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Emphysema in α1-Antitrypsin Deficiency

Does Replacement Therapy Affect Outcome?

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Abstract

Severe α1-antitrypsin (AAT) deficiency is an inherited disorder that leads to the development of emphysema in smokers at a relatively young age; most are disabled in their forties. Emphysema is caused by the protease-antiprotease imbalance when smoking-induced release of neutrophil elastase in the lung is inadequately inhibited by the deficient levels of AAT, the major inhibitor of neutrophil elastase. This protease-antiprotease imbalance leads to proteolytic damage to lung connective tissue (primarily elastic fibers), and the development of panacinar emphysema. AAT replacement therapy, most often applied by weekly intravenous infusions of AAT purified from human plasma, has been used to partially correct the biochemical defect and raise the serum AAT level above a theoretically protective threshold level of 0.8 g/L. A randomized controlled clinical trial was not considered feasible when purified antitrypsin was released for clinical use. However, AAT replacement therapy has not yet been proven to be clinically effective in reducing the progression of disease in AAT-deficient patients. There was a suggestion of a slower progression of emphysema by computed tomography (CT) scan in a small randomized trial. Two nonrandomized studies comparing AAT-deficient patients already receiving replacement therapy with those not receiving it, and a retrospective study evaluating a decline in FEV1 before and after replacement therapy, suggested a possible benefit for selected patients.

Because of the lack of definitive proof of the clinical effectiveness of AAT replacement therapy and its cost, we recommend reserving AAT replacement therapy for deficient patients with impaired FEV1 (35–65% of predicted value), who have quit smoking and are on optimal medical therapy but continue to show a rapid decline in FEV1 after a period of observation of at least 18 months. A randomized placebo-controlled trial using CT scan as the primary outcome measure is required. Screening for AAT deficiency is recommended in patients with chronic irreversible airflow obstruction with atypical features such as early onset of disease or disability in their forties or fifties, or positive family history, and in immediate family members of patients with AAT deficiency.

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Notes

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    1 The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgment

This paper is based in part on the Canadian Thoracic Society Position Statement on α1-Antitrypsin deficiency, which was prepared by the authors on behalf of the Standards Committee, and which was published in the Canadian Respiratory Journal in 2001.

No sources of funding were used to assist in the preparation of this article. The authors have no conflicts of interest that are directly relevant to the content of this article.

Dr Chapman is Director of the Canadian AAT Registry, which is supported by Grants from the Pharmaceutical Industry (Atlana, Astra-Zeneca, Baxter, Bayer, Boehringer-Ingelheim, GlaxoSmithKline), but Dr Chapman has not received remuneration for this position.

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Correspondence to Dr Raja T. Abboud.

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Abboud, R.T., Ford, G.T. & Chapman, K.R. Emphysema in α1-Antitrypsin Deficiency. Treat Respir Med 4, 1–8 (2005). https://doi.org/10.2165/00151829-200504010-00001

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Keywords

  • Neutrophil Elastase
  • FEV1 Decline
  • Lifetime Nonsmoker
  • Prolastin
  • Canadian Thoracic Society