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 Research and Public Health 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 3

Some participants become repeatedly culture negative for CF pathogens after ETI.

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Some participants become repeatedly culture negative for CF pathogens af...
(A–C) The number of participants with sputum cultures positive for Staphylococcus aureus (A), Pseudomonas aeruginosa (B), or Stenotrophomonas maltophilia (C) at the baseline visit who provided at least 2 post-ETI samples are indicated as “Total”. The number of participants whose sputum became repeatedly culture negative (i.e., all samples after the baseline visit were culture negative) for the indicted pathogen are indicated as “Culture –”. The number of participants whose sputum became repeatedly culture and ddPCR negative (i.e., all samples after the baseline visit were culture and ddPCR negative) are indicated as “Culture – & ddPCR –”. (D) Inverse relationship between P. aeruginosa sputum culture density at the baseline visit and transition to repeatedly P. aeruginosa culture–negative status after ETI. Baseline P. aeruginosa culture density was categorized by tertile; the highest tertile exceeded 1.08 × 107, middle was between 1.08 × 107 and 4.21 × 104, and lowest was less than or equal to 4.21 × 104 P. aeruginosa CFU/gm of sputum. Significance of differences was significant by Fisher’s exact test, P = 0.005. See Supplemental Table 8 for the number of participants analyzed and statistical analysis. (E–G) ddPCR assays detect pathogens in some culture-negative sputum samples. Participants becoming repeatedly culture negative for S. aureus (E), P. aeruginosa (F), or S. maltophilia (G) are indicated in rows and results of pathogen detection by culture and ddPCR are indicated by study time point in columns. Positive culture or ddPCR results are indicated in blue; negative culture or ddPCR results are indicated in yellow; missing data are indicated by white. See Supplemental Figure 7 for results of ddPCR assays in participants culture positive for P. aeruginosa and S. aureus. (H and I) Selective media used for P. aeruginosa culture reduced recovery of P. aeruginosa. Three isolates each from 4 PROMISE participants and the reference strain PAO1 (H) grown to late stationary phase, and sputum from 6 people with CF (I) were cultured on nonselective LB agar (LB) or the selective MacConkey agar (Mac) used for sputum P. aeruginosa culture in this study and by clinical labs generally, and viable P. aeruginosa counts measured (see Methods). CFU recovered from LB was higher than CFU recovered from MacConkey (P < 0.05 for all samples) by multiple unpaired, 2-tailed t tests on log-transformed values.