Treatment for A1AD patients is of two types. The modalities used for all COPD patientsincluding lung volume reduction surgeryare appropriate. These therapies are fully discussed in the relevant chapters elsewhere in this book. In addition, you now have access to augmentation therapy. This is directed at treating your primary defectminimal or ineffective AATby giving you significant doses of the healthy human enzyme.

Augmentation therapy was not an existing option until the late 1980s, when purified human AAT was approved by the U.S. Food and Drug Administration (FDA) as an orphan drug. It had not yet been proven effective, but it was safe. Although preliminary studies since then have shown a modest improvement in lung function, a conclusive clinical trial is highly unlikely. Because it would have to be randomizedmeaning that some patients would be blindly assigned to receive the real treatment and others to receive a fake (placebo)it will probably be impossible to find patients who would consent to possibly not receiving the real treatment. If the treatment turns out to be highly effective, volunteers assigned to the placebo will have jeopardized their lives. There is also the ethical question: Do we have the right to ask people to risk sacrificing their lives for the possible future benefit of others?

Instead, the natural history of this disease and the effect of intravenous enzyme delivery in patients with a severe deficiency are being studied through several large multicenter registries (a coordinated listingcovering a large area or entire countryof patients with a particular disease). One is the registry maintained by the United States National Heart, Lung, and Blood Institute, one is the Danish-Dutch registry, and the other is the German registry. The Spanish registry of PI-ZZ patients (begun in 1993) is also collecting data. Unfortunately, each study has been designed differently, which will probably make it impossible to add these observations together or even compare them. Two other factors make clear conclusions even more unlikely: each registry involves a relatively small number of patients, and this disease progresses relatively slowly. It is an irony that even if this treatment actually significantly slows the loss of lung function, it may be impossible to carry out the kind of experiment that can demonstrate this in a scientifically and medically meaningful way.

About 2,000 people worldwide are using commercial enzyme augmentation products. Because their half-life in the body is five days at the most, intravenous infusions have to be given weekly to maintain protective effects. Side effectsalthough few and minorinclude headache and a variety of muscle and joint aches and pains.

Because the therapeutic benefit of augmentation therapy is uncertain and this therapy is costly, the criteria for selecting patients is controversial. The American Thoracic Society recommends that only patients with seriously inadequate AAT levelsand who do not smoke or have stopped smokingshould be treated. Although it is common sense that therapy be started before irreparable lung damage has developed, there are no data yet supporting this judgment.

Because intravenous dosing is inconvenient and adds significantly to this therapy's cost, aerosol delivery of human AAT is currently being evaluated to see if it increases the amount of enzyme in the fluid that bathes the airway tissues. Not only would this permit patients to use this treatment at home, but smaller doses would be needed because the protein is administered directly to the lungs. The hope for the relatively near future is gene therapy. Instead of adding the actual enzyme, the gene responsible for making it would be delivered to the respiratory tract. In this way, enough of the protein would be continuously manufactured in the airways and alveoli to raise levels high enough to prevent deterioration of pulmonary function.

The official prognosis for A1AD people is still poor. Only 16% of those with the PI-ZZ variant survive to age 60. This compares to 85% of the healthy population. The actual picture, though, is probably better than this statistic. The beneficial effects of both AAT augmentation and new surgical procedures have come about too recently to have affected a large enough percentage of patients to make a significant dent in these figures. In actual fact, it is likely that both longevity and quality of life for A1AD people have been improvingand will continue to improveas newer therapies come into regular use.