Infection Control & Hospital Epidemiology Data sources and searches
Two investigators (S.A. and Z.H.) systematically searched the literature independently using the following predetermined inclu- sion criteria: (1) observational studies (including case control and cohort) evaluating risk factors for primary CDI, (2) pediatric patients (≤19 years), (3) study population includes >10 pediatric patients, (4) in-patients admitted to a hospital, and (5) studies evalu- ated>1CDI risk factor. Studies were excluded if (1) they exclusively studiedCDI in children<2 years, in which the role of C. difficile was unclear and testing was not routinely recommended,9 and (2) if they exclusively studied CDI patients in an outpatient setting. The following databases were searched fromJanuary 1975 toAugust 2017:MEDLINE (PubMed),EMBASE,Web of Science, and Scopus. The following search terms were used: C. diff infection, Clostridium difficile infection, CDI, Clostridium difficile associated infection, CDAD, pediatric, paediatric, children, infants, adolescents, risk, risk factors, predictor, andmarker.Wealso conducted amodified search from September 2016 to August 2017 including Clostridioides difficile in our search criteria, but we did not find any additional eligible studies (data not shown). The electronic PubMed search strategy is available in the supplemental appendix online.
Study selection and data extraction
A list of retrieved articles that met the inclusion criteria was reviewed by 2 investigators independently (S.A. and Z.H.). These investigators also independently extracted data from the full text of the included studies. The data collected included study design, study population, patient demographics, clinical character- istics, and identified risk factors for CDI. Any disagreement was resolved in consensus with a third investigator (A.D.). Authors were contacted if relevant information was not available for a particular study. The Cohen’s interrater κ statistics for inclusion agreement and data extraction were 0.85 and 0.90 respectively, which indicated excellent interrater agreement.
Quality assessment
The quality of the observational studies (including cohort and case-control) was assessed independently by 2 investigators (S.A. and Z.H.) using the Newcastle-Ottawa Scale (NOS).15 Studies with NOS scores >7 were considered high-quality studies, and those withNOS scores of 5–7 were considered moderate-quality studies. Any disagreements or discrepancies were resolved by consensus with a third investigator (A.D.). The Cohen’s interrater κ statistic for study quality assessment was 0.90, which indicated excellent interrater agreement.
Data synthesis and analysis
Due to the diversity of risk factors evaluated in studies of C. difficile, we decided a priori that all risk factors reported in ≥3 studies were eligible for inclusion in the meta-analysis. For all studies, when possible, we extracted the adjusted odds
ratios (ORs) and relative risks. When adjusted data were not avail- able, crude odds ratios and relative risks with their 95% confidence intervals (CIs) were calculated from the number of events. We decided a priori that adjusted data would be used for all meta-analyses with≥3 studies. When adjusted data were not avail- able for≥3 studies, we combined the adjusted and unadjusted data. DerSimonian and Laird random-effects models were used for all meta-analyses.16 The meta-analysis was performed using the inverse variance method to obtain pooledORs and 95% confidence
421
intervals (CIs). We assumed similarity between the OR and other relative measures, such as relative risk or rate ratios, because of low disease frequency and prevalence of CDI in this population. We evaluated statistical heterogeneity using the Cochran χ2 (Cochran Q) and the I2 statistic. We defined significant heterogeneity as a χ2 <0.10 or an I2 statistic >66%.17 Moderate heterogeneity was defined as an I2 statistic between 33% and 66%. Low heterogeneity was defined as an I2 statistic <33%.
Assessment of publication bias
To check for publication bias, we generated funnel plots and used Egger’s regression asymmetry test. Where asymmetry was detected, we assessed the potential impact of the publication bias using the Duval and Tweedie nonparametric “trim-and-fill” method.18 We used Review Manager software (RevMan, version 5.3 for
Windows, Oxford, UK; The Cochrane Collaboration, 2014) for our statistical analyses.
Results Study characteristics
The preliminary literature search identified 2,032 publications (Fig. 1). After removing duplicates and screening titles for poten- tially relevant articles, 127 studies were considered relevant. On further screening of the abstracts of these potentially relevant stud- ies, 56 were selected for full text review. Finally, a total of 14 articles met the full inclusion criteria and were included in the systematic review. The reasons for excluding the remaining 42 articles are listed in Figure 1. The main characteristics of the included studies are summarized
in Supplemental Table 2. The final study population consisted of 10,531,669 children, of which 22,320 patients developed CDI. In analyzing the 14 included studies, 7were retrospective cohort studies and 6 were retrospective case-control studies, while the remaining study was a prospective cohort study. Six of the studies were conducted in theUnited States, 2were conducted in Italy, with a sin- gle study was conducted in each of the following countries: Canada, China, Croatia, Japan, Spain, and Turkey. The testingmethodology for CDI consisted of a C. difficile toxin assay for 10 studies. Clostridium difficile culture and/or toxin assay for 2 studies and the use of the International Classification of Diseases Ninth Edition (ICD-9) code 008.45 or other billing codes were used in the remaining 3 studies.
Quality assessment
Using the NOS scale, all included studies were identified as moderate or high in quality (Supplemental Table 1 online). Most included studies clearly identified the study population and defined the outcome and outcome assessment. Most studies identified important confounders that were used for adjustment of the association exposures and risk of CDI. We found consider- able variation in the selection of available confounding variables for adjustment. A few confounding variables may not have been fully identified and recorded. The most common confounders adjusted were age, gender, and antibiotic exposure. Information on the dose and duration of antibiotic therapy prior to the diagno- sis of CDI was
limited.Various methods were used to identify anti- biotic use, including review of patient medical records, patient prescription records, and ICD-9 codes.
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100 |
Page 101 |
Page 102 |
Page 103 |
Page 104 |
Page 105 |
Page 106 |
Page 107 |
Page 108 |
Page 109 |
Page 110 |
Page 111 |
Page 112 |
Page 113 |
Page 114 |
Page 115 |
Page 116 |
Page 117 |
Page 118 |
Page 119 |
Page 120 |
Page 121 |
Page 122
