In a nested case-control study conducted by Laheij[38
], 5551 new cases of documented pneumonia were observed from a total of 364 683 individuals enrolled in a general practice research database in the Netherlands. Patients were required to have one year of medical history documented in the database prior to being enrolled in the study and the pneumonia diagnosis was determined both objectively and subjectively. The objective assessments included thorax radiography and microbiological culture results; while subjective assessments included determining whether the patient’s clinical symptoms were consistent with a pneumonia diagnosis.
In this study, patients were approximately four times more likely to acquire pneumonia when using PPIs compared to non-users, regardless of the appropriateness of the therapy. Furthermore, when adjusted for individuals currently using PPIs and those who stopped using PPIs, the relative risk of developing pneumonia was nearly 1.89 (95% CI: 1.36-2.62) with current use. In an attempt to make the study more conservative, patients were excluded if they did not have an objective laboratory measure of pneumonia. Patients were still approximately two times more likely to acquire pneumonia following PPI administration.
This study identified a positive correlation between the incidence of pneumonia and the PPI dose administered. Based on the defined daily dose (DDD), the dose of the specific PPI administered could be compared across the class. As the DDD increased, the incidence of pneumonia also increased. Relative to patients who had stopped taking PPIs 30 d to 180 d prior to their pneumonia diagnosis, the increased incidence of pneumonia achieved statistical significance at a DDD of at least one (Table ).
Community-acquired pneumonia in patients administered proton pump inhibitors based on dose and duration of use
This study also identified an inverse correlation between the incidence of pneumonia and the duration of PPI use prior to the pneumonia diagnosis. Although all the durations of exposure achieved statistical significance, there was a trend in the odds ration. As the duration of PPI use prior to the pneumonia diagnosis increased, the incidence of pneumonia decreased (Table ).
PPI administration was attributed to an incidence of 1.05 cases of pneumonia per 100 person-years of PPI exposure. Assuming the average duration of use for PPIs is 0.42 years (approximately 5.5 mo), 1 patient would acquire pneumonia out of 226 patients treated with PPIs.
Thinking that the association to pneumonia incidence may be a class effect, the study also assessed which PPI was associated with an increased incidence of pneumonia.Unfortunately, this study was not powered to detect a difference in the incidence of pneumonia based on the agent administered.
An editorial by Gregor[46
] introduced potential limitations of Laheij’s study[38
]. In order to confirm the correlation between PPI use and pneumonia incidence, a trial of 9000 individuals would have needed to be conducted with pneumonia as the primary outcome measure, rather than the 5551 used in the study. Additionally, he suggested that the individuals with more severe reflux were more apt to develop pneumonia as they were unable to discontinue the PPI due to the severity of their condition. Consequently, these individuals would be at an increased risk for chemical aspiration and the subsequent complication of infectious pneumonia.
In a case-control study conducted by Gulmez[47
], 7642 patients with their first diagnosis of community-acquired pneumonia (CAP) were compared with 34 176 healthy controls matched by age and gender from 2000 to 2004. PPI exposure was assessed by determining if the patients had redeemed a prescription for a PPI during the past 90 d. If a prescription had not been redeemed in the past 90 d, the patients were considered to be past users of PPIs and patients who had redeemed a PPI prescription within 90 d were assumed to be current users. Of the 2401 patients who were deemed to be current users of PPIs in this study, 818 patients were diagnosed with CAP for the first time.
The Gulmez study[45
] also identified a temporal relationship between PPI treatment and pneumonia. The highest incidence of pneumonia was associated with PPI administration within seven days of diagnosis, with an odds ratio of 5.0 (95% CI: 2.1-11.7). This temporal relationship declined to an odds ratio of 1.3 (95% CI: 1.2-1.4) when PPI therapy was started more than 84 d before the diagnosis of pneumonia. This correlation was contrary to the independent variable belief, which would suggest an increased incidence of pneumonia with continued administration and increased pH. Previous use of PPIs was not associated with an increased incidence of pneumonia. Nor was a dose-response relationship between PPIs and pneumonia found.
Despite the current dogma suggesting that older patients are more susceptible to acquiring pneumonia, the strongest association of the first-time CAP diagnosis with PPI administration appeared to be in younger patients and those without hospital contacts. Among current PPI users, an inverse correlation was found between the patient’s age and the incidence of pneumonia. The incidence of pneumonia appeared to decrease as the patient aged (Table ).
Community-acquired pneumonia based on age and current proton pump inhibitor use
The Gulmez study[47
] suggested that young, healthy patients who have not had a previous hospital admission and have not been administered antibiotics in the past 90 d are actually at an increased risk of contracting community-acquired pneumonia (Table ). Unfortunately, this study only included patients who have never had a prior diagnosis of pneumonia.
A nested-case control study by Dublin et al[48
] evaluated the risk of pneumonia in community-dwelling adults between the age of 65 and 94 years. Pneumonia was identified based on ICD-9 codes and PPI use was determined from computerized pharmacy records. PPIs were being administered to 12% (132/1125) of the population who acquired pneumonia. Meanwhile, PPIs were administered to 7% (160/2235) of the population who remained pneumonia-free. There was no difference detected between these PPI exposure rates, suggesting PPIs were not contributing to the incidence of pneumonia in this study.
However, in a study conducted by Roughead et al[49
], an increased incidence of pneumonia was identified in an elderly population. Of the 185 533 veterans enrolled in this study, 58% were men with an average age of 79.4 years. There was a 16% increase in hospitalization for pneumonia in the population receiving PPIs. This study also evaluated the association of bacterial pneumonia in patients administered antibiotics. The incidence of bacterial pneumonia was similar but patients prescribed antibiotics were also likely to be prescribed a PPI.
Myles et al[50
] identified 3709 cases of pneumonia and 22 174 controls to evaluate the risk of pneumonia in patients taking PPIs. Patients were at least 40 years of age but the majority of the cases were at least 70 years of age. This study found the risk of pneumonia increased by 55% in patients who were taking PPIs. However, patients diagnosed with pneumonia were more likely to be smokers, have greater heart disease and chronic lung disease compared to the general population.
Rodriguez et al[51
] found an increased association of pneumonia in patients between 20 and 79 years of age enrolled in the Health Improvement Network database. Patients taking PPIs had a 16% increase in the incidence of pneumonia relative to the matched controls. Although this was only a slight increase in incidence, this study found that the association occurred only in the first 12 mo of treatment with PPIs.
An additional study, like Laheij, also assessed the impact of dose and duration of PPI exposure was conducted by Sarkar[1
]. This study further demonstrated the temporal relationship between PPI administration and the first diagnosis of CAP. This nested case-control study included patients who were enrolled in the general practice research database from the United Kingdom.
Just like the Laheij study[38
], a dose-dependent correlation between the administration of PPI therapy and the incidence of pneumonia was detected. This study[1
] divided the population into two dosage categories. Only the patients who received greater than 1.5 DDDs of a PPI achieved statistical significance. This further suggested a dose-dependent association between PPI therapy and the first incidence of pneumonia.
Sakar et al
further confirmed the inverse correlation between the duration of PPI use and the incidence of CAP realized by Laheij[38
]. The association of recent PPI initiation with the incidence of pneumonia determined the risk for pneumonia progressively increased as PPIs were started 14 d, 7 d and even 2 d prior to the onset of pneumonia symptoms (Table ). As long as the PPI exposure was within 30 d of symptom presentation, the increased incidence of CAP achieved statistical significance. The risk of pneumonia significantly decreased beyond 30 d of use. PPI exposure between 30 d and 180 d was not statistically significant.
Community-acquired pneumonia based on proton pump inhibitor exposure
A meta-analysis conducted by Johnstone et al[52
] included six studies evaluating nearly 1 million patients. Despite the heterogeneity of the studies included in the meta-analysis, there was a significant increase in the incidence of pneumonia in patients taking PPIs. This increased incidence appeared to be limited to the short-term exposure, specifically the first 30 d. There was no difference in the risk of pneumonia in patients chronically exposed to PPIs.
A second meta-analysis conducted by Eom et al[53
] expanded their analysis to include 18 studies. Similar to the Johstone meta-analysis, there was significant heterogeneity in the study population and PPIs use was associated with a 27% increase in the incidence of pneumonia.