CYP2C19 Phenotype and Risk of Proton Pump Inhibitor-Associated Infections

• Published in: Pediatrics (Evanston) 2019-12, Vol.144 (6), p.e20190857
• Main Authors: Bernal, Christiana J, Aka, Ida, Carroll, Robert J, Coco, Joseph R, Lima, John J, Acra, Sari A, Roden, Dan M, Van Driest, Sara L
• Format: Article
• Language: English
• Subjects: Children; Cohort Studies; Cytochrome P-450 CYP2C19 - genetics; Decision making; Exposure; Female; Gastrointestinal diseases; Gastrointestinal tract; Genetic diversity; Genetic variance; Genotypes; Health risks; Humans; Infant; Infections; Infections - chemically induced; Infections - diagnosis; Infections - genetics; Male; Pediatrics; Phenotype; Phenotypes; Proton pump inhibitors; Proton Pump Inhibitors - adverse effects; Respiratory tract; Respiratory tract diseases; Retrospective Studies; Risk Factors
• ISSN: 0031-4005; 1098-4275; 1098-4275
• DOI: 10.1542/peds.2019-0857

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. 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 codes in the year after the first PPI mention. Variants defining , , , , , and 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. In all, 670 individuals were included (median age 7 months; 44% girls). CYP2C19 NMs ( = 267; 40%) had a higher infection rate than RM/UMs ( = 220; 33%; median 2 vs 1 infections per person per year; = .03). There was no difference between poor or intermediate ( = 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). 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 genotypes to PPI therapeutic decision-making.