Nashville, TN—With increased use of proton pump inhibitors (PPIs) in pediatric patients, a new study cautions about potential adverse effects in small children.

A retrospective, biorepository, cohort study in the journal Pediatrics documents concerns about the drugs used for gastrointestinal-acid reduction. Researchers examined DNA from patients ages 0 to 3 years at the time of PPI exposure.

“PPIs are commonly used in children to treat gastrointestinal disorders, and we are seeing an increase in the number of adverse infection events associated with their use,” explained Sara Van Driest, MD, PhD, assistant professor of Pediatrics at Monroe Carell Jr. Children’s Hospital at Vanderbilt University. “Because these medications are available over the counter for adults, they are thought to be a safe option for children. These medicines are seen as very low risk with few downsides. But what we have found is that PPIs aren't without risk.”

Van Driest points out that a specific enzyme, CYP2C19, helps break down these medications but works differently in each person—slow, normal, or fast—and sometimes not at all. That can affect the ability of the medication to be safely metabolized, she adds.

The study suggests that, because CYP2C19 inactivates PPIs, genetic variants that decrease the enzyme’s function may increase the medicine levels in the body, which, in turn, could lead to more infection events. Background information in the report describes how stomach acid naturally protects the body from dangerous organisms that can be found in water and food. Researchers sought to test the hypothesis that CYP2C19 metabolizer phenotypes are associated with infection event rates in children exposed to PPIs.

The study, which included 670 children, median age 7 months and 44% girls, identified respiratory tract and gastrointestinal tract infection events by using International Classification of Diseases codes in the year after the first PPI mention. With variants defining CYP2C19 *2, *3, *4, *8, *9, and *17 genotyped, all children were classified as CYP2C19 poor or intermediate, normal metabolizers (NMs), or rapid or ultrarapid metabolizers (RM/UMs). Infection rates then were compared by using univariate and multivariate analyses.

Results indicated that the CYP2C19 NMs, which represented about 40% of the participants, had a higher infection rate than RM/UMs, which represented about 33%. The median was calculated as two versus one infections per person per year; (P = .03). No difference was identified between children who were poor or intermediate metabolizers compared with NMs.

Using multivariable analysis of NMs and RM/UMs adjusting for age, sex, PPI dose, and comorbidities, the authors determined that CYP2C19 metabolizer status remained a significant risk factor for infection events (odds ratio 0.70 [95% confidence interval 0.50–0.97] for RM/UMs vs. NMs).

“PPI therapy is associated with higher infection rates in children with normal CYP2C19 function than in those with increased CYP2C19 function, highlighting this adverse effect of PPI therapy and the relevance of CYP2C19 genotypes to PPI therapeutic decision-making,” the researchers concluded.

“The fact that children who have been characterized as normal CYP2C19 metabolizers actually had more infection events than the fast metabolizers tells us that being exposed to these drug levels actually puts the child at risk for having an extra infection event,” Van Driest added. “We were able to highlight that these medicines do have side effects, and as clinicians we need to think very carefully about the benefits and the risks. We can consider doing a genetic test to identify if a patient is a slow, normal or fast metabolizer.”

Genetic testing can be a useful tool to determine if a patient requires a lower or higher dose of the drug, she noted.

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