Pharmacologic improvement of CFTR function rapidly decreases sputum pathogen density, but lung infections generally persist
David P. Nichols, … , Pradeep K. Singh, the PROMISE-Micro Study Group
David P. Nichols, … , Pradeep K. Singh, the PROMISE-Micro Study Group
Published March 28, 2023
Citation Information: J Clin Invest. 2023;133(10):e167957. https://doi.org/10.1172/JCI167957.
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Clinical Medicine Microbiology Pulmonology

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

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.

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

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Figure 4

Sequence-based analyses find marked declines in the sputum density of traditional CF pathogens, but little change in other organisms.

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Sequence-based analyses find marked declines in the sputum density of tr...
(A) By-participant change in calculated absolute abundance after 1 (circles), 3 (triangles), and 6 (squares) months of ETI for genera detected at an average of 1% or greater in baseline sputum samples. Genera containing a traditional CF pathogen are indicated with red symbols, other bacterial genera are indicated in blue symbols. Mean and CIs as determined by mixed-model repeated measures analysis are shown. Both groups are ordered by the average cohort-wide relative abundance at baseline (high to low). Gray shading indicates technical variation in measurements of control samples (see Supplemental Figure 10C). See Supplemental Table 9 for number participants studied per time point and statistical analysis. (B–D) Proportion of Haemophilus (B), Pseudomonas (C), and Staphylococcus (D) genera abundance attributable to the corresponding CF pathogen species. The proportion of Haemophilus, Pseudomonas, and Staphylococcus genera genomes that are H. influenzae, P. aeruginosa, or S. aureus species, respectively, was calculated by dividing H. influenzae, P. aeruginosa, or S. aureus species genome abundance measured by species-specific ddPCR by the corresponding genera absolute abundance. Sputum from participants with prior evidence of H. influenzae, P. aeruginosa, or S. aureus (from patient registry data) were studied. “Controls” were replicate cultures of laboratory strains of the indicated species. Values for controls sometimes exceed 100% due to variations in measurements of genera absolute abundance (using the product of total 16S rRNA and genera relative abundance) and species absolute abundance (using species specific ddPCR data). The difference between Haemophilus genera and H. influenzae abundance was significant (P = 0.0014); differences between Pseudomonas and P. aeruginosa abundance (P = 0.09) and Staphylococcus and S. aureus abundance (P = 0.38) were not different by 2-tailed t test on log-transformed data.