Pseudomonas aeruginosa in the era of modulator therapies for cystic fibrosis
File(s)
Author(s)
King, John Andrew
Type
Thesis
Abstract
Introduction
CFTR modulators (CFTRm) improve CFTR function, improving lung function and pulmonary exacerbation rate. Impact on sputum expectoration and Pseudomonas aeruginosa (Pa) infection remains unclear. Primary hypotheses explored were: (i) CFTRm reduce Pa culture frequency, density and shift virulence/persistence behaviours, (ii) alternative, non-invasive infection surveillance methods can be developed for those no longer expectorating.
Methods
A retrospective cohort study of people with Leeds defined chronic Pa infection pre-CFTRm was performed, examining sputum sample provision, Pa isolation frequency/abundance pre-/post-CFTRm. Virulence/persistence behaviours in Pa clinical isolates, induced in vivo pre-/post-CFTRm and in vitro in experiments mimicking lung environmental changes from CFTRm were examined. A lab model for a novel, non-sputum based, airway sampling method called ‘huff tubes’ was tested with PCR, mass spectrometry and sniffer dogs.
Results
Use of CFTRm led to reduction in number of surveillance samples provided; a majority no longer met Standards of Care. Adjusting for number of samples provided per year, there was reduction in Pa positivity rate and abundance in those with chronic Pa infection. Restoration of CF lung microenvironment oxygen state may lead to changes in virulence (increased pyoverdine production) and persistence phenotype (decreased mucoid alginate). PCR showed promise as an alternative Pa detection method in the huff tube model; sniffer dogs exceeded previous limits of detection of Pa. However, clinical pilot of huff tubes failed to capture sufficient bacteria for testing.
Conclusion
Reduction in surveillance sample provision poses a risk of missing lower airway infection and challenges current accepted definitions of chronic airway infection. Novel ways to sample the airway are urgently needed; alternatives to standard culture are available to detect Pa. Changes to the CF lung microenvironment post-CFTRm and the effect on Pa phenotype warrants further exploration as changes may be exploited to better treat those with persisting infection post-CFTRm.
CFTR modulators (CFTRm) improve CFTR function, improving lung function and pulmonary exacerbation rate. Impact on sputum expectoration and Pseudomonas aeruginosa (Pa) infection remains unclear. Primary hypotheses explored were: (i) CFTRm reduce Pa culture frequency, density and shift virulence/persistence behaviours, (ii) alternative, non-invasive infection surveillance methods can be developed for those no longer expectorating.
Methods
A retrospective cohort study of people with Leeds defined chronic Pa infection pre-CFTRm was performed, examining sputum sample provision, Pa isolation frequency/abundance pre-/post-CFTRm. Virulence/persistence behaviours in Pa clinical isolates, induced in vivo pre-/post-CFTRm and in vitro in experiments mimicking lung environmental changes from CFTRm were examined. A lab model for a novel, non-sputum based, airway sampling method called ‘huff tubes’ was tested with PCR, mass spectrometry and sniffer dogs.
Results
Use of CFTRm led to reduction in number of surveillance samples provided; a majority no longer met Standards of Care. Adjusting for number of samples provided per year, there was reduction in Pa positivity rate and abundance in those with chronic Pa infection. Restoration of CF lung microenvironment oxygen state may lead to changes in virulence (increased pyoverdine production) and persistence phenotype (decreased mucoid alginate). PCR showed promise as an alternative Pa detection method in the huff tube model; sniffer dogs exceeded previous limits of detection of Pa. However, clinical pilot of huff tubes failed to capture sufficient bacteria for testing.
Conclusion
Reduction in surveillance sample provision poses a risk of missing lower airway infection and challenges current accepted definitions of chronic airway infection. Novel ways to sample the airway are urgently needed; alternatives to standard culture are available to detect Pa. Changes to the CF lung microenvironment post-CFTRm and the effect on Pa phenotype warrants further exploration as changes may be exploited to better treat those with persisting infection post-CFTRm.
Version
Open Access
Date Issued
2025-10-11
Date Awarded
2026-03-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Davies, Jane C.
Sponsor
Cystic Fibrosis Trust
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Medicine (Research) MD (Res)