COVID-19 Mortality: The Culprit May Not Be Proton Pump Inhibitors

Dear Editor:

We read with interest the study by Israelsen et al¹ and congratulate the authors on conducting this nationwide study and meta-analysis. In their study, they found a slightly increased risk of infection and hospital admission in 4473 current proton pump inhibitor users but no association with other severe outcomes. Their updated meta-analysis showed no association with risk of infection or mortality.¹ This study is very interesting and important in the context of the COVID-19 pandemic. However, several confounding factors that might blur the association between proton pump inhibitors and COVID-19 disease severity were not described. Furthermore, we would like to put forth several suggestions for future studies regarding COVID-19 and proton pump inhibitors.

It has been known that COVID-19 mortality is affected by multiple factors, including male sex, age, geographic region, comorbidities, and mechanical ventilation.^{2 , 3} Thus, when discussing COVID-19-related mortality, the results need to be interpreted in relation to a specific population.

First, Gao et al⁴ reported that patients with a body mass index (BMI) greater than 23 kg/m² had a linear increase in the risk of severe COVID-19 leading to death. However, BMI was not discussed in the study.¹ Thus, the effect of the BMI of the patients on the study’s outcomes is unknown.

Second, a recent study published in Science showed that socioeconomic status affected COVID-19-related mortality in Santiago, Chile.⁵ Therefore, socioeconomic status should be considered in future studies regarding COVID-19 mortality.

Third, the diet of the patients with COVID-19 in the study of Israelsen et al¹ was unknown. As reported by Perez-Araluce et al,⁶ adherence to the Mediterranean diet was associated with a lower risk of COVID-19. It could be explained by the benefits of such high-quality diet to the immune system.⁶ Therefore, the effect of a patient’s diet on survival cannot be ignored.

Fourth, as reported by Burchill et al,⁷ COVID-19 pandemic has direct and indirect impact on the gut microbiota. Such factors as repeated lockdowns, frequent hand hygiene, changes in alcohol intake and smoking habit, travel limitation, reduction in social interaction, a shift toward working from home, poor sleep, and low mood could all affect the gut microbiome.⁷ It has been reported that gut microbiome is involved in the magnitude of COVID-19 severity possibly via modulating host immune responses.⁸ In addition, usual use of masks, types of masks, how and how often masks are worn, social distancing, working in crowded/enclosed spaces, and other factors may also affect COVID-19 outcomes. Taking all these factors into account is more relevant and more reliable for the study.

In summary, we believed that Israelsen et al¹ have shown that current proton pump inhibitor use does not have a significant clinical impact on risk of SARS-CoV-2 infection or related severe outcomes, and previous conflicting results rather arise from between-study differences. However, as the authors mentioned, although a wide range of relevant comorbidity and medication was used to adjust their analyses, there may inherently remain residual confounding by imperfectly measured, unmeasured, or unknown factors. In fact, considering all the potential confounders, such as BMI, socioeconomic status, diet, travel, hand-washing, smoking, alcohol use, mask use, and other unknown factors, seems impossible in the real world in the context of COVID-19. These studies have shown that although valuable knowledge about COVID-19 has been amassed, more information is needed to address the pandemic. To reduce confounding effects of potential risk factors on COVID-19 mortality and proton pump inhibitor use, we encourage health professionals, including nutritionists, social economists, pharmacists, epidemiologists, and those in other departments, to participate in the study of COVID-19.