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Augmentation therapy for alpha-1 antitrypsin deficiency: towards a personalised approach.

ABSTRACT: Intravenous augmentation therapy is the only specific treatment available for emphysema associated with alpha-1 antitrypsin deficiency. Despite large observational studies and limited interventional studies there remains controversy about the efficacy of this treatment due to the impracticality of conducting adequately powered studies to evaluate the rate of decline in lung function, due to the low prevalence and the slow progression of the disease. However, measurement of lung density by computed tomography is a more specific and sensitive marker of the evolution of emphysema and two small placebo-controlled clinical trials have provided evidence supporting a reduction in the rate of decline in lung density with augmentation therapy.Where augmentation therapy has become available there has been little consideration of a structured approach to therapy which is often introduced on the basis of functional impairment at diagnosis. Data from registries have shown a great variability in the evolution of lung disease according to patient acquisition and the presence of recognised risk factors. Avoidance of risk factors may, in many cases, stabilise the disease. Since augmentation therapy itself will at best preserve the presenting level of lung damage yet require intravenous administration for life with associated costs, identification of patients at risk of continued rapid or long term progression is essential to select those for whom this treatment can be most appropriate and hence generally more cost-effective. This represents a major reconsideration of the current practice in order to develop a consistent approach to management world wide.The current review assesses the evidence for efficacy of augmentation therapy and considers how the combination of age, physiological impairment, exacerbation history and rate of decline in spirometry and other measures of emphysema may be used to improve therapeutic decision making, until a reliable predictive biomarker of the evolution of lung impairment can be identified. In addition, individual pharmacokinetic studies may permit the selection of the best regimen of administration for those who need it.The rarity and variable characteristics of the disease imply the need for an individualised approach to therapy in specialised centres with sufficient experience to apply a systematic approach to monitoring and management.

SUBMITTER: Stockley RA

PROVIDER: S-EPMC3852071 | biostudies-other | 2013 Sep

REPOSITORIES: biostudies-other

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Augmentation therapy for alpha-1 antitrypsin deficiency: towards a personalised approach.

Stockley Robert A RA Miravitlles Marc M Vogelmeier Claus C

Orphanet journal of rare diseases 20130924

<h4>Background</h4>Intravenous augmentation therapy is the only specific treatment available for emphysema associated with alpha-1 antitrypsin deficiency. Despite large observational studies and limited interventional studies there remains controversy about the efficacy of this treatment due to the impracticality of conducting adequately powered studies to evaluate the rate of decline in lung function, due to the low prevalence and the slow progression of the disease. However, measurement of lun ...[more]

PMID: 24063809

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Project description:BackgroundAlpha-1 antitrypsin deficiency is an inherited disorder that can cause chronic obstructive pulmonary disease (COPD). People who smoke are more seriously affected and have a greater risk of dying from the disease. Therefore, the primary treatment is to help people give up smoking. There are now also preparations available that contain alpha-1 antitrypsin, but it is uncertain what their clinical effect is.ObjectivesTo review the benefits and harms of augmentation therapy with intravenous alpha-1 antitrypsin in patients with alpha-1 antitrypsin deficiency and lung disease.Search methodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed and ClinicalTrials.gov to 25 March 2016.Selection criteriaWe included randomised trials of augmentation therapy with alpha-1 antitrypsin compared with placebo or no treatment.Data collection and analysisThe two review authors independently selected trials, extracted outcome data and assessed the risk of bias.Main resultsWe included three trials (283 participants in the analyses) that ran for two to three years. All participants were ex- or never-smokers and had genetic variants that carried a high risk of developing COPD. Only one trial reported mortality data (one person of 93 died in the treatment group and three of 87 died in the placebo group). There was no information on harms in the oldest trial. Another trial reported serious adverse events in 10 participants in the treatment group and 18 participants in the placebo group. In the most recent trial, serious adverse events occurred in 28 participants in each group. None of the trials reported mean number of lung infections or hospital admissions. In the two trials that reported exacerbations, there were more exacerbations in the treatment group than in the placebo group, but the results of both trials included the possibility of no difference. Quality of life was similar in the two groups. Forced expiratory volume in one second (FEV1) deteriorated more in participants in the treatment group than in the placebo group but the confidence interval (CI) included no difference (standardised mean difference -0.19, 95% CI -0.42 to 0.05; P = 0.12). For carbon monoxide diffusion, the difference was -0.11 mmol/minute/kPa (95% CI -0.35 to 0.12; P = 0.34). Lung density measured by computer tomography (CT) scan deteriorated significantly less in the treatment group than in the placebo group (mean difference (MD) 0.86 g/L, 95% CI 0.31 to 1.42; P = 0.002). Several secondary outcomes were unreported in the largest and most recent trial whose authors had numerous financial conflicts of interest.Authors' conclusionsThis review update added one new study and 143 new participants, but the conclusions remain unchanged. Due to sparse data, we could not arrive at a conclusion about the impact of augmentation therapy on mortality, exacerbations, lung infections, hospital admission and quality of life, and there was uncertainty about possible harms. Therefore, it is our opinion that augmentation therapy with alpha-1 antitrypsin cannot be recommended.

Project description:BackgroundComputed tomography (CT) lung densitometry has been demonstrated to be the most sensitive and specific outcome measure for the assessment of emphysema-modifying therapy, but the optimum densitometric index has yet to be determined and targeted sampling may be more sensitive than whole lung assessment. The EXAcerbations and CT scan as Lung Endpoints (EXACTLE) trial aimed to clarify the optimum approach to the use of CT densitometry data for the assessment of alpha 1-antitrypsin (AAT) augmentation therapy on the progression of emphysema in AAT deficiency (AATD).MethodsPatients with AATD (n = 77) were randomised to weekly infusions of 60 mg/kg human AAT (Prolastin) or placebo over 2 to 2.5 years. Lung volume was included as a covariate in an endpoint analysis and a comparison was made of different CT densitometric indices (15th percentile lung density [PD15], mean lung density [MLD] and voxel index at a threshold of -910 [VI-910] and -950 [VI-950] Hounsfield Units) obtained from whole lung scans at baseline and at 24 to 30 months. Targeted regional sampling was compared with whole lung assessment.ResultsWhole lung analysis of the total change (baseline to last CT scan) compared with placebo indicated a concordant trend that was suggestive of a treatment effect for all densitometric indices (MLD [1.402 g/L, p = 0.204]; VI-910 [-0.611, p = 0.389]; VI-950 [-0.432, p = 0.452]) and that was significant using PD15 (1.472 g/L, p = 0.049). Assessment of the progression of emphysema in the apical, middle and basal regions of the lung by measurement with PD15 showed that this treatment effect was more evident when the basal third was sampled (1.722 g/L, p = 0.040). A comparison between different densitometric indices indicated that the influence of inspiratory variability between scans was greatest for PD15, but when adjustment for lung volume was made this index was the most sensitive measure of emphysema progression.ConclusionPD15 is the most sensitive index of emphysema progression and of treatment modification. Targeted sampling may be more sensitive than whole lung analysis.Trial registrationRegistered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.

Project description:IntroductionAlpha-1 antitrypsin (AAT) deficiency is an autosomal co-dominant genetic condition that predisposes individuals to pulmonary and hepatic disease, and in severe cases is treated with augmentation by intravenous infusion. Our aim was to assess patient reluctance to transition to self-administered augmentation of alpha-1-antitrypsin, during the pandemic of SARS-CoV-2.MethodsA phone questionnaire was administered to 22 patients with severe alpha-1-antitrypsin deficiency who were currently receiving AAT augmentation therapy. Inclusion criteria included patients [Formula: see text] 18 years old, diagnosed with AATD, and receiving intravenous AAT protein augmentation therapy. Information was gathered regarding demographics, perspectives on transitioning to self-administered treatment, and anxiety and depression prevalence. Results were collected anonymously using REDCap. Joint and marginal statistical analysis was done to quantify links between participants' willingness to transition to self-infusion and correlations with sex, age, years of therapy, anxiety, and depression.ResultsOf 22 patients, 14 were male and eight were female. Ages ranged from 36 to 79 years, with an average of 62.5. Genotypes were ZZ (14), MZ (3), and SZ (2) among others. Average length of intravenous augmentation was 9.5 years. The majority, 16 participants, were aware self-infusion was an option. Eight participants were willing to consider transitioning to self-infusion if trained and educated. Eight patients reported that fear of COVID-19 transmission influenced their decision-making. Above-normal anxiety, and depression scores, were found in four, and six patients, respectively. Neither sex, age, years of treatment, anxiety, or depression were found to be associated with willingness to consider self-infusion therapy.ConclusionsAlthough there are many reasons AATD patients may benefit from AAT self-infusion, including decreased exposure to SARS-CoV-2, the majority preferred home nurse-infused therapy.

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Augmentation therapy for alpha-1 antitrypsin deficiency: towards a personalised approach.

Publications

Augmentation therapy for alpha-1 antitrypsin deficiency: towards a personalised approach.

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