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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.

Background: Chronic Obstructive Pulmonary Disease (COPD) influences different aspects of patient's health-related quality of life (HRQL). While disease-specific HRQL instruments focus on symptoms and functional impairments, generic instruments cover a broader view on health. This study compares the generic EQ-5D-3 L and two disease-specific questionnaires (St.-George's Respiratory Questionnaire (SGRQ-C), COPD Assessment Test (CAT)) in a comprehensive spectrum of COPD disease grades with particular attention on comorbidities and assesses the discriminative abilities of these instruments., Methods: Using data from the baseline visit of the German COPD cohort COSYCONET, mean HRQL scores in different COPD grades were compared by linear regression models adjusting for age, sex, education, smoking status, BMI, and low vs. high number of comorbidities or a list of several self-reported comorbid conditions. Discriminative abilities of HRQL instruments to differentiate between COPD grades were assessed by standardized mean differences., Results: In 2,291 subjects in COPD GOLD grades 1-4 EQ-5D-3 L utility, EQ-5D VAS, SGRQ, and CAT were found able to discriminate between COPD grades, with some limitations for the EQ-5D utility in mild disease. Both generic and disease-specific HRQL instruments reflected the burden of comorbid conditions. The SGRQ showed the best discrimination between COPD grades and was less influenced by comorbidities, while EQ-5D utility put a higher weight on comorbid conditions. For all instruments, psychiatric disorders and peripheral artery disease showed the strongest negative associations with HRQL., Conclusion: All HRQL instruments considered reflect considerable impairment of HRQL in COPD patients, worsening with increasing COPD grade and number of comorbidities. Findings may support clinical assessment, choice of HRQL instrument in future studies, and parameterization of decision-analytic models.

Background: A variety of large randomized controlled trials (RCT's) evaluating pharmacotherapy in chronic obstructive pulmonary disease (COPD) patients does exist. One of the drugs that has been tested is the new long-acting anticholinergic glycopyrronium bromide., Methods: As the generalizability of results from RCT's is questionable we designed a longitudinal, prospective non-interventional study (DACCORD) of two years duration plus two years extension with at least 6000 participants in approximately 500 primary and secondary care practices in Germany (within the new established COPD National Prospective Registry), to assess patient reported outcomes (PRO's), lung function, adherence and drug safety. To circumvent the hurdle of inappropriate COPD diagnosis in a non-interventional trial, patients have to fulfill the inclusion criteria of the COPD disease management program (DMP) of the German statutory health insurances. Patient management should follow the German national COPD guidelines, which are based on Global Initiative for Chronic Obstructive Lung Disease 2007 (GOLD) report. Labels of prescribed drugs should also be taken into account. Patients received treatment as part of their standard care: at the discretion of the investigator patients were included in one of two arms. A: standard care with glycopyrronium containing regimen, and arm B: standard care without glycopyrronium., Discussion: For 2016 we expect important results regarding longitudinal development of PRO's including exacerbations, lung function, adherence and side effects. We also investigate applicability of the new GOLD staging system in usual care. Data on diagnostic and treatment modalities in current German primary and secondary care, as well as pharmaco-economic data will be generated., Trial Registration: 1. German Register for non-interventional studies: http://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb . 2. EMA EnCePP http://www.encepp.eu/ .

Background: Acute Aspergillus fumigatus infection in immunocompetent patients is rare. This is the first known case of a patient who survived Aspergillus sepsis after being treated early with veno-venous extracorporeal membrane (ECMO) and antifungal therapy., Case Presentation: An immunocompetent 54-year-old woman was exposed to plant mulch during gardening and subsequently developed pulmonary failure that progressed to sepsis with multiorgan failure. Owing to her severe clinical condition, she was treated for acute respiratory distress syndrome (ARDS) with veno-venous ECMO. Empiric antifungal therapy comprising voriconazole was also initiated owing to her history and a previous case report of aspergillosis after plant mulch exposure, though there was no microbiological proof at the time. A. fumigatus was later cultured and detected on antibody testing. The patient recovered, and ECMO was discontinued 1 week later. After 7 days of antifungal treatment, Aspergillus antibodies were undetectable., Conclusions: In cases of sepsis that occur after gardening, clinicians should consider Aspergillus inhalation as an aetiology, and early antimycotic therapy is recommended.

Background: Indacaterol is a long-acting beta-2 agonist for once-daily treatment of COPD. We evaluated the effects of indacaterol 150 μg on lung hyperinflation compared with placebo and open-label tiotropium 18 μg. We measured physical activity during treatment with indacaterol 150 μg and matched placebo., Methods: We performed a randomized, three-period, cross-over study (21 days of treatment separated by two wash-out periods of 13 days) with indacaterol 150 μg or matching placebo and tiotropium 18 μg. Lung function was assessed by body plethysmography and spirometry. Physical activity was measured for one week by a multisensory armband at the end of both treatment periods with indacaterol/matched placebo. The primary endpoint was peak inspiratory capacity at the end of each treatment period., Results: 129 patients (mean age, 61 years; mean post-bronchodilator FEV1, 64%), were randomized and 110 patients completed the study. Peak inspiratory capacity was 0.22 L greater with Indacaterol at day 21 compared to placebo (p < 0.001). Similar results were observed for tiotropium. Both bronchodilators also significantly improved other parameters of lung hyperinflation compared with placebo. All parameters of physical activity were significantly increased during treatment with indacaterol versus placebo., Conclusions: Indacaterol 150 μg improved lung hyperinflation in patients with moderate COPD, which was associated with an increase of physical activity., Trial Registration: ClinicalTrials.gov registration number: NCT01012765.

Background: Patients with stable COPD show improvements in exercise capacity and muscular function after the application of whole body vibration. We aimed to evaluate whether this modality added to conventional physiotherapy in exacerbated hospitalised COPD patients would be safe and would improve exercise capacity and quality of life., Methods: 49 hospitalised exacerbated COPD patients were randomized (1:1) to undergo physiotherapy alone or physiotherapy with the addition of whole body vibration. The primary endpoint was the between-group difference of the 6-minute walking test (day of discharge - day of admission). Secondary assessments included chair rising test, quality of life, and serum marker analysis., Results: Whole body vibration did not cause procedure-related adverse events. Compared to physiotherapy alone, it led to significantly stronger improvements in 6-minute walking test (95.55 ± 76.29 m vs. 6.13 ± 81.65 m; p = 0.007) and St. Georges Respiratory Questionnaire (-6.43 ± 14.25 vs. 5.59 ± 19.15, p = 0.049). Whole body vibration increased the expression of the transcription factor peroxisome proliferator receptor gamma coactivator-1-α and serum levels of irisin, while it decreased serum interleukin-8., Conclusion: Whole body vibration during hospitalised exacerbations did not cause procedure-related adverse events and induced clinically significant benefits regarding exercise capacity and health-related quality of life that were associated with increased serum levels of irisin, a marker of muscle activity., Trial Registration: German Clinical Trials Register DRKS00005979. Registered 17 March 2014.

Background: Intravenous augmentation therapy is the only specific treatment available for emphysema associated with alpha-1 antitrypsin deficiency. Despite large observational studies and limited interventional studies there remains controversy about the efficacy of this treatment due to the impracticality of conducting adequately powered studies to evaluate the rate of decline in lung function, due to the low prevalence and the slow progression of the disease. However, measurement of lung density by computed tomography is a more specific and sensitive marker of the evolution of emphysema and two small placebo-controlled clinical trials have provided evidence supporting a reduction in the rate of decline in lung density with augmentation therapy., The Problem: Where augmentation therapy has become available there has been little consideration of a structured approach to therapy which is often introduced on the basis of functional impairment at diagnosis. Data from registries have shown a great variability in the evolution of lung disease according to patient acquisition and the presence of recognised risk factors. Avoidance of risk factors may, in many cases, stabilise the disease. Since augmentation therapy itself will at best preserve the presenting level of lung damage yet require intravenous administration for life with associated costs, identification of patients at risk of continued rapid or long term progression is essential to select those for whom this treatment can be most appropriate and hence generally more cost-effective. This represents a major reconsideration of the current practice in order to develop a consistent approach to management world wide., Purpose of This Review: The current review assesses the evidence for efficacy of augmentation therapy and considers how the combination of age, physiological impairment, exacerbation history and rate of decline in spirometry and other measures of emphysema may be used to improve therapeutic decision making, until a reliable predictive biomarker of the evolution of lung impairment can be identified. In addition, individual pharmacokinetic studies may permit the selection of the best regimen of administration for those who need it., Summary: The rarity and variable characteristics of the disease imply the need for an individualised approach to therapy in specialised centres with sufficient experience to apply a systematic approach to monitoring and management.

Background: Chronic obstructive pulmonary disease (COPD) is influenced by environmental and genetic factors. An important fraction of COPD cases harbor a major genetic determinant, inherited ZZ (Glu342Lys) α1-antitrypsin deficiency (AATD). A study was undertaken to investigate gene expression patterns in end-stage COPD lungs from patients with and without AATD., Methods: Explanted lungs of end-stage ZZ AATD-related (treated and non-treated with AAT augmentation therapy) and "normal" MM COPD, and liver biopsies from patients suffering from liver cirrhosis with and without ZZ AATD were used for gene expression analysis by Affymetrix microarrays or RT-PCR., Results: A total of 162 genes were found to be differentially expressed (p-value ≤ 0.05 and |FC| ≥ 2) between MM and ZZ COPD patients. Of those, 134 gene sets were up-regulated and 28 were down-regulated in ZZ relative to MM lung tissue. A subgroup of genes, zinc finger protein 165, snail homolog 1 (Drosophila) (SNAI1), and Krüppel-like transcription factors (KLFs) 4 (gut), 9 and 10, perfectly segregated ZZ and MM COPD patients. The higher expression of KLF 9 and KLF10 has been verified in the replication cohort with AATD-related end-stage lung emphysema and liver cirrhosis. Furthermore, higher expression of KLF9, SNAI1 and DEFA1 was found in ZZ COPD lungs without augmentation therapy relative to MM COPD or ZZ COPD with augmentation therapy., Conclusions: These results reveal the involvement of transcriptional regulators of the zinc-finger family in COPD pathogenesis and provide deeper insight into the pathophysiological mechanisms of COPD with and without AATD.

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.

Pulmonary toxicity of inhaled materials is often evaluated by (repetitive) assessment of the composition of bronchoalveolar lavage (BAL) fluid or of epithelial lining fluid (ELF) in sheep and lambs. Knowledge of the typical constituents of these fluids obtained from healthy animals is essential for identification of pathologic changes. Few studies have dealt with normal constituents of BAL fluid or ELF in sheep and lamb. The comparability of these studies, however, is limited for reasons concerning the choice of model and BAL technique. The biochemical and cellular composition of alveolar ELF obtained by a standardized BAL procedure was examined in 15 pento-barbital anesthetized 4 months old Merino lambs unexposed to inhaled substances. ELF volume was calculated by using the urea dilution method. We found 20.3 x 10(5) leucocytes per ml ELF, 87.5% of which were alveolar macrophages. Basophils and neutrophils were practically absent while 5% of the counted cells were lymphocytes. 76% of recovered cells were viable. The ELF contained 7 mg/ml total protein; enzyme activities of LDH and AP were 1692 U/l and 145 U/l, respectively.

The pulmonary function of 88 consecutive leukemic patients who had undergone allogeneic bone marrow transplantation (BMT) was studied beforehand, at 3 months, at 6 months, and annually thereafter until 5 years after grafting. The parameters for function which are indicative for obstructive and restrictive lung disease deteriorated in all patient groups during the first 3 to 6 months after BMT but partially recovered within one year. Long-term decline in lung function was similar in all patient groups, and neither the onset nor the magnitude of pulmonary dysfunction was related to the occurrence of pulmonary impairment within 6 months after grafting. Multivariate analysis was then employed to assess predictors for long-term pulmonary disease. Despite the obvious effect of chronic graft versus host disease on the course of lung function, it was in itself not a significant predictor of long-term pulmonary outcome. Rather, the conditioning regimen turned out to be indicative; compared with busulfan, fractionated total body irradiation was demonstrated to be clearly superior with a lower incidence of both restrictive and obstructive long-term lung impairment. Our data indicate a previously unknown long-term side effect of busulfan conditioning.