WS08.01Reshaping but not restoring: The impact of elexacaftor/tezacaftor/ivacaftor on the lung microbiome and interactome in people with cystic fibrosis and advanced lung disease

Abstract

Lung disease, driven by bacterial chronic infection, is the leading cause of morbidity and mortality in adults with cystic fibrosis (awCF). The recent introduction of elexacaftor/tezacaftor/ivacaftor (ETI) has led to significant improvements in overall health, prompting investigation into its effects on chronic lung infections. However, traditional microbiology has limited sensitivity in capturing microbiological changes post-ETI. We aimed to assess microbiome and microbial interaction changes before and after ETI in awCF and advanced lung disease by the use of culture-independent technologies.

AwCF were prospectively recruited at the Adult CF Center, Policlinico Hospital, Milan, Italy. Participants were categorized into two groups: an ETI-treated group of 12 individuals with advanced lung disease and a control group of 20 individuals not eligible for early ETI access. Baseline and follow-up sputum samples were collected to examine lung microbiome and interactome changes.

We demonstrated an increase in microbiome alpha-diversity and a shift towards commensal species one month following ETI, though this effect diminished after one year. A progressive shift in bacterial community composition was observed over time, resembling that of bronchiectasis patients from the same geographic region. Interactome analysis revealed significant rewiring, with new potential CF pathogens emerging within the year.

These findings highlight the possible role of culture-independent approaches for personalized medicine in CF, indicating that while ETI induces microbiome shifts, a fully normalized microbiome may not be achieved. Therefore, maintaining chronic therapies, including inhaled antibiotics, in this population could be crucial for effectively managing persistent microbiome alterations.