Abstract
BackgroundIntravenous 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.The problemWhere 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.Purpose of this reviewThe 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.SummaryThe 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.
Highlights
Our understanding of the pathophysiology of COPD, but in particular emphysema was largely instigated by the observation that α1 antitrypsin deficiency (AATD) was associated with the early onset of basal panlobular emphysema [1]
Since AAT became characterised as an inhibitor of serine proteinases, data eventually showed that neutrophil elastase (NE) could produce emphysema like
What is the data? There is no doubt that augmentation therapy given intravenously increases the nadir antigenic AAT level to one that is consistent with the lower level for the heterozygote (MZ pheno/genotype) that carries no or, at least, very little risk to developing significant COPD [5], and above that for the SZ heterozygote where controversy still continues about whether such subjects are or are not at increased risk
Summary
Our understanding of the pathophysiology of COPD, but in particular emphysema was largely instigated by the observation that α1 antitrypsin deficiency (AATD) was associated with the early onset of basal panlobular emphysema [1]. The inflammatory burden associated with severe exacerbations may still accelerate the lung damage in patients with AATD, as illustrated in a published case study where, after a period of stabilisation of lung function with augmentation therapy, FEV1 decline accelerated after a series of admissions for exacerbations despite the continuation of the augmentation therapy [51] (Figure 2) This observation suggests that in some patients and/or in some situations the current dosage based on the stable state nadir plasma levels of heterozygotes or the route of administration may be insufficient to prevent lung deterioration [52] and perhaps bolus or inhaled therapy at the start of an exacerbation might prove effective [53].
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