Meta-analysis: Proton Pump Inhibitor Use and the Risk of Community-acquired Pneumonia

J. Johnstone; K. Nerenberg; M. Loeb


Aliment Pharmacol Ther. 2010;31(11):1165-1177. 

In This Article

Abstract and Introduction


Background Observational studies examining the association between proton pump inhibitor (PPI) use and risk of community-acquired pneumonia are conflicting.
Aim To assess systematically the association between risk of community-acquired pneumonia and PPI use in adults.
Methods We searched MEDLINE, EMBASE and CINAHL databases between 1988 and January 2010. Two reviewers independently selected studies based on eligibility criteria and extracted data. Included studies evaluated adults (≥18 years) who took PPIs as an out-patient. The primary outcome was community-acquired pneumonia. Only observational studies with a comparison arm were included.
Results Over 2600 citations were reviewed. Six studies were included. All were nested case-control studies. Meta-analysis found an increased risk of community-acquired pneumonia associated with PPI use [OR 1.36 (95% CI 1.12–1.65)]; significant heterogeneity remained (I 2 92%, P < 0.001). In exploratory subgroup analysis, short duration of use was associated with an increased odds of community-acquired pneumonia [OR 1.92 (95% CI 1.40–2.63), I 2 75%, P = 0.003], whereas chronic use was not [OR 1.11 (95% CI 0.90–1.38), I 2 91%, P < 0.001], a significant interaction (P < 0.005).
Conclusions Heterogeneity precluded interpretation of the summary statistic. Exploratory analysis revealed that duration of PPI use may impact the risk of community-acquired pneumonia, a finding that should be explored in future studies.


Proton pump inhibitors were introduced into clinical practice in 1988 and have since become the mainstay of therapy for many acid-related gastrointestinal disorders including peptic ulcer disease,[1,2] gastro-oesophageal reflux disease (GERD)[3–5] and non-ulcer dyspepsia.[6,7] Proton pump inhibitors are among the top five most prescribed drugs in North America,[8] which is, in part, due to their safety profile.[9] They are generally well tolerated and serious adverse events are rare; however, there have been an increasing number of reports linking the chronic use of proton pump inhibitors to significant adverse effects including drug-drug interactions,[10–12]Clostridium difficile associated diarrhoea,[13] hip fractures[14] and community-acquired pneumonia.[15–21] Results of observational studies describing the association between proton pump inhibitors and risk of community-acquired pneumonia have been conflicting.[15–21]

A recent systematic review and meta-analysis of randomized controlled trials of proton pump inhibitors examined the association between their use and respiratory tract infections.[22] In the seven trials that fulfilled inclusion criteria, the reported prevalence of respiratory infections was low (4% overall; odds ratio 1.42, 95% CI 0.86–2.35) and the incidence of pneumonia was not specified. A separate review attempted to estimate the association of esomeprazole and community-acquired pneumonia by pooling data from an adverse events database of 31 clinical trials.[23] In total, there were 15/6534 (0.22%) cases of pneumonia in the esomeprazole group compared to 7/3358 (0.21%) in the placebo arm [RR 0.94 (99% CI 0.29–3.07)]; however, the low event rate precluded definitive conclusions.

At present, there are insufficient clinical trial data to determine whether an association between proton pump inhibitors and community-acquired pneumonia exists. Observational studies, which can evaluate rare outcomes, harms and outcomes not previously known to be important, are well-suited to address this clinical question.[24] As such, we systematically evaluated observational studies to determine the risk of community-acquired pneumonia in adults associated with out-patient proton pump inhibitor use when compared with non-users of proton pump inhibitors.


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