- To see a selection of video clips from the ERS Industry Evening Mini-symposium, please watch the video:
Alpha-1-antitrypsin (AAT) deficiency is one of the world’s most prevalent and serious hereditary disorders.1,2 However, AAT deficiency is easily confused with smoking-induced chronic obstructive pulmonary disease (COPD) or asthma.3,4 This may be why more than 90% of those with AAT deficiency remain undiagnosed.2
The longer AAT deficiency remains undiagnosed, the greater the risk of irreparable lung damage.2,5 Systematic screening provides the opportunity for genetic counselling and lifestyle recommendations (e.g. smoking prevention, smoking cessation, avoidance of high-risk occupations and limiting alcohol intake), as well as consideration for augmentation therapy.6
The industry evening mini-symposium on AAT deficiency, ‘Advances in Genetic COPD: Implementation of AATD Research Findings in Clinical Practice’, was organized during the 28th European Respiratory Society (ERS) International Congress in Paris, France, on 16 September 2018. The symposium elucidated outcomes from clinical trials, recent AAT research and the practical applications of managing patients with AAT deficiency. The symposium was chaired by Prof. Dr Noel Gerard McElvaney and was conducted by an international faculty of leading experts in the field of AAT deficiency.
The evening presentations began with an introduction to AAT deficiency. Prof. Dr Noel Gerard McElvaney discussed AAT deficiency at the cellular level and presented some of his work on neutrophil elastase, demonstrating its role in emphysema. He described the results from a fluorescence resonance energy transfer analysis of neutrophil elastase activity. The experiments demonstrated that increased membrane-bound neutrophil elastase activity in AAT deficiency patients could be normalized by augmentation therapy.
Prof. Dr Robert Stockley presented an overview of the clinical manifestations associated with AAT deficiency. He examined how this deficiency was classically identified and discussed the development of relevant endpoints that are used to describe and quantify disease progression. The use of forced expiratory volume in 1 second (FEV1) was used initially by the US National Institutes of Health to assess the treatment effect of augmentation therapy. Although the data suggest a treatment effect among patients with mid-expiratory flow rates, FEV1 is a poor surrogate of the emphysema process. Dr Stockley described the development of computed tomography (CT) densitometry and its use as the most sensitive measure to quantify the loss of lung tissue associated with AAT deficiency.7 Additionally, Dr Stockley presented results from clinical studies that used CT densitometry as a clinical endpoint. From these results, he concluded that augmentation therapy slows the loss of lung density in patients with AAT deficiency, and emphasized the importance of early detection.
Following the overview of AAT deficiency, Prof. Dr Robert Stockley presented the recently published ERS guidelines for managing AAT deficiency [Miravitlles M, et al. European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1-antitrypsin deficiency. Eur Resp J. 2017;50(5):1700610]. He acknowledged that this new document changes how the disease should be looked at and managed. He emphasized key aspects of the guidelines, mainly how to diagnose AAT deficiency and who should be tested. He also discussed the multidisciplinary approach to the management of patients who have been diagnosed with AAT deficiency.
The symposium transitioned from guidelines to the clinical applications of AAT deficiency, and individual patient cases. Dr Adolfo Baloira provided two case reports; the first was of a 49-year-old male, who was an ex-smoker and had been diagnosed with COPD. Six years later he was tested for AAT deficiency, and was confirmed as having severe deficiency. Once diagnosed, his treatment regimen was modified and his condition stabilised.
Dr Baloira’s second case report was of a 39-year-old male who had been described as a difficult patient. He had emphysema and had tested positive for AAT deficiency. He was a heavy smoker and in general had a very unhealthy lifestyle. Moreover, this patient initially refused treatment. Despite this decision, Dr Baloira and his team followed up with the patient on a monthly basis. The patient eventually learned more about AAT deficiency, stopped smoking and employed a healthier lifestyle. Eventually he was able to start augmentation therapy. His condition stabilised, his hospital admissions decreased and he has started exercising daily.
Apart from the introductory information regarding AAT deficiency, some additional research findings were presented. Prof. Dr Sabina Janciauskiene discussed how AAT can have different molecular forms and these forms affect which circulatory proteins it might bind to. Thus, different complexes may have different biological activities. She proposed that AAT deficiency might be related not only to the quantity of AAT in the body, but also to the quality of the protein.
Building on that insight, Prof. Dr Noel Gerard McElvaney discussed how AAT can affect neutrophil chemotaxis when it is in a specific form. He also discussed how neutrophil elastase reacts in patients with AAT deficiency, and how it leads to many inflammatory processes. He also stated that this situation can be ameliorated by augmentation therapy.
In summary, the industry mini-symposium generated awareness of AAT deficiency as a unique phenotype of COPD and provided the scientific rationale for early detection and appropriate intervention.
Support: The ERS Industry Evening Mini-symposium and the preparation of the associated content by the speakers were sponsored by Grifols.
1. de Serres FJ. Alpha-1 antitrypsin deficiency is not a rare disease but a disease that is rarely diagnosed. Environ Health Perspect. 2003;111:1851–4.
2. Campos MA, Wanner A, Zhang G, et al. Trends in the diagnosis of symptomatic patients with alpha1-antitrypsin deficiency between 1968 and 2003. Chest. 2005;128:1179–86.
3. Rachelefsky G, Hogarth DK. Issues in the diagnosis of alpha 1-antitrypsin deficiency. J Allergy Clin Immunol. 2008;121:833‒8.
4. Strange C, Stoller JK, Sandhaus RA, et al. Results of a survey of patients with alpha-1 antitrypsin deficiency. Respiration. 2006;73:185–90.
5. Vidal R, Blanco I, Casas F, et al. [Guidelines for the diagnosis and management of alpha1-antitrypsin deficiency]. Arch Bronconeumol. 2006;42:645–59.
6. Miravitlles M, Dirksen A, Ferrarotti I, et al. European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1-antitrypsin deficiency. Eur Respir J. 2017;50:1700610.
7. Stockley RA, Parr DG, Piitulainen E, et al. 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.