CYP2C19 Phenotype and Risk of Proton Pump Inhibitor-Associated Infections

Abstract

Objectives: Proton pump inhibitors (PPIs) are often used in pediatrics to treat common gastrointestinal disorders, and there are growing concerns for infectious adverse events. Because CYP2C19 inactivates PPIs, genetic variants that increase CYP2C19 function may decrease PPI exposure and infections. We tested the hypothesis that CYP2C19 metabolizer phenotypes are associated with infection event rates in children exposed to PPIs.

Methods: This retrospective biorepository cohort study included individuals aged 0 to 36 months at the time of PPI exposure. Respiratory tract and gastrointestinal tract infection events were identified by using International Classification of Diseases codes in the year after the first PPI mention. Variants defining CYP2C19 *2, *3, *4, *8, *9, and *17 were genotyped, and all individuals were classified as CYP2C19 poor or intermediate, normal metabolizers (NMs), or rapid or ultrarapid metabolizers (RM/UMs). Infection rates were compared by using univariate and multivariate analyses.

Results: In all, 670 individuals were included (median age 7 months; 44% girls). CYP2C19 NMs (n = 267; 40%) had a higher infection rate than RM/UMs (n = 220; 33%; median 2 vs 1 infections per person per year; P = .03). There was no difference between poor or intermediate (n = 183; 27%) and NMs. In multivariable analysis of NMs and RM/UMs adjusting for age, sex, PPI dose, and comorbidities, 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 versus NMs).

Conclusions: 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.

FIGURE 1

Multivariable analysis of total infection events in CYP2C19 NMs versus RM/UMs. Shown are the ORs (diamonds) and 95% CIs (horizontal lines) for each of the variables included in the ordinal regression model for association to infection events in the 670 children treated with PPIs. ORs are for CYP2C19 phenotype (NM versus RM/UM), age (each additional month), sex (male versus female), and dose (each additional mg/kg per day) and 7 additional dichotomous variables (presence of comorbidity, congenital heart disease, chronic lung disease, gastrointestinal motility disorder, gastrointestinal structural pathology, chronic diarrhea, and prematurity, all yes versus no). Point estimates for the ORs and 95% CIs are listed to the right of each plot.