PPI-associated Infections Tied to Gene Variants

PPI-associated Infections Tied to Gene Variants
Study in children finds risk may hinge on CYP2C19 status.

A new study in Pediatrics identified genotypes that alter a child’s risk of developing an infection following treatment with proton pump inhibitors (PPIs, such as Prilosec and similar drugs). While common, the acid-suppressing medications may not be appropriate for everyone, said principal investigator Sara Van Driest, M.D., assistant professor of pediatrics at Vanderbilt University Medical Center.

“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 said.

PPIs Suppress Defenses

PPIs are staples of the gastroenterology arsenal, yet their very mechanism may increase infection risk. They block gastric acid production that the body relies upon to kill ingested pathogens. Emerging studies associate long-term PPI use in children with gastrointestinal and respiratory tract infections. Children treated with PPIs are also more likely to be hospitalized.

“We are seeing an increase in the number of adverse events associated with their use.”

Said Van Driest, “PPIs are commonly used in children to treat gastrointestinal disorders, and we are seeing an increase in the number of adverse events associated with their use.”

An enzyme called CYP2C19 metabolizes and inactivates PPIs. In the new study, Van Driest tested whether or not genetic variants that increase this enzyme’s activity might also help lower PPI exposure and infection rates in children treated with PPIs.

Mining EHR

Van Driest led a team of researchers in mining EHR for children up to 36 months old who received PPIs. They searched each record to see who later developed gastrointestinal or respiratory tract infections. They reported each child’s CYP2C19 genotype, and divided the variants into three groups: poor/intermediate, normal, or rapid/ultra-rapid metabolizers.

Across 670 patients, normal metabolizers had a higher infection rate than children in the other groups. The risk was nearly double; children with normal CYP2C19 genotypes experienced a median of two infections annually, as compared to one in the other groups. Even after adjusting for age, sex, PPI dose and comorbidities, CYP2C19 genotype remained a significant risk factor.

“The fact that children who have been characterized as normal CYP2C19 metabolizers had more infection events than the fast metabolizers tells us that being exposed to these drug levels actually puts the child at risk for infection events,” Van Driest said.

Caution for Prescribers

The findings add to a growing body of evidence identifying risks associated with PPI use, particularly in children.

Said Van Driest, “We were able to highlight that these medicines do have side effects, and as pediatricians 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.”

While the infections associated with PPIs are often treatable, genetic tests could help mitigate risk and inform dosing, Van Driest said.

“We are hoping that clinicians will pause before starting PPIs knowing that there is an increased risk of infections while their patients are on this drug,” Van Driest said. “If there is a need to start the drug, they can consider genetic testing to find out their patient’s CYP2C19 status.”