In the context that current evidence demonstrating a clinically significant acceleration of lung function decline in PI*MZ heterozygotes is sparse, augmentation therapy seems unlikely to hold great promise for most PI*MZ heterozygotes. That said, many clinicians with significant AAT experience cite at least a few instances of PI*MZ individuals who have severe airflow obstruction despite never having smoked. As such, the first needed inquiry would be to clarify the prevalence of these “rapidly accelerated decliners” among all PI*MZ individuals in order to identify a cohort that is potentially amenable to further study. Next, in keeping with the lines of evidence by which the efficacy of augmentation therapy has been judged to date and by which available drugs have achieved US Food and Drug Administration approval, endorsing the use of augmentation therapy for this (presumably small) subset of rapidly declining PI*MZ heterozygotes would require demonstrating, ideally in a randomized controlled trial, that receipt of augmentation therapy slows the development of emphysema and its sequelae, whether by measuring lung function, lung density on CT, functional status, COPD-attributed morbidity, and/or survival. While we cannot completely discount the feasibility of such research, the challenges of identifying a subset of rapidly accelerating PI*MZ heterozygotes and then enlisting this subset in a prospective trial seem daunting. On this basis, we regard the prospects of demonstrating the benefit of currently “unconventional” indications to be very dim.