The Prediction of Complicated Clostridium difficile Infections in Children Author(s): Sarah Tschudin-Sutter, MD, MSc; Pranita D. Tamma, MD, MHS; Aaron M. Milstone, MD, MHS; Trish M. Perl, MD, MSc Source: Infection Control and Hospital Epidemiology, Vol. 35, No. 7 (July 2014), pp. 901-903 Published by: Cambridge University Press on behalf of The Society for Healthcare Epidemiology of America

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infection control and hospital epidemiology

july 2014, vol. 35, no. 7

concise communication

The Prediction of Complicated Clostridium difficile Infections in Children Sarah Tschudin-Sutter, MD, MSc;1,2 Pranita D. Tamma, MD, MHS;3 Aaron M. Milstone, MD, MHS;2,3 Trish M. Perl, MD, MSc1,2

We validated proposed definitions for severe Clostridium difficile infection (CDI) in adults for prediction of complicated CDI in children. Complicated CDI occurred in 9 of 202 cases. Definitions for severe CDI in adults showed poor measures for discrimination of complicated CDI in children, which calls into question the usefulness of such definitions in pediatric cohorts. Infect Control Hosp Epidemiol 2014;35(7):901-903

Over the past decade, Clostridium difficile infection (CDI) has been increasingly reported in pediatric populations and has been associated with heightened mortality, longer hospital lengths of stay, and higher costs among hospitalized children.1,2 The Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America (SHEA),3 and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID)4 have proposed definitions for severe CDI in adults that are based on the presence of clinical and laboratory characteristics at disease onset without making specific recommendations for children. All 3 societies state, however, that the prognostic value of proposed definitions to predict complicated CDI requires further validation. Little is known regarding predictors of complications of CDI in children. We therefore aimed to assess whether the proposed definition for severe CDI in adults predicted complicated CDI in a pediatric cohort.

methods Retrospectively, we assessed the severity of CDI at disease diagnosis in a previously published cohort of pediatric inpatients hospitalized at Johns Hopkins Charlotte R. Bloomberg Children’s Center between July 2003 and July 2012.5 In brief, a child met criteria for CDI if appropriate clinical symptoms were identified (ie, diarrhea defined as 3 or more loose stools per day alone or in combination with other gastrointestinal symptoms, such as abdominal pain or emesis) in the presence of confirmatory laboratory testing and no other identified cause of diarrhea. Screening of stool specimens for C. difficile glutamate dehydrogenase antigen and consecutive toxin testing by a toxin A/B assay for screen-positive speci-

mens was performed until June 2009 and replaced by polymerase chain reaction (PCR; BD GeneOhm Cdiff) thereafter. Standard therapies for CDI in children hospitalized at Johns Hopkins Hospital are described elsewhere.2 Severe CDI was defined with 2 set of criteria, those specified in the SHEA/IDSA guidelines and those specified by ESCMID. Those specified in the SHEA/IDSA guidelines require a white blood cell count of 15,000 cells/mL or greater or a serum creatinine level of 1.5 times the premorbid level or greater,3 and those specified by ESCMID require the presence of any of the following signs: fever (temperature greater than 38.5⬚C), rigors, hemodynamic instability, signs of peritonitis (including decreased bowel sounds, abdominal tenderness, rebound tenderness, and guarding), signs of ileus (including vomiting and absent passage of stool), marked leukocytosis (leukocyte count greater than 15,000 cells/mL), marked left shift (band neutrophils greater than 20% of leukocytes), increase in serum creatinine (1.5 times the premorbid level or greater), elevated serum lactate level, pseudomembranous colitis (endoscopy), distension of large intestine (imaging), colonic wall thickening (including low-attenuation mural thickening; imaging), pericolonic fat stranding (imaging), and ascites not explained by other causes (imaging).4 The primary outcome of interest was severe complicated CDI, defined as an episode of CDI associated with hypotension or shock, ileus, or toxic megacolon, as defined by the SHEA/IDSA guidelines.3 Proportions were compared using the Fisher exact test, and the Mann-Whitney U test was applied to analyze nonnormally distributed continuous variables. Discrimination was defined as the ability of either the IDSA/SHEA or the ESCMID severe CDI criteria to separate complicated disease from uncomplicated disease. The c statistic was quantified as if analogous to the area under the receiver operating characteristic curve (AUC). The Bonferroni-adjusted significance level for multiple comparisons was P p .003. Analyses were performed using Stata version 12.0 (Stata). The Johns Hopkins University School of Medicine institutional review board waived the need for informed consent.

results From July 2003 to July 2012, 202 pediatric inpatients with CDI (193 with first episodes of CDI and 9 with recurrent CDI) were identified. Complications attributable to CDI occurred in 9 children (4.5%) who presented with septic shock. In addition, toxic megacolon was diagnosed in 2 children. In univariable analyses, presence of fever and vomiting at diagnosis of CDI tended to be associated with severe complicated CDI (Table 1). None of the laboratory markers collected at diagnosis, including C-reactive protein level, white blood cell count, serum albumin level, and an increase in serum creatinine level, were associated with the development of se-

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infection control and hospital epidemiology

july 2014, vol. 35, no. 7

table 1. Comparison of Clinical and Laboratory Features between Children with and Children without Complicated Clostridium difficile Infection (CDI) Clinical, laboratory, and radiologic features at CDI onset Demographic characteristic Age, years, median (range) Male sex Clinical feature at diagnosis Diarrhea Abdominal pain Fever Vomiting Laboratory feature at diagnosis C-reactive protein level, mg/dL, median (range) Albumin level, g/dL White blood cell count, mm3, median (range) Creatinine increase ≥1.5 times the premorbid level Leukocyte count 115,000 cells/mm3 Comorbid condition Any Cancer Bone marrow transplantation Solid organ transplantation Initial treatment regimen Metronidazole only Vancomycin only Vancomycin and metronidazole Rifaximin only Severe CDI as defined by IDSA/SHEA guidelines ESCMID guidelines

CDI with complications (n p 9) 12.7 (1–21) 6 (66.7) 8 5 8 4

(88.9) (55.6) (88.9) (44.4)

10.3 (7.5–18.2) 3.1 (2–4.4) 8,800 (660–32,150) 0 (0) 4 (44.4)

CDI without complications (n p 193)

Pa

8.43 (1–21) 112 (58.0)

.38 .74

179 72 75 30

(92.7) (37.3) (38.9) (15.5)

.51 .31 !.01 .05

4.6 (0.1–25.5) 3.6 (2.1–5.3) 9,745 (36–46,390) 16 (8.3) 47 (24.4)

.12 .30 .79 1.00 .23

8 4 3 0

(88.9) (44.4) (33.3) (0.0)

180 33 11 11

(93.3) (17.1) (5.7) (5.7)

6 0 3 0

(66.7) (0.0) (33.3) (0)

161 19 12 1

(83.4) (9.8) (6.2) (0.5)

4 (44.4) 9 (100.0)

61 (31.6) 128 (66.3)

.48 .06 .02 1.00 .063

.47 .06

note. Data are no. (%) of cases, unless otherwise indicated. ESCMID, European Society of Clinical Microbiology and Infectious Diseases; IDSA, Infectious Diseases Society of America; SHEA, Society for Healthcare Epidemiology of America. a Bonferroni-adjusted significance level for multiple comparisons: P p .003.

vere complicated CDI. Among children with comorbid conditions, those with hematopoietic stem cell transplantation were more likely to develop complicated CDI (Table 1), although once corrected for multiple comparisons, the associations were no longer statistically significant. Criteria developed by the IDSA/SHEA and ESCMID in adults did not identify cases at risk for complicated CDI with an AUC of 0.56 and 0.50 for the IDSA/SHEA and ESCMID definition of severe CDI, respectively. No deaths were attributable to CDI in this cohort.

discussion Severe complicated CDI is a feared diagnosis and occurred in 4.5% of this pediatric cohort. We found that the proposed definitions for severe CDI developed for adults and endorsed by the SHEA/IDSA and ESCMID performed poorly in predicting and discriminating severe complicated CDI in children. Approximately half of all children with severe complicated CDI fulfilled the SHEA/IDSA criteria, whereas the ESCMID criteria were met for all; this is explained by the

fact that the latter include the defining criteria of severe complicated CDI. The proportion of severe complicated CDI detected in our study is similar to what has been previously reported among children. In 3 recent studies that included 299, 92, and 75 cases of CDI, severe complicated CDI was reported in 2%,6 3%,7 and 4%8 of children with CDI, respectively. A higher proportion of CDI-related complications (17%) has been reported in another pediatric cohort, however, using a broader definition of complicated CDI, including the documentation of pseudomembranous colitis.9 This percentage is half that reported among adults, for whom severe CDI complicates up to 10% of cases.10 Older age and specific PCR ribotypes (018 and 056) are independent risk factors for complications. The lower rates of complicated CDI reported in pediatric populations suggests that children may have milder courses of disease compared with adults.6,8 Disease severity was overestimated using adult criteria, as has recently been reported for a pediatric cohort of 75 cases of CDI that used the UK Department of Health criteria for

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complicated c. difficile infection in children

severe CDI.11 These criteria are based on parameters similar to those in the ESCMID guidelines, underscoring our results.4 These authors also concluded that adult scoring criteria are not useful in guiding management of CDI in children. Although we were not powered to study this, clinical symptoms, such as fever, signs of peritonitis, and vomiting, may be more useful predictors for severe complicated CDI in children than laboratory features. In addition, the small number of complicated CDI cases identified in this cohort hampered additional statistical analyses, which highlights the limitations this study’s retrospective design at a single center. Because proposed definitions for severe CDI in adults fail to predict severe complicated CDI in children, additional investigation is needed to identify factors that are useful in pediatrics for both clinical and research purposes.

acknowledgments Financial support. S.T.-S. is funded by the Swiss National Science Foundation; the Medical Division of the Lichtenstein Foundation of the University of Basel, Switzerland; and the Scientific Society Basle, Switzerland. Potential conflicts of interest. All authors report no conflicts of interest relevant to this article. All authors submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest, and the conflicts that the editors consider relevant to this article are disclosed here.

Affiliations: 1. Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland; 2. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland; 3. Department of Pediatrics, Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland. Address correspondence to Sarah Tschudin-Sutter, MD, MSc, Department of Medicine, Division of Infectious Diseases, 327 A Billings Building, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287 ([email protected]). Received January 27, 2014; accepted March 15, 2014; electronically published May 20, 2014. 䉷 2014 by The Society for Healthcare Epidemiology of America. All rights reserved. 0899-823X/2014/3507-0023$15.00. DOI: 10.1086/676874

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The prediction of complicated Clostridium difficile infections in children.

We validated proposed definitions for severe Clostridium difficile infection (CDI) in adults for prediction of complicated CDI in children. Complicate...
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