Augmentation therapy for severe α₁-antitrypsin deficiency: is the jury still out on a trial?

As with the administration of insulin for diabetes mellitus, the rationale for administering purified α₁-antiprotease in severe α₁-antitrypsin (α₁AT) deficiency—a treatment dubbed “augmentation therapy”—is to provide the substance whose deficiency is deemed responsible for the pulmonary sequelae of α₁AT deficiency. Indeed, even as intravenous augmentation therapy has been advocated for severely deficient individuals with established airflow obstruction by some official societies (but not all),1 2 and even as one commercial product has been licensed by the United States Federal Drug Administration with other intravenous and inhaled preparations currently under investigation, the efficacy of augmentation therapy continues to be actively debated. As with many controversies in medicine, this one centres on the nature and adequacy of available supportive evidence versus the gaps in current knowledge. In the wake of the recently published outcome data from the American National Heart, Lung, and Blood Institute (NHLBI) sponsored Registry of Patients with Severe Deficiency of α₁-Antitrypsin,3and a European comparison between rates of decline in forced expiratory volume in one second (FEV₁ ) in untreated Danish versus treated German subjects with α₁AT deficiency,4 it is appropriate to examine the current state of evidence regarding augmentation therapy for severe α₁AT deficiency and to re-assess the evidence supporting this practice. This editorial takes an epistemological view of the evidence—how do we know what we know and is the evidence compelling? Also, in the context of current views, what are the implications of present knowledge on future studies of emerging treatments?

To consider current evidence about the efficacy of augmentation therapy, it is useful to recall a debate in medicine that consumed attention approximately 100 years ago—how to prove that an infectious agent was responsible for causing infection? Just …