P74 Raised neutrophil elastase activity in asthma supports a neutrophilic-asthma endotype

<h3>Introduction</h3> 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. <h3>Methods</h3> 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 <h3>Results</h3> 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&lt;0.0001). Both populations had similar pack-year smoking history (median (IQR): controls, 16 (6.5–31.0), asthma 18 pack-years (3.3–35.5), p=0.4205). 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&gt;0.9999) or paucigranulocytic (n=14, 10.3 nM (5.4) p&gt;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). <h3>Conclusions</h3> 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. <h3>References</h3> Simpson JL, <i>et al</i>. <i>ERJ</i> 2014. Carter RI, <i>et al</i>. <i>Thorax</i> 2015.