Proton Pump Inhibitors Tied to COVID-19 Risk

Laird Harrison

July 09, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

People who use proton pump inhibitors (PPIs) may be more likely to get COVID-19, researchers say.

In light of this finding, physicians should consider which patients truly need these powerful acid-lowering drugs, said Brennan Spiegel, MD, MSHS, professor of medicine and public health at Cedars Sinai Medical Center in Los Angeles, California.

"All it means is that we're going to have a conversation with our patients," he told Medscape Medical News. "We don't normally have that conversation because we don't live in an environment with a high risk of enteric infection. But now we're in a pandemic."

The study by Spiegel and his colleagues was published online on July 7 in The American Journal of Gastroenterology.

Use of PPIs has skyrocketed over the past 2 decades. For ambulatory care visits, their use increased from 1.6% in 1998 to 7.6% in 2015, as reported by Medscape Medical News. The increase raised questions about overprescription.

Although studies have not borne out many of the other concerns raised about adverse reactions, they have shown that the drugs increase the risk for enteric infections, including infections by SARS-CoV-1, a virus that is related to the COVID-19 virus, SARS-CoV-2, Spiegel said.

SARS-CoV-2 uses the angiotensin-converting enzyme–2 receptor to invade enterocytes. Spiegel theorized that an increase in stomach pH above 3 as a result of use of PPIs might allow the virus to enter the GI tract more easily, leading to enteritis, colitis, and systemic spread to other organs, including the lungs. "There is a reason we have acid in our stomachs," Spiegel said.

To see how PPI use relates to COVID-19 infections, Spiegel and his colleagues surveyed online a nationally representative sample of Americans between May 3 and June 24, 2020, as part of a larger survey on gastroenterologic health.

Participants answered questions about gastrointestinal symptoms, current use of PPIs, and COVID-19 test results. They also answered questions about histamine-2 receptor agonists (H2RAs), also known as H2 blockers, which are used to treat some of the same conditions as PPIs but that do not reduce stomach acid as much.

The surveying firm, Cint, contacted 264,058 people. Of the 86,602 eligible participants who completed the survey, 53,130 said they had experienced abdominal discomfort, acid reflux, heartburn, or regurgitation. These survey participants were subsequently asked about PPI and H2RA use.

Of these, 6.4% reported testing positive for SARS-CoV-2. The researchers adjusted for age, sex, race/ethnicity, education, marital status, household income, body mass index, smoking, alcohol consumption, US region, insurance status, and the presence of irritable bowel syndrome, celiac disease, gastroesophageal reflux disease, liver cirrhosis, Crohn's disease, ulcerative colitis, diabetes, and HIV/AIDS.

After adjusting for these factors, the researchers found that those who took PPIs up to once a day were twice as likely to have had a positive COVID-19 test result than those who did not take the drugs (odds ratio [OR], 2.15; 95% CI, 1.90 – 2.44).

Those who took PPIs twice a day were almost four times as likely to have tested positive for the disease (OR, 3.67; 95% CI, 2.93 – 4.60).

By contrast, those taking H2RA drugs once daily were 15% less likely to report a positive COVID-19 test result (OR, 0.85; 95% CI, 0.74 – 0.99). Research is currently underway to determine whether H2RAs might protect against the disease for reasons unrelated to pH balance.

Spiegel cautioned that the current data show only an association between PPI use and COVID-19 positivity; it cannot prove cause and effect.

Nevertheless, Spiegel said the findings should encourage physicians to prescribe PPIs only when clearly indicated. "If somebody is not yet on a PPI and you're considering whether to start them on a PPI, it's a good idea to consider H2 blockers," he said.

People who need a daily dose of a PPI to control a severe condition can safely continue doing so, but such patients should take care to follow standard public health recommendations for avoiding exposure to the virus. These recommendations include wearing a mask, maintaining social distance, and washing hands frequently.

"People who are older, comorbid, or smokers ― if they get infected, it could be severe," he said. "[For] someone like that, it's reasonable to ask, do we really need to be on twice-daily PPIs? There is good evidence that they are no better off than if they are taking once-daily doses."

Brian Lacy, MD, PhD, a professor of medicine at the Mayo Clinic in Jacksonville, Florida, agreed that the study should prompt physicians to take a second look at their patients' PPI prescriptions. "My view is that PPIs are frequently overused, and maybe this is one more piece of data that if someone is on PPIs, maybe they don't need to be on this medication."

On the other hand, the drugs are important for treating conditions such as erosive esophagitis and healing ulcers, said Lacy, who is also co–editor-in-chief of The American Journal of Gastroenterology. The overall risk of contracting COVID-19 is low, so even this finding of a 3.7-fold increased risk should not lead patients or providers to stop taking or prescribing PPIs.

The study also lends support to the idea that the gastrointestinal tract could be involved in SARS-CoV-2 transmission, and it supports warnings about aerosols emitted from flushing toilets and through exhalation, Spiegel said. There is less evidence of the virus being transmitted through food. "It may not be fecal-oral; it may be fecal-respiratory," he said.

On Twitter, several physicians and epidemiologists have pointed out surprises in the demographics of the cohort of patients who reported positive COVID-19 tests. That this cohort made up 6.4% of respondents is noteworthy, as fewer than 1% of the overall American population has been diagnosed with the disease, said Darren Dahly, PhD, principal statistician at the Clinical Research Facility at University College Cork in Cork, Ireland.

More surprising still, Dahly pointed out, 69.6% of the cohort that was positive for COVID-19 had a high school degree or less, yet 63.5% were in households making $200,001 or more per year. "I can't find a plausible reason for any of these extremes," Dahly told Medscape Medical News. "These data cannot be accurate data from a representative sample of Americans. There is no way."

Study co-author Christopher V. Almario, MD, MSHPM, assistant professor of medicine Cedars Sinai, responded that there are plausible explanations for these apparent discrepancies. The cohort with positive tests was drawn from the subset of those respondents who reported gastrointestinal symptoms, not from the total population surveyed. COVID-19 is known to cause such symptoms, he pointed out.

Also, he said, respondents reported their individual education attainment but their household income. It’s possible that someone with a high school education could live in a wealthy household. And people in households with more income may be more likely to gain access to tests, he theorized.

The overall population of the survey corresponded closely to US Census data, Almario said. "It would be unclear why someone would be forthcoming as to their demographics but mislead with respect to their COVID-19 status," he told Medscape Medical News. And in many respects, he said, the cohort with a positive test reflected what has been reported in news stories about those most likely to test positive: younger, more Latinx, more likely to smoke, and more obese.

The study was part of a larger survey on gastroenterological diseases funded by Ironwood Pharmaceuticals. Spiegel reported relationships with Alnylam Pharmaceuticals, Arena Pharmaceuticals, Ironwood Pharmaceuticals, Salix Pharmaceuticals, Shire Pharmaceuticals, Synergy Pharmaceuticals, and Takeda Pharmaceuticals. He is co–editor-in-chief of The American Journal of Gastroenterology. Lacy, who is also co-editor of The American Journal of Gastroenterology, disclosed no relevant financial relationships. Dahly reported no relevant financial relationships. Almario relationships with My Total Health, Bayer Healthcare, Synergy Pharmaceuticals, Alnylam Pharmaceuticals, Arena Pharmaceuticals, and Takeda Pharmaceuticals.

Am J Gastroenterol. Published online July 7, 2020. Full text

Laird Harrison writes about science, health and culture. His work has appeared in magazines, newspapers, and online publications. He is at work on a novel about alternate realities in physics. Harrison has taught writing at San Francisco State University, UC Berkeley Extension, and the Writers Grotto. Visit him at or follow him on Twitter: @LairdH .


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