PPIs Tied to Infections in Children With Normal CYP2C19 Function

By Marilynn Larkin

November 09, 2019

NEW YORK (Reuters Health) - Proton pump inhibitor (PPI) therapy is associated with higher infection rates in children with normal CYP2C19 function, with infections occurring in 40% of such infants in a retrospective study.

Infections were significantly less common in children who were rapid or ultrarapid CYP2C19 metabolizers, researchers found.

"We believe these additional infection events, which include common infections like upper respiratory illnesses, are side effects from the PPIs," Dr. Sara Van Driest of Vanderbilt University Medical Center in Nashville told Reuters Health by email.

"There are very common genetic variations in the CYP2C19 gene that determine how quickly a patient can metabolize these drugs, and for some patients it may be helpful to perform a genetic test before starting a PPI to choose the right drug and the right dose," she said. "In patients where the medication is not working, the genetic test might help figure out why."

"Perhaps more importantly, she noted, "this study highlights the side effects from PPI medications when they are used in infants and young children. Many infants and children need these medications, and for them, the benefit outweighs the risk of an additional infection event."

"There are also many infants who do not need these medications - e.g., infants who spit up after feeding but are growing well and have no other symptoms," she said. "When we prescribe PPIs for these infants, there is little chance they will benefit from the medication and we are increasing their risk for infection events."

Her team's retrospective biorepository cohort study included children up to age three at the time of PPI exposure. Respiratory tract and gastrointestinal tract infection events were identified using International Classification of Diseases codes in the year after the first PPI mention. CYP2C19 variants *2, *3, *4, *8, *9, and *17 were genotyped, and participants were classified as CYP2C19 poor or intermediate, normal metabolizers (NMs), or rapid or ultrarapid metabolizers (RM/UMs).

As reported online November 7 in Pediatrics, 670 infants were included (median age 7 months; 44% girls; 40% NMs). CYP2C19 RMs/UMs had fewer total infections than NMs (1.85 vs. 2.38 per child in the first year of PPI use). There was no difference in infection events between poor or intermediate metabolizers (27% of participants) and NMs.

After adjustment for age, sex, PPI dose, and comorbidities, CYP2C19 metabolizer status remained a significant risk factor for infections, with an odds ratio of 0.70 for RM/UMs versus NMs.

Analyses showed that comorbidities of chronic lung disease, gastrointestinal motility disorder, gastrointestinal structural pathology, and chronic diarrhea were also associated with more total infections.

A similar multivariable analysis for respiratory tract infections (RTIs) and gastrointestinal infections (GTIs) showed no significant difference between CYP2C19 RM/UMs and NMs, but did reveal that, specifically, chronic lung disease and gastrointestinal structural pathology were associated with increased RTIs, and comorbid gastrointestinal disease (motility disorder, structural pathology, chronic diarrhea) was associated with increased GTIs.

The authors state, "In patients who require PPI treatment, preprescription pharmacogenetic testing may assist in achieving an effective dosing regimen."

Dr. Michael Rieder of Children's Hospital of Western Ontario, coauthor of a related editorial, commented in an email to Reuters Health, "The findings have significant implications for pediatric practice, both with respect to the use of PPIs and to the broader area of precision medicine in children."

"The demonstration that genotyping of children to determine CYP2C19 phenotype prior to prescribing, and adjusting dose accordingly, may significantly reduce the risk of infection for children with the NM phenotype has immediate implications for dosing of one of the most commonly prescribed classes of drugs," he said.

"The mechanism by which this group was able to make this important observation - the use of big data via linked large administrative databases - points to where precision medicine in children needs to move to achieve the transformational outcomes that this approach promises with important implications for researchers, health care systems administrators and government," he concluded.

SOURCE: http://bit.ly/2Q35bRg

Pediatrics 2019.