Although cigarette smoking generally accelerates lung function decline in AATD never smokers and ex-smokers have variable rates of progression with respect to FEV1, gas transfer and CT densitometry. Many patients retain normal lung function and smoking cessation alone can stabilise lung function in others. The limited clinical trials to date based on cross sectional demographic recruitment parameters have supported a benefit of augmentation therapy on progression of lung densitometry although not lung function or general health status. For this reason augmentation has remained unavailable in many countries and may be overprescribed in others. It is likely that the generalised inclusion of patients based on cross sectional static inclusion parameter hides potential benefits particularly in the limited numbers able to be recruited. For instance, in studies of therapy for exacerbations it is easier to demonstrate an effect of treatment when patients with a history of such episodes are recruited. Hence a physiological outcome in augmentation trials will only be shown to be beneficial in those in whom it is rapidly declining at the point of entry.