Title: Airway microbiome driven mechanisms of disease after optimised self management: Colour-COPD trial
Funder: Medical Research Council

Abstract: Chronic obstructive pulmonary disease (COPD) is a common lung problem mostly affecting adults over the age of 40. It causes breathlessness and cough, and patients often experience flare ups of their symptoms, known as exacerbations. These may be caused by environmental factors, viruses or bacteria. Despite the fact that bacteria only cause around half of flare ups it is common for patients to be given a ‘rescue pack’ which includes antibiotics and steroids for use in all episodes. This means that antibiotics can be overused, such that resistance could build up and the antibiotic may not work properly in future. It is therefore important to find ways we can safely reduce antibiotic use, but without causing harm to COPD patients. One way of recognising that the flare-up is caused by bacteria is to look at the colour of sputum (phlegm) patients produce, and compare this to a colour chart - antibiotics are only suggested if the colour indicates an infection. We think that appropriate use of a chart could reduce antibiotic use but without worsening the chance that patients will need to be admitted to hospital. This study adds laboratory work to a trial of sputum colour charts in COPD (Colour COPD), starting by processing and storing sputum during the study, and then going on to see if the trial has affected basic processes in the lung that could determine how patients feel, as well as their longer term health._x000D_ _x000D_ To do this we will separate sputum being collected in the trial already from saliva and store it in a way that preserves bacterial and viral DNA (microbiome), as well as liquid parts of the sputum which contain chemicals that can cause inflammation to occur in the lung. We know that the amount of antibiotics patients take affects the patterns in bacterial DNA, and that inflammation is a process partly driven by infection which relates to disease progression and quality of life. We will look at whether the microbiome in the stored sputum samples relates to outcomes within the Colour COPD trial, such as quality of life, and also compare it between trial arms. Finally, we will look at whether the microbiome influences inflammation and risks of exacerbations._x000D_ _x000D_ If beneficial effects are seen within airway bacteria or inflammation that relate to the trial outcomes then we will understand why it works, and may be able to start personalising care for COPD patients based on how their sputum looks on these tests. It may also enable us to design new interventions that alter the same basic processes._x000D_ _x000D_ The specific study team comprises a COPD specialist, a scientist specialising in cellular processes underlying COPD and a microbiologist experienced in complex analyses of the microbiome. All of the team have experience of conducting studies on COPD sputum. All investigators on the Colour COPD trial, including two patients, are also supporting the study as collaborators. We estimate the study will complete in 4 years, with 3 years of this being sample collection in the Colour-COPD trial.

Lay abstract: Research question: Do alterations in the airway microbiome and downstream inflammation occur if patients optimise self-management of exacerbations of chronic obstructive pulmonary disease (COPD)?_x000D_ Background: Our hypothesis is that reduced antibiotic consumption due to better self-management (SM) may change airway bacterial profile, and that this will benefit health of COPD patients. To test this we plan to use sputum samples already being collected from Colour COPD trial patients for mechanistic work. The main 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. There are two main routes by which our intervention could improve patient outcomes (i) it could alter the airway microbiome, and subsequent pathological processes (ii) enhancing SM technique might result in more prompt treatment of AECOPD, thereby reducing loss of physical health in each event. The parent trial will assess the latter; this add on study would assess the first, likely more important, route._x000D_ Aims and objectives_x000D_ 1. Describe the airway microbiome in a primary care COPD population_x000D_ 2. Describe the relationship between antibiotic consumption and changes in airway microbiome_x000D_ 3. Explore the relationship between microbiome profile, inflammation and prognosis_x000D_ Methods: We will store all sputum samples submitted by Colour COPD patients, and add microbiome and cytokine analyses to stable state samples. At the end of the parent trial stable state baseline samples will be measured to assess objectives 1 and 3. Sputum plugs will be split with one half being diluted in PBS, dispersed using glass beads and stored for qPCR/16S analysis of both virus and bacteria. The second portion will be dispersed using sequential PBS and DTT treatment generating supernatants and cytospins for analysis of inflammatory markers and cells. Analysis of the microbial patterns seen 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. We will also assess viral patterns and determine if baseline colonisation impacts efficacy of the intervention, and conduct a between trial arm analysis for the microbiome. Finally we will measure inflammatory markers linked to neutrophilic and eosinophilic inflammation to determine if altering the microbiome has potential to reduce factors which drive disease progression. _x000D_ Timelines: Colour COPD patients are recruited over 2 years and followed up for 1 year, thus samples will be received over 3 years. Post-trial processing and analysis will take 1 year_x000D_ Anticipated impact and dissemination: Dissemination will occur through conferences, publications, the parent trial PPI group and newsletter. Impact is anticipated through changes in antibiotic prescribing in primary care.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RESPIRATORY