Use of proton pump inhibitors is associated with a higher risk of pneumonia in cirrhotic patients: a systematic review and meta-analysis.

BACKGROUND: Proton pump inhibitors (PPIs) are commonly prescribed for cirrhotic patients. However, the use of PPIs in these patients may increase the risk of bacterial infection. The current study aimed to investigate the risk of developing pneumonia among cirrhotic patients exposed to PPIs.
METHODS: A literature search was independently conducted by 2 investigators using the MEDLINE and EMBASE databases up to September 2019. To be eligible, a study had to be an observational (cohort, case-control or cross-sectional) study that included one group of cirrhotic patients with PPI use and another group of cirrhotic patients without PPI use. Effect estimates of the association between PPI use and pneumonia had to be reported. Point estimates and standard errors from each eligible study were combined together using the generic inverse variance method of DerSimonian and Laird.
RESULTS: Of 1947 articles identified from the 2 databases, 3 cohort and 5 cross-sectional studies with 40,295 participants met the eligibility criteria and were included in the meta-analysis. The pooled analysis found that cirrhotic patients with a history of PPI use had a significantly higher risk of developing pneumonia than those without PPI use, with a pooled risk ratio of 1.36 (95% confidence interval 1.00-1.85; I 2 47%).
CONCLUSION: A significantly increased risk of pneumonia among cirrhotic patients exposed to PPIs was demonstrated in this study. Copyright: © Hellenic Society of Gastroenterology.

Introduction

Cirrhosis accounts for approximately 1 million deaths annually [1]. Common complications of liver cirrhosis include variceal bleeding, ascites, hepatic encephalopathy, hepatorenal syndrome, and spontaneous bacterial peritonitis (SBP) [2]. In addition, cirrhosis is associated with an increased risk and poorer prognosis of several other types of bacterial infection, such as bacteremia, enterocolitis, skin and soft tissue infection, urinary tract infection, meningitis, and infective endocarditis [3]. Cirrhosis-associated immune dysfunction is thought to be the key player in this increased risk [4].

Proton pump inhibitors (PPI) are commonly prescribed for cirrhotic patients, although studies have shown that over half of PPI use was without valid indications [5], which may lead to an unnecessary increased incidence of several complications, such as hepatic encephalopathy, Clostridium difficile infection and SBP [6]. The possible explanation for the increased likelihood of developing SBP among PPI users is that acid suppression facilitates bacterial overgrowth and translocation [7-9]. The use of PPI may also lead to an increased risk of other types of organ-specific bacterial infection. In fact, studies have suggested an increased risk of bacterial pneumonia among cirrhotic patients who use PPIs, although the results are inconsistent [10-17]. The current study aimed to further investigate this risk by identifying all available studies and summarizing their results together.

Materials and methods

Information sources and search strategy

A systematic literature review based on the EMBASE and MEDLINE databases was performed independently by 2 investigators (WW and NC) from inception to September 2019 to identify all published studies that examined the risk or association between pneumonia and PPI use in cirrhotic patients. The search strategy, which included the terms “proton pump inhibitors” and “cirrhosis”, is available as Supplementary Table 1. In addition, we manually reviewed the references of the eligible studies to identify any additional potential articles. This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (Supplementary Table 2).

Selection criteria

To be eligible, a study had to be an observational study (cohort, case-control or cross-sectional study) that included one group of cirrhotic patients with PPI use and another group of cirrhotic patients without PPI use.

Eligible cohort studies started with recruitment of cirrhotic patients who used and did not use PPIs and followed them for incident pneumonia. Relative risk (RR), incidence rate ratio (IRR), hazard risk ratio (HR) or standardized incidence ratio (SIR) with associated 95% confidence interval (CI) comparing the incidence of pneumonia between cirrhotic patients with and without PPI use had to be provided.

Eligible case-control studies started with recruitment of cases of cirrhotic patients with pneumonia and controls who were cirrhotic patients without pneumonia and explored their history of PPI use. Odds ratio (OR) with associated 95%CI comparing the prevalence of PPI use between cases versus controls had to be reported.

Eligible cross-sectional studies recruited cirrhotic patients and explored the history of PPI use and pneumonia at the same time. OR with associated 95%CI of this association had to be reported. No language limitation was applied during the systematic review.

Data extraction

We used a standardized data collection form to extract the following information: last name of the first author, country where the study was conducted, study design, year of publication, number of participants, recruitment of participants, how the diagnosis of pneumonia and ascertainment of PPI use were justified, follow-up period and duration (for cohort studies), baseline characteristics of participants, confounders adjusted in multivariate analysis and adjusted effect estimates with corresponding 95%CI. We appraised the quality of the included cohort and case-control studies using the Newcastle-Ottawa quality assessment scale [18]. The modified version of this scale was used for cross-sectional studies.

Statistical analysis

We utilized Review Manager 5.3 software from the Cochrane Collaboration (London, United Kingdom) to analyze all data. Point estimates and standard errors from each study were pooled together using the generic inverse variance method of DerSimonian and Laird, which assigns the weight of the study in reverse to its variance [19]. A random-effect model, rather than a fixed-effect model, was used, as the assumption of the fixed-effect model that every study should give rise to the same result is not justified under almost all circumstances, especially in a meta-analysis of observational studies. Statistical heterogeneity was assessed by Cochran’s Q test, complimented by the I2 statistic. This I2 statistic quantifies the proportion of total variation across studies due to heterogeneity rather than chance. A value of I2 of 0-25% represents insignificant heterogeneity, 26-50% represents low heterogeneity, 51-75% represents moderate heterogeneity, and 76% or higher represents high heterogeneity [20]. The presence of publication bias was assessed by visualization of a funnel plot along with Egger’s regression test. Egger’s regression test was conducted using Comprehensive Meta-analysis 3.0 software (Englewood, New Jersey, United States).

Results

A total of 1947 articles (276 from MEDLINE and 1671 from EMBASE) were identified, from which 237 duplicated articles were removed, leaving 1710 articles for title and abstract review. At this stage of review, 1675 articles were excluded because they were clearly ineligible based on study design and type of article. Therefore, 35 full-length articles were thoroughly reviewed, and 27 articles were further excluded as they did not report the outcome of interest. Finally, 3 cohort and 5 cross-sectional studies with a total of 40,295 participants met the eligibility criteria and were included in the meta-analysis [10-17]. Two of the 3 included cohort studies were published as conference abstracts [10,14]. No eligible case-control study was identified. Fig. 1 summarizes the literature review and study selection process. Tables 1 and 2 describe the characteristics and Newcastle-Ottawa assessment scales of the included cross-sectional and cohort studies, respectively.

Figure 1

Literature review and study selection process

Table 1

Main characteristics of the cross-sectional studies included in this meta-analysis

Table 2

Main characteristics of the cohort studies included in the meta-analysis

Risk of pneumonia among cirrhotic patients exposed to PPI

Cirrhotic patients with a history of PPI use had a significantly higher risk of developing pneumonia than those without PPI use, with a pooled RR of 1.36 (95%CI 1.00-1.85). The statistical heterogeneity was low, with an I2 of 47%.

Subgroup analysis by study design showed an increased risk in both cohort and cross-sectional study subgroups, although the number of included studies was not large enough to demonstrate statistical significance (pooled RR 1.26, 95%CI 0.80-1.99, I2 57%, for cohort studies; pooled RR 1.49, 95%CI 0.98-2.26, I2 22%, for cross-sectional studies). Fig. 2 shows the forest plot of this meta-analysis.

Figure 2

Forest plot of this meta-analysis

Evaluation for publication bias

The funnel plot of this meta-analysis (Fig. 3) was fairly asymmetric. In addition, publication bias was detected by Egger’s regression test with a P-value of 0.003.

Figure 3

Funnel plot of this meta-analysis

Discussion

The current study is the first systematic review and meta-analysis to comprehensively identify all observational studies that evaluated the risk of pneumonia associated with PPI use among patients with cirrhosis. The pooled analysis from over 40,000 patients found an approximately 1.4-fold higher risk of pneumonia among cirrhotic patients with exposure to PPI. An increased risk of pneumonia among PPI-users has also been observed in the general population, as demonstrated by a recent meta-analysis [21]. In fact, the magnitude of the increased risk in the general population studies, 1.49-fold, is comparable to this study. The mechanisms accounting for the increased risk of pneumonia have not been clearly elucidated, but there are several possible explanations.

The first possible mechanism is that PPI use decreases gastric acidity, thus facilitating the proliferation of Streptococcus spp. and Lactobacillus spp. in the stomach [22]. Aspiration of colonized gastric fluid may have a higher tendency to cause pneumonia than aspiration of relatively sterile gastric fluid [23]. In fact, a study by Viasus et al identified an increased proportion of Streptococcus pneumoniae as a causative organism of community-acquired pneumonia in patients with cirrhosis compared with the general population [24].

The second possible mechanism is related to intestinal bacterial overgrowth and translocation. PPIs, as acid suppressors, are known to induce intestinal dysbiosis and subsequent development of small intestinal bacterial overgrowth [25-27]. The complication of small intestinal bacterial overgrowth is more problematic among patients with cirrhosis than in healthy individuals, as they tend to have some degree of immunodeficiency through several mechanisms, including loss of Kupffer in the hepatic reticuloendothelial system, imbalance of cytokines causing immune cell dysfunction, and decreased hepatic synthesis of complements and acute phase reactants [4,11,28,29]. In addition, a significant portion of patients with cirrhosis develop portal hypertension with portal-system shunting that would bypass the normal process of hepatic bacterial clearance [4]. All of these factors may predispose cirrhotic patients to a higher likelihood of intestinal bacterial translocation and bacteremia that would ultimately lead to organ-specific infection, including pneumonia.

The current study has some limitations that should be acknowledged. First, publication bias was present in this systematic review and meta-analysis, as evidenced by the asymmetric funnel plot and positive Egger’s regression test. Second, more than half of the studies included were cross-sectional in nature. Therefore, the causality of the observed association cannot be reliably established. Third, the majority of studies included in this meta-analysis did not adjust their results for potential confounders. Therefore, the observed association could be a result of a confounding effect rather than a true association. Fourth, none of the included studies specifically aimed to investigate the relationship between PPI use and the occurrence of pneumonia. Their primary objective was to investigate the relationship between PPI use and the occurrence of either SBP or overall infection. Therefore, the number of patients with pneumonia was relatively small. Finally, the dosing of PPIs varied considerably across the included studies, especially among cross-sectional studies.

In conclusion, the present systematic review and meta-analysis demonstrated a significantly increased risk of pneumonia among cirrhotic patients with PPI use, although some limitations that may jeopardize the validity of the results were noted.

What is already known:

Proton pump inhibitors (PPIs) are commonly prescribed for cirrhotic patients

However, over half of PPI regimens are prescribed without valid indications

This increases the risk of several complications, such as hepatic encephalopathy, Clostridium difficile infection and spontaneous bacterial peritonitis

What the new findings are:

The pooled analysis found that cirrhotic patients with a history of PPI use had a significantly higher risk of developing pneumonia than those without PPI use

Based on the pooled analysis of 8 eligible studies, the risk was increased by 1.36 times

Possible mechanisms included decreased gastric acidity and intestinal bacterial overgrowth

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