Disease 'activity', 'severity' and 'impact': interrelationships in COPD; is a measure of disease 'activity' the Holy Grail for COPD, or a variable impossible to quantify?

It is increasingly recognised that new measures of disease 'activity' for COPD are required, however the relationship between markers of disease 'activity', 'severity' and 'impact' though closely linked, is poorly understood. Additionally, while change in markers of disease 'severity' (e.g. change in FEV1) may be considered a marker of disease 'activity', these quantify a single aspect of disease 'activity' in COPD rather than measuring the overall disease process and this has stimulated the search for new biomarkers of COPD that reflect the 'activity' of the disease process. The ideal biomarker of disease 'activity' would be stable with respect to time since measurement at any time point would then relate to subsequent disease progression. This would allow the influence of a therapeutic intervention to be assessed early, facilitating both phase 2 and 3 clinical trials. Although a number of potential biomarkers of COPD disease 'activity' have been studied, to date none have been shown to conclusively relate to disease progression and the stability of underlying disease 'activity' therefore requires further consideration. Interestingly, while the variability of disease 'activity' of COPD is rarely mentioned in the current literature, and there is uncertainty whether 'activity' is constant or highly variable, there are clues from available data as discussed in the current article. Finally we consider how markers of disease 'activity', 'severity' and 'impact' may relate, which is of utmost importance in the ongoing search for new biomarkers in COPD and a greater understanding of the pathogenesis of the disease process.

Aα-Val360: a marker of neutrophil elastase and COPD disease activity.

Forced expiratory volume in 1 s is currently the most widely used marker of chronic obstructive pulmonary disease (COPD) severity; however, it is a poor surrogate of the emphysematous component and the underlying pathophysiological mechanism, and therefore new markers are urgently needed. Neutrophil elastase (NE) is likely to play a key pathophysiological role in COPD and the current study explores a marker of NE activity as a potential indicator of COPD disease activity. Aα-Val(360) was measured in 81 subjects with a clinical diagnosis of COPD, both in the stable state and at presentation with an acute exacerbation, and comparisons were made using lung function tests and computed tomography imaging. The relationship of Aα-Val(360) with disease progression was also assessed in 40 of the subjects over a 4-yr period. Baseline Aα-Val(360) related to physiological and radiological markers of disease severity, was higher at presentation with an acute exacerbation than in the stable state and (at least partly) related to disease progression over the subsequent 4 yrs. We demonstrate that Aα-Val(360) is a marker of cross-sectional COPD disease severity and possibly disease progression, and represents a new concept of specific biomarkers. This study therefore reports the first in vivo data to support the pathophysiological role of NE in COPD.

The fibrinogen cleavage product Aα-Val360, a specific marker of neutrophil elastase activity in vivo.

BACKGROUND: Alpha-1-antitrypsin (A1AT) deficiency is the only recognised genetic risk factor for chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality worldwide. Since A1AT is the major inhibitor of neutrophil elastase (NE), this enzyme has become widely implicated in the pathogenesis of COPD in general; however, there is currently no specific biomarker for its pre-inhibition activity. Such a biomarker should be a measure of elastase-specific COPD disease activity with the potential to assess early targeted therapeutic intervention, in contrast to traditional and non-specific disease severity markers such as forced expiratory volume in 1 s. METHODS: In pilot studies, plasma Aα-Val(360) and markers of neutrophil activation were measured in 95 subjects with a range of A1AT concentrations. Aα-Val(360) and sputum elastase activity were also measured in a further seven PiZ A1AT-deficient subjects over the course of an acute exacerbation. Finally, Aα-Val(360) was measured in plasma from subjects randomised to receive A1AT replacement or placebo in the EXACTLE trial. RESULTS: The plasma concentrations of Aα-Val(360) and A1AT related exponentially, consistent with previous theoretical and in vitro experimental data. L-233 (an intracellular NE inhibitor) blocked generation of Aα-Val(360) and subsequent A1AT/NE complex formation. Aα-Val(360) was related to the spirometric severity of lung disease in A1AT deficiency, to sputum elastase activity in acute exacerbations and was decreased in subjects receiving A1AT replacement therapy (while remaining constant in those receiving placebo). CONCLUSIONS: Aα-Val(360) represents the first specific footprint of pre-inhibition NE activity and is a potential biomarker of disease activity and progression in subjects with elastase-dependent COPD. TRIAL REGISTRATION: The EXACTLE study was registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.

A specific proteinase 3 activity footprint in α1-antitrypsin deficiency.

α1-Antitrypsin (α1-AT) deficiency is a risk factor for emphysema due to tissue damage by serine proteases. Neutrophil elastase (NE) has long been considered the enzyme responsible. However, proteinase 3 (PR3) also produces the pathological features of chronic obstructive pulmonary disease (COPD), is present in the same granules in the neutrophil and is inhibited after NE. We developed a specific footprint assay for PR3 activity and assessed its relationship to an NE footprint in α1-AT deficiency. An ELISA was developed for the specific PR3 fibrinogen cleavage site Aα-Val541. Levels were measured in plasma from 239 PiZZ patients, 94 PiSZ patients, 53 nondeficient healthy smokers and 78 individuals with usual COPD. Subjects underwent extensive demographic characterisation including full lung function and lung computed tomography scanning. Aα-Val541 was greater than the NE footprint in all cohorts, consistent with differential activity. Values were highest in the PiZZ α1-AT-deficient patients and correlated with the NE marker Aα-Val360, but were ∼17 times higher than for the NE footprint, consistent with a greater potential contribution to lung damage. Aα-Val541 was related cross-sectionally to the severity of lung disease (forced expiratory volume in 1 s % pred: rs= -0.284; p<0.001) and was sensitive to augmentation therapy, falling from 287.2 to 48.6 nM (p<0.001). An in vivo plasma footprint of PR3 activity is present in greater quantities than an NE footprint in patients with α1-AT deficiency, is sensitive to augmentation therapy and represents a likely biomarker for dose-ranging studies.

The Relationship of the Fibrinogen Cleavage Biomarker Aα-Val360 With Disease Severity and Activity in α1-Antitrypsin Deficiency.

BACKGROUND: New markers of COPD and emphysema disease activity are urgently required since current measures of disease severity do not reflect the total disease burden nor predict disease progression. A recently described in vivo marker of neutrophil elastase activity (Aα-Val360) may be an effective marker of COPD and emphysema disease activity, and the current study explores its use in patients with α1-antitrypsin deficiency (AATD) across the disease severity spectrum with particular interest in whether it can be used as an early predictor of the need for intervention. METHODS: Cross-sectional and longitudinal relationships between Aα-Val360 and full lung-function tests, CT scan densitometry, and other biomarkers were explored in this study of a registry of untreated patients with PiZZ AATD. RESULTS: The Aα-Val360 related cross-sectionally to physiologic, radiologic, and symptomatic markers of disease severity though not disease progression. Similar cross-sectional relationships were observed in subjects with mild physiologic abnormalities; however, in this subgroup, baseline Aα-Val360 concentration did relate to subsequent disease progression. CONCLUSIONS: In cross-sectional studies, Aα-Val360 reflects disease severity in AATD and may be a useful marker of disease activity in patients with early disease in whom therapeutic intervention may be indicated.