RAISED NEUTROPHIL ELASTASE ACTIVITY IN ASTHMA SUPPORTS A NEUTROPHILIC-ASTHMA ENDOTYPE

Introduction Asthma is a common, chronic lung disease marked by reversible airflow obstruction driven by inflammation. There is increasing evidence for a neutrophil-dominant inflammatory endotype1 with clear mechanistic potential for neutrophil elastase (NE) to cause clinical manifestations of disease. However, the relationship between neutrophil proteinases and asthma pathophysiology remains uncertain. We hypothesised that patients with a neutrophilic-endotype would have increased NE activity compared to other asthma endotypes and healthy smokers. Methods Patients with respiratory physician-confirmed asthma diagnosis were recruited. Controls without asthma were age-matched with normal lung function and no symptoms suggestive of asthma/alternative respiratory disease Asthma patients were divided into endotypes by analysis of sputum cellular composition as previously described.1 NE activity was measured in plasma using an ELISA based on specific fibrinogen-cleavage product Aα–Val360.2 Results Forty-five asthma patients (Mean (SD): age 60.6 years (10.3); 40% male) and 45 controls (age 60.2 years (10.1); 51% male) were recruited. Asthma patients had evidence of airflow obstruction (mean (SD): FEV1/FVC% predicted asthma 64.3 (11.7) versus controls 77.5 (6.3), p When considered together, patients with asthma had a significantly higher NE activity footprint than controls (mean (SD): asthma 12.7 nM (5.7), control 9.4 nM (3.1), p=0.0011) When divided into phenotypes, patients with neutrophil-dominant asthma (n=15) had increased activity footprint compared to a specifically age-matched sub-group of controls (n=15, Mean (SD): asthma 15.0 nM (5.9), control 8.9 nM (2.9), p=0.0034). There were no differences between the NE activity footprint comparing patients with eosinophilic (n=11, 11.4 nM (5.5) p>0.9999) or paucigranulocytic (n=14, 10.3 nM (5.4) p>0.9999) endotypes to controls. In neutrophilic asthma, there was no correlation between NE activity and neutrophils in sputum (%) (R2=0.02677, p=0.5601), age (R2=0.08626, p=0.2880), FEV1/FVC% (R2=0.04410, p=0.4911), or smoking exposure (R2=0.5515, p=0.4766). Conclusions These findings suggest that there is a differing systemic proteolytic enzyme activity in neutrophil–dominant asthma patients compared to controls and between neutrophilic asthma and paucigranulocytic asthma, which may influence disease pathophysiology. References Simpson JL, et al. ERJ 2014. Carter RI, et al. Thorax 2015.