Title: Is the mechanism of action of hypertonic saline and/or carbocisteine in the treatment of patients with bronchiectasis due to a decrease in sputum viscoelasticity, inflammation and bacterial load?
Funder: Medical Research Council

Abstract: Bronchiectasis is a chronic lung condition resulting in airway widening, mucus build-up and a greater susceptibility to infection in the airways. Patients with bronchiectasis suffer from a persistent cough, daily sputum production and frequent exacerbations, all of which impact on health and quality of life. Current treatment approaches involves the use of airway clearance techniques, bronchodilators, inhaled corticosteroids and antibiotics, when needed. However, none of these approaches is curative. A clinical trial (the CLEAR trial) is currently underway to see whether two drugs, called hypertonic saline and carbocisteine, can help to improve the clearance of airway secretions, called mucus, and thus reduce the number of infections these patients experience during the course of the trial. Although previous clinical trials have demonstrated some success with hypertonic saline and carbocisteine in the treatment of other chronic airway conditions, little is known about how these drugs actually work. Therefore, we will focus on how these drugs might enhance clearance of mucus from the airway of patients. To do this, we will obtain sputum samples from patients before and during the CLEAR trial. We will primarily focus on the ability of these drugs to improve sputum clearance using a technology called rheometry. Rheometry works by measuring the stickiness of sputum samples and we will seek to find out if the use of hypertonic saline and/or carbocisteine can make sputum less sticky and less viscous. If this is the case then it may explain how these drugs work and, if the trial is successful, it may also explain any reduction in infection in bronchiectasis patients during the trial. Additionally, we will look at the amount of bacteria (and types of bacteria) present in sputum before and after treatment with hypertonic saline and carbocisteine as well as markers of inflammation (the body’s response to bacterial infection) to determine if treatment can reduce infection and inflammation in bronchiectasis. An understanding of how hypertonic saline and/or carbocisteine work to reduce lung infections and improve lung health, as outlined above, may result in their introduction as a treatment option for bronchiectasis.

Lay abstract: Background_x000D_ Patients with bronchiectasis experience frequent pulmonary infective episodes (exacerbations) which can cause irreversible damage to lung tissue and reduce lung function. The use of hypertonic saline (HS) and carbocisteine (CS) are now being evaluated in patients with bronchiectasis as part of the CLEAR trial and in this study we will focus on the mechanistic effects of HS and CS in patients with bronchiectasis._x000D_ Research question._x000D_ _x000D_ Is the mechanism of action of hypertonic saline and/or carbocisteine in the treatment of patients with bronchiectasis due to a decrease in sputum viscoelasticity, inflammation and bacterial load?_x000D_ _x000D_ Hypothesis_x000D_ Treatment of bronchiectasis patients with HS and/or CS can improve mucus clearance by altering the rheological parameters of lung secretions_x000D_ _x000D_ Aim and objectives_x000D_ _x000D_ Aim:_x000D_ Sputum samples collected from the CLEAR trial will be evaluated for sputum elasticity, sputum viscosity as well as IL-6, IL-8 and 8-isoprostane and changes in bacterial abundance and composition. _x000D_ The primary objective is to measure sputum elasticity (G’) and viscosity (G’’) (which combined give a single summary measure of sputum viscoelasticity called the yield stress, Tc) at 2 weeks following commencement of treatment with HS and/or CS._x000D_ _x000D_ The secondary objectives are to _x000D_ 1). Measure sputum elasticity (G’), viscosity (G’’) and yield stress, Tc, at 8 weeks following commencement of treatment with HS and/or CS._x000D_ 2). Evaluate sputum inflammation as measured by IL-6, IL-8 and 8-isoprostane levels at 2 and 8 weeks following commencement of treatment with HS and/or CS. _x000D_ 3). Evaluate sputum bacterial load/composition at 2 and 8 weeks following commencement of treatment with HS and/or CS. _x000D_ _x000D_ Methods_x000D_ We will obtain sputum samples from patients recruited to the CLEAR study. Sputum samples will be collected at baseline, 2 weeks and 8 weeks after commencement of treatment. Dynamic rheology measurements will be recorded including G’ and G” of samples from which the Tc value will be obtained. In addition, measurements of sputum bacterial abundance and inflammatory indices will also be evaluated. _x000D_ _x000D_ Delivery of project_x000D_ Recruitment of patients to the CLEAR trial is successfully underway and is on target. A period of 3 months will be required to obtain ethical approval and governance to collect sputum samples from the CLEAR trial. Another 15 months is allocated for collection and analysis of sputum by rheometry. A further 6 months will be used to evaluate changes in sputum bacterial load and community composition, determined by qPCR and Next Generation Sequencing (NGS), respectively. 2 months will be also be required to carry out sputum measurements of IL-6, IL-8 and isoprostane. Finally, 4 months will be required for data linking with trial outcomes and final reporting._x000D_ _x000D_ Impact_x000D_ The primary focus of this project is to show that treatment of Bronchiectasis with HS and/or CS may reduce sputum viscosity and elasticity thus improving mucus clearance from the lungs of Bronchiectasis patients. In addition, the impact of HS and/or CS on bacterial abundance and inflammation will be assessed. The positive effect of HS and/or CS to changes in any of these parameters may lead to the development of even more effective drugs for the treatment of BE. In addition, HS and/or CS could also be developed for other patient groups receiving these drugs eg. Cystic Fibrosis, COPD

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RESPIRATORY