In both A1AT deficient and replete subjects, it is widely believed that protease-antiprotease imbalance is central to the pathophysiology of COPD,1 although (in the absence of an exacerbation) it is difficult to detect free elastase activity.2 This is explained by recent mathematical and in vitro modelling suggesting proteolysis and subsequent enzyme inhibition occur within the immediate microenvironment of the neutrophil.3 We have therefore validated a (pre-inhibition) elastase cleavage product of fibrinogen (Aα-Val360) produced in this microenvironment as a potential marker for COPD.
Methods Pilot study: Plasma Aα-Val360 was measured in 68 subjects with a wide range of A1AT levels, and in a further 64 PiZ A1AT deficient subjects, spirometry and plasma Aα-Val360 were measured in the stable state. Subjects with COPD (Normal A1AT levels): 81 subjects were recruited in a primary care setting following an exacerbation associated with sputum production. Trial participants were assessed on day 1 of the exacerbation and in the stable clinical state when full lung function tests and HRCT were also performed. HRCT scans were analysed both densitometrically (voxel index) and visually.
Results Pilot study: There was an exponential relationship between Aα-Val360 and the A1AT concentration consistent with theoretical modelling and a negative correlation with FEV1 in the PiZ subjects (r=−0.321, p=0.005). COPD study (Normal A1AT levels): Aα-Val360 was greater in subjects with visible emphysema compared to those without (median 21.77 vs 16.98; p=0.013) and correlated well with both physiology and densitometry (Abstract S59 Table 1). Aα-Val360 was significantly higher in subjects experiencing a purulent versus non-purulent exacerbation (day 1 median 26.29 vs 21.22; p=0.03), and although values fell, the difference persisted even in the stable state (21.89 vs 17.01; p=0.002). Aα-Val360 was also higher on day 1 than in the stable state (23.72 vs 21.28; p=0.005) even when stratified into non-purulent (21.22 vs 20.00; p=0.022) or purulent subgroups (26.29 vs 21.83; p=0.043).
Conclusion Aα-Val360 correlates well with physiological and radiological markers of COPD disease severity (in subjects with and without A1AT deficiency) and increases during exacerbations (particularly in those with purulent sputum), both supporting the pathophysiological importance of elastase and demonstrating the potential of Aα-Val360 as a valid biomarker in COPD. Further work is required to relate Aα-Val360 to longitudinal measures of disease progression.