Proton-Pump Inhibitors and Long-Term Risk of Community-Acquired Pneumonia in Older Adults

Jan Zirk-Sadowski, PhD; Jane A. Masoli, MBChB; Joao Delgado, PhD; Willie Hamilton, MD; W. David Strain, MD; William Henley, PhD; David Melzer, MBBCh PhD; Alessandro Ble, MD


J Am Geriatr Soc. 2018;66(7):1332-1338. 

In This Article

Abstract and Introduction


Objectives: To estimate associations between long–term use of proton pump inhibitors (PPIs) and pneumonia incidence in older adults in primary care.

Design: Longitudinal analyses of electronic medical records.

Setting: England

Participants: Individuals aged 60 and older in primary care receiving PPIs for 1 year or longer (N=75,050) and age– and sex–matched controls (N=75,050).

Measurements: Net hazard ratios for pneumonia incidence in Year 2 of treatment were estimated using the prior event rate ratio (PERR), which adjusts for pneumonia incidence differences before initiation of treatment. Inverse probability weighted models adjusted for 78 demographic, disease, medication, and healthcare usage measures.

Results: During the second year after initiating treatment, PPIs were associated with greater hazard of incident pneumonia (PERR–adjusted hazard ratio=1.82, 95% confidence interval=1.27–2.54), accounting for pretreatment pneumonia rates. Estimates were similar across age and comorbidity subgroups. Similar results were also obtained from propensity score– and inverse probability–weighted models.

Conclusion: In a large cohort of older adults in primary care, PPI prescription was associated with greater risk of pneumonia in the second year of treatment. Results were robust across alternative analysis approaches. Controversies about the validity of reported short–term harms of PPIs should not divert attention from potential long–term effects of PPI prescriptions on older adults.


Proton pump inhibitors (PPIs) are widely prescribed to reduce gastric acid production and for gastroprotection,[1,2] but there is evidence of frequent prescribing of PPIs without adequate indication.[3] PPI use has been linked to higher rates of several conditions, including osteoporotic fractures,[4–6] cardiovascular disease,[7,8] and Clostridium difficile infection.[7–9]

PPIs act directly on H+/K+– ATPase enzymes, reducing acid secretion, but gastric acid plays a vital role in the innate response to bacterial infection. Without this protection, bacterial colonization occurs,[10] increasing the risk of bacterial micro–aspiration and pulmonary colonization. Several studies, including meta–analyses, have reported high risk of pneumonia soon after PPI therapy initiation,[11–15] although negative associations have also been reported.[16,17] A recent observational study of the first year after PPI prescription[16] used the prior event rate ratio (PERR),[18–21] which adjusts differences in postprescription pneumonia incidence between cases and controls with preexisting differences to correct for unmeasured confounding. That study used data from individuals in primary care in England and found that pneumonia rates increased during the first 30 days of PPI prescription (incidence rate ratio (IRR)=1.19, 95% confidence interval (CI)=1.14–1.25), but pneumonia rates were even higher during the 30 days immediately before the first PPI prescription (IRR=1.92, 95% CI=1.84–2.00), perhaps because the greater medical scrutiny of individuals with pneumonia led to more PPI prescribing for comorbidities, including medications commonly co–prescribed with PPIs. The PERR analysis, accounting for these prior differences, indicated no additional effect of PPIs on pneumonia risk in the 30 days or first year of treatment periods, but no data on longer–term effects have been reported.

Approximately 40% of elderly adults receive PPIs, and appropriate clinical indications may be lacking for up to 85% of PPIs prescribed.[22,23] Pneumonia is a major cause of death,[24,25] costing in excess of $17 billion per year in the United States alone.[26] It is therefore important to clarify associations between PPIs and pneumonia for short– and long–term exposure, especially in older adults, who may be most at risk from lack of barriers to respiratory infection. We therefore aimed to estimate long–term associations between PPI prescription and risk of pneumonia in individuals in primary care aged 60 and older, similarly applying the PERR approach to account for prior differences between PPI–treated individuals and controls.