Survival and FEV₁Decline in Individuals with Severe Deficiency of α₁-Antitrypsin

Abstract

Subjects >= 18 yr of age with serum alpha1-antitrypsin (alpha1-AT) levels <= 11 microM or a ZZ genotype were followed for 3.5 to 7 yr with spirometry measurements every 6 to 12 mo as part of a National Heart, Lung, and Blood Institute Registry of Patients with Severe Deficiency of Alpha-1-Antitrypsin. Among all 1,129 enrollees, 5-yr mortality was 19% (95% CI: 16 to 21%). In multivariate analyses of 1, 048 subjects who had been contacted >= 6 mo after enrolling, age and baseline FEV1% predicted were significant predictors of mortality. Results also showed that those subjects receiving augmentation therapy had decreased mortality (risk ratio [RR] = 0.64, 95% CI: 0. 43 to 0.94, p = 0.02) as compared with those not receiving therapy. Among 927 subjects with two or more FEV1 measurements >= 1 yr apart, the mean FEV1 decline was 54 ml/yr, with more rapid decline in males, those aged 30 to 44 yr, current smokers, those with FEV1 35 to 79% predicted, and those who ever had a bronchodilator response. Among all subjects, FEV1 decline was not different between augmentation-therapy groups (p = 0.40). However, among subjects with a mean FEV1 35 to 49% predicted, FEV1 decline was significantly slower for subjects receiving than for those not receiving augmentation therapy (mean difference = 27 ml/yr, 95% CI: 3 to 51 ml/yr; p = 0.03). Because this was not a randomized trial, we cannot exclude the possibility that these differences may have been due to other factors for which we could not control.

Alpha One Antitrypsin Deficiency: From Gene to Treatment

“…Although this study was small, it was enough for the product to gain a license for treatment of patients with the PiZ or null phenotypes [75] in the USA, Canada and parts of Europe. Observational work in the USA has since supported the use of AAT replacement, showing a slower decline in lung function in those with an FEV 1 of 35–49% predicted when receiving AAT augmentation [76]. Similar work in Europe has concurred [77, 78], whilst a Canadian study reported a beneficial effect but failed to show the association with baseline FEV 1 [79].…”

Treatment of lung disease in alpha-1 antitrypsin deficiency: a systematic review

“…The largest observational study analyzed data from 1,129 patients in the US AATD registry split into three groups “always receiving” (n=390), “partly receiving” (n=357), or “never receiving” (n=382) augmentation 33. Dosing was not standardized with only 51.3% being dosed weekly throughout the study.…”

“…Seventy-five patients had ≥1 exacerbation during the 18 months follow-up required prior to commencement of augmentation. Dosing regimens were not standardized with an average dose of 60.7±3.8 mg/kg/week (Table S1) different from other studies,33 and many patients had missing data. Fewer exacerbations were seen (1.2±1.6 vs 1.0±2.2 pre- vs posttreatment; P <0.01), an effect more marked in those exacerbating previously (2.0±1.6 vs 1.4±2.7; P <0.01).…”

A Fast Amplification-Reverse Hybridization Assay Kit to Detect the Most Frequent Deficient Variants in the Alpha-1-Antitrypsin Gene

“…Any discrepancies between the results of the assay and the quantitative test, as shown before, should prompt the physicians to ask for a plasma IEF or a more sophisticated molecular approach, such as allele-specific amplification, or sequence analysis [4]. Another, minor clinical application of the amplification-reverse hybridization assay kit, is to confirm a ZZ genotype in patients in whom, in spite of lacking precise AAT characterization, AAT replacement therapy has already been started [14]. …”