Although children who take proton pump inhibitors (PPIs) to treat gastroesophageal reflux disease (GERD) have a six times greater risk of gastroenteritis and a twelve times greater risk of pneumonia than healthy controls, the mechanism driving these risks is unknown. Understanding this mechanism is critical because PPIs are one of the most prescribed classes of medications in children and adults and this understanding will enable clinicians to identify and modify the medical treatment of patients at high risk for pneumonia or gastroenteritis. The central hypothesis of the proposed study is that PPIs promote a non-acidic gastric environment in which gastric microflora are altered, and those alterations result in gastrointestinal-wide changes to microflora that increase risk of infection. The rationale for the proposed study is that, despite the widespread belief that PPIs are safe and effective and a more than 400% increase in the frequency of pediatric PPI prescriptions dispensed during the last 7 years, evidence shows that almost 50% of children who take PPIs develop an infectious complication. From a public health perspective, understanding the mechanism behind the high complication rate is critical in order to reduce avoidable infections. Using advanced culturing, 16S deep sequencing, and viral metagenomics, the immediate goals of the proposed study are: (1) to identify the gastric, oropharyngeal, and stool microflora changes in children who take PPIs; (2) to determine the PPI- associated microflora changes that predict pneumonia and gastroenteritis risk; and (3) to identify potential bacterial and viral pathogens associated with PPI use. The long-term goal of the proposed study is to develop a screening tool to identify PPI-associated changes in microflora that enable clinicians to alter acid suppression therapy before infections develop.
The specific aims of the proposed study are: (1) to compare the abundance and diversity of gastric, oropharyngeal, and fecal microflora in children with GERD who are taking PPIs with those in untreated children with GERD and healthy control subjects; (2) to determine, within individuals, the longitudinal impact of PPI use on the abundance and diversity of gastric, oropharyngeal, and fecal microflora; and (3) to determine whether specific changes in oropharyngeal and fecal microflora in patients who are taking PPIs are associated with increased risk of pneumonia and gastroenteritis and to identify potential viral and bacterial pathogens associated with PPI use in children. The proposed research is significant because it will advance scientific understanding of the increased infection risk associated with one of the most commonly prescribed classes of medications in a vulnerable pediatric population. Ultimately, this knowledge can be used to develop new therapeutic algorithms for PPI use in children that reduce the risk of infectious complications.

Public Health Relevance

The proposed research is relevant to public health because the discovery of microflora changes in children who take proton pump inhibitors (PPIs) will directly impact the clinical care of a large number of children. The research is relevant to three of the NIH's missions: (1) Fostering research that ultimately improves health, by understanding the risk of pneumonia and gastroenteritis in the skyrocketing number of children who take PPIs; (2) Developing resources to prevent disease, by devising a microbiome screening tool to classify infection risk in patients who take PPIs; and (3) Expanding the knowledge base to enhance economic well-being, by identifying at-risk patients and ultimately intervening to reduce infectious complications and their resultant medical and financial costs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK097112-01A1
Application #
8963574
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Karp, Robert W
Project Start
2015-07-01
Project End
2020-05-31
Budget Start
2015-07-01
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
Rosen, Rachel; Vandenplas, Yvan; Singendonk, Maartje et al. (2018) Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutritio J Pediatr Gastroenterol Nutr 66:516-554
Rosen, R; Garza, J M; Tipnis, N et al. (2018) An ANMS-NASPGHAN consensus document on esophageal and antroduodenal manometry in children. Neurogastroenterol Motil 30:
Sallis, Benjamin F; Acar, Utkucan; Hawthorne, Kelsey et al. (2018) A Distinct Esophageal mRNA Pattern Identifies Eosinophilic Esophagitis Patients With Food Impactions. Front Immunol 9:2059
Rosen, Rachel L; Krishnan, Usha; Mousa, Hayat et al. (2018) The Case for Thoughtful Prescribing of Proton Pump Inhibitors in Infants. J Pediatr Gastroenterol Nutr 66:e26-e27
Duncan, Daniel R; Mitchell, Paul D; Larson, Kara et al. (2018) Presenting Signs and Symptoms do not Predict Aspiration Risk in Children. J Pediatr 201:141-146
McSweeney, Maireade E; Kerr, Jessica; Amirault, Janine et al. (2018) Preoperative Evaluation Is Not Predictive of Transpyloric Feeding Conversion in Gastrostomy-dependent Pediatric Patients. J Pediatr Gastroenterol Nutr 66:887-892
Mahoney, Lisa; Rosen, Rachel (2017) Feeding Problems and Their Underlying Mechanisms in the Esophageal Atresia-Tracheoesophageal Fistula Patient. Front Pediatr 5:127
Mahoney, Lisa B; Nurko, Samuel; Rosen, Rachel (2017) The Prevalence of Rome IV Nonerosive Esophageal Phenotypes in Children. J Pediatr 189:86-91
Duncan, Daniel R; Amirault, Janine; Mitchell, Paul D et al. (2017) Oropharyngeal Dysphagia Is Strongly Correlated With Apparent Life-Threatening Events. J Pediatr Gastroenterol Nutr 65:168-172
Rosen, Rachel; Mitchell, Paul D; Amirault, Janine et al. (2017) The Edematous and Erythematous Airway Does Not Denote Pathologic Gastroesophageal Reflux. J Pediatr 183:127-131

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