Poster: 36Longitudinal changes in the airway microbiome following elexacaftor/tezacaftor/ivacaftor treatment in cystic fibrosis

Abstract

Background

In cystic fibrosis (CF), airway microbial composition is closely associated with clinical outcomes, and pathogen predominance has been linked to disease progression. The use of elexacaftor/tezacaftor/ivacaftor (ETI) may modify the airway environment and thereby influence the respiratory microbiome, although its impact remains incompletely understood. We therefore aimed to characterize longitudinal changes in the respiratory microbiome following ETI initiation in a large real-world cohort.

In cystic fibrosis (CF), airway microbial composition is closely associated with clinical outcomes, and pathogen predominance has been linked to disease progression. The use of elexacaftor/tezacaftor/ivacaftor (ETI) may modify the airway environment and thereby influence the respiratory microbiome, although its impact remains incompletely understood. We therefore aimed to characterize longitudinal changes in the respiratory microbiome following ETI initiation in a large real-world cohort.

Methods

We conducted a retrospective cohort study of 461 people with CF (pwCF) who had microbiologic culture data both before and after ETI initiation. Associations between ETI exposure and organism detection were evaluated using generalized linear mixed-effects models with a binomial distribution, logit link, and random intercept for patient to account for repeated measures. ETI exposure was modeled as a time-varying variable. Outcomes included detection of Pseudomonas aeruginosa, Staphylococcus aureus, Aspergillus species, Burkholderia species, Haemophilus influenzae, and Stenotrophomonas maltophilia. Odds ratios (ORs) compared ETI with non-ETI exposure, with OR < 1 indicating lower odds and OR >1 indicating higher odds of organism detection during ETI treatment.

We conducted a retrospective cohort study of 461 people with CF (pwCF) who had microbiologic culture data both before and after ETI initiation. Associations between ETI exposure and organism detection were evaluated using generalized linear mixed-effects models with a binomial distribution, logit link, and random intercept for patient to account for repeated measures. ETI exposure was modeled as a time-varying variable. Outcomes included detection of Pseudomonas aeruginosa, Staphylococcus aureus, Aspergillus species, Burkholderia species, Haemophilus influenzae, and Stenotrophomonas maltophilia. Odds ratios (ORs) compared ETI with non-ETI exposure, with OR < 1 indicating lower odds and OR >1 indicating higher odds of organism detection during ETI treatment.

Results

Among the 461 pwCF, the median age was 20.8 years (IQR [10.6–31.4]); 48.4% were female, 96.2% were White, and 54.2% had homozygous F508del genotype. Relative to non-ETI therapy, ETI was associated with lower odds of detection of Pseudomonas aeruginosa (OR 0.25, 95% CI 0.20–0.30) and Stenotrophomonas maltophilia (OR 0.40, 95% CI 0.30–0.60), with a trend toward reduced detection of Haemophilus influenzae in sputum cultures (Figure 1). In contrast, ETI treatment was associated with higher odds of detection of Aspergillus, Burkholderia, and Staphylococcus aureus (OR 14.1, 95% CI 7.7–26.0; OR 4.9, 95% CI 2.4–10.3; and OR 1.5, 95% CI 1.2–1.9, respectively).

Among the 461 pwCF, the median age was 20.8 years (IQR [10.6–31.4]); 48.4% were female, 96.2% were White, and 54.2% had homozygous F508del genotype. Relative to non-ETI therapy, ETI was associated with lower odds of detection of Pseudomonas aeruginosa (OR 0.25, 95% CI 0.20–0.30) and Stenotrophomonas maltophilia (OR 0.40, 95% CI 0.30–0.60), with a trend toward reduced detection of Haemophilus influenzae in sputum cultures (Figure 1). In contrast, ETI treatment was associated with higher odds of detection of Aspergillus, Burkholderia, and Staphylococcus aureus (OR 14.1, 95% CI 7.7–26.0; OR 4.9, 95% CI 2.4–10.3; and OR 1.5, 95% CI 1.2–1.9, respectively).

Conclusions

ETI therapy was associated with reduced detection of several key gram-negative pathogens (Pseudomonas aeruginosa and Stenotrophomonas maltophilia) but increased detection of other organisms, suggesting a potential shift in airway microbial composition. Given the observational, population-level design, and variable follow-up duration, these findings should be considered hypothesis-generating and warrant confirmation in a prospective longitudinal, patient-level analysis with standardized sampling.

ETI therapy was associated with reduced detection of several key gram-negative pathogens (Pseudomonas aeruginosa and Stenotrophomonas maltophilia) but increased detection of other organisms, suggesting a potential shift in airway microbial composition. Given the observational, population-level design, and variable follow-up duration, these findings should be considered hypothesis-generating and warrant confirmation in a prospective longitudinal, patient-level analysis with standardized sampling.