(484) Change in pulmonary infections 12 months after elexacaftor/tezacaftor/ivacaftor introduction: Results from the Danish National Cystic Fibrosis Cohort

Background: CFTR protein channel malfunction causes mucus obstruction and impaired ciliary function leading to infection, biofilm establishment, chronic pulmonary inflammation, cyst formation, fibrosis, and respiratory insufficiency. Several pathogens colonize the lungs and cause intermittent or persistent infection. Elexacaftor/tezacaftor/ivacaftor therapy modulates CFTR protein channel function and will significantly improve prognosis. Studies of first generation CFTR modulators point to a decline in sputum and culture positive samples, but sub-groups of patients are persistently colonized due to irreversible structural lung damage with compromised secretion clearance from pulmonary cavities. Elexacaftor/tezacaftor/ivacaftor became available in 2018 to selected Danish patients and in 2021 for all patients with a delF508 mutation above 12 years of age. The objective of this study is to assess change in new acquisition and persistent infection with cystic fibrosis pulmonary pathogens before and 12 months after elexacaftor/tezacaftor/ivacaftor initiation.

Methods: The study includes all non-transplanted Danish cystic fibrosis patients ≥12 years with minimum one F508del mutation initiating elexacaftor/tezacaftor/ivacaftor therapy in a nation-wide prospective cohort study. Demographic and clinical data, airway secretion culture, biochemistry and serology results are collected in the Danish Cystic Fibrosis Registry. Data includes sex, age, cystic fibrosis complications, lung function, BMI, mutations, antibiotic categories, and sweat chloride levels. Airway secretion sample types, frequency and culture results are recorded on patient level every 6 weeks. Blood inflammatory markers are collected at initiation and after 1, 3, 6, 9, and 12 months. Elexacaftor/tezacaftor/ivacaftor is distributed at clinic visits, where information about adherence and discontinuation is recorded. Pulmonary pathogens included are S. aureus, H. influenzae, P. aeruginosa, Achromobacter, Burkholderia, Aspergillus, and non-tuberculous mycobacteria species. Descriptive statistical analysis is used to assess patient characteristics and infection status as well as change in prevalence and incidence of cystic fibrosis pulmonary pathogens before and 12 months after elexacaftor/tezacaftor/ivacaftor initiation.

Results: Baseline clinical and microbiology data was successfully collected and validated. 300 patients with minimum 12 months follow up by September 2022 were included. Median age was 26 years [IQR 18;35], and 52 % were female. 74% were homozygous and 26% heterozygous for the F508del mutation. 30% of patients were CFTR modulator treatment naïve at baseline. Mean ppFEV1 was 75% (SD± 25.3) and mean BMI was 21.4 (SD± 3.6). Preliminary analysis regarding pulmonary infection proposes a marked decline in culture positive samples after elexacaftor/tezacaftor/ivacaftor initiation.

Conclusions: Studies of pulmonary infection are essential for development of rational culture regimens and antibiotic strategies in future years of CFTR modulator therapy implementation. Early introduction of elexacaftor/tezacaftor/ivacaftor in the Danish National Cystic Fibrosis Cohort combined with accessible extensive clinical and microbiology data provides an excellent research opportunity. Concluding results from this study will be presented on the North American Cystic Fibrosis Conference 2022.

Acknowledgements:

References: