis on early life.
      ]. Studies have shown that the incidence of CDI in paediatric inpatients varies greatly with age, and the incidence of CDI was lowest for newborns (0.5/10,000), the incidence of CDI in children aged <1 year who were not newborns (32.01/10,000) was similar to that for children aged 5–9 years (35.27/10,000), and the incidence of CDI in children aged 1–4 years (44.87/10,000) was the highest [
      • Zilberberg M.D.
      • Tillotson G.S.
      • McDonald C.
      Clostridium difficile infections among hospitalized children, United States, 1997–2006.
      ,
      • Duleba K.
      • Pawlowska M.
      • Wietlicka-Piszcz M.
      Clostridium difficile infection in children hospitalized due to diarrhea.
      ]. When reviewing the studies included in this meta-analysis, children aged 1–4 years were found to account for approximately 40% of all children with CDI (ages 1–18 years) in the studies by Zhao et al. [
      • Zhao C.
      • Guo S.
      • Jia X.
      • Xu X.
      Distribution and risk factor analysis for Clostridium difficile-associated diarrhea among hospitalized children over one year of age.
      ], De Blank et al. [
      • de Blank P.
      • Zaoutis T.
      • Fisher B.
      • Troxel A.
      • Kim J.
      • Aplenc R.
      Trends in Clostridium difficile infection and risk factors for hospital acquisition of Clostridium difficile among children with cancer.
      ], Samady et al. [
      • Samady W.
      • Bush R.
      • Pong A.
      • Andrews A.
      • Fisher E.S.
      Predictors of Clostridium difficile infections in hospitalized children.
      ] and Jimenez et al. [
      • Jimenez J.
      • Drees M.
      • Loveridge-Lenza B.
      • Eppes S.
      • DelRosario F.
      Exposure to gastric acid-suppression therapy is associated with health care- and community-associated Clostridium difficile infection in children.
      ]. Unfortunately, the study did not further investigate whether there were differences in risk factors among children in this age group compared with children in other age groups. In addition, the included studies did not establish uniform age grouping criteria, and some studies did not distinguish between newborns and children. Secondly, these studies did not compare and analyse the risk factors of children in different age groups, so the present authors were unable to obtain specific factors for younger age groups. Considering the uniqueness of children's physiology at different ages [
      • Borali E.
      • De Giacomo C.
      Clostridium difficile infection in children: a review.
      ,
      • Pant C.
      • Deshpande A.
      • Altaf M.A.
      • Minocha A.
      • Sferra T.J.
      Clostridium difficile infection in children: a comprehensive review.
      ,
      • Sammons J.S.
      • Toltzis P.
      • Zaoutis T.E.
      Clostridium difficile infection in children.
      ], it is hoped that future studies can conduct more detailed grouping and analysis according to children's age in order to provide a theoretical basis for accurate prevention and control of CDI.
      This meta-analysis had several strengths. First, it was a comprehensive and detailed assessment of risk factors associated with CDI in children, and subgroup analysis based on study design, study setting, case selection, time interval after the interruption of antibiotic exposure, and type of gastric acid suppressants. Second, the study included a comprehensive literature review, and the cohort was larger than that of previous meta-analyses to provide an evidence base for the prevention and control of CDI in children.
      Several limitations were also observed in this systematic review. First, there was high variability in study design, patient population, and confounder adjustment methods, which was a major source of heterogeneity. Second, the dosage and number of antibiotics are risk factors for CDI [
      • Owens R.J.
      • Donskey C.J.
      • Gaynes R.P.
      • Loo V.G.
      • Muto C.A.
      Antimicrobial-associated risk factors for Clostridium difficile infection.
      ], but only a few studies evaluated a sufficient number of confounding factors, leading to high heterogeneity. Third, different enzyme immunoassays were used across studies to diagnose CDI. While most toxin enzyme immunoassays have excellent specificity, their sensitivity varies from 40% to 100%, and some toxin enzyme immunoassays have low positive and negative predictive values in diagnosing CDI [
      • Somily A.M.
      • Khan M.A.
      • Morshed M.
      The laboratory diagnosis of Clostridioides difficile infection: an update of current laboratory practice.
      ,
      • 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).
      ], leading to misdiagnosis.
      In conclusion, this systematic review and meta-analysis showed that antibiotic therapy, prolonged hospitalization, history of hospitalization, gastric acid suppressants, male gender and comorbidities increased the risk of CDI in children significantly. Thus, clinicians should be more aware of CDI, monitor susceptible and high-risk patients, and perform effective interventions. In addition, other potential risk factors need to be evaluated to improve clinicians' awareness of CDI and its risk factors to prevent CDI and associated diarrhoea in children.

      Author contributions

      N. Dong and Z.R. Li conceived the study and drafted the manuscript. J.H. Zhao, C.X. Qiang, J. Yang, Y.N. Niu, W.G. Wang, Y.L. Zhang, M. Zhao and J.Y.R. Li critically revised the manuscript for important intellectual content. X.R. Niu, X.X. Liu and Z.R. Ouyang collected data. N. Dong, P. Qin and B.J. Wen performed the statistical analysis. All authors read and approved the final version.

      Conflict of interest statement

      None declared.

      Funding sources

      This study was financially supported by the Special Foundation for National Science and Technology Basic Research Program of China (Grant Nos. 2019FY101200 and 2019FY101204), the Foundation of Hebei Provincial Department of Finance (Grant No. 361004), and the International Scientific and Technology Corporation Program of Hebei Provincial Department of Science and Technology of China (Grant No. 183977118D).

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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