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Pharmacologic improvement of CFTR function rapidly decreases sputum pathogen density, but lung infections generally persist

Authors :
David P. Nichols
Sarah J. Morgan
Michelle Skalland
Anh T. Vo
Jill M. Van Dalfsen
Sachinkumar B.P. Singh
Wendy Ni
Lucas R. Hoffman
Kailee McGeer
Sonya L. Heltshe
John P. Clancy
Steven M. Rowe
Peter Jorth
Pradeep K. Singh
the PROMISE-Micro Study Group
Source :
The Journal of Clinical Investigation, Vol 133, Iss 10 (2023)
Publication Year :
2023
Publisher :
American Society for Clinical Investigation, 2023.

Abstract

Background Lung infections are among the most consequential manifestations of cystic fibrosis (CF) and are associated with reduced lung function and shortened survival. Drugs called CF transmembrane conductance regulator (CFTR) modulators improve activity of dysfunctional CFTR channels, which is the physiological defect causing CF. However, it is unclear how improved CFTR activity affects CF lung infections.Methods We performed a prospective, multicenter, observational study to measure the effect of the newest and most effective CFTR modulator, elexacaftor/tezacaftor/ivacaftor (ETI), on CF lung infections. We studied sputum from 236 people with CF during their first 6 months of ETI using bacterial cultures, PCR, and sequencing.Results Mean sputum densities of Staphylococcus aureus, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Achromobacter spp., and Burkholderia spp. decreased by 2–3 log10 CFU/mL after 1 month of ETI. However, most participants remained culture positive for the pathogens cultured from their sputum before starting ETI. In those becoming culture negative after ETI, the pathogens present before treatment were often still detectable by PCR months after sputum converted to culture negative. Sequence-based analyses confirmed large reductions in CF pathogen genera, but other bacteria detected in sputum were largely unchanged. ETI treatment increased average sputum bacterial diversity and produced consistent shifts in sputum bacterial composition. However, these changes were caused by ETI-mediated decreases in CF pathogen abundance rather than changes in other bacteria.Conclusions Treatment with the most effective CFTR modulator currently available produced large and rapid reductions in traditional CF pathogens in sputum, but most participants remain infected with the pathogens present before modulator treatment.Trial Registration ClinicalTrials.gov NCT04038047.Funding The Cystic Fibrosis Foundation and the NIH.

Subjects

Subjects :
Microbiology
Pulmonology
Medicine

Details

Language :
English
ISSN :
15588238
Volume :
133
Issue :
10
Database :
Directory of Open Access Journals
Journal :
The Journal of Clinical Investigation
Publication Type :
Academic Journal
Accession number :
edsdoj.f38c402d2a6340749497b7d56e6094d6
Document Type :
article
Full Text :
https://doi.org/10.1172/JCI167957