Marion Wencker

Long-term treatment of alpha1-antitrypsin deficiency-related pulmonary emphysema with human alpha1-antitrypsin. Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL)-alpha1-AT-study group

α1-antitrypsin (α1-AT) is one of the most important human protease inhibitors, providing more than 90% of the antiproteolytic capacity of the lower respiratory tract [1]. Mutation of the α1-AT gene is one of the most frequently inherited abnormalities in humans. The most common mutation of the protease inhibitor is the Z variant, which is carried by 1 in 50 people of Northern European descent [2, 3]. Homozygocity for the Z allele is associated with α1-AT plasma levels in only 15% of normal subjects [4]. Subjects with this defect have an increased risk of pulmonary and liver disease [5]. Pulmonary disease is thought to be due to an imbalance of proteases and antiproteases. Surplus proteases result in an accelerated degradation of lung connective tissue. Many affected individuals suffer from early onset pulmonary emphysema that becomes symptomatic in the third or fourth decade [6]. It is therefore rational to augment α1-AT plasma levels to reduce the protease burden and to increase the protective antiprotease shield of the lower respiratory tract. Since 1989 i.v. therapy with human α1-AT has been available in several countries. For short-term i.v. therapy with human plasma-derived α1-AT, safety and biochemical efficacy was demonstrated [7–9]. However, although several thousand patients receive augmentation therapy on an regular basis, data on safety and tolerability of long-term treatment with α1-AT is only anecdotal [10, 11]. Also, it is not clear if biochemical efficacy also results in a decelerated course of pulmonary disease. Parameters correlating best with the clinical outcome of patients with chronic obstructive pulmonary disease are the decline in forced expiratory volume in one second (∆FEV1) and mortality. Because of the slow progression of the disease, the high intraand interindividual variations of lung function, and the small number of identified patients with α1-AT deficiency, investigators have found it difficult to conduct a controlled study to prove clinical efficacy [12] of α1-AT replacement therapy. The aim of this study was to prospectively evaluate results of long-term i.v. α1-AT augmentation in patients with pulmonary emphysema secondary to hereditary α1-AT deficiency, and particularly to monitor adverse reactions and changes in lung function.Alpha1-antitrypsin (alpha1-AT) deficiency is a genetic disorder characterized by low serum levels of alpha1-AT and a high risk of pulmonary emphysema at a young age. The resulting surplus of proteases, mainly of neutrophil elastase, can be balanced by i.v. augmentation with alpha1-AT. However, it is not clear if affected patients benefit from long-term augmentation therapy and no long-term safety data are available. We examined 443 patients with severe alpha1-AT deficiency and pulmonary emphysema receiving weekly i.v. infusions of 60 mg x kg body weight(-1) alpha1-AT in addition to their regular medication. The progression of the disease was assessed by repeated lung function measurements, particularly the decline in forced expiratory volume in one second (deltaFEV1). Four hundred and forty three patients with alpha1-AT deficiency tolerated augmentation therapy well with few adverse reactions. The deltaFEV1 in 287 patients with available follow-up data was 57.1+/-31.1 mL x yr(-1). Stratified for baseline FEV1, the decline was 35.6+/-21.3 mL in the 108 patients with an initial FEV1 <30% and 64.0+/-26.4 mL in the 164 with FEV1 30-65% of predicted normal (p=0.0008). The remaining 15 patients had an initial FEV1 >65% pred. Long-term treatment with i.v. alpha1-antitrypsin in patients with severe alpha1-antitrypsin deficiency is feasible and safe. The decline in forced expiratory volume in one second is related to the initial forced expiratory volume in one second as in alpha1-antitrypsin deficient patients not receiving augmentation therapy.

National Survey of Guideline-Compliant COPD Management Among Pneumologists and Primary Care Physicians

The aim of this survey was to investigate guideline-compliant COPD management among pneumologists and primary care physicians (PCPs). A multiple-choice questionnaire was sent out to 1836 PCPs and 863 pneumologists in Germany. The questions focused on the key aspects of current national and international COPD guidelines. Four hundred eighty-six PCPs and 359 pneumologists participated in the study. It was found that pneumologists held the GOLD guideline in high regard (60.4%), while PCPs tended to follow the German National COPD guideline (66.5%). Differences were also found with regard to diagnosis and classification of COPD on the basis of spirometric and clinical criteria. The current GOLD classification of moderate and severe COPD was used by 36.2% and 23.4% of the pneumologists, respectively, and by 32.1% and 20.2% of the PCPs. Although PCPs and pneumologists endorsed educational measures to help patients quit smoking, implementation was still inadequate. The two most important therapeutic goals were to improve quality of life and prevent exacerbations. Except for the criteria for the use of steroids and the implementation of pulmonary rehabilitation measures, treatment of COPD based on severity class was largely in compliance with guidelines. However, appreciably more PCPs than pneumologists incorrectly assessed the evidence-based clinical benefits of various therapeutic measures. The study shows that, despite the popularity of COPD guidelines, deficits exist among pneumologists and PCPs with respect to diagnosis and treatment of COPD and practical implementation of educational measures. These deficiencies in guideline conformity might be best addressed through targeted continuing-education measures.

Detection of obstructive sleep apnoea by an electronic nose

Diagnosis of obstructive sleep apnoea syndrome (OSAS) is technically demanding, cost-intensive and time-consuming. The measurement of volatile organic compounds by an electronic nose is an innovative method that determines distinct molecular patterns of exhaled breath in different patient groups. We addressed the following questions: What is the diagnostic accuracy of an electronic nose in the detection of OSAS and the ability to detect effects of standard therapy in patients with OSAS? Are these results related to changes in distinct markers of airway inflammation and extracellular remodelling? We included 40 OSAS patients and 20 healthy controls. Exhaled breath of all participants was analysed using the Cyranose 320 electronic nose. Pharyngeal washings were performed to sample the upper airway compartment. For statistical analysis linear discriminant analysis was employed. We identified a linear discriminant function separating OSAS from control (p<0.0001). The corresponding area under the receiver-operating curve was 0.85 (95% CI 0.75–0.96; sensitivity 0.93 and specificity 0.7). In pharyngeal washing fluids of OSAS patients, we observed higher levels of &agr;1-antitrypsin and markers of extracellular remodelling compared to controls. The electronic nose can distinguish between OSAS patients and controls with high accuracy.

Safety of biweekly alpha1 antitrypsin treatment in the RAPID program

α1-antitrypsin (α1-AT) deficiency is a hereditary disorder characterised by an abnormally low concentration of functional α1-AT in blood and tissues [1]. The primary role of α1-AT is to protect elastin-containing tissues, most notably the lung, against the destructive activity of proteolytic enzymes [2]. Patients with severe α1-AT deficiency present with serum α1-AT concentrations <11 μM and are prone to destruction of the lung tissue, often developing respiratory symptoms and emphysema in the fourth or fifth decade of life [3, 4]. Administration of 120 mg·kg−1 α1-antitrypsin on a biweekly basis was safe and well tolerated http://ow.ly/CVbz30lUBum