Association Between Acute Gastroenteritis and Continuous Use of Proton Pump Inhibitors During Winter Periods of Highest Circulation of Enteric Viruses

Abstract

IMPORTANCE An increased risk of acute bacterial enteric infections has been reported among patients receiving proton pump inhibitor (PPI) therapy. The risk of acute gastroenteritis (AGE) of viral origin associated with continuous PPI exposure has been less studied. OBJECTIVE To investigate the association between continuous PPI therapy and AGE occurrence during winter epidemic periods when the circulation of enteric viruses is the highest. DESIGN, SETTING, AND PARTICIPANTS A matched cohort study was performed using a prospectively collected drug dispensing database from a large panel of community pharmacies in continental France. All patients recorded in the database during the 2015 to 2016 winter season, with documented age, sex, and use of an identifiable regular panel pharmacy, were eligible for the study. Each patient exposed to continuous PPI therapy was matched to 3 unexposed patients, according to year of birth, sex, and identifiable regular panel pharmacy. Analyses were performed between January 2017 and December 2018. EXPOSURE Continuous PPI use during the 2015 to 2016 AGE winter epidemic. MAIN OUTCOMES AND MEASURES The occurrence of at least 1 AGE episode during the 2015 to 2016 AGE winter epidemic was the main outcome. Episodes of AGE were identified using a previously validated algorithm based on drug dispensing data. Relative risks of AGE were estimated using a multivariable log-binomial model adjusted for age, sex, and treatments for chronic conditions. RESULTS There were 233 596 patients receiving PPI therapy (median [interquartile range] age, 71 [62-81] years; 55.8% female) and 626 887 matched patients not receiving PPI therapy (median [interquartile range] age, 70 [61-80] years; 56.3% female) included in the analyses. At least 1 AGE epidemic episode was identified in 3131 patients (1.3%) receiving PPI therapy and in 4327 patients (0.7%) not receiving PPI therapy. The adjusted relative risk of AGE for those receiving PPI therapy was 1.81 (95% CI, 1.72-1.90) for all ages considered, 1.66 (95% CI, 1.54-1.80) among those aged 45 to 64 years, 2.19 (95% CI, 1.98-2.42) among those aged 65 to 74 years, and 1.98 (95% CI, 1.82-2.15) among those aged 75 years and older. CONCLUSIONS AND RELEVANCE Continuous PPI therapy was associated with an increased risk of developing AGE during periods of highest circulation of enteric viruses. These findings support the hypothesis that PPI use is associated with an increased risk of enteric viral infections.

Further Evidence to Monitor Long-term Proton Pump Inhibitor Use

“…5 These results align with those of previous studies 7,8 that identified associations between PPI use and incidence of specific enteric illnesses, including those caused by Clostridium difficile and norovirus (a prominent pathogen associated with AGE). 5 Although Vilcu et al 5 thoroughly address limitations of their study, including outcome ascertainment using drug dispensing data and confounding by indication, it is important to reiterate that the possibilities of residual confounding and protopathic bias remain, particularly because adjustment for comorbidities relied on drug dispensation information alone. In the study, as is common in many settings, patients receiving long-term PPI treatment were significantly sicker than non-PPI users.…”

“…1 Although PPIs are considered safe overall, they have now been linked to numerous adverse events, including drug-drug interactions, hypomagnesemia, osteoporotic fractures, and serious infections. 1 The study by Vilcu and colleagues 5 investigates an emerging concern of infectious complications associated with persistent PPI use: increased risk of acute gastroenteritis (AGE) during AGE epidemics.…”

“…The objective of the study by Vilcu and colleagues 5 was to measure the association between continuous PPI therapy and the occurrence of AGE using a large French community-pharmacy drug dispensation database. The authors used a retrospective matched cohort design to estimate the association between PPI use and AGE incidence during an AGE epidemic period (the 5 weeks of peak AGE incidence in the winter of 2015 to 2016) among patients with at least 1 PPI prescription in the 100 days before and 100 days after the epidemic period.…”

“…A significant association between PPI use and age was found, with older age groups (aged 45-64 years) at highest risk and younger age groups (aged 0-14 years and 15-44 years) at no significant increased risk. Vilcu et al 5 concluded that continuous exposure to PPIs was associated with an increased risk of AGE during epidemic periods.…”

“…Importantly, these results add to a growing body of literature supporting the importance of deprescribing of PPIs to reduce potential adverse effects.Deprescribing guidelines have been published to guide clinicians in stopping or dose-reducing inappropriate PPI therapy,1 particularly among those with no present, identifiable indication for the drug. Discontinuation of inappropriate PPI therapy in older adults (aged Ն65 years) is also a component of the STOPP/START criteria9 and Beers Criteria for Potentially Inappropriate Medication Use in Older Adults.10 In addition to medical record reviews to discontinue inappropriately In addition, an overall evaluation of the need for any acid-reducing therapy should be considered first, rather than simply switching from PPIs to histamine 2 receptor antagonist therapy, given that both PPIs and histamine 2 receptor antagonists were associated with AGE incidence in the study by Vilcu et al5 The study by Vilcu et al5 flags yet another potential risk of therapy with what was previously thought to be a generally safe drug class. Asking patients about all medication use, including overthe-counter drugs, and understanding why a patient is using a PPI are imperative to identifying deprescribing needs and reducing adverse drug effects.…”