Gastroesophageal reflux disease (GERD)—in which gastric acid flows upward out of the stomach into the esophagus—is one of the most common diagnoses seen in the pediatric gastroenterology clinic and causes a variety of symptoms such as heartburn, chest pain and vomiting. Patients with GERD also are at risk for atypical symptoms such as cough, wheezing and pneumonias. One of the proposed reasons for this is that stomach contents are refluxed into the mouth and are then aspirated into the airway.
Proving that aspiration is actually happening, however, is difficult. For this reason, children with GERD are often empirically put on prescription antacids such as proton pump inhibitors (PPIs) to try to alleviate their lung symptoms. Unfortunately, these medications have been associated with an increased risk of respiratory infections, which may make a child’s respiratory symptoms worse rather than better.
Based on our current understanding of aspiration and GERD-related lung disease, my colleagues at the Broad Institute and Brigham and Women’s Hospital and I developed two hypotheses that we thought could help us define quantitative biomarkers for aspiration risk:
- The stomach and lungs of GERD patients with chronic cough may harbor similar profiles of bacterial species, providing evidence of gastric aspiration.
- Patients taking PPIs may have a different profile of gastric, lung and oropharyngeal bacteria than those who are not.
To see if our hypotheses panned out, we turned to children with GERD with chronic cough seen in our aerodigestive clinic who were being evaluated by endoscopy, bronchoscopy and multichannel, intraluminal impedance testing (a novel method for measuring reflux entering the esophagus). We collected, cultured and performed 16S genetic sequencing (which can identify bacterial species in a sample) on the children’s gastric and lung fluid to profile the bacteria in their lungs and stomachs, looking in particular for any patterns among children who were taking PPIs and those who were not.
Similarities and differences
The sequencing data, which we recently published in the Journal of Pediatrics, revealed that patients carried remarkably similar profiles of bacteria in their stomachs and lungs—much more similar than the profile of bacteria in their mouths. These data suggested an exchange of bacteria between the stomach and the lungs in these patients. We also identified eight bacterial genera that were present in lung and stomach fluid but not in the mouth, suggesting that the bacteria were passing between the lungs and stomach without passing though the mouth—a sign of direct aspiration.
When we compared the bacterial profiles to the amount of reflux in these patients, we discovered that two of the eight species that were only in the stomach and lungs were highly correlated with full column reflux (reflux that travels from the stomach into the mouth).
Taken together, these data suggest that reflux is a viable mechanism for the lung disease seen in GERD patients, and that a patient’s profile of lung bacteria may serve as a future biomarker of reflux-related lung disease.
The PPI effect in GERD
Comparing bacterial profiles against PPI use, we also found that patients taking PPIs had higher concentrations of bacteria in their stomach, including higher proportions of Staphylococcus and Streptococcus genera (both of which play a role in upper respiratory infections) than patients not on prescription antacids. PPIs use was also associated with a distinct bacterial profile in the lungs, but the clinical significance of these bacteria will need to be determined in future studies.
Back to the clinic
This research has significant potential clinical implications. For the first time, we have identified possible bacterial biomarkers of reflux-related lung disease. We have also shown that acid-suppressing medications can alter the bacterial composition of the stomach and lungs, and that these changes may result in increased infection risk.
Rachel Rosen, MD, MPH, is director of the Aerodigestive Program in Boston Children’s Hospital’s Division of Gastroenterology, Hepatology and Nutrition, and an assistant professor of pediatrics at Harvard Medical School.
If you have questions about GERD and/or its respiratory complications, contact Boston Children’s Hospital’s Division of Gastroenterology, Hepatology and Nutrition.