Indeed recent data suggest that changes within the normal range can be detected as early as in the mid to late 20s in such subjects even if never smokers [45]. Thus if augmentation therapy is to be used in a preventative strategy it would be appropriate to consider earlier our website intervention in such subjects before significant disease and morbidity occurs. For these reasons it seems appropriate to obtain a baseline assessment of lung health in the mid to late teens and then monitor any deterioration on a frequent basis (perhaps every 2�C3 years) so that deterioration within the normal range can be determined early. Providing no risk factors can be implicated, summary statistics using 3�C4 data points will provide data likely to predict future progression.

The time at which augmentation is introduced will require a cost/benefit appraisal although an argument could be made to wait at least until the development of mild symptoms or physiological deterioration below the normal range. Whichever approach is used, data on previous rate of decline will provide some evidence of efficacy determined by observation of the subsequent rate of decline of lung function. Should frequent exacerbations influence decision making? Exacerbations of COPD have become widely recognised as episodes that can lead to a decline in spirometry, impairment in health status and increased risk of death [46]. Exacerbations caused by bacteria are neutrophilic and although largely confined to the airways, are associated with easily detectable excessive (or increased) NE activity [47].

The inflammation and amount of detectable NE is even greater in subjects with AATD [48] suggesting that NE generated progression is more likely in such patients and indeed there is a similar effect of exacerbations on spirometric decline as seen in usual COPD; furthermore, exacerbations are also associated with a decline in the gas transfer of the lung for carbon monoxide over time in patients with AATD [19,32]. Early retrospective analysis suggested that augmentation therapy reduced the number of exacerbations [49] although the increase in health care contact due to the regular AV-951 infusions could have influenced this result. In the EXACTLE trial exacerbation frequency was not reduced, although there was a reduction in severe episodes requiring hospitalisation [16]. This observation is consistent with the increased inflammation associated with exacerbations in AATD and the ability of augmentation to reduce lung inflammation [50] thereby reducing the clinical severity of the episodes.