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

Abstract

Background: 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.

The problem: 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.

Purpose of this review: 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.

Summary: 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.

Figure 1

The decline in FEV1 and Kco expressed as a % predicted is shown over time for a 43 year old female from the UK registry who stopped smoking after diagnosis in 2005.

Figure 2

The decline in FEV1 (l) for a 41 year-old male. Footnote: Between 1980 and 1985 a severe drop in FEV1 from 2.7 to 1.7 liters was noted. Started with augmentation therapy in 1985, the lung function parameters stabilised over a period of approximately 3 years. The number of severe pulmonary infections requiring hospitalisation increased from 1989 and were accompanied by a rapid decrease in FEV1. Published from reference 46 with permission from S. Karger AG Basel.

Figure 3

Recommendation for augmentation therapy. A new scale. Indications for augmentation therapy can vary from not to definitely indicated. Several factors will influence where the patient is placed on the scale including age, baseline lung function (FEV1 and/or Kco) and rate of decline expressed as a% predicted. A potential example is to divide the scale into quartiles with the lowest being age 60+ and/or lung function >80% predicted and/or decline < 0.1% predicted /year. The second quartile could be 50–60 years age and/or lung function 60-80% predicted and/or decline of 0.1-0.5% predicted /year. Third quartile 40–50 years age and/or lung function 40-60% predicted and/or decline of 0.5-1.0% predicted/year. Fourth quartile 30–40 years age and/or lung function 30-40% predicted and /or decline >1.0% predicted/year. This concept is summarised in Table 2. Footnote: Case 1. 75 years-old male, ex-smoker, or other non-index case with normal physiology. Indication for augmentation therapy 0% Case 2. 61 years-old male, exsmoker of 40 pack-years, index case. FEV1 = 58% predicted with KCO = 75% predicted. One ambulatory exacerbation the previous year. Previous spirometry one year ago FEV1 = 60% and 2 years ago = 62%. Indication for augmentation therapy 70%. Case 3. 42 years-old female, index case, exsmoker of 14 pack-years, FEV1 = 42% predicted and KCO = 32% predicted. Hospitalisation for exacerbation 5 months ago. Previous spirometry one year ago FEV1 = 51% predicted or patient with declining physiology despite smoking cessation and maximal usual therapy as in the patient in Figure 1 Indication for augmentation therapy 100%.