Baseline use of proton pump inhibitors (PPIs) was associated with future bronchiectasis exacerbations, based on new data from more than 3000 individuals presented at the World Bronchiectasis Conference.

PPIs are often prescribed to patients with bronchiectasis, but previous research has shown that their use may alter the aerodigestive microbiome and increase susceptibility to respiratory infections, according to George M. Solomon, MD, associate professor medicine and director of the UAB Bronchiectasis and NTM Program at The University of Alabama at Birmingham, and colleagues.

The relationship of acid reflux treatment and gastroesophageal reflux disease (GERD) in relation to lung diseases such as bronchiectasis remains poorly understood, and greater knowledge risks of other ancillary treatments is needed, said Solomon.

The researchers reviewed data from three patient cohorts using the US Bronchiectasis and NTM Research Registry: a baseline descriptive cohort of 3236 individuals, a 24-month longitudinal cohort of 363 individuals for exacerbation modeling, and a cohort of 200 individuals for a bronchoscopy microbiome substudy.

A total of 815 (25.2%) of the baseline cohort had a documented PPI prescription, and 102 (28.1%) of the longitudinal cohort had baseline exposure to PPIs. Baseline PPI prescription was independently associated with a higher exacerbation rate over the 24-month follow-up period, with an incidence rate ratio of 1.48 (95% CI, 1.09-2.00).

The researchers adjusted for smoking, clinician-documented GERD, H2-blocker use, chronic Pseudomonas aeruginosa infection, baseline exacerbation history, change in percent predicted forced expiratory volume in 1 second, and follow-up time.

In the microbiome substudy, the researchers conducted 16S rRNA gene sequencing on paired supraglottic and bronchoalveolar lavage samples. They found an association between baseline PPI exposure and fewer different types of bacteria in the back of the throat, as well as changes in the types of bacteria. An observed increase in potential infection-causing bacteria tracked similarly between upper and lower airways.

“We hypothesized that use of proton pump inhibitors may be associated with risk for deleterious outcomes in bronchiectasis, and the microbiome data gives us a glimpse of potential mechanism,” Solomon noted.

The findings were limited by several factors including the retrospective design and use of registry data, the researchers noted. The study also lacked long-term follow-up and a sufficiently large sample size to associate exacerbation outcomes and microbiome findings, Solomon said. However, the initial findings support the need for more data to understand the potential relationship, he said.

The results also support the need for regular review of indication-based PPI use in patients with bronchiectasis, and to offer them only when clinically indicated for GERD, Solomon said.

Clinical Implications

Clinicians increasingly recognize that PPIs alter the oropharyngeal and lung microbiome, with enrichment of potentially pathogenic organisms such as Streptococcus and Staphylococcus in gastric and bronchoalveolar lavage fluid, said Daniel A. Salerno, MD, MS, director of critical care services in the Respiratory Intensive Care Unit at Temple University Hospital in Philadelphia.

“These changes may increase susceptibility to respiratory infections,” Salerno said. For example, previous research has shown an increased risk in community-acquired pneumonia associated with PPI use in the general population, which could be amplified in patients with structurally damaged airways, he said.

In addition, there is a broader momentum toward PPI deprescribing, Salerno said. The American Gastroenterological Association (AGA) recommends a trial of deprescribing for patients without a definitive indication for chronic PPI use.

“This study fills a critical gap by combining longitudinal exacerbation data with airway microbiome analysis in a well-characterized bronchiectasis cohort, providing both clinical and mechanistic evidence,” he said.

In the current study, the incidence rate ratio of 1.48 for exacerbations associated with PPI use is notable, but broadly consistent with prior literature, said Salerno.

“What is particularly noteworthy is the microbiome substudy finding of concordant upper and lower airway enrichment patterns with PPI exposure,” Salerno emphasized. “The finding of lower supraglottic alpha diversity and enrichment of genera containing potential pathogens provides biological plausibility for the clinical association, as this mechanistic link had not previously been demonstrated in an adult bronchiectasis population,” he noted.

“The absence of significant global beta-diversity differences despite taxon-specific shifts is also instructive, suggesting that PPI effects on the airway microbiome may be subtle and pathogen-specific rather than causing wholesale community restructuring,” he added.

Takeaways and Next Steps

The study was limited by the retrospective, observational design, relatively small sample size, and potential for confounding by indication, as patients prescribed PPIs may have more severe GERD, said Salerno. Additional research should include a prospective randomized trial of PPI deprescribing in patients with bronchiectasis to measure exacerbation rates, lung function, and quality of life, he said.

However, the results of the new study suggest that PPI use in bronchiectasis should be regularly reassessed in clinical practice for ongoing indication, consistent with broader deprescribing guidance. Salerno advised documenting a patient’s indication for PPI therapy and establishing a planned review date, as recommended by the AGA. “For bronchiectasis patients without a definitive long-term indication, such as Barrett esophagus, severe erosive esophagitis, and chronic NSAID [nonsteroidal anti-inflammatory drugs] use with bleeding risk, a deprescribing trial should be considered,” he said. Strategies for deprescribing include tapering dosage, switching to on-demand use, or substituting H2-receptor antagonists, he added.

Ultimately, “the decision to deprescribe must balance the potential respiratory harms of PPIs against the consequences of uncontrolled reflux and aspiration,” Salerno said.

Looking ahead, longitudinal microbiome studies with shotgun metagenomic DNA sequencing are needed characterize species-level and functional changes associated with PPI use and withdrawal, as well as exploration of dose-depending effects and examination of whether H2 receptor antagonists may be a safer alternative. In addition, studies are needed to examine the interaction between PPI use and specific bronchiectasis endotypes, “particularly those with chronic Pseudomonas infection or NTM [nontuberculous mycobacteria] disease,” Salerno said.

The study used data from the Bronchiectasis and NTM Research Registry and was supported in part by a research grant from Insmed Incorporated and the Bronchiectasis and NTM Industry Advisory Committee. The Bronchiectasis and NTM Research Registry also received funding from the Richard H. Scarborough Bronchiectasis Research Fund and the Anna Maria and Stephen Kellen Foundation. The researchers and Salerno had no financial conflicts to disclose.