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

Introduction: Reduced antibiotic consumption due to better self-management (SM) could change the profile of bacteria present in the airway, which might benefit the health of COPD 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 COPD specific hospital admission. Secondary outcomes include antibiotic consumption and quality of life (QOL). Since only half of exacerbations of COPD (AECOPD) 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 patients and processed them to store for microbiome and cytokine analyses. Sputum plugs were split with one half being diluted in PBS, dispersed using glass beads and stored for qPCR/16S analysis. The second portion was dispersed using sequential PBS and DTT treatment generating supernatants and cytospins. Analysis of the microbial patterns which would have been obtained of the respiratory micobiome will be compared to antibiotic consumption for AECOPD (days/year) steroid load (days/year and mg/year), AECOPD rate, FEV1 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 AECOPD 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 termination of the trial. However since the research questions remained, could be answered in other ways, and patients had consented to 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 2 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 COPD 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.

Future work: We stored samples for a separately funded study to meet our objectives.

Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy Mechanisms Evaluation programme.
Trial registration: The parent trial was prospectively registered as ISRCTN14955629