PPIs and COVID-19 Risk: A Closer Look at the Data

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This transcript has been edited for clarity.

I'm Dr Darrell Gray, gastroenterologist and associate professor at The Ohio State University Wexner Medical Center in Columbus, Ohio.

In a novel study, Drs Christopher Almario and Brennan Spiegel of Cedars-Sinai Medical Center in Los Angeles and Dr William Chey of the University of Michigan conducted an online population-based survey of Americans from May 3 to June 24, 2020, amidst the COVID-19 pandemic. They collaborated with a research firm to collect a seemingly representative nationwide sample. Participants aged 18 years or older age were asked about gastrointestinal (GI) symptoms, particularly whether they've experienced abdominal discomfort, acid reflux, heartburn, or regurgitation, and separately about their proton pump inhibitor (PPI) or H2-receptor antagonist use. Participants were also asked whether they had tested positive for COVID-19 and, if so, about new symptoms they may have experienced.

Investigators analyzed this information through use of a logistic regression model to be able to describe the odds of reporting a positive COVID-19 test among those taking a PPI vs those not taking a PPI. One nice thing these investigators did was understanding that people who use PPIs are different from those who are not, such as potentially being older and with additional comorbidities. As such, they adjusted their analysis for potential confounders, particularly demographics, socioeconomic status, and comorbidity variables.

Of 53,130 participants, 3386 (6.4%) reported a positive COVID-19 test. Through regression analysis, PPI use was independently associated with increased odds for reporting a positive test, even after adjustment for other variables. Compared with individuals not using PPIs, those taking PPIs up to once or twice daily had significantly increased odds of reporting a positive COVID-19 test. The use of lower-dose H2-receptor antagonists was associated with slightly decreased odds of reporting a positive test, while no association was seen for the higher dose of H2-receptor antagonists.

It is quite compelling to think about what these results could mean.

Investigators suggest that taking PPIs once daily increases your risk for COVID-19 by twofold, whereas taking them twice daily can increase your risk by over three and a half fold, which is an important takeaway from this study. This is important because although twice-daily PPIs are commonly prescribed, it's not evidence-based and it's not cleared by the US Food and Drug Administration. Another interesting point not to miss is the finding that individuals taking H2-receptor antagonists were not at increased risk of acquiring COVID-19.

Possible Explanations and Weighing the Study Design

It has already been established by meta-analyses that PPIs can increase the risk for GI infections. In fact, stomach acid can be protective against bacteria and viruses. Coronavirus sheds into saliva and can rapidly invade and replicate within cells lining the intestinal tract. As stomach acid can be protective against acquisition of coronavirus, and certainly PPIs induce hypochlorhydria, this can facilitate an environment in which coronavirus may thrive. This was part of the biological plausibility for why PPIs can increase the risk for COVID-19 acquisition.

Now let's examine the strengths of this study. This is the first study to explore the relationship between PPIs and COVID-19 in a population-based sample. In addition, this study explored the impact of twice-daily dosing compared with once-daily dosing of PPIs on that risk, and also looked at H2-receptor antagonists as well. Furthermore, unlike other studies that have been done in the past to examine potential side effects of PPIs, this one was done prospectively with an a priori hypothesis. In doing so, the investigators mitigated some of the biases that this study was subject to.

Conversely, the authors also acknowledge that the study has significant limitations. This is an observational study and not a randomized controlled trial. There is recall bias on the part of the participants to report whether they tested positive for COVID-19, which we assume was the polymerase chain reaction test. There's residual confounding and selection bias, as well as protopathic bias that significantly affect the quality of the study. Of note, this study shows an association, but not causation.

In addition, although the authors did try to adjust for confounding, this study has also been widely criticized for being an unrepresentative sample. Certainly, there's overrepresentation of patients with COVID-19 and underrepresentation of those who were hospitalized with COVID-19. There's overrepresentation of people 30-39 years of age, as opposed to other age groups, particularly seniors, who may be more apt to take PPIs. There was large overrepresentation of people with incomes over $200,000. Therefore, it may not be representative of the general population as well.

Those certainly are legitimate criticisms, but I think them to be a little bit overly critical, particularly as we are growing in our understanding of a potential association between PPI use and COVID-19.

The study has several takeaways. This study is based on a biological plausibility of increased risk for enteric infections with PPI use. It was one of the first to examine the association between PPI use and COVID-19, and also the impact of dosing. And one of the key takeaways I got from this study was that we need to be more judicious with our PPI use. Meta-analyses have shown that twice-daily PPI dosing does not offer benefits over once-daily dosing for acid reflux, and it is not approved for the indication.

As I consider how this should or should not modify practice, I really return to the idea of ensuring we're using the lowest effective dose of PPIs for the shortest amount of time. The other thing to consider is that this study did not find an increased risk for COVID-19 among those who use H2-receptor antagonists. Therefore, we have to consider H2-receptor antagonists as an alternative to PPIs in those we're treating for abdominal discomfort or gastroesophageal reflux disease.

And it goes without saying, certainly, that further studies on the association between COVID-19 and PPI use are needed.

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