Heartburn & COVID-19: A Q&A With Kyle Staller, MD, MPH, on Proton Pump Inhibitors and Patient Risk

Proton pump inhibitors (PPIs) are the most widely used heartburn medication, and for good reason: They are the strongest available option for stopping acid production at its source. While PPIs do successfully abate heartburn, some studies indicate increased risks for certain conditions, such as enteric infections, dementia and osteoporotic fracture (among others).

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Recent headlines highlight survey findings from a paper published in the American Journal of Gastroenterology that indicate an increased risk of COVID-19 among PPI users. Given the popularity of PPIs, this news has raised questions:

• Do PPI users fall under the high-risk for COVID-19 category?
• Does heartburn put a person at high risk?
• What could these findings mean for the future of heartburn treatment?

According to Kyle Staller, MD, MPH, director of the Gastrointestinal Motility Laboratory in the Division of Gastroenterology at Massachusetts General Hospital, these findings aren't necessarily cause for alarm. In this Q&A, Dr. Staller disambiguates fact from hyperbole about the COVID-19-heartburn connection and provides treatment advice for physicians concerned about patient care.

Q: Do these survey findings mean PPIs increase a patient's risk of severe COVID-19 symptoms?

Staller: This was an observational study, meaning researchers aren't giving some people the drug and seeing what happens to those people versus what happens to the people who don't take it. Instead, they're comparing two different groups of people: A group of people with symptoms who happen to be taking the drug, and a group of people who don't.

On average, people who happen to be using PPIs are likely to be a little bit sicker. It's not that these people are compromised by their heartburn medication; rather, by virtue of having heartburn, they are probably more likely to be overweight or have an ailment associated with an unhealthy lifestyle that puts them in a high-risk group. That's probably what's driving the risk for COVID-19. The exception, of course, would be esophageal cancer, where there is a risk for increased esophageal cancer with heartburn because heartburn directly damages the esophagus lining and, over time, can lead to cancer—especially in middle-aged, overweight white males.

Studies like this are hypothesis-generating, meaning they give us a better understanding of all the mechanisms of how COVID-19 might infect the GI tract or the body in general. PPIs have their issues, but they're still an incredibly effective therapy. They've changed people's lives in a lot of different ways for a lot of different conditions.

In short, while PPIs shouldn't be in the water—these drugs are not for everyone—there are people who derive a great benefit from them, and we shouldn't scare them away.

Q: Why would these researchers choose PPIs over other heartburn treatments?

Staller: PPIs are very convenient to study because they're so commonly used. If you do a study, your likelihood of finding something statistically significant is higher because a good chunk of any population will be on PPIs. If you pick something rarer, you're less likely to see an effect.

Interestingly, they did look at H2 blockers—medicines that reduce the amount of acid produced by cells in the stomach lining—and found that there was not an associated risk of COVID-19. For the most part, people who take H2 blockers like ranitidine tend to take them infrequently and in response to acute heartburn. They aren't necessarily part of a group that is already at high risk.

In addition, we know that the ACE2 receptor, which is distributed through the digestive tract, acts as a COVID-19 receptor. You could see a mechanism where people might swallow the SARS-CoV-2 virus but it would never make it to their systems; however, because PPI patients' acid barrier is compromised more than a patient on an H2 blocker's would be, it could be more likely to cause an infection. We know that's the case for other types of infection, such as bacterial infections. SARS-CoV-2 is a virus, not a bacteria, but there is probably a more legitimate connection between PPIs and getting bacterial infections than some of the other connections we've seen in the news and literature. Similarly, by reducing stomach acid, PPIs may decrease the infectious dose of COVID-19.

Of course, this is all hypothesis. And there are problems with the studies connecting COVID-19 to PPIs that are important to remember when we think about this connection.

Q: How should physicians proceed with heartburn treatment during the pandemic?

Staller: Physicians should always look for opportunities to de-escalate PPI treatment. De-escalating could potentially decrease your patient's risk for a variety of things. That said, PPIs are not the bogeyman that they've been made out to be. They're simply an effective drug that is a victim of its own success.

Some patients inappropriately come off of PPIs because of fear. And I see a lot of primary care doctors who are really worried about continuing their patients on PPIs. But there is a nuance to determining which patients should be on them and which patients should be taken off.

By definition, PPIs have a rebound effect when you stop taking them. If you do stop a patient's PPI therapy, they will have extra acid temporarily. I recommend tapering patients off this medication slowly with an overlap of something else, like an H2 receptor blocker, for about a week to see whether the symptoms they're having are just the PPI rebound or if they actually need to be on PPIs for the long term.

Q: When should a patient be referred to a place like Mass General for treatment?

Staller: If you have a case where a nuanced discussion needs to happen—like a patient whose heartburn is not responding to PPIs, who has risk factors like a history of ulcers or who is struggling with Barrett's esophagus—it can be helpful to refer them to a gastroenterologist.

The same is true for heartburn that's associated with alarm symptoms like difficulty swallowing, weight loss, blood in the stool or black stools, anyone with a family history of esophageal or stomach cancer, and patients aged 50 and older who have developed new heartburn symptoms out of the blue. For these individuals, the heartburn conversation can get more complicated or require an endoscopy.

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