Alpha 1-proteinase Inhibitor Deficiency Research Articles

Alpha1-Proteinase Inhibitor (Human) (Zemaira)


 CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.
 The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.
 This review assesses alpha1-proteinase inhibitor (human) (Zemaira), 60 mg/kg body weight administered by IV infusion once weekly.
 Indication: Maintenance treatment of adults with severe alpha1-proteinase inhibitor deficiency and clinical evidence of emphysema.

Alpha1-Proteinase Inhibitor (Human) (Zemaira)

CADTH recommends that Zemaira be reimbursed for the treatment of severe alpha1-proteinase inhibitor (A1-PI) deficiency if certain conditions are met. Zemaira should only be covered to treat patients with severe A1-PI deficiency (e.g., genotypes PiZZ, PiZ(null), Pi(null,null), PiSZ) and clinical evidence of emphysema who are nonsmokers for at least 6 months. Zemaira should only be reimbursed if prescribed by a respirologist and the cost of Zemaira is reduced.

Chronic Obstructive Pulmonary Disease. A Biomarker and a Potential Therapy.

This article assesses developments in cardiorespiratory medicine since the Nobel Prize in Physiology or Medicine was awarded in 1956 for advancements in the study of cardiorespiratory disease. In chronic obstructive pulmonary disease, advances were accelerated by the discovery of a genetically determined cause for pulmonary emphysema in the genetic abnormality alpha-1 antitrypsin deficiency. This causes a deficiency of the inhibitor of neutrophil elastase, which results in increased degradation of lung elastin and the development of pulmonary emphysema. This discovery gave focus to two amino acids that reside only in body elastin, desmosine and isodesmosine, which can be measured as biomarkers of elastin degradation in body fluids with increased accuracy and sensitivity. Studies of this biomarker have shown that augmentation therapy in alpha-1 antitrypsin deficiency does decrease lung and body elastic tissue degradation and in the RAPID (Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha-1 Proteinase Inhibitor Deficiency) Study, over 4 years, showed a preservation of lung density by computer tomography correlating with decreases in plasma levels of desmosine and isodesmosine. This insight indicates the potential of agents that prevent lung elastin degradation. Such an agent is hyaluronan aerosol, which is deficient in post mortem lungs with chronic obstructive pulmonary disease and has been shown to block elastin degradation, possibly by a barrier function. Thus it would appear that hyaluronan could have therapeutic potential in chronic obstructive pulmonary disease.

Alpha 1 antitrypsin to treat lung disease in alpha 1 antitrypsin deficiency: recent developments and clinical implications.

Alpha 1 antitrypsin deficiency is a hereditary condition characterized by low alpha 1 proteinase inhibitor (also known as alpha 1 antitrypsin [AAT]) serum levels. Reduced levels of AAT allow abnormal degradation of lung tissue, which may ultimately lead to the development of early-onset emphysema. Intravenous infusion of AAT is the only therapeutic option that can be used to maintain levels above the protective threshold. Based on its biochemical efficacy, AAT replacement therapy was approved by the US Food and Drug administration in 1987. However, there remained considerable interest in selecting appropriate outcome measures that could confirm clinical efficacy in a randomized controlled trial setting. Using computed tomography as the primary measure of decline in lung density, the capacity for intravenously administered AAT replacement therapy to slow and modify the course of disease progression was demonstrated for the first time in the Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha-1 Proteinase Inhibitor Deficiency (RAPID) trial. Following these results, an expert review forum was held at the European Respiratory Society to discuss the findings of the RAPID trial program and how they may change the landscape of alpha 1 antitrypsin emphysema treatment. This review summarizes the results of the RAPID program and the implications for clinical considerations with respect to diagnosis, treatment and management of emphysema due to alpha 1 antitrypsin deficiency.

Epidemiology, Diagnosis and Available Treatment for Alpha 1 Antitrypsin Deficiency-related Emphysema in Europe

Alpha 1 antitrypsin (AAT) deficiency (AATD) is a rare genetic risk factor that predisposes an individual to develop early-onset emphysema. While accurate diagnosis of severe AATD is an important goal of clinical care, a minority of individuals with AATD are diagnosed and lack of awareness about the disease is the major suspected cause for this. Since the 1980s, therapy with human plasma-derived AAT has been the only specific treatment for AATD aiming to slow emphysema progression. The first randomised controlled trial to demonstrate this slowing of disease progression with AAT was the Randomized, placebo-controlled trial of augmentation therapy in Alpha1 Proteinase Inhibitor Deficiency (RAPID) study. The RAPID programme, consisting of the initial trial plus its open-label extension (OLE), is the largest completed clinical study of AAT therapy in AATD and the only trial designed specifically to explore the disease-modifying effect of AAT treatment. The RAPID-OLE data substantiate those of the RAPID trial, establishing the sustained efficacy and good tolerability for AAT treatment, providing evidence that AAT treatment modifies the disease course, and supporting the importance of early intervention.

Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency

Alpha-1-antitrypsin deficiency (AATD), also known as alpha1-proteinase inhibitor deficiency, is an autosomal co-dominant condition. The genotypes associated with AATD include null, deficient, and dysfunctional alpha-1-antitrypsin (A1AT) variants, which result in low levels of circulating functional A1AT, unbalanced protease activity, and an increased risk of developing lung emphysema, the leading cause of morbidity in these patients. Furthermore, the most common abnormal genotype, Pi*ZZ may also cause trapping of abnormally folded protein polymers in hepatocytes causing liver dysfunction. A major focus of therapy for patients with lung disease due to AATD is to correct the A1AT deficiency state by augmenting serum levels with intravenous infusions of human plasma-derived A1AT. This strategy has been associated with effective elevations of A1AT levels and function in serum and lung epithelial fluid and observational studies suggest that it may lead to attenuation in lung function decline, particularly in patients with moderate impairment of lung function. In addition, an observational study suggests that augmentation therapy is associated with a reduction of mortality in subjects with AATD and moderate to severe lung impairment. More recent randomized placebo-controlled studies utilizing computer scan densitometry suggest that this therapy attenuates lung tissue loss. Augmentation therapy has a relative paucity of side effects, but it is highly expensive. Therefore, this therapy is recommended for patients with AATD who have a high-risk A1AT genotype with plasma A1AT below protective levels (11 microM) and evidence of obstructive lung disease. In this article, we review the published evidence of A1AT augmentation therapy efficacy, side effects, and safety profile.

Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency

Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency Irina Petrache1, Joud Hajjar1, Michael Campos21Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA; 2Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Miller School of Medicine, University of Miami, Florida, USA Abstract: Alpha-1-antitrypsin deficiency (AATD), also known as alpha1-proteinase inhibitor deficiency, is an autosomal co-dominant condition. The genotypes associated with AATD include null, deficient, and dysfunctional alpha-1-antitrypsin (A1AT) variants, which result in low levels of circulating functional A1AT, unbalanced protease activity, and an increased risk of developing lung emphysema, the leading cause of morbidity in these patients. Furthermore, the most common abnormal genotype, Pi*ZZ may also cause trapping of abnormally folded protein polymers in hepatocytes causing liver dysfunction. A major focus of therapy for patients with lung disease due to AATD is to correct the A1AT deficiency state by augmenting serum levels with intravenous infusions of human plasma-derived A1AT. This strategy has been associated with effective elevations of A1AT levels and function in serum and lung epithelial fluid and observational studies suggest that it may lead to attenuation in lung function decline, particularly in patients with moderate impairment of lung function. In addition, an observational study suggests that augmentation therapy is associated with a reduction of mortality in subjects with AATD and moderate to severe lung impairment. More recent randomized placebo-controlled studies utilizing computer scan densitometry suggest that this therapy attenuates lung tissue loss. Augmentation therapy has a relative paucity of side effects, but it is highly expensive. Therefore, this therapy is recommended for patients with AATD who have a high-risk A1AT genotype with plasma A1AT below protective levels (11 µM) and evidence of obstructive lung disease. In this article, we review the published evidence of A1AT augmentation therapy efficacy, side effects, and safety profile.Keywords: alpha-1 antitrypsin, COPD, intravenous augmentation therapy

W1735 Sulforaphane Stimulates Histamine-Mediated Gastric Acid Secretion and Ameliorates Monochloramine-Induced Gastric Mucosal Injury

Background: Alpha 1 protease inhibitor (A1-PI) is the major circulating serine protease inhibitor. It is are critical factor in various inflammatory conditions, in particular in A1-PI deficiency in humans. Here, we analyzed the mucosal and systemic A1-PI levels with respect to two major etiological risk factors for gastroduodenal diseases, H. pylori infection and intake of low-dose aspirin. Patients and Methods: The study included 20 volunteers (H. pylori-positive and -negative: n=10) who received 2x50mg aspirin/day for 7 days. H. pyloripositive subjects underwent eradication therapy and repeated the protocol. Blood and tissue samples were obtained at day 0, 1, 3 and 7, and A1-PI levels were subsequently determined by ELISA. Results: Basal mucosal A1-PI expression were between 30 75 pg/10μg total protein in H. pylori-negative subjects, and found to be similar in antral, corpus and duodenal mucosa. In H. pylori-infected subjects, A1-PI levels were significantly increased in antrum (mean: 111 vs. 37.4 pg/10μg protein; p=0.019), whereas corresponding corpus, duodenum and serum levels were unchanged. Immunohistochemistry demonstrated that infiltrating immune cells and antral surface epithelium contributed to elevated A1-PI expression in H. pylori-infected subjects. The concomitant use of low-dose aspirin in all three groups was associated with no alterations of mucosal A1-PI levels, but a 2-fold induction of peripheral A1-PI levels that were identified in both H. pylori-infected (p=0.004) and -noninfected subjects (p=0.009). Conclusions: H. pylori infection leads to an induction of antral A1-PI levels, while low dose aspirin specifically increases circulating A1-PI levels, thus suggesting an effect of aspirin on hepatocytes. Both these anti-inflammatory mechanisms expand the pathophysiological importance of A1-PI to the gastrointestinal tract beyond its established role in A1-PI deficiency.

Indications for and Outcomes After Combined Lung and Liver Transplantation: A Single-Center Experience on 13 Consecutive Cases

Combined lung and liver transplantation (Lu-LTx) is a therapeutic option for selected patients with coexisting lung and liver disease. For several reasons, Lu-LTx is performed in few centers and information about the technical issues, posttransplant management and long-term outcomes associated with this procedure is limited. We analyzed data from 13 consecutive patients who underwent combined Lu-LTx at Hannover Medical School (Hannover, Germany) between April 1999 and December 2003. The main indications were cystic fibrosis, alpha1-proteinase inhibitor deficiency and portopulmonary hypertension. All patients had advanced cirrhosis and severe pulmonary disease manifestation. Ten patients received a sequential double Lu-LTx, one patient received a single Lu-LTx, one received a double lung and split liver transplantation, and one received an en-bloc heart-lung and liver transplantation. Immunosuppression was based on cyclosporine in a triple/quadruple regimen. Postoperative surgical complications occurred in eight patients. There were two perioperative deaths; two patients died during the first year on day 67 and 354, respectively, and one patient died at month 53. The overall patient survival rates at 1, 3, and 5 years were 69%, 62%, and 49%, respectively. Combined Lu-LTx is a therapeutic option for highly selected patients with end-stage lung and liver disease with acceptable long-term outcome.

Alpha1-Proteinase Inhibitor Deficiency and Bartonella Infection in Association with Panniculitis, Polyarthritis, and Meningitis in a Dog

Alpha1-Proteinase Inhibitor Deficiency and Bartonella Infection in Association with Panniculitis, Polyarthritis, and Meningitis in a Dog

Pathogenesis of COPD

Chronic obstructive pulmonary disease (COPD) is characterized and defined by limitation of expiratory airflow. This can result from several types of anatomical lesions, including loss of lung elastic recoil and fibrosis and narrowing of small airways. Inflammation, edema, and secretions also contribute variably to airflow limitation. Smoking can cause COPD through several mechanisms. First, smoke is a powerful inducer of an inflammatory response. Inflammatory mediators, including oxidants and proteases, are believed to play a major role in causing lung damage. Smoke can also alter lung repair responses in several ways. Inhibition of repair may lead to tissue destruction that characterizes emphysema, whereas abnormal repair can lead to the peribronchiolar fibrosis that causes airflow limitation in small airways. Genetic factors likely play a major role and probably account for much of the heterogeneity susceptibility to smoke and other factors. Many factors may play a role, but to date, only alpha-1 protease inhibitor deficiency has been unambiguously identified. Exposures other than cigarette smoke can contribute to the development of COPD. Inflammation of the lower respiratory tract that results from asthma or other chronic disorders may also contribute to the development of fixed airway obstruction. COPD is not only a disease of the lungs but is also a systemic inflammatory disorder. Muscular weakness, increased risk for atherosclerotic vascular disease, depression, osteoporosis, and abnormalities in fluids and electrolyte balance may all be consequences of COPD. Advances in understanding the pathogenesis of COPD have the potential for identifying new therapeutic targets that could alter the natural history of this devastating disorder.

Difficulties in controlled inhalation of alpha 1-protease inhibitor

In this paper a number of studies will be summarized which were designed to improve the inhalation of alpha 1 -protease inhibitor in patients with alpha 1-protease inhibitor deficiency. A pilot study has shown that the high inter-individual variability of drug deposition in the lungs is due to heterogeneous breathing patterns of the patients. Controlling the breathing pattern led to a significantly decreased variability. Then it was studied which particle size and breathing pattern resulted in highest peripheral lung deposition in patients with emphysema. It was found that for 3 - 4 microm particles and slow inhalation flow rate the peripheral deposition increases with increasing inhalation volume. After the development of an inhalation device which allows to perform controlled inhalations in clinical practice it was shown that this device, in combination with a breathing pattern individually normalized to the patients lung function, allows to deposit nearly 60 % of the drug into the patients lung periphery.

Genetic deficiency of alpha1-PI in mice influences lung responses to bleomycin.

It has recently been suggested that proteinase inhibitors modulate the fibrotic response in the lung. This study investigated the development of bleomycin-induced pulmonary changes in pallid mice, deficient in serum alpha1-proteinase inhibitor, and with a lower elastase inhibitory capacity, and in congenic C57Bl/6J mice. Male pallid and C57Bl/6J mice received a single intratracheal instillation of either saline or bleomycin. The investigation was carried out by means of biochemical, morphological and morphometrical methods. In both strains, 21 and 72 h after bleomycin, the lungs showed foci of inflammatory cell infiltration associated with emphysema. Fibrosis developed with time after bleomycin. At 14 days fibrosis affected 23.46+/-9.48% (mean +/- SD) and 40.62+/-13.34% (p < 0.01) of the lungs of C57Bl/6J and pallid mice, respectively. Emphysema affected 3.68+/-3.11% and 12.57+/-4.13% (p<0.01) of lung in C57Bl/6J and pallid mice, respectively. In C57Bl/6J mice bleomycin increased lung hydroxyproline content by 34% and desmosine content by 44% (p < 0.01 for both). In pallid mice these increases were only 21% (p < 0.01) and 6% which may reflect parenchymal loss. Thus, the lung destructive response (emphysema) and the subsequent proliferative reaction (fibrosis) to bleomycin are potentiated in alpha1-proteinase inhibitor deficiency.

Environmental and genetic risk factors and gene-environment interactions in the pathogenesis of chronic obstructive lung disease.

Current understanding of the pathogenesis of chronic obstructive pulmonary disease (COPD), a source of substantial morbidity and mortality in the United States, suggests that chronic inflammation leads to the airways obstruction and parenchymal destruction that characterize this condition. Environmental factors, especially tobacco smoke exposure, are known to accelerate longitudinal decline of lung function, and there is substantial evidence that upregulation of inflammatory pathways plays a vital role in this process. Genetic regulation of both inflammatory responses and anti-inflammatory protective mechanisms likely underlies the heritability of COPD observed in family studies. In alpha-1 protease inhibitor deficiency, the only genetic disorder known to cause COPD, lack of inhibition of elastase activity, results in the parenchymal destruction of emphysema. Other genetic polymorphisms have been hypothesized to alter the risk of COPD but have not been established as causes of this condition. It is likely that multiple genetic factors interacting with each other and with a number of environmental agents will be found to result in the development of COPD.

Alpha 1-protease inhibitor deficiency. Diagnosis, follow-up and therapy options

Alpha-1 antitrypsin (alpha-1 proteinase inhibitor) deficiency is characterized by a marked reduction of alpha-1 antitrypsin, the major antiprotease in man. Alpha-1 antitrypsin deficiency is one of the most common hereditary diseases in Caucasians of European descent. Alpha-1 antitrypsin deficiency is the underlying disorder in approximately 2% of all patients with chronic obstructive pulmonary disease and lung emphysema. Young adults by the age of 30 to 45 years have a high risk for the development of lung emphysema with cough, sputum expectoration and respiratory insufficiency. There is a moderate risk of liver disease. The diagnosis is obtained by measurement of alpha-1 antitrypsin serum levels. Recognition of the disorder is important to prevent deterioration of the pulmonary function by early initiation of preventive measures and treatment. Therapeutic options are physiotherapy, antiobstructive medication and antibiotics. The most direct approach is the intravenous augmentation therapy with purified alpha-1 antitrypsin.

Short- and long-term functional results after lung volume reduction surgery for severe emphysema.

Lung volume reduction surgery (LVRS) has emerged as a surgical therapeutic intervention for advanced emphysema. Designed for the relief of dyspnoea, LVRS has been demonstrated to be efficacious in a subset of carefully selected patients. Short-term improvements in dyspnoea are accompanied by improvements in forced expiratory volume in one second ranging 13-96%. Lung volumes likewise improve, with lessening of trapped gas, residual volume, and total lung capacity. Improvements in functional status and quality-of-life measures parallel the improvements in dyspnoea and lung function. One preliminary study suggests that life expectancy after 3 yrs may be improved following LVRS. Many questions regarding lung volume reduction surgery in terms of operative technique, selection of patients, and outcome remain to be answered. Data are available which begin to address some of these issues. Bilateral procedures have greater short-term improvements than unilateral procedures, but the rate of loss of function following the surgery may also be greater. Stapled resection of lung tissue has been demonstrated to be superior to laser ablation. In a majority of reports, outcome is superior in patients with heterogeneous distribution of their emphysema, and patients with alpha1-proteinase inhibitor deficiency emphysema do less well than patients with smoker's emphysema.

An enzyme immunoassay for polymorphonuclear leucocyte-mediated fibrinogenolysis.

Upon stimulation, polymorphonuclear leucocytes (PMNs) release potent serine proteases, i.e. elastase, cathepsin G and proteinase 3, which contribute to the degradation of tissue and plasma components. Here, we describe the development of a plasma test to assess PMN-mediated fibrinogenolysis as a biochemical marker for actual PMN-derived proteolysis in vivo, useful for monitoring therapeutic efficacy, i.e. of elastase inhibitors. We generated a monoclonal antibody (MAb), designated 1-1/B3, with a high affinity for elastase-degraded fibrinogen (EDF). The epitope for 1-1/B3 becomes exposed in a time-dependent manner during digestion of fibrinogen with purified PMN-derived serine proteases and with isolated PMNs in vitro. However, 1-1/B3 does not react with plasma fibrinogen or with fibrin(ogen) degradation products generated by plasmin or by other active proteases that may occur locally, i.e. metalloproteases and lysosomal cathepsins. On the basis of MAb 1-1/B3, we developed a plasma test for the assessment of PMN-mediated fibrin(ogen) degradation products (PMN-FDP). In a panel of control plasmas, we observed concentrations of PMN-FDP of 8.2 +/- 0.9 ng mL-1 (n = 18). These values were increased twofold in patients with alpha 1-proteinase inhibitor deficiency (18.6 +/- 3.3 ng mL-1; n = 12; P < 0.0001) and even more in patients with sepsis (365.7 +/- 97.7 ng mL-1; n = 16; P < 0.0001). Furthermore, synovial tissue extracts from patients with rheumatoid arthritis contained increased levels of PMN-FDP, compared with synovial tissue extracts (P < 0.005) from patients with osteoarthritis.

Pulmonary function in children with homozygous alpha1-protease inhibitor deficiency.

Alpha1-protease inhibitor (alpha1-PI) deficiency is a well-recognized cause of emphysema in adults; however, the natural history of this disorder in children is unclear. Because of the paucity of data in the paediatric age group, we performed whole body plethysmography, spirometry, and diffusing capacity, in a cohort of 17 homozygous (PiZZ phenotype) children (9 females, 8 males; mean age +/- SEM 13.4 +/- 0.9, range 7-18 years) and in 17 normal schoolchildren (13.5 +/- 0.9, 7-18 years), using a matched-pair design. Blood was drawn for determination of serum alpha1-PI levels, PI phenotype, and standard biochemical tests of liver function. Among the PiZZ subjects, 12 were detected during diagnostic workup of prolonged neonatal icterus, and 5 by routine testing in paediatric patients. None had chronic respiratory symptoms except for an 18-year-old PiZZ girl with a history of recent onset of exertional dyspnoea. All were non-smokers. The Wilcoxon test was used for statistical analysis. As expected, serum alpha1-PI levels were lower in the PiZZ group (16% of the control value). A few patients had slight elevations of their liver enzymes. As for the pulmonary function parameters, differences between groups were not significant. Individual data showed no consistent abnormality in lung function except for signs of mild expiratory obstructive airway disease with hyperinflation (elevated TGV/TLC ratio) in the only symptomatic 18-year-old subject (0.63, control subject 0.49). This was unresponsive to bronchodilators. For her, augmentation therapy with intravenous infusion of alpha1-PI may be considered. Our study confirms the absence of pulmonary function abnormalities in the vast majority of children with homozygous alpha1-PI deficiency. Serial measurements of lung function may help to distinguish those individuals who require treatment with alpha1-PI from those who do not.

The emphysemas: radiologic-pathologic correlations.

There are several forms of emphysema that should be considered as distinct disease entities. No university accepted classification system of these forms exists, but correlations of autopsy findings in 1,823 cases over a 12-year period confirm that the radiographic and pathologic features of the emphysemas are readily understood when centrilobular, panlobular, paracicatricial, and localized types of the disease are recognized. Centrilobular emphysema associated with cigarette smoking is the most common form. Panlobular emphysema is associated with alpha 1-protease inhibitor deficiency and pathologically produces uniform enlargement of all air spaces, with a mild basilar predominance. Paracicatricial emphysema is seen adjacent to areas of parenchymal scarring. Localized emphysema represents focal enlargement or destruction of air spaces with otherwise normal lung. A clear understanding of the computed tomographic appearance of all forms of emphysema is essential for the correct diagnosis of parenchymal lung abnormalities.

Protein S degradation in vitro by neutrophil elastase.

Human protein S is degraded by neutrophil elastase. The characteristics of cleavage are compared in a purified protein S preparation, a concentrate of vitamin K-dependent proteins (PPSB) and in normal plasma as well as in alpha-proteinase inhibitor (alpha PI)- deficient plasma. Elastase incubation of purified human protein S (molar enzyme-to-substrate-ratio 1:5500-1:55) reduces the molar mass of the native protein S (81-83 kDa) to about 79 kDa by cleavage of a small peptide. Incubation with very high elastase concentrations (molar enzyme-to-substrate-ratio 1:5.5) completely degrades protein S into small fragments. The elastase incubated protein S has a higher isoelectric point than the native form (Ip 5.9 vs. 5.3). Protein S in a PPSB coagulation factor concentrate is degraded in the same way as isolated protein S. By immunoblotting also smaller split products of molar masses between 34 and 70 kDa are demonstrated. In normal plasma protein S is not degraded by elastase concentrations up to 14 mumol l-1. In plasma of a patient with alpha 1-proteinase inhibitor deficiency protein S can be degraded by elastase. The native 82 kDa protein is degraded to a 72 kDa protein. PEG precipitation of the protein S- C4b- binding protein-complex shows that elastase predominantly splits the free protein S.