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Table 1. Characteristics of Included Studies First Author,Year Published
Study
Pascarella F,29 2009 Turco R,12 2010 Nylund CM,3 2011 Guo S,33 2012 Hojsak I,24 2012
De Blank P,32 2013 Price V,34 2013
Brown KE,28 2015 Santiago B,35 2015 Ciricillo J,36 2016 Finnerty C,37 2016 Karaaslan A,38 2016 Pant C,31 2016 Daida A,39 2017
Location Italy Italy USA
China
Croatia USA
Canada USA
Spain USA USA
Turkey USA
Japan
Scott Anjewierden et al
Study Period
2005–2007 2005–2009 1997–2006 2010–2011 2006–2011 1999–2011
1995–2004 2008–2012 2010–2011 2010–2013 1997–2008 2012–2014 2012–2012 2003–2012
Study Design
RCC RCC RC PC RC RC
RC
RCC RC RC
RCC RCC RC
RCC
Sample Size, No.
193 136
10,495,728 140 744
33,059
341 458 250 55 85
986
12,797 108
Boys, No. (%)
107 (55.4) 86 (63.2)
4,198,965 (40.0) 98 (70.0) 379 (51.0)
18,479 (55.9)
168 (49.3) 227 (49.6) 140 (56.0) N/A
57 (67.0) 552 (56.0)
6,760 (52.8) 64 (59.3)
Age
Range, y 1–18 1–18 1–17 0–18 0–18 1–18
1–18 1–17 0–15 0–18 0–18 0–18 1–17 0–19
Diagnostic Test/Criteria
Toxin A/B EIA Toxin A/B EIA
ICD9 Code (008.45) Toxin A/B PCR Toxin A/B EIA
ICD9 code (008.45), billing codesa
Culture Toxin B qPCR
Culture, Toxin A/B PCR Toxin A/B EIA, LAMP Toxin A/B EIA
Toxin A/B EIA, CTA ICD9 Code (008.45) Toxin A/B EIA
Note. N/A, not available; RCC, retrospective case-control; RC, retrospective cohort; NCC, nested case-control; EIA, enzyme immunoassay; DRG, Diagnosis-Related Group; ICD-9, International
Classification of Disease, 9th edition; PCR, polymerase chain reaction; CTA, cytotoxicity assay; LAMP, loop-mediated isothermal amplification; qPCR, quantitative polymerase chain reaction. aPresence of billing codes for Toxin A/B EIA and/or PCR, as well as metronidazole (PO or IV) or vancomycin (PO) within the period of 1 day before or 2 days after diagnostic test.
Figure 5. Forest plot of the association between gender and CDI. Vertical line corresponds to no difference point between the 2 groups. Squares correspond to risk ratios. Horizontal lines represent the 95% confidence intervals. The diamond indicates the pooled relative risk ratios. Note. df, degrees of freedom; M-H, Mantel-Haenszel.
gastrointestinal microbial diversity25 and prolong the survival of spores,26 both of which may predispose the host to susceptibility for C. difficile. PPI use was significantly associated with develop- ment of CDI in the pediatric inpatient population in this meta- analysis, although the effect size was small. Most recently, Oshima et al27 reported a 3-fold increase in risk of CDI with PPI use in their meta-analysis of pediatric patients. The discrepan- cies between our results may be explained by differences in our study methodologies. Specifically, Oshima et al included studies that examined community acquired CDI in the outpatient setting and exclusively used raw data from chosen studies that were not adjusted for potential confounding factors. In contrast, we avoided unadjusted data in our analysis of PPI use, and we used only data that had been adjusted by multivariable logistic regression in the original studies. In particular, we obtained unpublished multivari- ate data for the association of PPI use withCDI fromthe authors of Brown et al28 to include in thismeta-analysis, whereas Oshima et al used unadjusted data from the same study. Nonetheless, the 2 meta-analyses are consistent in demonstrating some degree of association between PPI use and CDI in the pediatric population. For many of the risk factors assessed by the included studies, we
were unable to pool the data due to either an insufficient number of studies or variability in reporting. For example, the presence of IBD as an underlying comorbidity was reported to be a statistically
significant risk factor, but was reported by only 2 studies.3,29 The association between IBD and CDI might be mediated by the increased use of immunosuppressive agents, antibiotics, and healthcare services, as well as the disruption of the gut mucosal barrier and flora that underlie the pathophysiology of IBD.30 Similarly, solid organ transplantation was also reported to be an independent risk factor by 2 separate studies, potentially due to the chronic immunosuppressive therapy in these patients.3,31 Malignancies in general as well as specific subtypes of tumors were reported to be independent risk factors in several studies. Again, the association may be mediated by the immunosuppressive and antimicrobial effects of chemotherapy, which was reported to be a statistically significant risk factor itself in 1 study.32 In general, additional studies examining these risk factors in the hospitalized pediatric population are needed to validate these findings. Our meta-analysis has several limitations. First, relatively few
studies were identified for our meta-analysis, and they were exclu- sively observational. To address this limitation, we searched 4 sep- arate databases and included >2,000 articles in our original search. Unfortunately, studies of risk factors for CDI in the pediatric pop- ulation are limited in nature, and they often include community acquired-CDI in combination to hospital acquired-CDI. Due to differences in the acquisition of these 2 conditions, we did not feel that using studies of exclusively outpatient CDI infections would
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