Impact of Elexacaftor/Tezacaftor/Ivacaftor Therapy on the Cystic Fibrosis Airway Microbial Metagenome

Abstract

Shotgun metagenome sequencing of respiratory secretions with spike-in controls for normalization demonstrated that 1 year of high-efficient CFTR modulation with elexacaftor/tezacaftor/ivacaftor extensively reduced the bacterial load. Longer observation periods will be necessary to resolve whether the partial reversion of the basic defect that is achieved with ELX/TEZ/IVA is sufficient in the long run to render the CF lungs robust against the recolonization with common opportunistic pathogens.

Post-approval studies with the CFTR modulators Elexacaftor-Tezacaftor—Ivacaftor

“…Neither monotherapy with IVA nor dual LUM/IVA changed the infection epidemiology in CF, but ELX/TEZ/IVA initiation was associated with a rapid reduction in infection-related visits and antimicrobial use among pwCF ( Miller et al, 2022 ). After 12-month of treatment with ELX/TEZ/IVA, the detection of Staphylococcus aureus and Pseudomonas aeruginosa decreased at single CF centers by 40% or more ( Pallenberg et al, 2022b ; Beck et al, 2023 ; Sheikh et al, 2023 ). Sputum microbiome diversity increased ( Sosinski et al, 2022 ).…”

“…However, the microbial network remained vulnerable to fragmentation. The initial shift of the CF airway microbiome was attributable to the ELX/TEZ/IVA-mediated gain of CFTR activity followed by a diversification driven by a group of commensals at the 1-year time point that are typical for healthy airways ( Pallenberg et al, 2022b ).…”

“…Domestic multicenter consortia like PROMISE ( Nichols et al, 2021 ; 2022 ) will probably resolve this issue by stratifying the course of quality of life, anthropometry and airway disease depending on age and disease status when triple therapy was started. Own data of the microbial airway metagenome suggest that after intermittent normalization the dysbiosis was coming back after 1 year of ELX/TEZ/IVA therapy ( Pallenberg et al, 2022b ). Bacterial load of the airways is reduced during ELX/TEZ/IVA but the typical CF pathogens are only rarely eradicated.…”

Mutual Effects of Single and Combined CFTR Modulators and Bacterial Infection in Cystic Fibrosis

“…IVA treatment showed an initial reduction in the prevalence of bacterial isolation, but P. aeruginosa density rebounded after 1 year ( 16 ), and P. aeruginosa strains present before treatment were found to persist even after intensive antibiotic therapy ( 17 ). Recent studies based on airway microbial metagenomic sequencing showed that ETI combination therapy reduced the load of P. aeruginosa and S. aureus in both mild and severe CF patients ( 18 ). This microbiological shift is attributable to the ETI-mediated gain of CFTR activity and the possible effect on the airway microbiota that is converted into a community of commensals.…”

Effects of Elexacaftor/Tezacaftor/Ivacaftor on Sputum Viscoelastic Properties, Airway Infection and Inflammation in Patients with Cystic Fibrosis

“…In a previous study, we showed that this level of rescue of F508del-CFTR function achieved by ELX/TEZ/IVA leads to substantial improvement in airway mucus obstruction, as evidenced by reduced mucus plugging detected by magnetic resonance imaging and improved ventilation homogeneity detected by multiple-breath washout [14]. However, the effects of ELX/TEZ/IVA on abnormal viscoelasticity of airway mucus and chronic inflammation in patients with CF have not been studied, and data of effects on the sputum microbiome remain limited [21,22].…”