Do proton pump inhibitors influence SARS-CoV-2 related outcomes? A meta-analysis

The article by Lee et al ¹ showed that the current use of proton pump inhibitors (PPIs) increased the risk of severe clinical outcomes of COVID-19 rather than the susceptibility to SARS-CoV-2 infection in a Korean nationwide cohort. Instead, a significant association between susceptibility to SARS-CoV-2 infection and current use of PPIs, either one time or two times a day, was found by another recent study² based on US nationwide data. The conflicting results of these two large-scale observational studies may be due to regional epidemiological differences or considerable between-study variance and might compromise clinical decision-making. As the impact of PPI use on SARS-CoV-2 infection has very relevant clinical implications, we performed a meta-analysis to address the aforementioned discrepancies, which could lead to better informed clinical decision-making on PPI use during the ongoing pandemic.

We scrutinised 3413 records retrieved from a comprehensive search using the COVID-19 Research Articles Downloadable Database maintained by the US CDC (https://www.cdc.gov/library/researchguides/2019novelcoronavirus/researcharticles.html) and ultimately included 16 studies^1–16 from 10 countries or regions reporting comparative data on PPI use and clinical outcomes of COVID-19 (online supplemental figure 1 and table). We pooled the data using an inverse variance-weighted random-effect model. Pooled estimates are presented as OR, HR or mean difference (MD), with associated 95% CIs. Intensive care unit admission, mechanical ventilation, acute respiratory distress syndrome or death were considered severe outcomes of COVID-19.

Six studies^1–6 including 318 261 participants reported data on PPI usage and the risk of SARS-CoV-2 infection. Among them, five studies had information of current PPI users compared with non-users and four on past PPI users versus non-users. Analysis of five studies^1–5 encompassing 145 428 patients who were tested for SARS-CoV-2 showed that the risk of SARS-CoV-2 infection was higher, although not significantly, among current PPI users (OR 1.33, 95% CI 0.86 to 2.07, p=0.20; figure 1) compared with PPI non-users, with evidence of substantial between-study heterogeneity (I ²=97%). Moreover, in a subgroup analysis of non-Korean cohorts,^2–4 we found a significant association between current use of PPIs and increased risk of SARS-CoV-2 infection (OR 1.94, 95% CI 1.59 to 2.36, p<0.0001; online supplemental figure 2). Furthermore, a leave-one-out sensitivity analysis revealed that the summary estimate of the association between current PPI usage and SARS-CoV-2 infection was overly influenced by a single Korean study⁵ (online supplemental figure 3).

Figure 1.

Forest plot showing the association between PPI use and SARS-CoV-2 infection. PPI, proton pump inhibitor.

Instead, current or regular PPI users were more likely to have severe outcomes of COVID-19 than PPI non-users, with a pooled OR of 1.67 (95% CI 1.19 to 2.33, p=0.003; n=42 405 from nine studies;1 3 7–13 I ²=63%; figure 2) and a pooled HR of 1.87 (95% CI 1.29 to 2.70, p<0.001; n=2977 from two studies;^{15 16} I ²=80%; figure 2). These results were consistent with our leave-one-out sensitivity analysis (online supplemental figure 4), indicating that this association was strong. Furthermore, current PPI users tended to hospitalised longer than PPI non-users, although not by a statistically significant margin (n=353 from two studies;^{7 14} MD 1.13, 95% CI −0.18 to 2.43, p=0.09; figure 2). Finally, past use of PPIs was not associated with increased susceptibility to SARS-CoV-2 infection (n=1 72 833 from four studies;1 3 5 6 OR 0.85, 95% CI 0.57 to 1.27, p=0.43; I ²=92%; figure 1) or with severe outcomes of COVID-19 (n=40 097 from three studies;^{1 3 9} OR 1.03, 95% CI 0.85 to 1.23, p=0.79; I ²=0%; figure 2).

Figure 2.

Forest plot showing the association of PPI use with severe outcomes of COVID-19 (A, OR; B, HR) or duration of hospital stay (C). PPI, proton pump inhibitor.

In summary, this meta-analysis shows that regional differences can explain the heterogeneous findings concerning the association between current PPI use and incidence of SARS-CoV-2 infection and further underscores the increased risk of severe COVID-19 outcomes associated with current PPI use, highlighting that caution should be exercised when treating patients receiving PPIs during the COVID-19 pandemic. Further studies investigating different dosing regimens and durations of PPI use on COVID-19 outcomes should be warranted.

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