Assessment of emphysema-modifying therapy is difficult, but newer outcome measures offer advantages over traditional methods. The EXAcerbations and Computed Tomography scan as Lung End-points (EXACTLE) trial explored the use of computed tomography (CT) densitometry and exacerbations for the assessment of the therapeutic effect of augmentation therapy in subjects with alpha(1)-antitrypsin (alpha(1)-AT) deficiency. In total, 77 subjects (protease inhibitor type Z) were randomised to weekly infusions of 60 mg x kg(-1) human alpha(1)-AT (Prolastin) or placebo for 2-2.5 yrs. The primary end-point was change in CT lung density, and an exploratory approach was adopted to identify optimal methodology, including two methods of adjustment for lung volume variability and two statistical approaches. Other end-points were exacerbations, health status and physiological indices. CT was more sensitive than other measures of emphysema progression, and the changes in CT and forced expiratory volume in 1 s were correlated. All methods of densitometric analysis concordantly showed a trend suggestive of treatment benefit (p-values for Prolastin versus placebo ranged 0.049-0.084). Exacerbation frequency was unaltered by treatment, but a reduction in exacerbation severity was observed. In patients with alpha(1)-AT deficiency, CT is a more sensitive outcome measure of emphysema-modifying therapy than physiology and health status, and demonstrates a trend of treatment benefit from alpha(1)-AT augmentation.

https://erj.ersjournals.com/content/erj/33/6/1345.full.pdf

Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha(1)-antitrypsin deficiency

The aim of the present study was to identify alpha(1)-antitrypsin (alpha(1)-AT)-deficient patients who had rapidly progressive disease. PiZ patients (n = 101) underwent annual lung function measurements over a 3-yr period, and the results were related to factors that may influence decline. The mean annual decline in forced expiratory volume in 1 s (FEV(1)) was 49.9 mL. The greatest FEV(1) decline occurred in the moderate severity group (FEV(1) 50-80% of the predicted value), with a mean annual decline of 90.1 mL, compared with 8.1 mL in the very severe group (FEV(1) <30% pred). However, annual decline in transfer coefficient of the lung for carbon monoxide (K(CO)) was greatest in the severe and very severe groups. When the whole group was divided into tertiles of FEV(1) decline, the fast tertile compared with the slow tertile had more patients with bronchodilator reversibility (BDR) (73 versus 41%; p = 0.010), more males (79 versus 56%; p = 0.048) and lower body mass index (BMI) (24.0 versus 26.1; p = 0.042). Logistic regression analyses confirmed that FEV(1) decline was independently associated with BMI, BDR, exacerbation rate and high physical component 36-item short-form health survey scores. In PiZ alpha(1)-AT-deficient patients, FEV(1) decline was greatest in moderate disease, unlike K(CO) decline, which was greatest in severe disease. The FEV(1) decline showed associations with BDR, BMI, sex and exacerbation rate.

https://erj.ersjournals.com/content/erj/33/6/1338.full.pdf

Rate of progression of lung function impairment in α1-antitrypsin deficiency

Patients with inherited alpha-1-antitrypsin (AAT) deficiency (ZZ-AATD) and severe chronic obstructive pulmonary disease (COPD) frequently suffer from exacerbations. We postulated that inhalation of nebulised AAT would be an effective treatment. We randomly assigned 168 patients to receive twice daily inhalations of 80 mg AAT solution or placebo for 50 weeks. Patients used an eDiary to capture exacerbations. The primary endpoint was time from randomisation to the first event-based exacerbation. Secondary end-points included change in the nature of the exacerbation by the Anthonisen criteria. Safety was also assessed. Time to first moderate or severe exacerbation was at median 112 days (IQR 40, 211) for AAT and 140 days (IQR 72, 142) for placebo, p=0·0952. The mean yearly rate of all exacerbations in the AAT and placebo groups was 3.12 and 2.67 (p=0.31), respectively. More patients receiving AAT reported treatment-related TEAEs (Treatment Emergent Adverse Events) compared to placebo (57·5% versus 46·9%, respectively) and they were more likely to withdraw from the study. After the first year of the study, the rate of safety events in the AAT treated group dropped to that of the placebo group. We conclude that in AATD patients with severe COPD and frequent exacerbations AAT inhalation for 50 weeks showed no effect on time to first exacerbation but may have changed the pattern of the episodes.

https://erj.ersjournals.com/content/erj/54/5/1900673.full.pdf

Efficacy and safety of inhaled α1-antitrypsin in patients with severe α1-antitrypsin deficiency and frequent exacerbations of COPD.

Objective: Severe exacerbations in alpha-1-antitrypsin (AAT)-deficient patients with chronic obstructive pulmonary disease (COPD) and/or emphysema are a major cause of hospitalization. A multicentr...

https://journals.sagepub.com/doi/pdf/10.1177/1753465812438387

Reduction of severe exacerbations and hospitalization-derived costs in alpha-1-antitrypsin-deficient patients treated with alpha-1-antitrypsin augmentation therapy.

Exacerbations in subjects with alpha-1 antitrypsin deficiency receiving augmentation therapy.

This study aimed to investigate the nature and effect of exacerbations in patients with alpha(1)-antitrypsin deficiency and to assess the impact of exacerbations on health status. Furthermore, the relationship of exacerbations to changes in lung function and health status was investigated. In total, 265 patients with severe deficiency (PiZ phenotype) were assessed over 12 months and a subgroup of 87 patients was studied for 3 yrs. Exacerbations were recorded and patients underwent full lung function testing and health status measurement. Exacerbations occurred in 142 patients (54%) over 12 months, with a median duration of 14 days (interquartile range 7-21). Health status was significantly worse in patients with exacerbations, especially those with frequent exacerbations. Neither the presence nor the frequency of exacerbations showed a relationship to decline in forced expiratory volume in one second, but the number of exacerbations was weakly associated with decline in gas transfer of the lung for carbon monoxide. Despite lung function decline, health status did not change significantly over 3 yrs. In conclusion, exacerbations occur commonly in patients with alpha(1)-antitrypsin deficiency and are associated with worse health status. Exacerbations were associated with a decline in the gas transfer of the lung for carbon monoxide over time, but show no relationship to changes in forced expiratory volume in one second. Despite lung function decline, patients do not show a progressive loss in health status.

https://erj.ersjournals.com/content/erj/25/6/992.full.pdf

Exacerbations in {alpha}1-antitrypsin deficiency.

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Exacerbations in {alpha}1-antitrypsin deficiency.