Airway-microbiome-driven mechanisms of disease during optimised self-management: a lesson learned from mechanistic study of the Colour-COPD trial

Turner, Alice M, Spittle, Daniella, Staples, Karl and Cleary, David W. (2025) Airway-microbiome-driven mechanisms of disease during optimised self-management: a lesson learned from mechanistic study of the Colour-COPD trial. Health Technology Assessment. (doi:10.3310/SYTH8546).

Abstract

Introduction
Reduced antibiotic consumption due to better self-management could change the profile of bacteria present in the airway, which might benefit the health of chronic obstructive pulmonary disease patients. To test this, we planned to use sputum samples already being collected from Colour-COPD trial patients for mechanistic work. The trial will test whether a sputum colour chart is non-inferior to usual self-management, and has a primary outcome of chronic obstructive pulmonary disease-specific hospital admission. Secondary outcomes include antibiotic consumption and quality of life. Since only half of exacerbations of chronic obstructive pulmonary disease (acute exacerbation of chronic obstructive pulmonary disease) are bacterial, and sputum colour has a good positive predictive value for bacterial presence, it is likely that our intervention will reduce antibiotic consumption. The main route by which our intervention could improve patient outcomes is that it could alter the airway microbiome, and subsequent pathological processes; this add-on study tried to assess that concept.

Methods
We used all sputum samples submitted by Colour-COPD trial patients and processed and stored them for microbiome and cytokine analyses. Sputum plugs were split with one-half being diluted in phosphate-buffered saline, dispersed using glass beads and stored for quantitative polymerase chain reaction/16S analysis. The second portion was dispersed using sequential phosphate-buffered saline and dithiothreitol treatment, generating supernatants and cytospins. Analysis of the microbial patterns, which would have been obtained from the respiratory microbiome, will be compared to antibiotic consumption for acute exacerbation of chronic obstructive pulmonary disease (days/year) steroid load (days/year and mg/year), acute exacerbation of chronic obstructive pulmonary disease rate, forced expiratory volume in 1 second and longitudinally within individuals to determine the impact of frequent courses of antibiotics at group and individual level. This work will now be completed outside the duration of this award. Selected inflammatory markers linked to neutrophilic and eosinophilic inflammation were planned to be measured, but this work was abandoned when the study was terminated early.

Results and study limitations
The trial was stopped prematurely due to low recruitment. This was due to a combination of insufficient trial sites, the impact of COVID-19 on research infrastructure and a reduced rate of acute exacerbation of chronic obstructive pulmonary disease during the COVID-19 pandemic, which affected eligibility in primary care sites, in particular. Since analysis of the microbiome was planned to occur only after trial results, this was abandoned within this award at the termination of the trial. However, since the research questions remained, could be answered in other ways, and patients had consented to the use of their samples for the proposed work, alternative ways to collect samples and fund microbiome analyses were sought. We are now at a point where we expect to have sufficient samples to have adequate power to answer two of our research questions by the time the trial ends, and will conduct their analysis thereafter.

Conclusion
Although we are not able to address our objectives of describing the airway microbiome in a primary care chronic obstructive pulmonary disease population, and describing the relationship between antibiotic consumption and changes in airway microbiome during the term of the award, we were able to learn lessons about matching mechanistic work to trials.

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Contributors

Author: Karl Staples

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