In a study published in the American Journal of Gastroenterology, researchers discovered significantly greater angiotensin-converting enzyme 2 (ACE2) expression and messenger RNA (mRNA) expression in the upper gastrointestinal (GI) tracts of proton pump inhibitor (PPI) users, which may predispose them to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. PPI use at admission was linked to heightened in-hospital mortality in patients with coronavirus disease 2019 (COVID-19), particularly African Americans. Most patients were taking PPIs for discretionary indications such as nonsteroidal anti-inflammatory drug (NSAID) prophylaxis and symptoms of gastroesophageal reflux disease (GERD).
The researchers conducted a prospective study of hospitalized COVID-19 patients and COVID-negative controls to understand how PPI use may affect ACE2 expression and stool SARS-CoV-2 RNA. A retrospective cohort of hospitalized patients (from six hospitals) with COVID-19 from March 15, 2020, to August 15, 2020, was assessed to explore the association between PPI use and mortality. Covariates with clinical relevance to COVID-19 outcomes were included in order to determine predictors of in-hospital mortality.
Salivary ACE2 mRNA levels were greater in control PPI users compared with nonusers (2.39 vs. 1.22; P = .02). PPI users and nonusers had similar salivary ACE2 levels and stool SARS-CoV-2 RNA detection rates. The authors noted, "In 694 hospitalized patients with COVID-19 (age = 58 years, 46% men, and 65% African American), mortality rate in PPI users and nonusers was 30% (68/227) vs. 12.1% (53/439), respectively."
According to the researchers, PPI use (adjusted odds ratio [aOR] = 2.72, P <.001); age (aOR = 1.66 per decade, P <.001); race (aOR = 3.03, P = .002); cancer (aOR = 2.22, P = .008); and diabetes (aOR = 1.95, P = .003) were predictors of mortality by logistic regression. African American patients had a greater PPI-correlated mortality risk (aOR = 4.16, 95% CI: 2.28-7.59) compared with other patients (aOR = 1.62, 95% CI: 0.82-3.19, P = .04 for interaction).
Lead author and study investigator Julia J. Liu, MD, MSc, and colleagues, wrote, "We found significantly higher [angiotensin-converting enzyme 2 (ACE2)] messenger RNA expression levels in upper [gastrointestinal] tract of PPI users, which may predispose them to SARS-CoV-2 infection. The association of the higher ACE2 expression in PPI users with respect to outcomes was assessed in our retrospective cohort of hospitalized patients with COVID-19, which included our prospective research participants: PPI usage at admission was associated with increased mortality."
"This mortality risk was particularly profound in African American patients with adjusted OR of 4.16, a finding that has not been previously reported. In fact, the majority (59%) of COVID-19 deaths in [African Americans] were in PPI users. Remarkably, most patients with COVID-19 (87%) were taking PPIs for discretionary indications, such as nonerosive [gastroesophageal reflux disease (GERD)] and/or NSAID ulcer prophylaxis. The increased ACE2 expression of the GI tract of COVID-negative patients on PPI provides a potential mechanistic basis for the increased SARS-CoV-2 infection and worse outcomes observed in PPI users during the pandemic reported in previous studies."
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