Use of proton pump inhibitors and risk of adverse clinical outcomes from COVID‐19: a meta‐analysis
We read with interest the study by Luxenburger et al.  which reported that patients with coronavirus disease 2019 (COVID‐19) receiving proton pump inhibitors (PPIs) were at increased risk for the development of secondary infection and acute respiratory distress syndrome. Understandably, the use of PPIs may lead to excessive suppression of gastric acid, and thus leading to impaired eradication of ingested pathogens, which results in the increased risk of secondary infection reported in the study. However, the association between the use of PPIs and adverse clinical outcomes such as acute respiratory syndrome in patients with COVID‐19 is not expected, since previous in vitro study has demonstrated the ability for PPIs to inhibit the production of pro‐inflammatory cytokines, which is suggestive of their potential to dampen cytokine storm associated with COVID‐19 . Since there have been few studies addressing the same issue, we aimed to perform a meta‐analysis to summarize the overall effect of PPI on the COVID‐19 associated adverse clinical outcomes.
We performed literature searches in PubMed, Google Scholar and medRxiv (preprint repository) databases, up to 5 September 2020, for studies evaluating the risk of adverse clinical outcomes among COVID‐19 patients with PPI use compared to nonuse of PPI, with the following keywords and their MeSH terms: ‘COVID‐19’, ‘proton pump inhibitor’ and ‘PPI’ without language restrictions. The inclusion criteria were studies that investigated the use of PPIs on the risk of adverse clinical outcomes in patients with COVID‐19 with reported adjusted measures of association. Each included article was independently evaluated by two authors (CSK and SSH) who extracted the study characteristics and measures of effect. The quality of included studies was evaluated with the Newcastle‐Ottawa Scale . The outcome of interest was the development of any COVID‐19 associated adverse clinical outcomes. Adjusted odds ratios (ORs) and adjusted relative risks and their corresponding 95% confidence intervals (CIs) from each study were pooled in a random‐effects model of meta‐analysis using Meta XL, version 5.3 (EpiGear International, Queensland, Australia). The I2 statistic was performed to estimate the heterogeneity.
Five studies that corresponded to inclusion criteria with a total of 37 372 patients were included for our meta‐analysis [1, 4-6]. Study characteristics are depicted in Table 1. All studies included are deemed good quality with a Newcastle‐Ottawa Scale of 8. There was nonuniformity in the definition of the adverse clinical outcomes utilized across the five included studies. In the study by McKeigue et al. , the adverse clinical outcome was defined as an entry to critical care, death within 28 days, or a death certificate with COVID‐19 as an underlying cause. In the study by Ramachandran et al. , the adverse clinical outcome was defined as in‐hospital mortality or the requirement for mechanical ventilation. In the study by Lee et al. , we utilized the composite endpoint of requirement of oxygen therapy, intensive care unit admission, administration of invasive ventilation, or death to define the adverse clinical outcome. In both the studies by Luxenburger et al.  and by Li et al. , the adverse clinical outcome was defined as the development of secondary infection.
The pooled analysis of studies by McKeigue et al. , Ramachandran et al.  and Lee et al.  revealed a significantly increased odds for a severe or fatal course of COVID‐19 with the use of PPIs in COVID‐19 patients relative to nonuse of PPIs (Fig. 1; pooled OR = 1.46; 95% CI 1.34–1.60). The pooled analysis of studies by Luxenburger et al.  and by Li et al.  observed a significantly increased odds for development of secondary infections with the use of PPIs in COVID‐19 patients relative to nonuse of PPIs (pooled OR = 2.91; 95% CI 1.58–5.36). Since excessive suppression of gastric acid production by PPIs may lead to bacterial overgrowth in the gut, it may be that the increased risk of severe or fatal course of illness observed with the use of PPIs in COVID‐19 patients is also due to the development of secondary pneumonia. However, since the increased risk for a severe or fatal course of COVID‐19 was small as observed in the effect size of our pooled analysis, the decision to discontinue PPIs in COVID‐19 patients should be based on an individual risk‐benefit assessment. Nevertheless, our findings again serve as a reminder for clinicians to regularly review the continuing need for acid suppression in every patient with PPI use. Since the studies included are of retrospective design with limited heterogeneity, more prospective studies are required to substantiate our findings.