ORIGINAL ARTICLE: GASTROENTEROLOGY
Exposure to Gastric Acid–Suppression Therapy Is Associated With Health Care– and CommunityAssociated Clostridium difficile Infection in Children
Jennifer Jimenez, yMarci Drees, Beth Loveridge-Lenza, zStephen Eppes, and §Fernando delRosario
ABSTRACT Objective: The aim of the study was to determine whether gastric acid– suppression therapy is associated with Clostridium difficile infection (CDI) in both inpatient and outpatient pediatric populations. Methods: We conducted a retrospective case-control study at a 200-bed academic pediatric hospital and associated outpatient clinics during 2005– 2010. We defined cases as children 1 to 18 years of age with a first positive test for C difficile toxin A/B, and matched each case to 2 controls without C difficile. We conducted chart review to elicit selected comorbidities and exposure to gastric acid–suppression therapy and antibiotics in the preceding 3 months of the infection or encounter date. We used bivariate and multivariable logistic regression to evaluate the association between antacid use and CDI, controlling for potential confounders. Results: We identified 138 children with health care– or communityassociated CDIs and 276 controls. The use of any acid suppression therapy was more common in cases compared with controls (34% vs 20%, P ¼ 0.002). When adjusted for demographic variables and comorbidities, gastric acid–suppression therapy remained significantly associated with CDI (adjusted odds ratio [aOR] 1.8, 95% confidence interval [CI] 1.0–3.1). Antibiotic use (aOR 1.7, 95% CI 1.1–2.7) and immunosuppressed state were also associated with CDI in our adjusted model (aOR 2.5, 95% CI 1.2–5.2). Conclusions: Gastric acid–suppression therapy was associated with both health care– and community-associated CDIs in children. Larger pediatric studies are necessary to determine the role of proton pump inhibitors specifically in causing CDI in children. Key Words: Clostridium difficile infection, gastric acid–suppression therapy, proton pump inhibitors
(JPGN 2015;61: 208–211)
Received August 6, 2014; accepted March 10, 2015. From the Division of Pediatric Gastroenterology, K. Hovnanian Children’s Hospital, Jersey Shore University Medical Center, Neptune, NJ, the yDepartment of Medicine, the zDepartment of Pediatric, Christiana Care Health System, Newark, DE, and the §Division of Pediatric Gastroenterology, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE. Address correspondence and reprint requests to Jennifer Jimenez, MD, Meridian Pediatric Associates, Pediatric Gastroenterology, K. Hovnanian Children’s Hospital, Jersey Shore University Medical Center, 61 Davis Ave, Suite 1-A, Neptune, NJ 07753 (e-mail: jxjimenez@meri dianhealth.com). The authors report no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000790
What Is Known
The incidence of Clostridium difficile infection in children has been increasing across the United States during the past decade. The use of gastric acid–suppression therapy has been linked to C difficile infection in adults with scarce data in children. Inappropriate prescription of gastric acid–suppression therapy such as transient physiologic reflux has contributed to the >7-fold increase in prescriptions for acid-suppressive medications.
What Is New
This study found that gastric acid–suppression therapy was significantly associated with both health care– and community-associated CDI in children. Pediatricians should weigh the risks versus benefits of prescribing acid suppression.
T
he incidence of Clostridium difficile infection (CDI) in children has been increasing across the United States during the past decade (1,2). CDI was once believed to affect only those patients who are elderly, frail and hospitalized, and in nursing homes. Recent studies, however, suggest that previously healthy persons, including minors who have not been exposed to hospitals or antimicrobial therapy, are also at risk for community-associated CDI (3,4). This increase in CDI in the pediatric population has prompted pediatricians to identify modifiable risk factors that may contribute to CDI in children. Antibiotic exposure is the primary risk factor for CDI (1,5–8). Other well-described risk factors in the adult population include severe underlying illness, hospitalization, and immunosuppressive therapy (8). The use of gastric acid–suppression therapy (proton pump inhibitors [PPIs] and/or histamine 2 receptor antagonists [H2RAs]) has been linked to community-acquired pneumonia, gastroenteritis, and CDI in adults (8,9). Two recent meta-analyses identified PPIs as a risk factor for CDI in inpatients and the community, with a relative risk of approximately 1.7 (8,9). The majority of studies in these meta-analyses included patients >18 years of age, with only 1 study in children (10). In this Italian pediatric study, PPI use was approximately 5 times higher among 68 C difficile–positive hospitalized cases compared with controls. This is particularly concerning because prescription of gastric
208 JPGN Volume 61, Number 2, August 2015 Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 61, Number 2, August 2015
acid–suppression therapy in children has increased during the past decade (11). Given limited pediatric data regarding the risk of CDI, it is unclear whether pediatricians should limit gastric acid–suppression therapy in children. Therefore, we conducted this study to determine whether exposure to gastric acid–suppression therapy was associated with CDI in both inpatient and outpatient pediatric populations cared for at a tertiary care children’s hospital in the United States.
Association of Gastric Acid–Suppression Therapy With CDI receipt of immunosuppressive medications posttransplant (eg, tacrolimus, cyclosporin). We also elicited use of any antibiotic or gastric acid–suppressive therapy (PPIs and/or H2RAs) within the preceding 3 months of the infection or encounter date. We analyzed age first as a continuous variable and then stratified into 3 categories: 1 to 2, 3 to 4, and 5 to 18 years.
Data Analysis METHODS Study Design and Population We conducted a retrospective case-control study at Nemours/ Alfred I. duPont Hospital for Children, a 200-bed, academic tertiary care children’s hospital in Wilmington, DE. Primary care and pediatric specialty practices throughout the Nemours system are linked by a common electronic medical record (EMR; Epic Systems, Inc, Madison, WI). The study population included children ages 1 to 18 years seen in any inpatient or outpatient setting between January 1, 2005, and December 31, 2010. This study was approved by the Nemours institutional review board. We defined cases as any patient who tested positive for C difficile (toxin A and/or B) from fecal samples processed in the hospital’s microbiology laboratory. Cases were excluded if they had any prior positive C difficile tests in the system. The laboratory used the Immunocard toxin A and B rapid enzyme immunoassay (Meridian Bioscience, Cincinnati, OH), which has a sensitivity of 67% and a negative predictive value of 88% (12). The laboratory rejects formed stool when performing this test. Each CDI case was categorized by the following standard epidemiologic definitions (13): health care facility–onset, health care facility–associated (HO-HCFA; CDI diagnosed >48 hours after hospital admission); community-onset, health care facility–associated (CO-HCFA; diagnosis within 48 hours of admission with 1 prior admission within the prior 4 weeks); community-associated (CA-CDI; diagnosis within 48 hours of admission with no discharges from a health care facility in the previous 12 weeks); and indeterminate (diagnosis within 48 hours of admission with a discharge >4 weeks but
Exposure to Gastric Acid–Suppression Therapy Is Associated With Health Care– and CommunityAssociated Clostridium difficile Infection in Children
Jennifer Jimenez, yMarci Drees, Beth Loveridge-Lenza, zStephen Eppes, and §Fernando delRosario
ABSTRACT Objective: The aim of the study was to determine whether gastric acid– suppression therapy is associated with Clostridium difficile infection (CDI) in both inpatient and outpatient pediatric populations. Methods: We conducted a retrospective case-control study at a 200-bed academic pediatric hospital and associated outpatient clinics during 2005– 2010. We defined cases as children 1 to 18 years of age with a first positive test for C difficile toxin A/B, and matched each case to 2 controls without C difficile. We conducted chart review to elicit selected comorbidities and exposure to gastric acid–suppression therapy and antibiotics in the preceding 3 months of the infection or encounter date. We used bivariate and multivariable logistic regression to evaluate the association between antacid use and CDI, controlling for potential confounders. Results: We identified 138 children with health care– or communityassociated CDIs and 276 controls. The use of any acid suppression therapy was more common in cases compared with controls (34% vs 20%, P ¼ 0.002). When adjusted for demographic variables and comorbidities, gastric acid–suppression therapy remained significantly associated with CDI (adjusted odds ratio [aOR] 1.8, 95% confidence interval [CI] 1.0–3.1). Antibiotic use (aOR 1.7, 95% CI 1.1–2.7) and immunosuppressed state were also associated with CDI in our adjusted model (aOR 2.5, 95% CI 1.2–5.2). Conclusions: Gastric acid–suppression therapy was associated with both health care– and community-associated CDIs in children. Larger pediatric studies are necessary to determine the role of proton pump inhibitors specifically in causing CDI in children. Key Words: Clostridium difficile infection, gastric acid–suppression therapy, proton pump inhibitors
(JPGN 2015;61: 208–211)
Received August 6, 2014; accepted March 10, 2015. From the Division of Pediatric Gastroenterology, K. Hovnanian Children’s Hospital, Jersey Shore University Medical Center, Neptune, NJ, the yDepartment of Medicine, the zDepartment of Pediatric, Christiana Care Health System, Newark, DE, and the §Division of Pediatric Gastroenterology, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE. Address correspondence and reprint requests to Jennifer Jimenez, MD, Meridian Pediatric Associates, Pediatric Gastroenterology, K. Hovnanian Children’s Hospital, Jersey Shore University Medical Center, 61 Davis Ave, Suite 1-A, Neptune, NJ 07753 (e-mail: jxjimenez@meri dianhealth.com). The authors report no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000790
What Is Known
The incidence of Clostridium difficile infection in children has been increasing across the United States during the past decade. The use of gastric acid–suppression therapy has been linked to C difficile infection in adults with scarce data in children. Inappropriate prescription of gastric acid–suppression therapy such as transient physiologic reflux has contributed to the >7-fold increase in prescriptions for acid-suppressive medications.
What Is New
This study found that gastric acid–suppression therapy was significantly associated with both health care– and community-associated CDI in children. Pediatricians should weigh the risks versus benefits of prescribing acid suppression.
T
he incidence of Clostridium difficile infection (CDI) in children has been increasing across the United States during the past decade (1,2). CDI was once believed to affect only those patients who are elderly, frail and hospitalized, and in nursing homes. Recent studies, however, suggest that previously healthy persons, including minors who have not been exposed to hospitals or antimicrobial therapy, are also at risk for community-associated CDI (3,4). This increase in CDI in the pediatric population has prompted pediatricians to identify modifiable risk factors that may contribute to CDI in children. Antibiotic exposure is the primary risk factor for CDI (1,5–8). Other well-described risk factors in the adult population include severe underlying illness, hospitalization, and immunosuppressive therapy (8). The use of gastric acid–suppression therapy (proton pump inhibitors [PPIs] and/or histamine 2 receptor antagonists [H2RAs]) has been linked to community-acquired pneumonia, gastroenteritis, and CDI in adults (8,9). Two recent meta-analyses identified PPIs as a risk factor for CDI in inpatients and the community, with a relative risk of approximately 1.7 (8,9). The majority of studies in these meta-analyses included patients >18 years of age, with only 1 study in children (10). In this Italian pediatric study, PPI use was approximately 5 times higher among 68 C difficile–positive hospitalized cases compared with controls. This is particularly concerning because prescription of gastric
208 JPGN Volume 61, Number 2, August 2015 Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 61, Number 2, August 2015
acid–suppression therapy in children has increased during the past decade (11). Given limited pediatric data regarding the risk of CDI, it is unclear whether pediatricians should limit gastric acid–suppression therapy in children. Therefore, we conducted this study to determine whether exposure to gastric acid–suppression therapy was associated with CDI in both inpatient and outpatient pediatric populations cared for at a tertiary care children’s hospital in the United States.
Association of Gastric Acid–Suppression Therapy With CDI receipt of immunosuppressive medications posttransplant (eg, tacrolimus, cyclosporin). We also elicited use of any antibiotic or gastric acid–suppressive therapy (PPIs and/or H2RAs) within the preceding 3 months of the infection or encounter date. We analyzed age first as a continuous variable and then stratified into 3 categories: 1 to 2, 3 to 4, and 5 to 18 years.
Data Analysis METHODS Study Design and Population We conducted a retrospective case-control study at Nemours/ Alfred I. duPont Hospital for Children, a 200-bed, academic tertiary care children’s hospital in Wilmington, DE. Primary care and pediatric specialty practices throughout the Nemours system are linked by a common electronic medical record (EMR; Epic Systems, Inc, Madison, WI). The study population included children ages 1 to 18 years seen in any inpatient or outpatient setting between January 1, 2005, and December 31, 2010. This study was approved by the Nemours institutional review board. We defined cases as any patient who tested positive for C difficile (toxin A and/or B) from fecal samples processed in the hospital’s microbiology laboratory. Cases were excluded if they had any prior positive C difficile tests in the system. The laboratory used the Immunocard toxin A and B rapid enzyme immunoassay (Meridian Bioscience, Cincinnati, OH), which has a sensitivity of 67% and a negative predictive value of 88% (12). The laboratory rejects formed stool when performing this test. Each CDI case was categorized by the following standard epidemiologic definitions (13): health care facility–onset, health care facility–associated (HO-HCFA; CDI diagnosed >48 hours after hospital admission); community-onset, health care facility–associated (CO-HCFA; diagnosis within 48 hours of admission with 1 prior admission within the prior 4 weeks); community-associated (CA-CDI; diagnosis within 48 hours of admission with no discharges from a health care facility in the previous 12 weeks); and indeterminate (diagnosis within 48 hours of admission with a discharge >4 weeks but
