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Taking proton pump inhibitors (PPIs) daily was associated with increased odds of testing positive for COVID-19, a population-based online survey found.

Compared with non-users, those taking PPIs once a day had an odds ratio (OR) for positivity of 2.15 (95% CI 1.90-2.44) and in twice-daily users the OR rose to 3.67 (95% CI 2.93-4.60), reported Christopher V. Almario, MD, MSHPM, of Cedars-Sinai Medical Center in Los Angeles, and colleagues.

Use of histamine-2 receptor antagonists, however, did not elevate the risk, the team reported in a

"We developed this hypothesis at the beginning of the COVID-19 pandemic when we started to see a high incidence of GI [gastrointestinal] symptoms and learned that the virus sheds into saliva, and thus can be swallowed into the stomach," Almario explained in a statement. "We have now tested the hypothesis in a rigorous study of more than 50,000 Americans and found it to bear out, albeit in an observational study."

If causal, the risk is likely related to PPI-induced hypochlorhydria, the team speculated, noting that the stomach acid suppressors have also been linked to an increased risk of viral gastroenteritis during seasonal outbreaks.

Almario and co-authors noted that previous research has indicated that an intragastric pH of less than 3 the infectivity of COVID-19's sister virus, SARS-CoV-1, while the virus survives in a more neutral pH such as that induced by PPIs. SARS-CoV-2, the COVID-19 virus, uses the abundant GI angiotensin-converting enzyme 2 receptors to rapidly replicate within enterocytes, and increases in stomach pH of more than 3 from PPIs might allow the virus to reach the more easily, leading to enteritis, colitis, and systemic spread to other organs, including the lungs.

Study Details

The survey, conducted from May 3 to June 24, 2020, was emailed to a total of 264,058 adults in the U.S., who were told the questionnaire was a "national health survey."

Of the 86,602 eligible respondents who completed the survey, 53,130 (61.3%) reported having acid reflux and similar symptoms and were queried about their use of anti-secretory medications. In this group, ages ranged from 18 to more than 60; 51% were women, and 64.8% were non-Hispanic white. Among these, 3,386 (6.4%) reported having a positive COVID-19 test and of these, 71.9% reported daily or less use of PPIs, with 5.8% reporting twice-daily use.

"There is a biological plausibility for our findings as the similar SARS-CoV-1 is pH-sensitive and remains infective at a pH >3," the researchers explained. "Twice-daily PPI use can lead to 24-hour median intragastric pH >6 and sustain pH >4 for more than 20 hours (20-22)."

Regarding the finding of a dose-dependent risk, the team pointed to a 2017 that showed that twice-daily use of PPIs did not offer clinically meaningful benefits over once-daily dosing for gastroesophageal reflux disease. "Our findings further emphasize that PPIs should only be used when clinically indicated at the lowest effective dose," Almario and co-authors said.

They called for further studies to clarify the association between PPIs and COVID-19 and their potential for possibly increasing the risk for more severe disease.

Asked for his perspective, Brooks Cash, MD, director of the division of gastroenterology, hepatology, and nutrition at the University of Texas Health Science Center at Houston, who was not involved with the study, said: "While this data is intriguing and provocative, making widespread changes to our use of PPIs or other acid-suppressant medications is not supported by this one report."

He said that PPIs provide significant benefits when used appropriately and while the relatively modest odds ratios reported in this study are suggestive of a possible association with COVID-19, they should not be interpreted as equivalent to a cause-and-effect relationship. "So I would not endorse changing therapy for patients who are benefiting from acid-suppressant medications for appropriate conditions," Cash told MedPage Today. "In fact, there are now several reports suggesting that some acid-suppressing medications, namely famotidine, a histamine-2 receptor antagonist, may actually have a beneficial effect in patients infected with SARS-CoV-2."

Furthermore, he added, since gastric acid is important for preventing infection by many pathogens, "one of the potential concerns with the widespread use of acid-suppressing medications, and PPIs in particular, is that their effects on gastric acid may predispose some individuals to infections that gain access to the body via the gastrointestinal tract. The GI tract has been implicated as a potential source of entry for SARS-CoV-2."

Study limitations, the investigators said, included its observational nature and susceptibility to residual confounding and selection bias since severely ill COVID-19 patients were not likely to have taken the survey. The study was also subject to protopathic bias (also called reverse causality) since some respondents may actually have started a PPI in response to certain COVID-19 symptoms such as nausea and abdominal pain or to ease the effects of related treatments such as nonsteroidal anti-inflammatory drugs for fever. In addition, there were potential risks for misclassification and recall biases because the medication and COVID-19 testing data were self-reported, the researchers continued. And, since the survey was administered online and only in English and did not assess reading ability, the findings may not be applicable to non-English speakers or those with limited literacy or no access to the internet.

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