European Bronchiectasis Network (EMBARC).

Rationale: Sputum neutrophil elastase and serum desmosine, which is a linked marker of endogenous elastin degradation, are possible biomarkers of disease severity and progression in bronchiectasis. This study aimed to determine the association of elastase activity and desmosine with exacerbations and lung function decline in bronchiectasis.Methods: This was a single-center prospective cohort study using the TAYBRIDGE (Tayside Bronchiectasis Registry Integrating Datasets, Genomics, and Enrolment into Clinical Trials) registry in Dundee, UK. A total of 433 patients with high-resolution computed tomographyconfirmed bronchiectasis provided blood samples for desmosine measurement, and 381 provided sputum for baseline elastase activity measurements using an activity-based immunosassay and fluorometric substrate assay. Candidate biomarkers were tested for their relationship with cross-sectional markers of disease severity, and with future exacerbations, mortality and lung function decline over 3 years.Measurement and Main Results: Elastase activity in sputum was associated with the bronchiectasis severity index (r = 0.49; P , 0.0001) and was also correlated with the Medical Research Council dyspnea score (r = 0.34; P , 0.0001), FEV 1 % predicted (r = 20.33; P , 0.0001), and the radiological extent of bronchiectasis (r = 0.29; P , 0.0001). During a 3-year follow-up, elevated sputum elastase activity was associated with a higher frequency of exacerbations (P , 0.0001) but was not independently associated with mortality. Sputum elastase activity was independently associated with FEV 1 decline (b coefficient, 20.139; P = 0.001). Elastase showed good discrimination for severe exacerbations with an area under the curve of 0.75 (95% confidence interval [CI], 0.72-0.79) and all-cause mortality (area under the curve, 0.70; 95% CI, 0.67-0.73). Sputum elastase activity increased at exacerbations (P = 0.001) and was responsive to treatment with antibiotics. Desmosine was correlated with sputum elastase (r = 0.42; P , 0.0001) and was associated with risk of severe exacerbations (hazard ratio 2.7; 95% CI, 1.42-5.29; P = 0.003) but not lung function decline.Conclusions: Sputum neutrophil elastase activity is a biomarker of disease severity and future risk in adults with bronchiectasis.

Eradication and suppression of Pseudomonas aeruginosa is a key priority in national guidelines for bronchiectasis, and is a major focus of drug development and clinical trials. An accurate estimation of the clinical impact of P. aeruginosa in bronchiectasis is, therefore, essential. Methods Data from 21 observational cohort studies comparing patients with P. aeruginosa colonisation to those without were pooled by random effects meta-analysis with data collected for key longitudinal clinical outcomes of mortality, hospital admissions, exacerbations and lung function decline along with cross sectional outcomes such as quality of life. Measurements and main results: Studies included 3683 patients. P. aeruginosa was associated with a highly significant and consistent increase in all markers of disease severity including mortality (odds ratio (OR) 2.95, 95% CI 1.98-4.40; p<0.0001), hospital admissions (OR 6.57, 95% CI 3.19-13.51; p<0.0001) and exacerbations (mean difference 0.97 per year, 95% CI 0.64-1.30; p<0.0001). Patients with P. aeruginosa also had worse quality of life using the St Georges Respiratory Questionnaire (mean difference 18.2 points, 95% CI 14.7-21.8; p<0.0001). There were also large differences in lung function and radiological severity. Definitions of colonisation were inconsistent but findings were robust irrespective of the definition used. Conclusion: P. aeruginosa is associated with an approximate 3-fold increased risk of death and an increase in hospital admissions and exacerbations in adult bronchiectasis.

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