Alpha-1-antitrypsin deficiency: what next?

Alpha-1-antitrypsin deficiency was first identified in 1963, together with its association with the early onset of severe lower zone emphysema. Although the mechanisms for the development of emphysema were not clearly understood, it was reasonably assumed that the alveolar destruction was a direct consequence of the release of neutrophil elastase which was then able to digest lung connective tissue because of the low concentrations of á1antitrypsin. This led to the concept and development of augmentation therapy which was shown to restore both the serum and alveolar concentration 3 of á1-antitrypsin to a level thought to be adequately protective. This represented a relatively simplistic approach and augmentation therapy became an accepted form of management, initially in the USA, but subsequently in Germany and, more recently, for some patients in several other European countries. The eYcacy of such an approach remains contentious. For many years it has been thought that an appropriate clinical trial would not be feasible in view of patient numbers required and the expense of designing and monitoring such a trial. This has led to recent editorials raising the issue of whether an appropriate clinical trial will ever be conducted, 5 although most clinicians and research workers remain firmly supportive of such a trial. In 1996 the WHO held a meeting of world experts and concluded that many questions still needed answering, including the nature of the lung pathology of á1-antitrypsin deficiency, the relative impact of deficiency on disease development, and rationalisation of the standards of care, and concluded that further research was necessary into the pathological processes in order to facilitate the design of adequately powered controlled clinical trials. This review addresses the more recent developments in á1-antitrypsin deficiency and outlines the potential methodologies that may enable the implementation of such a trial to clarify the eYcacy of augmentation therapy.