Long-term therapy of alpha 1-antitrypsin-deficiency-associated pulmonary emphysema with human 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.     

Alpha 1-antitrypsin deficiency and asthma. The continuing search for the relationship

Patients with alpha 1-antitrypsin (AAT) deficiency, like those with asthma and chronic obstructive pulmonary disease, usually present with dyspnea, wheeze, and cough. The similarity in presentation and unfamiliarity among clinicians with AAT deficiency account for much of the delay in diagnosis. Normally, AAT inhibits serine proteases, which cause alveolar destruction, and alters the function of cells that release mediators of inflammation. Diagnostic findings suggesting deficiency include irreversible airflow obstruction, a decreased diffusing capacity of the lung for carbon monoxide, bibasilar bullous disease on chest films, and a low serum level of AAT. Asthma is usually diagnosed on the basis of clinical findings and response to inhaled beta agonists. The presence of inflammation is believed to be necessary for development of clinically significant asthma. Inflammation added to a deficiency of antiprotease inhibitor activity significantly worsens bronchial hyperreactivity. This is only one mechanism by which AAT deficiency may potentiate allergic and bronchospastic responses. The prevalence of bronchial asthma in patients with AAT deficiency is unknown. Studies by the National Institutes of Health regarding the natural history of AAT deficiency and its response to therapy are under way. Perhaps more will be discovered about the relationship between the disorder and bronchial asthma.     

Secretory leukoprotease inhibitor: partnering alpha 1-proteinase inhibitor to combat pulmonary inflammation

Secretory leukoprotease inhibitor (SLPI) is a low molecular weight serine proteinase inhibitor, notably of neutrophil elastase (NE), which is synthesised and secreted by the pulmonary epithelium. SLPI plays an important role in limiting NE-induced pulmonary inflammation and, significantly, it also possesses anti-HIV activity. SLPI is a significant component of the anti-NE shield in the lung which has different reactivity from, and is therefore complementary to, the anti-NE action of alpha 1-proteinase inhibitor (alpha 1-PI). Inhaled recombinant SLPI (rSLPI) could prove beneficial in partnership with alpha 1-PI in the treatment of a number of inflammatory lung disorders including emphysema, chronic bronchitis, cystic fibrosis, and adult respiratory distress syndrome.     

Latex hypersensitivity/glove component reaction as a contributing factor to osteomyelitis of the hand: a case report and review of the literature

High-resolution computed tomography (HRCT) can be used to diagnose and quantify emphysema noninvasively, as significant correlations have been found between the histological grade on resected lung specimens and quantified (q) computed tomography (CT). In this study, we performed thin section qHRCT in patients with severe hereditary alpha-1-antitrypsin (AAT) deficiency. AAT deficiency is the most common genetic cause of emphysema in adults, and exercise intolerance is the most disabling, distressing consequence of emphysema for the majority of patients. qHRCT was used to quantify precisely the alterations in the lung parenchyma due to pulmonary emphysema. Up until now, the important relationship between the severity of emphysema and the reduced exercise capacity has received little attention. Therefore the purpose of the study was to investigate the relationship between emphysema as displayed by qHRCT and cardiopulmonary exercise testing (CPX) in patients with severe cardiopulmonary impairment. - qHRCT was performed in 21 patients with homozygous AAT deficiency. CT scans were obtained at three spirometrically standardized levels at the carina and (5 cm above and below the carina). The mean lung density at 50% of vital capacity and a quantitative histogram analysis of the frequencies of CT values were determined. All patients underwent symptom-limited CPX to analyse simultaneously cardiovascular and ventilatory systems responses. - In all patients, qualitative CT assessment demonstrated panlobular emphysema with large and extensive areas of uniform low attenuation, characteristically with a lower-lobe distribution. Mean CT density values of the patients (-845 +/- 6.9 (mean +/- SEM)) were significantly correlated with work capacity (r = 0.55, p <0.01), oxygen-pulse (r = 0.54, p <0.01) and functional dead space ventilation (r = -0.54, p <0.01). Moreover, severe emphysema index (CT values below a threshold value of 950 HU) correlated positively with functional dead space ventilation (r = 0.60, p <0.01) and alveolar-arterial oxygen difference (r = 0.70, p <0.001). - These results clearly demonstrate that CPX parameters, indicating a disturbed pulmonary gas exchange and a ventilation-perfusion-mismatch during exercise, are significantly related to the extent of lung emphysema.     

Effect of environmental and clinical factors on lung function and respiratory symptoms in adolescents with alpha1-antitrypsin deficiency

Individuals identified in the Swedish neonatal alpha1-antitrypsin (AAT) screening study were followed prospectively from their first to their eighteenth year of life. The aim of this study was to analyse the effect of environmental factors, i.e. active and passive smoking, and of clinical factors on lung function and the occurrence of respiratory symptoms in AAT-deficient adolescents. The study group consisted of 88 protease inhibitor (Pi)ZZ and 40 PiSZ adolescents. Medical history including respiratory symptoms, and active and passive smoking were recorded at each follow-up up to the age of 18 y. Lung function tests were performed at the present check-up. At the age of 18 y, both forced expiratory volume in one second (FEV ) and FEV1/vital capacity (VC) were significantly lower in the smoking than in the non-smoking subgroup, and significantly more smokers than non-smokers reported the presence of phlegm. The mean FEV1/VC ratio was lower for those presently exposed to parental smoking. Multiple linear regression analysis indicated that clinical liver disease in early life, active smoking and parental smoking were independent determinants of FEV1/VC. The results suggest that marginal deviations in lung function and the symptom of phlegm among AAT-deficient adolescents occur characteristically early in the subgroup of smokers. Parental smoking may contribute to decreased lung function.     

Current issues in the management of chronic obstructive pulmonary diseases

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality, especially among smokers. Many guidelines that have recently been issued emphasize that COPD is not inaccessible to therapeutic measures: although few interventions are capable of affecting its natural history (i.e. smoking cessation and, in patients with severe resting hypoxaemia, oxygen therapy), several others have a demonstrated effect on symptoms and, thereby, quality of life. The effects of inhaled corticosteroids, and alpha 1-antitrypsin replacement therapy in emphysema due to alpha 1-antitrypsin deficiency are currently being studied. When there is a marked increase in mucus production, chest physiotherapy using controlled expiration and directed cough may be useful. Inhaled bronchodilators are frequently effective on dyspnoea, anticholinergic agents being more suitable for continuous symptoms. Rehabilitation, which includes education and psychosocial care, chest physiotherapy, nutritional care and exercise training, also improves quality of life. When there is persistent severe alveolar hypoventilation despite oxygen therapy, long-term mechanical ventilation may be considered. Surgical options in the treatment of emphysema include resection of giant bullae and lung volume reduction surgery. Lung transplantation should be proposed only in patients with end-stage disease, the difficulty here being to define what 'end-stage' means. Finally, all preventive and some therapeutic interventions are likely to be more effective early in the course of the disease. Thus, efforts should be made to detect airways obstruction early in subjects at risk, such as smokers.     

Usefulness of a national registry of alpha-1-antitrypsin deficiency. The Spanish experience

Severe alpha-1-antitrypsin (AAT) deficiency, phenotype Pi ZZ, is a rare condition with an estimated prevalence of 1/4500 individuals in Spain. Given this low prevalence, it seems useful to accumulate all the information derived from the care of these patients. In this context, the Spanish Registry of patients with AAT deficiency was founded in 1993; its main objectives were to establish guidelines adapted to our country for the treatment and management of AAT-deficient patients, offer expert support to physicians all over the country treating these patients, and provide technical support on the determination of Pi phenotyping and genotyping of individuals suspected of being AAT-deficient. From 1993 to January 1998 the number of enrollees increased from 48 to 223, of which 216 were Pi ZZ. Seventy-three per cent were male and only 31.5% were never smokers, mean age was 46 years (SD = 13 years) and mean FEV1 53% predicted (SD = 31%). 83% were index cases who, compared with non-index cases, were older (49 +/- 11 vs. 35 +/- 13 years, P < 0.001), more likely to have a smoking history (85% vs. 47%, P < 0.01) and displayed more severe impairment in pulmonary function (FEV1% = 40% +/- 19% vs. 96% +/- 23%, P < 0.001). Augmentation therapy was administered to 129 patients (58%). Treated patients had more severe impairment in pulmonary function than the untreated (FEV1% = 40% +/- 21% vs. 72% +/- 32%, P < 0.001) and were more likely to be index cases (81% vs. 43%, P < 0.001). Characteristics of the patients included are similar to those described for other Registries. The Registry has extended knowledge of the disease throughout the country and has established local guidelines for treatment and follow-up. It may be a valid database for future co-operation in international initiatives.     

Transplantation for end stage liver disease related to alpha 1 antitrypsin

Alpha 1 antitrypsin deficiency (AT) is an autosomal recessive disease associated with chronic liver disease in adults and children and emphysema in adults. The disease is one of the most common inherited disorders of the Caucasian population of North Europe and North America and is the most common genetic reason for pediatric orthotopic liver transplantation (OLTx), although it is a rare indication in adults. The natural history of the disease is unpredictable and the pathogenesis of the liver injury unclear. Thirty-five patients with histologically apparent alpha 1 AT accumulation in the liver (22 adults, 13 children) have been transplanted in this center. Clinical features were correlated with the pretransplant phenotype, serum alpha 1 antitrypsin levels and potential precipitating factors. All children were PiZZ homozygotes, most of whom had presented with neonatal hepatitis. The majority of adult patients were heterozygotes presenting with portal hypertension and liver cirrhosis. Current one-year posttransplant survival figures are 73% for adults and 87.5% for children. Replacement of the cirrhotic liver results in acquisition of the donor phenotype, a rise in serum levels of alpha 1 antitrypsin, and apparent prevention of associated disease.     

Apparent total alpha1-antitrypsin deficiency: report of a case

A 29-year-old female, with chronic renal failure and chronic bilateral emphysema, was admitted with severe uremia and septicemia secondary to multiple abscesses in the right kidney. Her condition improved after right nephrectomy. Pulmonary function studies showed marked obstructive and restrictive lung disease consistent witht the diagnosis of primary emphysema. On biochemical and histological examination, the liver was found to be normal. Alpha1-antitrypsin could not be demonstrated in the patient's serum at normal pH by any of the known techniques, but protein molecules with alpha1-antitrypsin antigencity were found at pH 4.8; this suggests a pH-dependent structural difference in alpha1-antitrypsin protein. Starch gel electrophoresis gave a multibanding pattern not previously described. A new form of apparent total alpha-1-antitrypsin deficiency is postulated.     

Pressor and subpressor angiotensin II administration. Two experimental models of hypertension

BACKGROUND: The neutrophil elastase inhibitor, secretory leucocyte protease inhibitor (SLPI), is a potential therapeutic tool in inflammatory lung diseases such as cystic fibrosis and pulmonary emphysema. The distribution and disappearance in the lung of aerosolised recombinant SLPI (rSLPI) was investigated in healthy humans and in patients with cystic fibrosis or alpha 1-antitrypsin-associated emphysema. METHODS: To distinguish aerosolised rSLPI from endogenous SLPI the recombinant inhibitor was radiolabelled with 99m-technetium (99mTc) pertechnetate. Distribution and disappearance of aerosolised 99mTc-rSLPI in the lungs were studied by gamma radiation imaging. RESULTS: The deposition of 99mTc-rSLPI in normal volunteers was homogeneous in all lung lobes, while in patients with cystic fibrosis or emphysema only well ventilated areas showed deposition of the aerosol. The disappearance rate of 99mTc-rSLPI was biexponential. The half life of the rapid phase was 0.2-2.8 hours, while that of the slow phase was more than 24 hours. CONCLUSIONS: Future aerosol therapy with rSLPI will be most beneficial for well ventilated lung tissue that needs protection against neutrophil derived elastase. It may be more difficult to neutralise the burden of elastase in poorly ventilated, highly inflamed areas as are seen in cystic fibrosis.     

Divergent expression of alpha1-protease inhibitor genes in mouse and human

The alpha1-protease inhibitor proteins of laboratory mice are homologous in sequence and function to human alpha1-antitrypsin and are encoded by a highly conserved multigene family comprised of five members. In humans, the inhibitor is expressed in liver and in macrophages and decreased expression or inhibitory activity is associated with a deficiency syndrome which can result in emphysema and liver disease in affected individuals. It has been proposed that macrophage expression may be an important component of the function of human alpha1-antitrypsin. Clearly, it is desirable to develop a mouse model of this deficiency syndrome, however, efforts to do this have been largely unsuccessful. In this paper, we report that aside from the issues of potentially redundant gene function, the mouse may not be a suitable animal for such studies, because there is no significant expression of murine alpha1-protease inhibitor in the macrophages of mice. This difference between the species appears to result from an absence of a functional macrophage-specific promoter in mice.     

Oral delivery of low molecular weight heparin in rat cardiac allografts

A 44 yr-old female with severe pulmonary emphysema and reduced alpha-1-protease inhibitor (alpha1-PI) serum levels developed an acute anaphylactic reaction following the third intravenous infusion of human alpha1-PI which was administered to prevent the progression of pulmonary emphysema. Specific immunoglobulin E-antibodies against human alpha1-PI could be demonstrated in the patient's serum using an enzyme allergosorbent test. Because of the risk of further severe anaphylactic reaction, the replacement therapy with alpha1-PI was discontinued. Physicians should be aware of this rare complication.     

The sensitivity of hyaluronan analysis of pleural fluid from patients with malignant mesothelioma and a comparison of different methods

This retrospective chart review describes the efficacy and safety of long-term administration of intravenous alpha1-antitrypsin (AAT) in 14 patients with hereditary AAT deficiency and COPD. During the 12- to 48-month observation period, 12 to 14 patients had stabilization of functional status; 4 patients had reductions in hospitalizations. Thirteen of 14 patients had no decline in pulmonary function. Three patients had self-limited adverse reactions to the AAT with one patient requiring a brief hospitalization.     

Lactulose and neomycin attenuate leukocyte-endothelial cell adhesion in an animal model of inflammatory bowel disease

OBJECTIVE AND SIGNIFICANCE: To examine functional performance in people with emphysema because of alpha-1 antitrypsin (AAT) deficiency. A severe deficiency of AAT affects 1:3,500 to 1:1,670 Americans who can develop debilitating emphysema in the third to fifth decades of life. DESIGN: Exploratory. POPULATION: People with a severe deficiency of AAT. SAMPLE AND DEMOGRAPHICS: Thirty-three patients (21 men) with a mean age of 47 (SD = 7) years. YEARS: Data were collected 1993-1996. METHODS: Activities patients identified as important on the dyspnea subscale of the Chronic Respiratory Disease Questionnaire were categorized and interpreted within the context of an integrity framework (i.e., effectiveness--or connectedness-related). FINDINGS: Patients identified over 25 activities. Effectiveness activities, such as bathing, were mentioned most frequently (78%). Connectedness activities, such as playing with children, were mentioned less often (22%) but were ranked more important. Two patients reviewed and supported the content validity of the framework. CONCLUSIONS: Results offer insight into the activities patients with genetic emphysema choose to perform and the factors that influence the decision that "the dyspnea is worth it." IMPLICATIONS: Identifying the activities people with AAT deficiency choose to perform and understanding why these activities are meaningful can guide interventions to help patients maintain a sense of integrity.     

Hyperplasia of pulmonary neuroendocrine cells in a case of childhood pulmonary emphysema

Pulmonary emphysema is very uncommon in children in the first decade of life. The few cases documented in the literature were all due to alpha1-antitrypsin deficiency. We present the case of a 6-year-old white boy with chronic cough and dyspnea on exertion. Lung biopsy showed panacinar type emphysema with patent airways and diffuse hyperplasia of pulmonary neuroendocrine cells revealed after immunostaining for bombesin, a peptide produced by these cells. We speculate that idiopathic diffuse hyperplasia of bombesin-producing pulmonary neuroendocrine cells may contribute to the pathogenesis of unusual COPD in childhood.     

Laparoscopy and thoracostomy in children

A variety of biologic products derived from bacteria, inflammatory cells, and active degraded proteins have been identified as having chemotactic activity essential for polymorphonuclear leukocyte (PMN) recruitment to the site of inflammation. Little is known, however, concerning factors responsible for regulating the intensity and duration of PMN recruitment. Evidence is growing that proteinase inhibitors modify the migrating ability of PMNs, although the physiologic implications of this have eluded clarification. In an attempt to hypothesize a role of alpha 1-proteinase inhibitor (alpha 1-Pi) in PMN recruitment to inflammatory sites, we examined the effects of alpha 1-Pi in different physiologic concentrations on PMN migration with a microchemotaxis chamber technique. Alpha 1-proteinase inhibitor had both stimulatory and inhibitory effects on cell migration, depending on its concentration. The inhibitor was active in inducing both directed locomotion (chemotaxis) and nondirected locomotion (chemokinesis) in concentrations of 0.02, 0.2, and 2 mg/ml, with maximum potency in both cases at 0.2 mg/ml (corresponding to the normal alveolar surface fluid level in the lung). Alpha 1-proteinase inhibitor impaired chemotactic responsiveness to known chemoattractants at 2 and 10 mg/ml (corresponding to normal and inflammatory blood levels, respectively) in order of potency. These results suggest that alpha 1-Pi may play a role in regulating inflammatory processes, especially in the lung, through its stimulatory and inhibitory effects, depending on its concentration.     

Variability of the adaptive response to low dose radiation in peripheral blood lymphocytes of twins and unrelated donors

This review concerns the reasons why only an estimated 10-15% of patients with alpha-1-antitrypsin (A1AT) deficiency develop the destructive lung disease known as emphysema. The arguments presented revolve around the proteinase-antiproteinase balance in the 'microenvironment' of the epithelial space of the lung. Attention is focused on the balance between destructive enzymes such as neutrophil elastase and protective proteins such as A1AT, secretory leucocyte proteinase inhibitor (SLPI), human elastase inhibitor (HEI) and elafin. When neutrophil elastase is already attached to the elastin fibres the smaller molecules SLPI and elafin appear to be better inhibitors of this enzyme than larger inhibitors such as A1AT and HEI. Furthermore, SLPI and elafin may provide the first line of defence against proteinase attack from neutrophil elastase. In trying to explain the variability in the clinical expression of A1AT-deficiency and the development of emphysema, the importance of changes to A1AT, SLPI and elafin molecules induced by smoking and/or oxygen free radicals has been considered. It is possible that emphysema only develops in patients who have SLPI/elafin deficiency as well as A1AT deficiency.     

The effect of maternal restraint on developmental toxicity of aluminum in mice

We have estimated lung volume, bronchial volume, vessel volume, alveolar surface area and capillary length in patients who died of lung failure due to emphysema and chronic obstructive pulmonary disease (COPD) and in patients with no clinical signs of respiratory disease. Unbiased morphometric methods were applied to the right lung. The patients with emphysema had equal lung volumes and bronchial and vessel volumes compared to the control group. The alveolar surface area and surface density were significantly decreased to about 67%, of control values. The capillary length and length density were significantly decreased to about 68% of control values. The proportional decreases in alveolar surface area and capillary length suggest that compensatory capillary proliferation has not occurred. These unbiased morphometric studies of emphysema have yielded results in end-stage emphysema that are comparable to those previously reported using biased methods. However, the unbiased methods may provide new insights when applied to earlier stages of the disease.     

Cigarette smoking: CT and pathologic findings of associated pulmonary diseases

The health risks associated with cigarette smoking are well known. Cigarette smoking is the most important causative factor in the development of bronchogenic carcinoma. Pulmonary diseases such as chronic bronchitis, centrilobular and panacinar emphysema, respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), and pulmonary Langerhans cell histiocytosis are also related to cigarette smoking. In adenocarcinoma and squamous cell carcinoma, the most common manifestation at computed tomography (CT) is a solitary pulmonary nodule; in small cell carcinoma, hilar and mediastinal adenopathy secondary to metastases; and in large cell carcinoma, a mass with central necrosis or cavitation in the lung periphery. For chronic bronchitis, the most common CT finding is bronchial wall thickening, but this finding is nonspecific. Emphysema, both centrilobular and panacinar associated with alpha-1-antitrypsin deficiency, usually manifests as areas of decreased attenuation and may involve bullous changes. However, centrilobular emphysema more commonly involves the upper lungs, whereas panacinar emphysema more commonly involves the lower lungs. Most patients with RB-ILD have normal high-resolution CT scans; however, abnormalities may be present, the most common of which are areas of ground-glass attenuation. CT appearance of pulmonary Langerhans cell histiocytosis varies depending on the disease stage: In the early stage, typical CT findings include multiple nodules, usually accompanied by cystic spaces with thin, well-defined walls. As the disease progresses, the cystic spaces become more numerous and the number of nodules decreases.