Neutrophil Elastase Activity Is Associated with Exacerbations and Lung Function Decline in Bronchiectasis

Abstract

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 tomography-confirmed 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), FEV₁% predicted (r = -0.33; 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 FEV₁ decline (β coefficient, -0.139; 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.

Keywords: biomarker; bronchiectasis; exacerbations; inflammation; neutrophils.

Figure 1.

Strengthening the Reporting of Observational Studies in Epidemiology flowchart of study inclusion and exclusions. Patients with elastase levels below the lower limit of detection (“not detected”) were included in the analysis with values treated as zero. ABI-NE = activity-based immunoassay for neutrophil elastase; ABPA = allergic bronchopulmonary aspergillosis, Bx = bronchiectasis, CT = computed tomography; NTM = nontuberculous mycobacteria.

Figure 2.

Association between neutrophil elastase (NE) and severity of disease. The activity-based immunoassay (ABI)-NE assay (upper panels) and kinetic NE assay (lower panels) are significantly different between bronchiectasis severity index and FEV₁% predicted groups and correlate with the St. George’s Respiratory Questionnaire (SGRQ). *P < 0.05 compared with >80% predicted FEV₁; ***P < 0.0001 compared with >80% FEV₁% predicted. Across-group comparisons for FEV₁, P < 0.0001 by Kruskal-Walis test. Bronchiectasis severity index and FEV₁ cutoffs were chosen as those used in Reference . The median and interquartile range are shown. NS = no significant difference compared with FEV₁ >80% predicted.

Figure 3.

Association between neutrophil elastase (NE) and sputum bacterial load. (A) Data for the activity-based immunoassay (ABI)-NE assay. (B) Data for the kinetic assay. ***P < 0.0001 compared with no organism isolated. The median and interquartile range are shown.

Figure 4.

Association between neutrophil elastase and longitudinal clinical outcomes. (A) Rate ratio from Poisson regression; elastase levels >0.016 µg/ml are associated with significantly increased risk of moderate exacerbations (P < 0.0001), and levels >20 µg/ml are associated with increased severe exacerbations (P < 0.0001). (B) Time to next exacerbation. Elevated neutrophil elastase is associated with shorter time to next exacerbation (P < 0.0001 by log rank test). (C) Time to next hospitalization for severe exacerbation over 36 months (P < 0.0001 by log rank test). (D) All-cause mortality over 3 years (P < 0.0001 by log rank test; comparison between <0.016 and 0.016–20 µg/ml, not significant). Less than 0.016 µg/ml, n = 132; 0.016 to 20 µg/ml, n = 143; >20 µg/ml, n = 106.

Figure 5.

Spearman rank correlation analysis of the relationship between serum total desmosine and age, bronchiectasis severity index (BSI), St. George’s Respiratory Questionnaire, and FEV₁% predicted.

Figure 6.

Changes in sputum neutrophil elastase (NE) activity at exacerbation and recovery. ABI = activity-based immunoassay.