We read with great interest the study written by Liu et al. (1). The authors found higher salivary ACE2 mRNA levels of proton pump inhibitor (PPI) users than nonusers and discovered the association between PPI use and increased mortality risk in patients with coronavirus disease 2019 (COVID-19). These results provide some new evidence on the role of PPI in patients with COVID-19 and tend to indicate a negative effect of PPI. However, we wish to emphasize that the specific role of PPI in patients with COVID-19 is still unclear based on studies currently available.
We systematically reviewed the published cohorts on the relationship between PPI and COVID-19 up to July 1, 2021, and presented them in Supplementary Table 1, Supplementary Digital Content 1, https://links.lww.com/AJG/C149. These studies explored the possible effects of PPI on patients with COVID-19 in the following 3 main aspects: susceptibility, severity, and mortality. We find that studies from different countries show different results for the same outcome, and different conclusions can also be reached in different regions of the same country. On the other hand, we also summarized recently published meta-analyses relating to this topic and presented them in Supplementary Table 2, Supplementary Digital Content 1, https://links.lww.com/AJG/C150. The conclusions of these systematic reviews were also inconsistent, and almost all of them showed significant heterogeneity during the meta-analysis of major outcomes. All these pieces of evidence suggest that the correlation between PPI and COVID-19 is still unclear. Although there seem to be more studies supporting the association between PPI use and multiple adverse outcomes in patients with COVID-19 at present, conclusions of instructive significance for clinical practice always need to be drawn with caution; potential biases existed in current studies and the results based on retrospective studies are often susceptible to multiple confounding factors and cannot provide a clear causal relationship (2).
Possible explanations for the role of PPI in COVID-19 progression seem to have varied aspects. PPIs have shown antiviral potencies in various studies and therefore are considered to play a possible anti-severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 role through a variety of pathways. These pathways include exerting anti-inflammatory and antifibrotic effects, raising endolysosomal pH through vacuolar ATPase pumps, and targeting endosomal complexes (3). On the other hand, PPIs may also show a promoting effect on COVID-19 progression although inhibiting gastric acid (removes the protective barrier toward ingested microorganisms and results in dysbiosis conditions in the digestive tract), causing serious adverse events (include cardiovascular disease and nephrotoxicity), and modulating the immune response (4). Although we find that many studies published so far cite these pathophysiological mechanisms to explain their clinical findings, there is still a lack of actual evidence to support them and therefore cannot guide clinical decision-making. The association between PPI and COVID-19 still needs to be further explored at both the mechanism level and the clinical observation level.
In conclusion, we call for more well-designed studies to address the current confusion about the relationship between PPI and COVID-19. Until there is clear evidence, individualized medical decision based on a patient's need for PPIs seems to be a reasonable choice rather than blocking the use of PPIs during this pandemic.
CONFLICTS OF INTEREST
Guarantor of the article: Jin-Lin Yang, MD.
Specific author contributions: Xiu-He Lv, MD, and Zi-Jing Wang, MD, contributed equally to this article. X.-H.L. and Z.-J.W. developed the concept and wrote the article. J.-L.Y. revised the article. All authors approved the final version of the article.
Financial support: None to report.
Potential competing interests: None to report.
1. Liu JJ, Sloan ME, Owings AH, et al. Increased ACE2 levels and mortality risk of patients with COVID-19 on proton pump inhibitor therapy. Am J Gastroenterol 2021;116(8):1638–45.
2. Etminan M, Nazemipour M, Candidate MS, et al. Potential biases in studies of acid-suppressing drugs and COVID-19 infection. Gastroenterology 2021;160:1443–6.
3. Ray A, Sharma S, Sadasivam B. The potential therapeutic role of proton pump inhibitors in COVID-19: Hypotheses based on existing evidences. Drug Res 2020;70:484–8.
4. Charpiat B, Bleyzac N, Tod M. Proton pump inhibitors are risk factors for viral infections: Even for COVID-19? Clin Drug Investig 2020;40:897–9.