[Rare diseases in pulmonary medicine and its challenges]. / Seltene Erkrankungen in der Pneumologie und damit verbundene Herausforderungen.

The importance of rare disease is appreciated by all parties and tremendous effort is made to increase the knowledge about the individual disorders and improve the care of affected patients. Political initiatives on a European level aim to improve the structure of medical care for patients with rare diseases in each member state. The provided incentives for the development of medicines for orphan diseases have led to increased research activities and numbers of licensed Orphan Drugs. Patients are organized nationally and internationally in various patient organizations and umbrella organizations. They are involved in health care policy, support the detection and research of rare diseases and offer support to affected patients and families with educational meetings and materials as well as options for discussions. Many experts are engaged in national and international networks and registries that generate and publish high quality research data on rare diseases. A well developed infrastructure is in place to support the search for qualified partners that can be of assistance with specific questions in a rare lung disease.

Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency.

Assessment of emphysema-modifying therapy is difficult, but newer outcome measures offer advantages over traditional methods. The EXAcerbations and Computed Tomography scan as Lung End-points (EXACTLE) trial explored the use of computed tomography (CT) densitometry and exacerbations for the assessment of the therapeutic effect of augmentation therapy in subjects with alpha(1)-antitrypsin (alpha(1)-AT) deficiency. In total, 77 subjects (protease inhibitor type Z) were randomised to weekly infusions of 60 mg x kg(-1) human alpha(1)-AT (Prolastin) or placebo for 2-2.5 yrs. The primary end-point was change in CT lung density, and an exploratory approach was adopted to identify optimal methodology, including two methods of adjustment for lung volume variability and two statistical approaches. Other end-points were exacerbations, health status and physiological indices. CT was more sensitive than other measures of emphysema progression, and the changes in CT and forced expiratory volume in 1 s were correlated. All methods of densitometric analysis concordantly showed a trend suggestive of treatment benefit (p-values for Prolastin versus placebo ranged 0.049-0.084). Exacerbation frequency was unaltered by treatment, but a reduction in exacerbation severity was observed. In patients with alpha(1)-AT deficiency, CT is a more sensitive outcome measure of emphysema-modifying therapy than physiology and health status, and demonstrates a trend of treatment benefit from alpha(1)-AT augmentation.

Lung deposition of inhaled alpha1-proteinase inhibitor in cystic fibrosis and alpha1-antitrypsin deficiency.

Individuals with alpha(1)-antitrypsin (AAT) deficiency and cystic fibrosis (CF) have a protease-antiprotease imbalance in their lungs, which leads to early onset progressive lung disease. Inhalation of AAT may restore protective levels in the lungs. This study aimed to determine the efficiency of delivering AAT using a novel inhalation device in subjects with AAT deficiency and CF compared with healthy subjects. In total, 20 subjects (six healthy, seven with AAT deficiency and seven with CF) inhaled approximately 70 mg of radiolabelled active AAT, with controlled breathing patterns adjusted to lung function. Post-inhalation, total and regional lung deposition and extrathoracic deposition of radiolabelled AAT were measured. Total lung deposition of AAT was approximately 70% of the filling dose. The magnitude of deposition was similar in all treatment groups, with no adverse effect on lung function or any influence of disease severity on total lung deposition. Inhalation with controlled breathing patterns using the AKITA(2) device (lung function adapted) leads to high total lung deposition regardless of the degree of lung function impairment. Delivery of large amounts of AAT was achieved in a short period of time. This device may be an ideal option for aerosol therapy.

New Findings in PiZZ alpha1-antitrypsin deficiency-related panniculitis. Demonstration of skin polymers and high dosing requirements of intravenous augmentation therapy.

Panniculitis is a recognized but unusual complication of a severe deficiency of alpha1-antitrypsin (AAT), with fewer than 100 cases described to date. Like the pathogenesis of emphysema in severe PiZZ deficiency of AAT, panniculitis has been hypothesized to be an inflammatory process, possibly related to Z AAT polymer formation and to an unopposed anti-inflammatory screen in the context of deficient serum levels of AAT. The current report presents a 31-year-old woman with PiZZ AAT deficiency-associated panniculitis. Our case extends current knowledge of AAT-associated panniculitis in 2 ways: (1) we demonstrate Z-type AAT polymers in the skin, which supports the inflammatory pathogenesis of panniculitis and the potential pro-inflammatory role of polymers; (2) we show that a high dose and long-term use of intravenous augmentation therapy (90 mg/kg body weight once weekly during 3 years) can ameliorate the frequency and severity of panniculitis associated with AAT deficiency.

Inhalation of [123I]alpha1-protease inhibitor: toward a new therapeutic concept of alpha1-protease inhibitor deficiency?

UNLABELLED: The alpha1-protease inhibitor (alpha1-Pi) is separated from human serum and is therefore extremely expensive. Because only 2%-3% concentrates in the lung after intravenous administration, inhalational therapy for alpha1-Pi deficiency would seem likely to be better. The aims of this study were therefore to determine the pattern of deposition of inhaled alpha1-Pi labeled with 123I and measure the amount deposited in the lungs. METHODS: Eighteen patients with congenital severe alpha1-Pi deficiency were enrolled in the study. The low-specific-activity 123I-labeled alpha1-Pi aerosol (median particle size +/- SD, 3.9 +/- 2.5 microm) was generated by an air pressure-driven nebulizer. The patients inhaled for an average of 23.6 +/- 8.9 min. Static scintigrams in two projections were acquired immediately after (T1) and 1 (T2), 4 (T3), and 24 h (T4) after inhalation. The patients were divided into the following three groups according to their forced expiratory volume in 1 s (FEV1): group I, < or =40% of predicted normal (n = 8); group II, 40% < FEV1 < or = 60% of predicted normal (n = 4); group III, >60% of predicted normal (n = 6). RESULTS: The absolute percentage uptake values of alpha1-Pi in group I were 12.4 for T1, 7.3 for T2, 4.6 for T3, and 1.2 for T4; in group II the values were 13.0, 9.6, 6.2, and 2.0, respectively; and in group III, 14.6, 11.4, 6.5, and 3.6, respectively. Differences between the groups were generally statistically significant. Between T1 and T2, the probability value was <0.05 for group I versus group II, <0.006 for group I versus group III, and <0.39 for group II versus group III. Between T1 and T3, the probability value was <0.29 for group I versus group II, <0.22 for group I versus group III, and <0.94 for group II versus group III. Retention (between T1 and T4) was also dependent on the grade of the disease: P < 0.2 for group I versus group II, P < 0.001 for group I versus group III, and P < 0.02 for group II versus group III. Grading of the uptake pattern by three independent experienced investigators (87% agreement) revealed a peripheral deposition that was group dependent. We found that greater peripheral deposition corresponded with lower lung functional impairment: P < 0.5 for group I versus group II, P < 0.01 for group I versus group III, and P < 0.08 for group II versus group III. Degradation also corresponded with functional impairment: P < 0.05 for group I versus group II, P < 0.006 for group I versus group III, and P < 0.3 for group II versus group III. CONCLUSION: The results of this study show that sufficient amounts of alpha1-Pi can be deposited in the periphery of the lung by inhalation at least in patients with low-grade disease. Inhalation of alpha1-Pi may thus represent a new and more convenient route of drug administration.

Longitudinal follow-up of patients with alpha(1)-protease inhibitor deficiency before and during therapy with IV alpha(1)-protease inhibitor.

BACKGROUND: The efficacy of IV augmentation therapy with human alpha(1)-protease inhibitor (alpha(1)-Pi) in patients with severe alpha(1)-Pi deficiency is still under debate. STUDY OBJECTIVES: To evaluate the progression of emphysema in patients with alpha(1)-Pi deficiency before and during a period in which they received treatment with alpha(1)-Pi. DESIGN: Multicenter, retrospective cohort study. SETTING: Outpatient clinics of 26 university clinics and pulmonary hospitals. PATIENTS: Ninety-six patients with severe alpha(1)-Pi deficiency receiving weekly augmentation therapy with human alpha(1)-Pi, 60 mg/kg of body weight, had a minimum of two lung function measurements before and two lung function measurements after augmentation therapy was started. Lung function data were followed up for a minimum of 12 months both before and during treatment (mean, 47.5 months and 50.2 months, respectively). MEASUREMENTS AND RESULTS: Patients were grouped according to the severity of their lung function impairment. The change in FEV(1) was compared during nontreatment and treatment periods. In the whole group, the decline in FEV(1) was significantly lower during the treatment period (49.2 mL/yr vs 34.2 mL/yr, p = 0.019). In patients with FEV(1) > 65%, IV alpha(1)-Pi treatment reduced the decline in FEV(1) by 73.6 mL/yr (p = 0.045). Seven individuals had a rapid decline of FEV(1) before treatment, and the loss in FEV(1) could be reduced from 256 mL/yr to 53 mL/yr (p = 0.001). CONCLUSION: Some patients with severe alpha(1)-Pi deficiency and well-preserved lung function show a rapid decline in FEV(1). These patients profit from weekly IV therapy with human alpha(1)-Pi and have less rapid decline if treated. Early detection of patients at risk and early start of augmentation therapy may prevent accelerated loss of lung tissue.

Blood gases at rest and during exercise in patients with alpha1-Pi deficiency.

Alpha1-protease inhibitor (Pi) deficiency is associated with a protease-anti-protease imbalance leading to premature destruction of lung tissue and early emphysema. Little is known about the blood gases of these patients in the various stages of the disease. The purpose of this study was to evaluate blood gases in patients with alpha1-Pi deficiency when patients were at rest and during exercise, and to correlate these with lung function measurements. A total of 369 patients with severe alpha1-Pi deficiency had pulmonary function test and blood gas analysis, 282 also had blood gases taken during steady state submaximal exercise testing. Only 21% of the patients had normal blood gases at rest; 71% had mild hypoxaemia; 8% had severe hypoxaemia. Surprisingly, 61% of the patients with mild lung disease and a FEV1 of more than 65% predicted were hypoxaemic. During exercise 65% of the patients had a drop in PO2 of more than 0.40 kPa. FEV1 was a significant predictor for the PO2 values at rest and during exercise. During exercise the arterial-alveolar gradient increased in about 50% and decreased in 25% of the patients. Many patients with alpha1-Pi have blood gas abnormalities. Impaired blood gases in early stages of the disease result in a discrepancy between lung function parameters and blood gases. FEV1 measurements inadequately capture the extent of lung disease in patients with alpha1-Pi deficiency, and both blood gases at rest and during exercise are needed in the assessment of all stages of the disease.

Transsternal transpericardial operations in the treatment of bronchopleural fistulas after pneumonectomy.

Between 1972 and 1993, 19 patients (15 males and 4 females) with bronchopleural fistulae and pleural empyema after pneumonectomy were treated with transsternal transpericardial operations and closure of the fistula. The underlying malignant disease was a non-small cell carcinoma in 12, a malignant epithelial mesothelioma in two, and an atypical carcinoid tumor in one case. One patient each presented with tuberculosis, chest trauma, and lung destroyed by bronchiectasis. Fistulas affected the right bronchial stump in 17, and the left in 2, cases after pneumonectomy. The time between pneumonectomy and transsternal transpericardial operation ranged between 1 month and 4 years. All patients were submitted to drainage and irrigation of the empyema cavity (2-4 weeks). In 16 patients a long bronchial stump was sutured or stapled, in three cases resection of a short stump with the distal trachea was followed by anastomosis of the trachea and left main stem bronchus. Irrigation of the pneumonectomy cavity was continued in all patients for 2 weeks. Transsternal transpericardial operation was successful in 15 patients. Two patients died in the first 30 days, of renal or respiratory failure without fistula recurrence. In two cases the fistula recurred; definitive healing was achieved using a great omentum flap and endoscopic application of fibrin glue and bone spongiosa. Transsternal transpericardial management of bronchus stump fistula after pneumonectomy is highly effective and offers advantages over the direct approach through the infected empyema cavity.

[Augmentation therapy with human alpha 1-protease inhibitor: whom to treat when?]. / Was ist gesichert in der Substitutionstherapie mit humanem alpha 1-Proteasen-Inhibitor?

BACKGROUND: Patients with a congenital alpha 1-protease inhibitor (alpha 1-Pi) deficiency frequently develop a pulmonary emphysema early in life. The replacement of the missing glycoprotein can correct the protease-antiprotease imbalance. STUDIES: Clinical studies evaluating the course of the lung disease show a slowed progression of the emphysema in patients with moderately impaired lung function (forced expiratory volume in one second between 30 and 65% of predicted normal) as well as a reduced mortality. In this group of patients, weekly augmentation therapy with human alpha 1-Pi seem to be efficacious. However, from these studies no final conclusion can be drawn regarding the augmentation therapy of patients with normal lung function without a rapid progression of the disease or patients with severely impaired lung function.

[Anesthesia for cardioversion. A comparison of propofol and etomidate]. / Anesthésie pour cardioversion. Comparaison du propofol et de l'étomidate.

Anaesthesia for elective direct current cardioversion (DCC) was induced with propofol (Diprivan) 1.2 mg/kg in 28 patients and with 0.2 mg/kg etomidate (Hypnomidate) in 20 patients. These mostly high risk patients (NYHA class II to III) were successfully treated with defibrillation. Blood pressure and heart rate were recorded before and after induction and at 2 minutes intervals up to 20 minutes after DCC. Both anaesthetic agents caused mild hypotension. Heart rate did not change significantly after induction but fell significantly after DCC from the mean value of 124 +/- 26 bpm and 122 +/- 37 bpm to 94 +/- 19 bpm and to 91 +/- 19 bpm in propofol and etomidate treated patients respectively. Four patients became apnoeic necessitating assisted ventilation for approximately four minutes. All propofol treated patients had rapid recovery times and opened eyes on command within 5.6 +/- 1.9 minutes after induction, and were fully orientated about 4 minutes later also. Complete amnesia was observed in all patients in this group. In contrast etomidate induced anaesthesia did not cause respiratory depression, but the recovery time was longer. Four patients of this group complained of recall of DCC. In 7 patients due to involuntary movements or myoclonus, after induction with etomidate reliable EKG monitoring appeared to be difficult.

The effects of weekly augmentation therapy in patients with PiZZ α1-antitrypsin deficiency.

BACKGROUND: The major concept behind augmentation therapy with human α(1)-antitrypsin (AAT) is to raise the levels of AAT in patients with protease inhibitor phenotype ZZ (Glu342Lys)-inherited AAT deficiency and to protect lung tissues from proteolysis and progression of emphysema. OBJECTIVE: To evaluate the short-term effects of augmentation therapy (Prolastin) on plasma levels of AAT, C-reactive protein, and chemokines/cytokines. MATERIALS AND METHODS: Serum and exhaled breath condensate were collected from individuals with protease inhibitor phenotype ZZ AAT deficiency-related emphysema (n = 12) on the first, third, and seventh day after the infusion of intravenous Prolastin. Concentrations of total and polymeric AAT, interleukin-8 (IL-8), monocyte chemotactic protein-1, IL-6, tumor necrosis factor-α, vascular endothelial growth factor, and C-reactive protein were determined. Blood neutrophils and primary epithelial cells were also exposed to Prolastin (1 mg/mL). RESULTS: There were significant fluctuations in serum (but not in exhaled breath condensate) levels of AAT polymers, IL-8, monocyte chemotactic protein-1, IL-6, tumor necrosis factor-α, and vascular endothelial growth factor within a week of augmentation therapy. In general, augmented individuals had higher AAT and lower serum levels of IL-8 than nonaugmented subjects. Prolastin added for 3 hours to neutrophils from protease inhibitor phenotype ZZ individuals in vitro reduced IL-8 release but showed no effect on cytokine/chemokine release from human bronchial epithelial cells. CONCLUSION: Within a week, augmentation with Prolastin induced fluctuations in serum levels of AAT polymers and cytokine/chemokines but specifically lowered IL-8 levels. It remains to be determined whether these effects are related to the Prolastin preparation per se or to the therapeutic efficacy of augmentation with AAT.

[Guideline conformance for outpatient management of COPD in Germany]. / Leitlinienkonforme ambulante COPD-Behandlung in Deutschland.

BACKGROUND AND OBJECTIVE: Primary care physicians (PCPs) are the ones mainly responsible for the initial diagnosis and outpatient care of patients with COPD. The aim of the present survey was to investigate their initial management of COPD in Germany based on current guidelines and to identify any deviations. METHODS: A prospective cross-sectional survey was conducted as a multiple-choice questionnaire sent out to 1836 PCPs in seven Federal States of Germany (one large town and surrounding country in each). The product-neutral questions focused on the key aspects of current national and international (GLOBAL) COPD guidelines. RESULTS: 486 physicians participated in the study (response rate 26.5%). 66.5% of the physicians used the German COPD guidelines, 20.8% used GOLD guidelines, and only 11.7% observed no guidelines. The physicians were aware of the epidemiological and public health significance of COPD. 76.5% saw spirometry as the diagnostic standard: it was available in 90.1% of the practices. However, only 60-65% were able to cite the correct spirometric criteria for classifying severity of the disease. Educational measures to help patients quit smoking and the teaching and monitoring of patients' inhalation technique were inadequately implemented. The two most important therapeutic goals cited were to improve quality of life (69.1%) and prevent exacerbations (53.1%). 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 the guidelines. However, a significant percentage of the physicians incorrectly assessed the evidence-based clinical benefits of various therapeutic measures. CONCLUSION: The study shows that, despite the high regard in which COPD guidelines are held, deficiencies exist with regard to the diagnosis and treatment of COPD and the practical implementation of educational measures.

[Guideline-conformity of outpatient COPD management by pneumologists]. / COPD-Management nach aktuellen Leitlinien bei niedergelassenen Pneumologen.

BACKGROUND: Several evidenced-based clinical guidelines are available for COPD which is the most frequent chronic respiratory disease. The purpose of this study was to evaluate the outpatient COPD management of pneumologists based on current national and international guidelines for the first time and to identify any deviations. METHODS: A nationwide prospective cross-sectional survey was performed as a multiple-choice questionnaire sent to 863 pneumologists in Germany. The product-neutral questions focused on the knowledge about, acceptance of and practical experience with current national and international COPD guidelines. RESULTS: 359 pneumologists (41.6 %) participated in the survey. 60.4 % of the participants preferred the GOLD guideline over the German COPD guideline (33.4 %). 54.3 % considered bodyplethysmography as the diagnostic standard, followed by spirometry (38.4 %). However, only about 80 % were able to cite the correct spirometric criteria for classifying COPD severity. It is remarkable that many physicians still oriented to the outdated GOLD classification of 2001. The two most important treatment goals cited were to improve quality of life (82.2 %) and prevent exacerbations (63 %). 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 the guidelines. However, a significant percentage of the pneumologists incorrectly assessed the evidence-based clinical benefits of various therapeutic measures. CONCLUSION: The results of this survey show that most pneumologists adhere to guideline recommendations in daily practice and prefer the GOLD over the national COPD guideline. However, deficiencies in guideline conformity still exist with regard to severity classification and treatment of COPD.

Serial measurements of FEV1 over 12 years in a patient with alpha-1-protease inhibitor deficiency:influence of augmentation therapy and infections.

In patients with severe alpha-1-protease inhibitor (alpha 1-Pi) deficiency forced expiratory volume in 1 s (FEV1) is an accepted parameter to monitor the progression of emphysema. In a patient with severe alpha 1-Pi deficiency (PiZZ) more than 1,000 FEV1 measurements were performed over a period of 12 years. FEV1 dramatically decreased initially (delta FEV1 > 500 ml/year), but stabilized after augmentation therapy was instituted. Three years later, the FEV1 decreased again abruptly; the deterioration was paralleled by an increasing number of severe bronchopulmonary infections. This nonlinear decline implies a positive influence of augmentation therapy and a deleterious effect of bronchopulmonary infections in the disease (p < 0.0005). Daily variation of FEV1 in infection-free intervals exceeded 30% and were thus higher than the mean decrease in FEV1 per year. In this instance, FEV1 measurements performed once or twice per year may reveal a deterioration, whereas the change of FEV1 is still within the range of spontaneous variation. More frequent measurements of FEV1 can be useful to minimize the influence of high intraindividual variation.

Omentopexy and muscle transposition: two alternative methods in the treatment of pleural empyema and mediastinitis.

From March 1987 to March 1993, 64 patients with chronic empyema and mediastinitis were treated with omentum and thoracic muscle transposition. There were 36 male and 28 female patients, age range 29 to 76 years. 31 patients suffered from chronic empyema and bronchopleural fistula after lung surgery, 18 patients had chronic empyema after pulmonary inflammatory disease, and 15 patients developed a mediastinitis with or without pleural empyema after cardiac surgery or irradiation of the chest wall. The pedicled omentum was used in 33, the thoracic muscles latissimus dorsi, pectoralis major, serratus anterior, and trapezius either alone or combined in 31 cases. There were no perioperative deaths. Bronchopleural fistulas and infected spaces were successfully closed in 61 patients (95.3%). Postoperative CT scan, angiography, bronchoscopy, and lung function tests demonstrate the efficacy of both surgical methods. Omentum pedicle and thoracic muscle flaps supply excellent vascularised tissue to fill infected pleural space and mediastinum, particularly in patients with limited cardiopulmonary function.

Influence of blood pressure, heart rate, age, and sex on concentrations of atrial natriuretic factor and cyclic GMP in 124 volunteers.

The significance of increased atrial natriuretic factor (ANF) in relation to blood pressure and age is still controversial. We investigated the influence of blood pressure, age, and some other variables on ANF and its putative second messenger, cGMP. Samples for ANF and cGMP detection were taken from 124 ostensibly healthy individuals who were donating blood. Samples were also collected from 27 volunteers before and after blood donation, to study the influence of bleeding. During blood donation, ANF increased from 78.9 to 87.4 ng/L (P = 0.0035), whereas cGMP remained unchanged. ANF concentrations in 124 healthy individuals, corrected for the influence of bleeding, were 61.5 (SD 26.1) ng/L, with a 95% confidence interval of 10.0 to 112.1 ng/L. Mean cGMP concentrations in plasma were 2.9 (SD 1.45) nmol/L, with a 95% confidence interval of 0.4 to 5.75 nmol/L. Multivariance analysis revealed no significant influence of blood pressure, age, heart rate, or sex on concentrations of either ANF or cGMP in plasma.

[Long-term therapy of alpha 1-antitrypsin-deficiency-associated pulmonary emphysema with human alpha 1-antitrypsin]. / Langzeittherapie des alpha 1-Antitrypsin-mangelassoziierten Lungenemphysems mit humanem alpha 1-Antitrypsin.

alpha 1-antitrypsin (alpha 1-AT) deficiency is a genetic disorder characterized by low serum levels of alpha 1-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 alpha 1-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 alpha 1-AT deficiency and pulmonary emphysema receiving weekly i.v. infusions of 60 mg/kg body weight alpha 1-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 1 second (delta FEV1). 443 patients with alpha 1-AT deficiency tolerated augmentation therapy well with few adverse reactions. The delta FEV1 in 287 patients with available follow-up data was 57.1 +/- 31.1 ml per year. 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 30% < FEV1 < or = 65% of predicted normal (p = 0.0008). The remaining 15 patients had an initial FEV1 > 65%. Long-term treatment with i.v. alpha 1-antitrypsin in patients with severe alpha 1-Pi 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 alpha 1-antitrypsin deficient patients not receiving augmentation therapy.

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.

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.