Alpha-1 antitrypsin deficiency (AATD) is a hereditary disease characterized by low plasma levels of alpha-1 antitrypsin (AAT) and an increased risk of developing liver disease and pulmonary emphysema. AAT protects the lung tissue from destruction by elastase released by the neutrophils, so individuals with serum AAT concentrations below 0.50g/l have a high risk of developing emphysema, particularly if they are smokers.

The only specific treatment available to date has been intravenous infusion of purified AAT derived from donor plasma. The aim of this therapy is restore AAT to normal levels, in order to inhibit the destructive action of proteases and thus prevent or decelerate the development of emphysema.1

This augmentation therapy has been shown to be effective, both biochemically and clinically. Biochemical efficacy is demonstrated by protective levels of AAT being maintained in blood and lung tissue,2 and by the inhibition of elastase in the lung.3 Moreover, this in vivo anti-elastase activity is confirmed by a reduction in urinary levels of desmosine and isodesmosine, indirect markers of elastin degradation in the lung and, thus, markers of reduced lung tissue destruction.4 Clinical evidence of this phenomenon is demonstrated by a change in the natural history of the disease, as observed in the 3 clinical trials conducted to date.5–7 Initially, 2 trials with small patient numbers5 showed a reduction in lung density loss measured by computed tomography (CT) in patients receiving replacement therapy compared to placebo. Although the differences in both studies were at the limit of statistical significance due to the small sample size, a combined analysis found that replacement treatment was statistically highly superior.5

More recently, the RAPID study confirmed the efficacy of replacement therapy in preserving the pulmonary parenchyma.6 This study, the largest conducted to date, included 180 patients with AATD and FEV1 35%–70%, randomized to receive replacement therapy or placebo for 2 years. Results showed that augmentation treatment delayed lung density loss. Moreover, in a 2-year open-label extension of the same study in which all patients received active treatment,7 lung density loss decelerated significantly and to the same extent in patients who had previously received placebo (late treatment starters) and treatment (early treatment starters). However, lung density lost by the late starters during the first phase of the study was not recovered. This reduction in lung tissue loss has been also extrapolated to improved survival, with an estimated gain of 5.6 life years.8 These data are consistent with results obtained from the American registry, which reported a significant reduction in mortality in severely ill patients who received treatment.9 This increase in survival has been used to calculate the cost-effectiveness of augmentation therapy.10 Using an estimated gain of between 7.4 and 10.6 years life years with augmentation treatment according to sex and smoking habit, the cost per year of life gained is between $59234 and $248361. While this may appear high at first glance, the cost/effectiveness ratio is similar to other widely used treatments, such as simvastatin for the prevention of ischemic heart disease at $195000 per year of life gained.10

Why are questions still being raised about augmentation therapy?11 Mainly because we are trying to evaluate its clinical efficacy using the same criteria applied to drug treatment for chronic obstructive pulmonary disease (COPD). If we base our conclusions on rate of decline of FEV1as the primary outcome of treatment efficacy, a great many patients will be needed to achieve sufficient statistical power.12 For example, the primary outcome of the UPLIFT study was to evaluate the rate of decline of FEV1, and for that 6000 patients were required.13 Obviously, this sample size is impossible to achieve with a rare disease like AATD. For the same reason, it is equally unfeasible to conduct a study powered to analyze mortality.12

Another argument against this therapy is its ineffectiveness against other COPD variables, such as exacerbations. Although AAT can inhibit the growth of certain bacteria,14 its antiprotease mechanism does not suggest that it could be beneficial in the prevention of exacerbations. Moreover, a much greater number of patients than those included in the AAT studies would be required to design a study evaluating exacerbations.

Augmentation therapy has also failed to show benefits in patient-reported outcomes, such as dyspnea or physical activity, but this should not be surprising given that AAT replacement is not a symptomatic treatment. In this respect, emphysema could be compared to osteoporosis, another disease caused by tissue destruction, in which treatment efficacy is determined mainly by densitometry and not by clinical parameters. AAT treatment efficacy should also be measured by lung densitometry, which is also the best predictor of mortality.1

More important evidence in favor of the efficacy of this treatment derives from a post hoc analysis of the RAPID study, which showed that the magnitude of lung tissue loss is inversely related with AAT levels achieved during augmentation therapy.6 These data on the dose/response effect of the treatment reaffirm its efficacy, and have prompted the design of clinical trials using higher doses of AAT.15

In conclusion, augmentation therapy has proven its efficacy in reducing loss of lung density and, as such, the progression of emphysema. Clinical trials available to date have shown consistent results and provide sufficient evidence to support the use of this treatment in AATD patients with emphysema. The lack of evidence of its impact on clinical variables such as exacerbations or symptoms must not be used as an argument against its use, since this is an etiological approach rather than a symptomatic treatment, and accordingly, cannot be expected to affect those variables. For this reason, national and international guidelines1,16 recommend the use of augmentation therapy in AATD patients with emphysema who meet the established criteria.