Comparison of different algorithms in laboratory diagnosis of alpha1-antitrypsin deficiency.

OBJECTIVES: Alpha1-antitrypsin deficiency (AATD) is an inherited condition that predisposes individuals to an increased risk of developing lung and liver disease. Even though AATD is one of the most widespread inherited diseases in Caucasian populations, only a minority of affected individuals has been detected. Whereas methods have been validated for AATD testing, there is no universally-established algorithm for the detection and diagnosis of the disorder. In order to compare different methods for diagnosing AATD, we carried out a systematic review of the literature on AATD diagnostic algorithms. METHODS: Complete biochemical and molecular analyses of 5,352 samples processed in our laboratory were retrospectively studied using each of the selected algorithms. RESULTS: When applying the diagnostic algorithms to the same samples, the frequency of False Negatives varied from 1.94 to 12.9%, the frequency of True Negatives was 62.91% for each algorithm and the frequency of True Positives ranged from 24.19 to 35.15%. We, therefore, highlighted some differences among Negative Predictive Values, ranging from 0.83 to 0.97. Accordingly, the sensitivity of each algorithm ranged between 0.61 and 0.95. We also postulated 1.108 g/L as optimal AAT cut-off value, in absence of inflammatory status, which points to the possible presence of genetic AATD. CONCLUSIONS: The choice of the diagnostic algorithm has a significant impact on the correct diagnosis of AATD, which is essential for appropriate treatment and medical care. The fairly large number of possible false negative diagnoses revealed by the present paper should also warn clinicians of negative results in patients with clinically-suspected AATD.

Clinical considerations in individuals with α1-antitrypsin PI*SZ genotype.

α1-Antitrypsin deficiency (AATD), characterised by reduced levels or functionality of α1-antitrypsin (AAT), is a significantly underdiagnosed genetic condition that predisposes individuals to lung and liver disease. Most of the available data on AATD are based on the most common, severe deficiency genotype (PI*ZZ); therefore, treatment and monitoring requirements for individuals with the PI*SZ genotype, which is associated with a less severe AATD, are not as clear. Recent genetic data suggest the PI*SZ genotype may be significantly more prevalent than currently thought, due in part to less frequent identification in the clinic and less frequent reporting in registries. Intravenous AAT therapy, the only specific treatment for patients with AATD, has been shown to slow disease progression in PI*ZZ individuals; however, there is no specific evidence for AAT therapy in PI*SZ individuals, and it remains unclear whether AAT therapy should be considered in these patients. This narrative review evaluates the available data on the PI*SZ genotype, including genetic prevalence, the age of diagnosis and development of respiratory symptoms compared with PI*ZZ individuals, and the impact of factors such as index versus non-index identification and smoking history. In addition, the relevance of the putative 11 µM "protective threshold" for AAT therapy and the risk of liver disease in PI*SZ individuals is explored. The purpose of this review is to identify open research questions in this area, with the aim of optimising the future identification and management of PI*SZ individuals.

The importance of effective registries in pulmonary diseases and how to optimize their output.

Randomized controlled trials (RCTs) are essential for the approval of new therapies; however, because of their design, they provide little insight concerning disease epidemiology/etiology and current clinical practice. Particularly, in lung disease, rigid inclusion/exclusion criteria can limit the generalizability of pivotal trial data. Noninterventional studies (NIS), conducted through the well-established mechanism of patient registries, are undervalued as a means to close data gaps left by RCTs by providing essential data that can guide patient care at different levels from clinical decision-making to health-care policy. While NIS contribute valuable data in all disease areas, their importance in rare diseases cannot be underestimated. In respiratory disease, registries have been essential in understanding the natural history and different phenotypes of rare conditions, such as alpha 1 antitrypsin deficiency, cystic fibrosis, and idiopathic pulmonary fibrosis. Importantly, additional therapeutic outcome data were generated. While measures for enhancing data quality in RCTs have evolved significantly, the approach and effectiveness of registries is variable. Within this article, we review the contribution of registries to pulmonary disease and make recommendations for their effective management. Additionally, we assess limitations of registry data as well as challenges to registry operation, including the impact of the European Union General Data Protection Regulation.

Different Training-Induced Skeletal Muscle Adaptations in COPD Patients with and without Alpha-1 Antitrypsin Deficiency.

BACKGROUND: Pulmonary rehabilitation (PR) improves oxidative capacity of peripheral muscles in patients with chronic obstructive pulmonary disease (COPD). The exercise-induced oxidative skeletal muscle adaptation in COPD patients with inherited alpha-1 antitrypsin deficiency (A1ATD) has not been studied. OBJECTIVES: To compare PR effects on skeletal muscle adaptation in COPD patients with and without A1ATD. METHODS: Nine COPD patients with A1ATD (genotype PiZZ, 6 receiving A1AT augmentation therapy), and 10 'usual' COPD patients (genotype PiMM) performed an incremental cycling test and underwent musculus vastus lateralis biopsies before and after a 3-week PR program including exercise training. RESULTS: PiZZ and PiMM patients improved peak work rate following PR (+9 ± 11 W, p < 0.05, and +18 ± 9 W, p < 0.001, between-group difference p < 0.05). PiMM patients increased fibre type I (+8.1%), reduced fibre type IIA (-2.1%) and hybrid fibre type IIA/IIX proportion (-3.9%). Following PR, PiMM patients also raised mitochondrial signalling proteins PGC-1α (4.5-fold), and TFAM (6.4-fold). PiZZ patients had no change in fibre type I but showed a shift of type IIA/IIX (-8.8%) towards fibre type IIA distribution (+8.9%). The capillary to fibre ratio increased by 28% (p < 0.05) in PiZZ, whereas no change was observed in PiMM patients. Linear regression analysis revealed that diffusion capacity and A1AT therapy are predictor variables for myofibre type I response to PR (r2 = 0.684, p < 0.01). CONCLUSIONS: Following a 3-week PR with comparable training modalities, PiMM but not PiZZ patients increased the oxidative myofibre type I proportion. This skeletal muscle adaptation pattern suggests better improvement of exercise capacity in PiMM than in PiZZ patients with COPD.

Rare variants in alpha 1 antitrypsin deficiency: a systematic literature review.

BACKGROUND: Alpha 1 Antitrypsin Deficiency (AATD) is a largely underrecognized genetic condition characterized by low Alpha 1 Antitrypsin (AAT) serum levels, resulting from variations in SERPINA1. Many individuals affected by AATD are thought to be undiagnosed, leading to poor patient outcomes. The Z (c.1096G > A; p.Glu366Lys) and S (c.863A > T; p.Glu288Val) deficiency variants are the most frequently found variants in AATD, with the Z variant present in most individuals diagnosed with AATD. However, there are many other less frequent variants known to contribute to lung and/or liver disease in AATD. To identify the most common rare variants associated with AATD, we conducted a systematic literature review with the aim of assessing AATD variation patterns across the world. METHODS: A systematic literature search was performed to identify published studies reporting AATD/SERPINA1 variants. Study eligibility was assessed for the potential to contain relevant information, with quality assessment and data extraction performed on studies meeting all eligibility criteria. AATD variants were grouped by variant type and linked to the geographical region identified from the reporting article. RESULTS: Of the 4945 articles identified by the search string, 864 contained useful information for this study. Most articles came from the United States, followed by the United Kingdom, Germany, Spain, and Italy. Collectively, the articles identified a total of 7631 rare variants and 216 types of rare variant across 80 counties. The F (c.739C > T; p.Arg247Cys) variant was identified 1,281 times and was the most reported known rare variant worldwide, followed by the I (c.187C > T; p.Arg63Cys) variant. Worldwide, there were 1492 Null/rare variants that were unidentified at the time of source article publication and 75 rare novel variants reported only once. CONCLUSION: AATD goes far beyond the Z and S variants, suggesting there may be widespread underdiagnosis of patients with the condition. Each geographical region has its own distinctive variety of AATD variants and, therefore, comprehensive testing is needed to fully understand the true number and type of variants that exist. Comprehensive testing is also needed to ensure accurate diagnosis, optimize treatment strategies, and improve outcomes for patients with AATD.

Detection of obstructive sleep apnoea by an electronic nose.

Diagnosis of obstructive sleep apnoea syndrome (OSAS) is technically demanding, cost-intensive and time-consuming. The measurement of volatile organic compounds by an electronic nose is an innovative method that determines distinct molecular patterns of exhaled breath in different patient groups. We addressed the following questions: What is the diagnostic accuracy of an electronic nose in the detection of OSAS and the ability to detect effects of standard therapy in patients with OSAS? Are these results related to changes in distinct markers of airway inflammation and extracellular remodelling? We included 40 OSAS patients and 20 healthy controls. Exhaled breath of all participants was analysed using the Cyranose 320 electronic nose. Pharyngeal washings were performed to sample the upper airway compartment. For statistical analysis linear discriminant analysis was employed. We identified a linear discriminant function separating OSAS from control (p<0.0001). The corresponding area under the receiver-operating curve was 0.85 (95% CI 0.75-0.96; sensitivity 0.93 and specificity 0.7). In pharyngeal washing fluids of OSAS patients, we observed higher levels of α1-antitrypsin and markers of extracellular remodelling compared to controls. The electronic nose can distinguish between OSAS patients and controls with high accuracy.

The effect of exacerbations on lung density in α1-antitrypsin deficiency.

Background: Acute exacerbations of COPD (AECOPD) have unclear impacts on emphysema measurement using computed tomography (CT)-derived 15th percentile lung density (PD15). The aim of this study was to assess the influence of AECOPD on PD15 lung density in α1-antitrypsin deficiency. Methods: In a post hoc analysis of the RAPID (Randomised Trial of Augmentation Therapy in α1-Proteinase Inhibitor Deficiency) trial, raw marginal residuals of PD15 (measured - predicted) were determined by fitting a regression line to individual patient CT data. These deviations from the expected slope were compared by age, sex, baseline forced expiratory volume in 1 s, diffusing capacity of the lungs for carbon monoxide % predicted and PD15, inhaled corticosteroid use and treatment group. Results: Positive and negative residuals (reflecting higher or lower lung density than predicted from regression) were observed, which declined in magnitude over time following AECOPD events. Logistic regression confirmed a limited effect of patient characteristics on the absolute size of residuals, whereas AECOPD within 6 weeks of CT had a notable effect versus no AECOPD within 6 weeks (OR 5.707, 95% CI 3.375-9.652; p<0.0001). Conclusion: AECOPD result in higher or lower CT lung density estimates; the effect is greatest in the 2 weeks immediately after an AECOPD and persists for <6 weeks. Patient characteristics were less relevant than AECOPD within 6 weeks, supporting the reliability of PD15 as a measure of lung density. An exacerbation-free period prior to CT scan is advisable to reduce signal-to-noise ratio in future clinical trials.

Imaging in alpha-1 antitrypsin deficiency: a window into the disease.

Imaging modalities such as plain chest radiograph and computed tomography (CT) are important tools in the assessment of patients with chronic obstructive pulmonary disease (COPD) of any etiology. These methods facilitate differential diagnoses and the assessment of individual lung pathologies, such as the presence of emphysema, bullae, or fibrosis. However, as emphysema is the core pathological consequence in the lungs of patients with alpha-1 antitrypsin deficiency (AATD), and because AATD is associated with the development of other lung pathologies such as bronchiectasis, there is a greater need for patients with AATD than those with non-AATD-related COPD to undergo more detailed assessment using CT. In the field of AATD, CT provides essential information regarding the presence, distribution, and morphology of emphysema. In addition, it offers the option to quantify the extent of emphysema. These data have implications for treatment decisions such as initiation of alpha-1 antitrypsin (AAT) therapy, or suitability for surgical or endoscopic interventions for reducing lung volume. Furthermore, CT has provided vital insight regarding the natural history of emphysema progression in AATD, and CT densitometry has underpinned research into the efficacy of AAT therapy. Moving forward, hyperpolarized xenon gas (129Xe) lung magnetic resonance imaging (MRI) is emerging as a promising complement to CT by adding comprehensive measures of regional lung function. It also avoids the main disadvantage of CT: the associated radiation. This chapter provides an overview of technological aspects of imaging in AATD, as well as its role in the management of patients and clinical research. In addition, perspectives on the future potential role of lung MRI in AATD are outlined.

Exploring the optimum approach to the use of CT densitometry in a randomised placebo-controlled study of augmentation therapy in alpha 1-antitrypsin deficiency.

BACKGROUND: Computed tomography (CT) lung densitometry has been demonstrated to be the most sensitive and specific outcome measure for the assessment of emphysema-modifying therapy, but the optimum densitometric index has yet to be determined and targeted sampling may be more sensitive than whole lung assessment. The EXAcerbations and CT scan as Lung Endpoints (EXACTLE) trial aimed to clarify the optimum approach to the use of CT densitometry data for the assessment of alpha 1-antitrypsin (AAT) augmentation therapy on the progression of emphysema in AAT deficiency (AATD). METHODS: Patients with AATD (n = 77) were randomised to weekly infusions of 60 mg/kg human AAT (Prolastin) or placebo over 2 to 2.5 years. Lung volume was included as a covariate in an endpoint analysis and a comparison was made of different CT densitometric indices (15th percentile lung density [PD15], mean lung density [MLD] and voxel index at a threshold of -910 [VI-910] and -950 [VI-950] Hounsfield Units) obtained from whole lung scans at baseline and at 24 to 30 months. Targeted regional sampling was compared with whole lung assessment. RESULTS: Whole lung analysis of the total change (baseline to last CT scan) compared with placebo indicated a concordant trend that was suggestive of a treatment effect for all densitometric indices (MLD [1.402 g/L, p = 0.204]; VI-910 [-0.611, p = 0.389]; VI-950 [-0.432, p = 0.452]) and that was significant using PD15 (1.472 g/L, p = 0.049). Assessment of the progression of emphysema in the apical, middle and basal regions of the lung by measurement with PD15 showed that this treatment effect was more evident when the basal third was sampled (1.722 g/L, p = 0.040). A comparison between different densitometric indices indicated that the influence of inspiratory variability between scans was greatest for PD15, but when adjustment for lung volume was made this index was the most sensitive measure of emphysema progression. CONCLUSION: PD15 is the most sensitive index of emphysema progression and of treatment modification. Targeted sampling may be more sensitive than whole lung analysis. TRIAL REGISTRATION: Registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.

Comparison of exercise training responses in COPD patients with and without Alpha-1 antitrypsin deficiency.

BACKGROUND: The benefits of pulmonary rehabilitation (PR) on fatigue-resistant skeletal muscle fibre type I have been found to be smaller in COPD patients with alpha-1 antitrypsin deficiency (AATD) than in those without AATD. Alpha-1 antitrypsin (AAT) augmentation therapy was suggested as a potential factor of influence. Whether this finding mirrors different improvements in 6-min walk distance (6MWD) between both groups remains unknown. METHODS: 140 patients with AATD-related COPD (phenotype PiZZ, FEV1: 31 ± 8%pred.) and 280 COPD patients without AATD (FEV1: 31 ± 8%pred.) were matched for baseline 6MWD and included in a retrospective analysis. AATD patients were divided into those "on" (AATDAUG+) or "off" (AATDAUG-) augmentation therapy. 6MWD was assessed pre and post an inpatient 4-week PR program. Plasma level of creatinine was analysed at baseline. RESULTS: In AATD and COPD patients with comparable initial 6MWD (331 ± 106 m and 326 ± 101 m, p = n.s.), improvements in 6MWD following PR were similar (+49 ± 49 m and +53 ± 52 m, intra-group change: p < 0.001). Notably, 68% of AATD and 65% of COPD responded well with a clinically relevant 6MWD improvement of ?30 m. The improvement in 6MWD was independent of gender, age, pack years, SF36 mental score and body mass index. The augmentation therapy with AAT did not influence 6MWD outcome (AATDAUG+: +51 ± 55 m, AATDAUG-: +47 ± 40 m, p = n.s.). Only in AATD group, higher baseline creatinine levels and lower 6MWD were positive predictors for the PR-related increase in 6MWD. CONCLUSIONS: Independently of the genetic variant of AAT, COPD patients achieved the same training-related benefit in 6MWD. Augmentation therapy showed no effect on 6MWD adaptation during PR.

Long-term efficacy and safety of α1 proteinase inhibitor treatment for emphysema caused by severe α1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE).

BACKGROUND: Purified α1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe α1 antitrypsin deficiency in a randomised controlled trial (RAPID-RCT), which was followed by an open-label extension trial (RAPID-OLE). The aim was to investigate the prolonged treatment effect of A1PI on the progression of emphysema as assessed by the loss of lung density in relation to RAPID-RCT. METHODS: Patients who had received either A1PI treatment (Zemaira or Respreeza; early-start group) or placebo (delayed-start group) in the RAPID-RCT trial were included in this 2-year open-label extension trial (RAPID-OLE). Patients from 22 hospitals in 11 countries outside of the USA received 60 mg/kg per week A1PI. The primary endpoint was annual rate of adjusted 15th percentile lung density loss measured using CT in the intention-to-treat population with a mixed-effects regression model. This trial is registered with ClinicalTrials.gov, number NCT00670007. FINDINGS: Between March 1, 2006, and Oct 13, 2010, 140 patients from RAPID-RCT entered RAPID-OLE: 76 from the early-start group and 64 from the delayed-start group. Between day 1 and month 24 (RAPID-RCT), the rate of lung density loss in RAPID-OLE patients was lower in the early-start group (-1·51 g/L per year [SE 0·25] at total lung capacity [TLC]; -1·55 g/L per year [0·24] at TLC plus functional residual capacity [FRC]; and -1·60 g/L per year [0·26] at FRC) than in the delayed-start group (-2·26 g/L per year [0·27] at TLC; -2·16 g/L per year [0·26] at TLC plus FRC, and -2·05 g/L per year [0·28] at FRC). Between months 24 and 48, the rate of lung density loss was reduced in delayed-start patients (from -2·26 g/L per year to -1·26 g/L per year), but no significant difference was seen in the rate in early-start patients during this time period (-1·51 g/L per year to -1·63 g/L per year), thus in early-start patients the efficacy was sustained to month 48. INTERPRETATION: RAPID-OLE supports the continued efficacy of A1PI in slowing disease progression during 4 years of treatment. Lost lung density was never recovered, highlighting the importance of early intervention with A1PI treatment. FUNDING: CSL Behring.

Results from a large targeted screening program for alpha-1-antitrypsin deficiency: 2003 - 2015.

BACKGROUND: Alpha-1-antitrypsin deficiency (AATD) is an autosomal codominant inherited disease that is significantly underdiagnosed. We have previously shown that the combination of an awareness campaign with the offer of free diagnostic testing results in the detection of a relevant number of severely deficient AATD patients. The present study provides an update on the results of our targeted screening program (German AAT laboratory, University of Marburg) covering a period from August 2003 to May 2015. METHODS: Diagnostic AATD detection test kits were offered free of charge. Dried blood samples were sent to our laboratory and used for the semiquantitative measurement of the AAT-level (nephelometry) and the detection of the S- or Z-allele (PCR). Isoelectric focusing was performed when either of the initial tests was indicative for at least one mutation. Besides, we evaluated the impact of additional screening efforts and the changes of the detection rate over time, and analysed the relevance of clinical parameters in the prediction of severe AATD. RESULTS: Between 2003 and 2015, 18,638 testing kits were analysed. 6919 (37.12 %) carried at least one mutation. Of those, we identified 1835 patients with severe AATD (9.82 % of the total test population) including 194 individuals with rare genotypes. Test initiatives offered to an unselected population resulted in a dramatically decreased detection rate. Among clinical characteristics, a history of COPD, emphysema, and bronchiectasis were significant predictors for Pi*ZZ, whereas a history of asthma, cough and phlegm were predictors of not carrying the genotype Pi*ZZ. CONCLUSION: A targeted screening program, combining measures to increase awareness with cost-free diagnostic testing, resulted in a high rate of AATD detection. The clinical data suggest that testing should be primarily offered to patients with COPD, emphysema, and/or bronchiectasis.

Handling of and preferences for available dry powder inhaler systems by patients with asthma and COPD.

The correct handling of dry powder inhalers (DPIs) is crucial for efficient therapy, and acceptance of the device can improve compliance. The handling of seven different dry powder inhalers was studied in 72 patients with asthma and chronic obstructive pulmonary disease (COPD). The aim of this study was to identify possible handling errors and investigate patient preferences. Patients inhaled twice with each inhaler; first after reading the device leaflet, and second after device handling was explained by the investigator. The investigator identified handling errors and critical handling errors, which might lead to insufficient or no dose delivery. Afterward, the patients selected their preferred device and judged different aspects of device handling. The lowest number of patients with critical handling errors was observed for the Diskus/Accuhaler, the highest numbers for the Jethaler and the Easyhaler (% of patients during first/second use): Diskus/Accuhaler 25%/13.9% (group A) and 38.9%/8.3% (group B); Clickhaler 50.0%/52.8%, Cyclohaler 58.3%/13.9%, Jethaler 66.7%/30.6% (group A) and Benosid N Inhaler 52.8%/22.2%, Novolizer 52.8%/25.0%, Easyhaler 72.2%/47.2% (group B). Device handling improved after instruction by the investigator. Device handling and preferences of patients closely correlated in this study. Both devices producing the lowest numbers of handling errors (Diskus/Accuhaler and Clickhaler) had the highest preference by the subjects (score from 1 = very good to 7 = very bad): Diskus/Accuhaler 2.21 (group A) and 2.02 (group B); Clickhaler 2.21, Cyclohaler 2.80, Jethaler 3.16 (group A); Novolizer 2.33, Easyhaler 2.37, Benosid N Inhaler 2.43 (group B). Critical handling errors may reduce therapy outcome due to a reduced dose delivery. In addition, reduced patients acceptance of a device, being dependent on device handling, may have a similar effect by reducing patients' compliance.

Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease.

RATIONALE: Exacerbations of chronic obstructive pulmonary disease (COPD) greatly contribute to declining health status and the progression of the disease, thereby incurring significant direct and indirect health care costs. The prevention of exacerbations, therefore, is an important treatment goal. OBJECTIVES: To assess the impact of combination therapy with salmeterol/fluticasone propionate compared with salmeterol alone on moderate and severe exacerbations in patients with severe COPD and a history of repeated exacerbations. METHODS: Randomized, double-blind, parallel-group study. After a 4-wk run-in period, 994 clinically stable patients were randomized to one of two treatment groups: 507 patients received the salmeterol/fluticasone combination 50/500 micro g twice daily and 487 received salmeterol 50 micro g twice daily for 44 wk. MAIN RESULTS: The total number of exacerbations was 334 in the combination therapy and 464 in the salmeterol group (p < 0.0001). The annualized rate of moderate and severe exacerbations per patient was 0.92 in the combination therapy and 1.4 in the salmeterol group, corresponding to a 35% decrease. In addition, the mean time to first exacerbation in the combination therapy group was significantly longer compared with that of the salmeterol group (128 vs. 93 d, p < 0.0001). Other endpoints, including health-related quality of life, peak expiratory flow, and use of rescue medication, were significantly improved in the combination therapy group. Both treatments were well tolerated. CONCLUSIONS: This study demonstrates that combination therapy with salmeterol/fluticasone compared with salmeterol monotherapy significantly reduces the frequency of moderate/severe exacerbations in patients with severe COPD.

National survey of guideline-compliant COPD management among pneumologists and primary care physicians.

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

Cytotoxic concentrations of alpha-defensins in the lungs of individuals with alpha 1-antitrypsin deficiency and moderate to severe lung disease.

The lungs of individuals with alpha(1)-antitrypsin (alpha(1)-AT) deficiency have a reduced antiprotease protective shield. Typically, numbers of neutrophils are elevated in the lungs of affected individuals, carrying large amounts of neutrophil elastase (NE) and alpha-defensins that are released upon activation. We hypothesized that in individuals with advanced lung disease associated with alpha(1)-AT deficiency cytotoxic concentrations of alpha-defensins might be present and unopposed, thus further aggravating lung disease. To evaluate this hypothesis, bronchoalveolar lavage was performed in 20 alpha(1)-AT deficient individuals with moderate to severe lung function impairment and 13 healthy volunteers. Cell counts as well as concentrations of NE and alpha-defensins were determined. While concentrations of NE were low (23+/-14nM) and alpha-defensins were undetectable in volunteers, they were significantly elevated in individuals with alpha(1)-AT deficiency (1313+/-723nM and 6605+/-2856nM, both p<0.0001). These concentrations were significantly higher than those found in a historical control of alpha(1)-AT deficient individuals with mild lung disease. Neutrophil numbers and NE concentration correlated with alpha-defensins concentration (r=0.612 and r=0.758, p=0.005 and p=0.0001, respectively). Individuals with alpha(1)-AT deficiency and moderate to severe lung function impairment have lung alpha-defensins concentrations in a range known to induce cytotoxicity in vitro in the absence of normal amounts alpha(1)-AT and thus may contribute to the development of lung disease in this population.