The Importance of Early Diagnosis and Treatment of AATD in Preventing Pulmonary Emphysema

Deficiency of AAT and Possible Treatment

AATD is a rare genetic risk factor, predisposing individuals to a range of diseases, most commonly pulmonary emphysema (which develops as early as the 3rd decade of life), chronic hepatitis, liver cirrhosis, hepatocellular carcinoma, as well as panniculitis and so-called c-ANCA-associated vasculitis. It is most commonly found among Europeans.

The only specific treatment for AATD is the administration of purified AAT derived from human plasma. This can increase the plasma concentration of AAT above the value considered protective in terms of lung function and slowing the development of emphysema. Early intervention requires the detection of individuals with severe AATD.

Screening for AAT Deficiency

Screening is conducted by measuring the level of AAT in the blood.

If the level is < 1.0 g/l, phenotyping or genotyping is indicated. The patient should be referred to a specialized center dealing with AATD. Measuring the AAT level in blood is a generally available biochemical test that can be ordered by any doctor.

If the AAT level is between 0.5–1.0 g/l, this indicates a mild deficiency, and the patient is recommended to consult an AATD center. If the AAT level is < 0.5 g/l, this indicates a severe deficiency, warranting re-evaluation and consideration of augmentation therapy.

Efficacy and Safety of Augmentation Therapy with AAT

The randomized placebo-controlled RAPID study evaluated augmentation therapy with AAT and was the first to demonstrate a slowdown in the progression of emphysema in individuals with AATD. Its open-label extension (RAPID-OLE) represents the largest clinical study of AATD treatment to date. It confirmed the ongoing efficacy and tolerability of the human alpha-1 proteinase inhibitor (Respreeza) and suggested that it slows lung density loss regardless of the timing of treatment initiation.

However, in the group initially randomized to receive a placebo, where augmentation therapy with AAT was started two years later in the open-label extension, a more pronounced decrease in lung density was observed than in the group with early AAT therapy. The loss of lung tissue during the placebo phase remained greater even after 24 months of active treatment compared to the group with early initiation of augmentation therapy.

The therapy was well tolerated, and the incidence of adverse events during drug administration was similar to that of the placebo.

Conclusion

The RAPID study was the first randomized placebo-controlled study to show that administration of purified human AAT significantly slows the progression of emphysema according to lung tissue density measurements. The benefit lies in the early initiation of treatment, particularly based on targeted screening for AATD. In patients with severe emphysema caused by AATD, early treatment can prolong life and delay the need for lung transplantation or respiratory failure.

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Sources:
1. Thabut G., Corda L. Epidemiology, diagnosis, and available treatment for alpha 1 antitrypsin deficiency-related emphysema in Europe. Eur Respir Pulm Dis 2018; 4 (1): 25–31, doi: 10.17925/erpd.2018.4.1.25.
2. Chlumský J. Standard for diagnosis and treatment of patients with COPD with proven alpha-1 antitrypsin deficiency (AATD). Bronchial Obstruction Disease Section of ČPFS, 2019. Available at:  www.pneumologie.cz/upload/1583105752.959.pdf