Intermediate alpha1-antitrypsin deficiency and chronic obstructive pulmonary disease in Yugoslavia.

As part of a larger investigation of factors associated with chronic obstructive pulmonary disease among Yugoslavian men, an attempt was made to measure the role played by alpha1-antitrypsin deficiency in the causation of those diseases. Almost 3,000 men from Tuzla, an industrial and mining center in central Bosnia, were screened for alpha1-antitrypsin deficiency. Twenty-six men heterozygous for the Pi MZ phenotype were found in this population. The men with the Pi MZ phenotype were compared with a random sample from the total population. The analysis of the data showed that there is an apparent physiologic impairment associated with Pi Z heterozygosity that produces a shift in the relationships between the different lung volumes without over-all hyperinflation, namely, an increase in residual volume at the expense of vital capacity. However, because of the low prevalence of the Pi Z gene, it does not appear to account for much of the high rate of chronic obstructive pulmonary disease found in this population.     

alpha 1-antitrypsin TAQ I polymorphism and alpha 1-antichymotrypsin mutations in patients with obstructive pulmonary disease.

Obstructive pulmonary disease is a multifactorial condition deriving from the interaction of environmental and genetic factors. From biochemical knowledge of the basis of the disease, alpha 1-antitrypsin and alpha 1-antichymotrypsin are considered two likely candidate genes. We therefore designed an association study comprising 232 unrelated Italian individuals divided as follows: 89 individuals with obstructive lung disease (66 with COPD and 23 with disseminated bronchiectasis) and 143 controls (45 patients with non-obstructive lung disease and 98 healthy individuals). We screened for Taq I (G1237A) polymorphism of the alpha 1-antitrypsin gene as well as the rare variants Bonn-1 (Pro229Ala), Bochum-1 (Leu55Pro), Isehara-1 (Met389Val) and Isehara-2 (1258delAA), and the common signal peptide polymorphism Thr-15Ala of the alpha 1-antichymotrypsin gene. The frequencies of Taq I G1237A alleles were 11.7 and 10.8% in obstructed patients and controls, respectively (P = 0.43), while those of signal peptide Thr-15Ala alleles were 51.6 and 50.3% in obstructed patients and controls, respectively (P = 0.42). We conclude that alpha 1-antitrypsin Taq I polymorphism and alpha 1-antichymotrypsin Thr-15Ala mutation are not major genetic risk factors for the development of obstructive lung disease in Italian patients. The alpha 1-antichymotrypsin rare variants were not detected: our results do not exclude the possibility that other alpha 1-antichymotrypsin gene mutations might be present in Italian obstructed patients but, if so, these genetic defects must be rare.     

Functional assay of alpha 1-antitrypsin in obstructive lung disease

A decreased concentration of alpha 1-antitrypsin is associated with a high risk for obstructive lung disease. We measured the elastase inhibitory capacity, the most important biologic measure of alpha 1-AT function, using a natural substrate. The gel plate assay that we developed uses a commercial gelatin film and is more sensitive, faster, and cheaper than similar elastin-elastase methods. In serum samples from 76 patients with emphysema, there was a high correlation between the immunologically measured alpha 1-AT and the elastase inhibitory capacity. There was no evidence for a functionally deficient alpha 1-AT in any of these patients.     

Factors associated with hospital admission for exacerbation of chronic obstructive pulmonary disease

Introduction

Exacerbations of Chronic Obstructive Pulmonary Disease (COPD) that require hospital admission have a major impact on the progression of disease and generate high health costs.

Method

A multi-center, cross-sectional, observational, study was conducted with the aim to identify factors associated with hospital admission in patients with COPD. We obtained data of socio-demographic and anthropometric characteristics, quality of life, respiratory symptoms, anxiety and depression, physical activity and pulmonary function tests. We analyzed their association with hospital admission with a multivariate analysis using a logistic regression model.

Results

We analyzed 127 patients, 50 (39%) of whom had been hospitalized. 93.7% were men, mean age 67 years (SD = 9) and a FEV1 of 41.9% (SD = 15.3). In the first model obtained, the baseline SpO2, the BODE index and emergency room (ER) visits were associated with hospital admission and the area under the ROC curve (AUC) was 0.809. In a second model we included only variables readily available (without the 6 minutes walking test) and only the SpO2 and previous visits to the ER weresignificant with an AUC ROC 0.783.

Conclusions

hospital admission for exacerbation of COPD is associated with poor SpO2, higher BODE index score and a greater number of visits to the ER. In case you do not have the 6 minutes walking test, the other two variables offer a similar discriminative ability.     

Risk for liver disease in adults with alpha1-antitrypsin deficiency

Risk for the development of liver disease was estimated in 115 adults with α₁-antitrypsin deficiency, most of whom were of PI type (protease inhibitor type) Z. Seventy-one subjects were ascertained through their disease; 44 were ascertained independently of disease. A low concentration of serum prealbumin was sensitive in detecting impaired liver function and may indicate functioning cell mass, a different parameter than is measured by liver enzymes.Liver disease has usually been considered rare in adults with α₁-antitrypsin deficiency. However, the risk for the development of liver disease was relatively high for men between 51 and 60 years of age. The risk for women was lower than that for men. Our study indicates that a periodic assessment of liver function may be warranted for patients with α₁-antitrypsin deficiency who are over 40 years of age.     

Evidence for excessive bronchial inflammation during an acute exacerbation of chronic obstructive pulmonary disease in patients with alpha(1)-antitrypsin deficiency (PiZ)

Patients with homozygous (PiZ) alpha(1)-antitrypsin (AAT) deficiency have not only low baseline serum AAT levels (approximately 10 to 15% normal) but also an attenuated acute phase response. They are susceptible to the development of premature emphysema but may also be particularly susceptible to lung damage during bacterial exacerbations when there will be a significant neutrophil influx. The purposes of the present study were to assess the inflammatory nature of acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD) in subjects with AAT deficiency, to compare this with COPD patients without deficiency, and to monitor the inflammatory process and its resolution following appropriate antibacterial therapy. At the start of the exacerbation, patients with AAT deficiency had lower sputum AAT (p < 0.001) and secretory leukoprotease inhibitor (SLPI; p = 0.02) with higher elastase activity (p = 0.02) compared with COPD patients without deficiency. Both groups had a comparable acute phase response as assessed by C-reactive protein (CRP) but the AAT-deficient patients had a minimal rise in serum AAT (to < 6 microM). After treatment with antibiotics, in patients with AAT deficiency, there were significant changes in many sputum proteins including a rise in SLPI levels, and a reduction in myeloperoxidase (MPO) and elastase activity (p < 0. 005 for all measures); the sputum chemoattractants interleukin-8 (IL-8) and leukotriene B(4) (LTB(4)) fell (p < 0.01), and protein leak (sputum/serum albumin ratio) became lower (p < 0.01). The changes were rapid and within 3 d of the commencement of antibiotic therapy the biochemical markers had decreased significantly, but took a variable time thereafter to return to baseline values. In conclusion, patients with AAT deficiency had evidence of increased elastase activity at the start of the exacerbation when compared with nondeficient COPD patients which probably reflects a deficient antiproteinase screen (lower sputum AAT and SLPI). The increased bronchial inflammation at presentation resolved rapidly with 14 d of antibiotic therapy.     

Rapid screening for alpha1-antitrypsin deficiency in patients with chronic obstructive pulmonary disease using dried blood specimens

We describe two reliable methods for high-throughput screening of proteinase inhibitor (PI) S and PI Z alpha(1)-antitrypsin (alpha(1)-AT) deficiency alleles from dried blood spot (DBS) specimens using the LightCycler fluorimetric analyzer. The method was used to study 72 patients with chronic obstructive pulmonary disease. Results were confirmed with DNA sequencing. The alpha(1)-AT concentration in DBS was determined with immune nephelometry. Sixteen patients (22%) showed no PI Z or PI S mutations. Five patients (7%) had a heterozygous genotype consisting of a PI S allele and a normal allele for the Z and S positions (non-S non-Z). Twenty-five patients (35%) had a heterozygous genotype consisting of a PI Z and a non-S non-Z allele. Two (3%) had the PI SS genotype, 2 (3%) the PI SZ, and 20 (28%) the PI ZZ. All patients with two normal alpha(1)-AT alleles and 10 heterozygous carriers of one normal and one deficient allele had alpha(1)-AT levels that fell within the alpha(1)-AT DBS normal range (1.8-3.1 mg/dl). Two patients with the rare PI MM(malton)- and PI MM(heerlen)-deficient variants showed deficient alpha(1)-AT levels; PI S and PI Z were not detected. Processing 32 samples requires only 40 minutes. This single-step, cost-effective technology is optimal for working with small amounts of DNA, as are present in DBS. The method is suitable for large-scale screening, in cases where PI type is important.     

Mortality of elderly patients in Ontario after hospital admission for chronic obstructive pulmonary disease

BACKGROUND:

Chronic obstructive pulmonary disease (COPD) is associated with significant mortality. It is currently the fourth leading cause of death in Canada and the world.

OBJECTIVES:

To describe the mortality of elderly patients in Ontario after hospital admission for COPD.

METHODS:

A retrospective cohort study was conducted using the Discharge Abstract Database from the Canadian Institute for Health Information. Patients aged 65 years and older who were admitted to hospital between 2001 and 2004 with primary discharge diagnoses labelled with International Classification of Diseases, Ninth Revision codes 491, 492 and 496 were included in the study.

RESULTS:

Mortality rates were 8.81, 12.10, 14.53 and 27.72 per 100 COPD hospital admissions at 30, 60, 90 and 365 days after hospital discharge, respectively. Mortality also increased with age, and men had higher rates than women. No significant differences in mortality rates were found between different socioeconomic groups (P>0.05). Patients with shared care of a family physician or general practitioner and a specialist had significantly lower mortality rates than the overall rate (P<0.05), and their rates were approximately one-half the rate of patients with only one physician.

CONCLUSIONS:

Hospitalization with COPD is associated with significant mortality. Patients who were cared for by both a family physician or general practitioner and a specialist had significantly lower mortality rates than those cared for by only one physician, suggesting that continuous and coordinated care results in better survival.     

Relation of functional characteristics and serum alpha-1-antitrypsin (AAT) concentration in patients with PiMM phenotype and chronic obstructive pulmonary disease (COPD)

Introduction

The relation of AAT phenotype and COPD still raises lots of controversy. In this study we aimed to investigate relation lung function characteristics, AAT serum level and COPD in smoking and non smoking population.

Patients and methods

This was a prospective non-randomized study in which we evaluated 45 patients with severe (stage IV) COPD. In all patients we determined AAT phenotype, serum AAT levels and lung function tests. We correlated findings in relation to the smoking status.

Results

All patients were MM type homozygotes. Serum AAT concentrations were within the reference values, amounting to 1.66 g/l in smokers and 1.80 g/l in nonsmokers. There was no significant correlation between serum AAT concentrations and lung function parameters. We have observed the higher mean values of ITGV, RV, TLC and RV/TLC in smokers and a statistically significant difference only in ITGV.

Conclusion

All of the investigated patients with severe COPD were MM type homozygotes with normal plasma level of AAT. There was no significant correlation between the phenotype and severity of COPD. We did not find significant relation of plasma AAT level and lung function impairment.