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

Orphanet Journal of Rare Diseases

Claus Vogelmeier²  Marc Miravitlles¹  Robert A Stockley³ 

[1] Pneumology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain;Universitätsklinikum Gieβen und Marburg, Standort Marburg, Baldingerstraβe, D-35043, Marburg, Germany;Lung Investigation Unit, Queen Elizabeth Hospital Birmingham, Mindelsohn way, Edgbaston, Birmingham B15 2WB, UK

关键词: Augmentation therapy;    Risk factors;    COPD;    Alpha-1 antitrypsin deficiency;   

Others  :  863515
DOI  :  10.1186/1750-1172-8-149

 received in 2013-07-18, accepted in 2013-09-13,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Stockley et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Laurell CB, Eriksson SA: The electrophoretic alpha-1-globulin patttern of serum in alpha-1-antitrypsin deficiency. Scand J Clin Lab 1963, 15:132-140.
• [2]Senior RM, Tegner H, Kuhn C, et al.: The induction of pulmonary emphysema with human leukocyte elastase. Am Rev Respir Dis 1977, 116(3):469-745.
• [3]Sullivan AL, Stockley RA: Proteinases and COPD. Boca Raton, Florida USA: Blackwell Publishing Ltd; 2007:349-366. [Chronic Obstructive Pulmonary Disease]
• [4]Schluchter MD, Stoller JK, Barker AF, Buist AS, Crystal RG, Donohue JF, et al.: Feasibility of a clinical trial of augmentation therapy for alpha-1-antitrypsin deficiency. Am J Respir Crit Care Med 2000, 161:796-801.
• [5]Bruce RM, Cohen BH, Diamond EL, Fallat RJ, Knudson RJ, Lebowitz MD, et al.: Collaborative study to assess risk of lung disease in Pi MZ phenotype subjects. Am Rev Respir Dis 1984, 130:386-390.
• [6]Hubbard RC, Sellers S, Czerski D, Stephens L, Crystal RG: Biochemical efficacy and safety on monthly augmentation therapy for alpha-1-antitrypsin deficiency. JAMA 1988, 260:1259-1264.
• [7]Fregonese L, Ferrari F, Fumagalli M, Luisetti M, Stolk J, Iadarola P: Long-term variability of Desmosine/Isodesmosine as biomarker in alpha-a-antitrypsin deficiency-related COPD. COPD 2011, 8:329-333.
• [8]Carter RI, Mumford RA, Treonze KM, Finke PE, Davies P, Si Q, et al.: The fibrinogen cleavage product Aa-Val360, a specific marker of neutrophil elastase activity in vivo. Thorax 2011, 66:686-691.
• [9]The Alpha-l-Antitrypsin Deficiency Registry Study Group: Survival and FEVl decline in individuals with severe deficiency of alpha-l antitrypsin. Am J Respir Crit Care Med 1998, 158:49-59.
• [10]Seersholm N, Wencker M, Banik N, et al.: Does alpha1-antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary alpha1-antitrypsin deficiency? Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL) alpha1-AT study group. Eur Respir J 1997, 10:2260-2263.
• [11]Wencker M, Fuhrmann B, Banik N, Konietzko N: Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen. Longitudinal follow-up of patients with alpha (1)-protease inhibitor deficiency before and during therapy with IV alpha(1)-protease inhibitor. Chest 2001, 119:737-744.
• [12]Chapman KR, Stockley RA, Dawkins C, Wilkes MM, Navickis RJ: Augmentation therapy for alpha1 antitrypsin deficiency: a meta-analysis. COPD 2009, 6:177-184.
• [13]Parr DG, Stoel BC, Stolk J, Stockley RA: Validation of computed tomography lung densitometry for monitoring emphysema in alpha-1 antitrypsin deficiency. Thorax 2006, 61:485-490.
• [14]Dawkins PA, Dawkins CL, Wood AM, Nightingale PG, Stockley JA, Stockley RA: Rate of progression of lung function impairment in alpha-1 antitrypsin deficiency. Eur Respir J 2009, 33:1338-1344.
• [15]Dirksen A, Dijkman JH, Madsen F, Stoel B, Hutchison DC, Ulrik CS, et al.: A randomized clinical trial of alpha-1-antitrypsin augmentation therapy. Am J Respir Crit Care Med 1999, 160:1468-1472.
• [16]Dirksen A, Piitulainen E, Parr DG, Deng C, Wencker M, Shaker SB, Stockley RA: Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency. Eur Respir J 2009, 33:1345-1353.
• [17]Gøtzsche PC, Johansen HK: Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease (Review). Cochrane Database Syst Rev 2010., 7CD007851
• [18]Stockley RA, Parr DG, Piitulainen E, Stolk J, Stoel BC, Dirksen A: Therapeutic efficacy of alpha-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry. Respir Res 2010, 11:136. BioMed Central Full Text
• [19]Dowson LJ, Guest PJ, Stockley RA: Longitudinal changes in physiological, radiological, and health status measurements in alpha-1 antitrypsin deficiency and factors associated with decline. Am J Respir Crit Care Med 2001, 164:1805-1809.
• [20]Stolk J, Cooper BG, Stoel B, Rames A, Rutman O, Soliman S, Stockley R: Retinoid treatment of emphysema in patients on the Alpha-1 International Registry. The REPAIR study: study design, methodology and quality control of study assessments. Ther Adv Respir Dis 2010, 4:319-332.
• [21]Parr DG, Dirksen A, Piitulainen E, Deng C, Wencker M, Stockley RA: Exploring the optimum approach to the use of CT densitometry in a randomised placebo-controlled study augmentation therapy in alpha-1-antitrypsin deficiency. Respir Res 2009, 10:75. BioMed Central Full Text
• [22]Piras B, Ferrarotti I, Lara B, Martinez MT, Bustamante A, Ottaviani S, Pirina P, Luisetti M, Miravitlles M: Characteristics of Italian and Spanish patients with alpha-1-antitrypsin deficiency: Identifying clinical phenotypes. Eur Respir J 2012., 2012in press
• [23]Stoller JK, Sandhaus RA, Turino G, Dickson R, Rodgers K, Strange C: Delay in diagnosis of alpha-1 antitrypsin deficiency. A continuing problem. Chest 2005, 128:1989-1994.
• [24]Köhlein T, Janciauskiene S, Welte T: Diagnostic delay and clinical modifiers in alpha-1 antitrypsin deficiency. Ther Adv Respir Dis 2010, 4:279-287.
• [25]Seersholm N, Kok-Jensen A, Dirksen A: Survival of patients with severe alpha-1 antitrypsin deficiency with special reference to non-index cases. Thorax 1994, 49:695-698.
• [26]Wood AM, Needham M, Simmonds MJ, Newby PR, Gough SC, Stockley RA: Phenotypic differences in alpha 1 antitrypsin deficient sibling pairs may relate to genetic variation. Journal of COPD 2008, 5:353-359.
• [27]Sveger T: Liver disease in a1 antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 1976, 294:1316-1321.
• [28]Corda L, Bertella E, La Piana GE, Boni E, Redolfi S, Tantucci C: Inhaled corticosteroids as additional treatment in alpha-1 antitrypsin-deficiency-related COPD. Respiration 2008, 76:61-68.
• [29]DeMeo D, Sandhaus RA, Barker AF, Brantly ML, Eden E, Gerard N, et al.: Determinants of airflow obstruction in severe alpha-1 antitrypsin deficiency. Thorax 2007, 62:805-812.
• [30]Castaldi PJ, DeMeo DL, Kent DM, Campbell EJ, Barker AF, Brantly ML, et al.: Development of predictive models for airflow obstruction in alpha-1 antitrypsin deficiency. Am J Epidemiol 2009, 170:1005-1013.
• [31]Mayer AS, Stoller JK, Ruttenber AJ, Strand M, Sandhaus RA, Newman LS: Risk factors for symptom onset in PI*Z alpha-1 antitrypsin deficiency. Int J Chron Obst Pulmon Dis 2007, 1:485-492.
• [32]Needham M, Stockley RA: Exacerbations in alpha-1 antitrypsin deficiency. Eur Respir J 2005, 25:992-1000.
• [33]Silverman EK, Pierce JA, Province MA, Rao DC, Campbell EJ: Variability of pulmonary function in alpha-1 antitrypsin deficiency: clinical correlates. Ann Intern Med 1989, 111:982-991.
• [34]Dowson LJ, Guest PJ, Stockley RA: The relationship of chronic sputum expectoration to physiologic, radiologic, and health status characteristics in alpha-1antitrypsin deficiency (PiZ). Chest 2002, 122:1247-1255.
• [35]Seersholm N: Body mass index and mortality in patients with severe alpha-1 antitrypsin deficiency. Respir Med 1997, 91:77-82.
• [36]Piitulainen E, Tornling G, Eriksson S: Effect of age and occupational exposure to airway irritants on lung function in non-smoking individuals with alpha-1-antitrypsin deficiency (PiZZ). Thorax 1997, 52:244-248.
• [37]Mayer AS, Stoller JK, Bartelson BB, Ruttenber AJ, Sandhaus RA, Newman LS: Occupational exposure risks in individuals with PI*Z alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2000, 162:553-558.
• [38]Wood AM, Harrison RM, Semple S, Ayres JG, Stockley RA: Outdoor air pollution is associated with disease severity in alpha-1 antitrypsin deficiency. Eur Respir J 2009, 34:346-353.
• [39]Tirado-Conde G, Lara B, Casas F, Blanco I, Bustamante A, Cadenas S, Martínez MT, Lázaro L, Torres M, Hernández Pérez JM, et al.: Factors associated with the evolution of lung function in patients with alpha-1-antitrypsin deficiency in the Spanish Registry. Arch Bronconeumol 2011, 47:495-503.
• [40]Seersholm N, Kok-Jensen A: Clinical features and prognosis of life time non-smokers with severe alpha-1-antitrypsin deficiency. Thorax 1998, 53:265-268.
• [41]Campos MA, Alazemi S, Zhang G, Salathe M, Wanner A, Sandhaus RA, Baier H: Clinical characteristics of subjects with symptoms of alpha-1 antitrypsin deficiency older than 60 years. Chest 2009, 135:600-608.
• [42]Seersholm N, Dirksen A, Kok-Jensen A: Airways obstruction and two year survival in patients with severe alpha 1-antitrypsin deficiency. Eur Respir J 1994, 7:1985-1987.
• [43]Tanash HA, Nilsson PM, Nilsson JA, Piitulainen E: Clinical course and prognosis of never-smokers with severe alpha-1 antitrypsin deficiency (PiZZ). Thorax 2008, 63:1091-1095.
• [44]Bernspang E, Wollmer P, Sveger T, Piitulainen E: Lung function in 30-year-old alpha-1 antitrypsin deficient individuals. Respir Med 2009, 103:861-865.
• [45]Holme J, Stockley JA, Stockley R: Age related development of respiratory abnormalities in non-index α-1antitrypsin deficient studies. Respir Med 2013, 107:387-393.
• [46]Soler-Cataluña JJ, Martinez-García MA, Roman Sánchez P, Salcedo E, Navarro M, Ochando R: Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax 2005, 60:925-931.
• [47]Stockley RA, Burnett D: Alpha1-antitrypsin and leukocyte elastase in infected and non-infected sputum. Am Rev Respir Dis 1979, 120:1081-1086.
• [48]Hill AT, Campbell EJ, Bayley DL, Hill SL, Stockley RA: Evidence for excessive bronchial inflammation during an acute exacerbation of chronic obstructive pulmonary disease in patients with alpha-1-antitrypsin deficiency (PiZ). Am J Respir Crit Care Med 1999, 160:1968-1975.
• [49]Lieberman J: Augmentation therapy reduces frequency of lung infections in antitrypsin deficiency: a new hypothesis with supporting data. Chest 2000, 118:1480-1485.
• [50]Stockley RA, Bayley DL, Unsal I, Dowson LJ: The effect of augmentation therapy on bronchial inflammation in alpha1-antitrypsin deficiency. Am J Respir Crit Care Med 2002, 165:1494-1498.
• [51]Wencker M, Denker J, Konietzko N: Serial measurements of FEV1 over 12 years in a patient with alpha-1-protease inhibitor deficiency: influence of augmentation therapy and infections. Respiration 1994, 61:195-198.
• [52]Campos MA, Alazemi S, Zhang G, Wanner A, Salathe M, Baier H, Sandhaus RA: Exacerbations in subjects with alpha-1 antitrypsin deficiency receiving augmentation therapy. Respir Med 2009, 103:1532-1539.
• [53]Stolk J, Nieuwenhuizen W: High dose intravenous AAT and plasma neutrophil derived fibrinogen fragments. Thorax 2005, 60:84-85.
• [54]Miravitlles M, Murio C, Guerrero T, Gisbert R, on behalf of the DAFNE study group: Costs of chronic bronchitis and COPD. A one year follow-up study. Chest 2003, 123:784-791.
• [55]Garcia-Aymerich J, Serra Pons I, Mannino DM, Maas AK, Miller DP, Davis KJ: Lung function impairment, COPD hospitalisations and subsequent mortality. Thorax 2011, 66:585-590.
• [56]Brand P, Schulte M, Wencker M, Herpich CH, Klein G, Hanna K, et al.: Lung deposition of inhaled alpha-1-proteinase inhibitor in cystic fibrosis and alpha-1-antitrypsin deficiency. Eur Respir J 2009, 34:354-360.
• [57]International Study Evaluating the Safety and Efficacy of Inhaled, Human: Alpha-1 Antitrypsin Deficient Patients With Emphysema. 2010. [Alpha-1 Antitrypsin (AAT)] ClinicalTrials.gov NCT01217671
• [58]Miravitlles M, de Gracia J, Rodrigo MJ, Cruz MJ, Vendrell M, Vidal R, Morell F: Specific antibody response against the 23-valent pneumococcal vaccine in patients with alpha-1-antitrypsin deficiency with and without bronchiectasis. Chest 1999, 116:946-952.
• [59]Parr DG, Guest PG, Reynolds JH, Dowson LJ, Stockley RA: Prevalence and impact of bronchiectasis in alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2007, 176:1215-1221.
• [60]El-Kassimi FA, Warsy AS, Uz-Zaman A, Pillai DK: Alpha-1 antitrypsin serum levels in widespread bronchiectasis. Respir Med 1989, 83:119-121.
• [61]O’Brien C, Guest PJ, Hill SL, Stockley RA: Physiological and radiological characterisation of patients diagnosed with chronic obstructive pulmonary disease in primary care. Thorax 2000, 55:635-642.
• [62]Martínez-Garcia MA, Soler-Cataluña JJ, Donat Y, Catalán S, Agramunt M, Ballestín J, et al.: Factors associated with bronchiectasis in chronic obstructive pulmonary disease patients. Chest 2011, 140:1130-1137.
• [63]Patel IS, Vlahos I, Wilkinson TMA, Lloyd-Owen SJ, Donaldson GC, Wilks M, et al.: Bronchiectasis, exacerbation índices, and inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004, 170:400-407.
• [64]American Thoracic Society/ European Respiratory Society Statement: Standards for the diagnosis and management of individuals with alpha1-antitrypsin deficiency. Am J Respir Crit Care Med 2003, 168:818-900.
• [65]Luisetti M, Balfour-Lynn IM, Johnson S, Miravitlles M, Strange C, Trapnell B, van Bronswijk H, Vogelmeier C: Perspectives for improving the evaluation and access of therapies for rare lung diseases in Europe. Respir Med 2012, 106:759-768.
• [66]Holme J, Stockley RA: CT scan appearance, densitometry and health status in protease inhibitor SZ a1-antitrypsin deficiency. Chest 2009, 136:1284-1290.
• [67]Soy D, de la Roza C, Lara B, Esquinas C, Torres A, Miravitlles M: Alpha-1-antitrypsin deficiency: optimal therapeutic regimen based on population pharmacokinetics. Thorax 2006, 61:1059-1064.