Associations of proton pump inhibitors with susceptibility to influenza, pneumonia, and COVID-19: Evidence from a large population based cohort study

Adverse effects of proton pump inhibitors (PPIs) have raised wide concerns. The association of PPIs with influenza is unexplored, while that with pneumonia or COVID-19 remains controversial. Our study aims to evaluate whether PPI use increases the risks of these respiratory infections. The current study included 160,923 eligible participants at baseline who completed questionnaires on medication use, which included PPI or histamine-2 receptor antagonist (H2RA), from the UK Biobank. Cox proportional hazards regression and propensity score-matching analyses were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). Comparisons with H2RA users were tested. PPI use was associated with increased risks of developing influenza (HR 1.32, 95%CI 1.12-1.56) and pneumonia (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.26-1.59). In contrast, the risk of COVID-19 infection was not significant with regular PPI use (HR 1.08, 95%CI 0.99-1.17), while the risks of severe COVID-19 (HR 1.19. 95%CI 1.11-1.27) and mortality (HR 1.37. 95%CI 1.29-1.46) were increased. However, when compared with H2RA users, PPI users were associated with a higher risk of influenza (HR 1.74, 95%CI 1.19-2.54), but the risks with pneumonia or COVID-19-related outcomes were not evident. In conclusion, PPI users are associated with increased risks of influenza, pneumonia, as well as COVID-19 severity and mortality compared to non-users, while the effects on pneumonia or COVID-19-related outcomes under PPI use were attenuated when compared to the use of H2RAs. Appropriate use of PPIs based on comprehensive evaluation is required.