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The new international and german asthma guidelines recommend a 5-step treatment approach, to achieve asthma control and to minimize future risk. Inhaled corticosteroids (ICS) are still the mainstay of treatment, which should be combined with long-acting bronchodilators in patients with more severe disease. Specific treatment options such as allergen-Immunotherapy (AIT) or biologics, which can be very efficacious in individual patients, are forerunners of a new era of precision medicine in asthma., Competing Interests: ML erhielt Honorare für Beratungen und Vorträge von den Firmen ALK Abelló, Allergopharma, Astra Zeneca, Bencard, Berlin-Chemie, Boehringer-Ingelheim, Boston Scientic, Chiesi, GSK, Janssen-Cilag, MSD, Mundipharma, Novartis, Nycomed/Takeda, Sanofi, TEVA, UCB. ML erhielt Forschungsförderung von der Deutschen Forschungsgemeinschaft (DFG), dem Land Mecklenburg-Vorpommern, GSK, AstraZeneca., (© Georg Thieme Verlag KG Stuttgart · New York.)

The present guideline is a new version and an update of the guideline for the diagnosis and treatment of asthma, which replaces the previous version for german speaking countries from the year 2006. The wealth of new data on the pathophysiology and the phenotypes of asthma, and the expanded spectrum of diagnostic and therapeutic options necessitated a new version and an update. This guideline presents the current, evidence-based recommendations for the diagnosis and treatment of asthma, for children and adolescents as well as for adults with asthma., Competing Interests: Interessenkonflikt: Eine Übersicht der Interessenkonflikte findet sich im Internet unter http://www.awmf.org; AWMF-Registernummer 020-009., (© Georg Thieme Verlag KG Stuttgart · New York.)

A long and winding road led to the discovery of immunoglobulin E (IgE) in 1966 and 1967. We are currently on a long and winding road to understand the immunologic basis of the clinical effects of the anti-IgE antibody omalizumab in asthma. It is possible that patients with asthma (as patients with chronic spontaneous urticaria) benefit in different immunologic ways from omalizumab treatment. This article reviews the history of IgE discovery and current concepts of anti-IgE therapy in asthma., Competing Interests: Interessenkonflikt: M. Lommatzsch erhielt Honorare für Beratungen und Vorträge von den Firmen ALK Abelló, Allergopharma, AstraZeneca, Bencard, Berlin-Chemie, Boehringer-Ingelheim, Boston Scientific, Chiesi, GSK, Janssen-Cilag, MSD, Mundipharma, Novartis, Nycomed/Takeda, Sanofi, TEVA, UCB. ML erhielt Forschungsförderung von der Deutschen Forschungsgemeinschaft (DFG), dem Land Mecklenburg-Vorpommern, GSK, AstraZeneca. K. Geißler hat Vortragshonorare von den Firmen AstraZeneca, Novartis und Teva erhalten. KG hat Forschungsförderung von den Firmen AstraZeneca und Teva erhalten. K.-C. Bergmann hat Vortrags- und Beraterhonorare von den Firmen AstraZeneca, ALK, Bencard, HAL, Lofarma, Novartis, Stallergenes und Teva erhalten. J. C. Virchow hat Vorträge gehalten und Honoraria erhalten von: AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed/Altana, Pfizer, Revotar, Sanofi/Regeneron, Sandoz-Hexal, Stallergens, TEVA, UCB/Schwarz-Pharma, Zydus/Cadila und als Berater fungiert für: Avontec, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, MEDA, MSD, Mundipharma, Novartis, Regeneron, Revotar, Roche, Sanofi-Aventis, Sanofi/Regeneron, Sandoz-Hexal, TEVA, UCB/Schwarz-Pharma. JCV hat Forschungsförderung erhalten von der Deutschen Forschungsgemeinschaft (DFG), dem Land Mecklenburg-Vorpommern, GSK, MSD., (© Georg Thieme Verlag KG Stuttgart · New York.)

Asthma is a heterogeneous, complex disease with clinical phenotypes that incorporate persistent symptoms and acute exacerbations. It affects many millions of Europeans throughout their education and working lives and puts a heavy cost on European productivity. There is a wide spectrum of disease severity and control. Therapeutic advances have been slow despite greater understanding of basic mechanisms and the lack of satisfactory preventative and disease modifying management for asthma constitutes a significant unmet clinical need. Preventing, treating and ultimately curing asthma requires co-ordinated research and innovation across Europe. The European Asthma Research and Innovation Partnership (EARIP) is an FP7-funded programme which has taken a co-ordinated and integrated approach to analysing the future of asthma research and development. This report aims to identify the mechanistic areas in which investment is required to bring about significant improvements in asthma outcomes., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Background: Benralizumab is a humanised, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils. We aimed to assess the efficacy and safety of benralizumab as add-on therapy for patients with severe, uncontrolled asthma and elevated blood eosinophil counts., Methods: In this randomised, double-blind, parallel-group, placebo-controlled, phase 3 study (CALIMA) undertaken at 303 sites in 11 countries, we enrolled patients aged 12-75 years with severe asthma uncontrolled by medium-dosage to high-dosage inhaled corticosteroids plus long-acting β₂-agonists (ICS plus LABA) and a history of two or more exacerbations in the previous year. Patients were randomly assigned (1:1:1) to receive 56 weeks of benralizumab 30 mg every 4 weeks (Q4W), benralizumab 30 mg every 8 weeks (Q8W; first three doses 4 weeks apart), or placebo (all subcutaneous injection). Patients were stratified (2:1) by baseline blood eosinophil counts 300 cells per μL or greater and less than 300 cells per μL, respectively. Patients and study centre staff were masked to treatment allocation. The primary endpoint was annual exacerbation rate ratio versus placebo for patients receiving high-dosage ICS plus LABA with baseline blood eosinophils 300 cells per μL or greater (intention-to-treat analysis). Key secondary endpoints were pre-bronchodilator forced expiratory volume in 1 s (FEV 1 ) and total asthma symptom score. This study is registered with ClinicalTrials.gov, number NCT01914757., Findings: Between Aug 21, 2013, and March 16, 2015, 2505 patients were enrolled, of whom 1306 patients were randomised; 425 patients were randomly assigned to and received benralizumab 30 mg Q4W, 441 to benralizumab 30 mg Q8W, and 440 to placebo. 728 patients were included in the primary analysis population. Benralizumab resulted in significantly lower annual exacerbation rates with the Q4W regimen (rate 0·60 [95% CI 0·48-0·74], rate ratio 0·64 [95% CI 0·49-0·85], p=0·0018, n=241) and Q8W regimen (rate 0·66 [95% CI 0·54-0·82], rate ratio 0·72 [95% CI 0·54-0·95], p=0·0188, n=239) compared with placebo (rate 0·93 [95% CI 0·77-1·12], n=248). Benralizumab also significantly improved pre-bronchodilator FEV 1 (Q4W and Q8W) and total asthma symptom score (Q8W only) in these patients. The most common adverse events were nasopharyngitis (90 [21%] in the Q4W group, 79 [18%] in the Q8W group, and 92 [21%] in the placebo group) and worsening asthma (61 [14%] in the Q4W group, 47 [11%] in the Q8W group, and 68 [15%] in the group)., Interpretation: Benralizumab significantly reduced annual exacerbation rates and was generally well tolerated for patients with severe, uncontrolled asthma with blood eosinophils 300 cells per μL or greater. Our data further refine the patient population likely to receive the greatest benefit from benralizumab treatment., Funding: AstraZeneca and Kyowa Hakko Kirin., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The histologic diagnosis of Pulmonary Langerhans cell histiocytosis (PLCH) is invasive and can cause complications. To confirm the diagnosis of PLCH, guidelines therefore recommend measuring CD1a-positive bronchoalveolar lavage fluid (BALF) cells despite its poor sensitivity and specificity. Thus, an improved diagnostic accuracy of BALF cell analysis would be desirable., Methods: Using four-colour flow cytometry, plasmacytoid and myeloid dendritic cells (DCs) were analysed in BALF of 10 newly diagnosed, untreated, smoking patients with PLCH, and compared with BALF DCs from 40 asymptomatic smokers and 21 never-smokers., Results: Compared with controls, myeloid DCs (median: 0.79% of BALF leukocytes) and their subpopulation of Langerhans cells (median: 0.44% of BALF leukocytes) were not increased in PLCH. Patients with PLCH displayed a normal expression of the maturity marker CD83 on BALF myeloid DCs. However, the expression of the co-signaling molecule CD80 on BALF myeloid DCs was significantly lower than in both control groups, with the lowest expression found in more severe disease (presence of cysts > 2 cm in diameter). Based on receiver operating characteristic (ROC) curve analysis, a cut-off of 53% CD80-positive BALF myeloid DCs was optimal for the diagnosis of PLCH, yielding a sensitivity of 0.90 and a specificity of 0.90., Conclusions: BALF Langerhans cells are not increased in PLCH. However, PLCH is characterised by a low expression of CD80 on BALF myeloid DCs. Due to its considerably higher sensitivity and specificity, this marker appears to be more appropriate to diagnose PLCH than the currently recommended marker CD1a., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The prevalence and the characteristics of poor asthma control among adults treated with combinations of inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA) are not completely understood., Methods: Data from adult patients in Germany with self-reported asthma treated with an ICS-LABA combination in the National Health and Wellness Survey (NHWS) were analysed. Patients with well-controlled and not well-controlled asthma according to the Asthma Control Test (ACT) score were compared, with respect to socio-demographic characteristics, attitudes, adherence and outcomes., Results: Among the German patients with self-reported asthma (5.2% of the respondents), 16.2% (382 patients) were treated with an ICS-LABA combination and did not report concomitant chronic obstructive pulmonary disease, chronic bronchitis or emphysema. In this subgroup, 55.8% had not well-controlled asthma (ACT < 20). ICS-LABA treated patients with not well-controlled asthma were more likely to report emergency visits (16.4% vs. 8.9%), missed more time from work (absenteeism: 12.9% vs. 4.3%), were more impaired while at work (presenteeism: 29.0% vs. 14.9%) and were more likely to be women (69.0% vs. 57.4%), compared with well-controlled patients. There were no significant differences in age, body mass index, smoking, income, education or self-reported adherence between the two groups, but different attitudes regarding the patient-physician relationship., Conclusions: A substantial proportion of patients treated with ICS and LABA had not well-controlled asthma. These patients did not differ from well-controlled patients in terms of education or self-reported adherence, but in terms of their attitudes regarding the patient-physician relationship., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Although hospitalisations due to an exacerbation of chronic obstructive pulmonary disease (COPD) are associated with increased risk of mortality, there is little information on long-term survival after severe COPD exacerbations., Methods: The 5-year and 8-year overall survival after hospitalisation due to a COPD exacerbation was explored. In addition, potential predictors of survival were analysed., Results: The 57 patients with COPD included in this analysis had a median age of 70 years, a median smoking history of 30 pack years and a median forced expiratory volume in the first second (FEV1) of 41.6% predicted at the time of COPD exacerbation. The majority of the patients had either normal weight (body mass index, BMI 18.5-24.99 kg/m(2): 42%) or overweight (BMI ≥ 25 kg/m(2): 54%). The 5-year overall survival after exacerbation was 54%, the 8-year overall survival 42%. The presence of cardiac comorbidities, a FEV1 <50% predicted, an age >70 years and a BMI <25 kg/m(2), but not smoking history or current smoking, were associated with decreased overall survival. Multivariate regression analysis revealed that only BMI, age and FEV1 were independent predictors of long-term survival. Overweight patients (BMI ≥ 25 kg/m(2)) had a substantially higher 5-year overall survival (74%) than patients with a BMI < 25 kg/m(2) (31%)., Conclusion: Nearly half of the patients hospitalised due to an exacerbation of COPD die within 5 years after the event. Overweight is a positive predictor of long-term survival in these patients., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Current guidelines of the global initiative for asthma (GINA) recommend the addition of biologics in step 5 of the stepwise asthma treatment approach. This review gives an overview on the effects and the clinical role of antibodies targeting immunoglobulin E, IgE (Omalizumab), Interleukin-5, IL-5 (Mepolizumab, Reslizumab) or the IL-5 receptor (Benralizumab). In addition, potential future treatment options of refractory asthma with antibodies (for instance Dupilumab) are discussed., (© Georg Thieme Verlag KG Stuttgart · New York.)

Hot-melt adhesives are widely utilised to glue cardboard boxes used as food packaging material. They have to comply with the requirements of Article 3 of the European Framework Regulation for food contact materials (1935/2004). The hot melt raw materials analysed mainly consisted of paraffinic waxes, hydrocarbon resins and polyolefins. The hydrocarbon resins, functioning as tackifiers, were the predominant source of hydrocarbons of sufficient volatility to migrate into dry foods: the 18 hydrocarbon resins analysed contained 8.2-118 g kg(-1) saturated and up to 59 g kg(-1) aromatic hydrocarbons eluted from GC between n-C16 and n-C24, substantially more than the paraffinic waxes and the polyolefins. These tackfier resins, especially the oligomers ≤ C24, have been characterised structurally by GC×GC-MS and (1)H-NMR spectroscopy. Migration into food was estimated using a simulating system with polenta as food simulant, which was verified by the analysis of a commercial risotto rice sample packed in a virgin fibre folding box sealed with a hot melt. About 0.5-1.5% of the potentially migrating substances (between n-C16 and n-C24) of a hot melt were found to be transferred into food under storage conditions, which can result in a food contamination in the order of 1 mg kg(-1) food (depending on the amount of potentially migrating substances from the hot melt, the hot melt surface, amount of food, contact time etc.). Migrates from hot melts are easily mistaken for mineral oil hydrocarbons from recycled cardboard.

Novel treatment strategies are currently emerging for patients with inadequately controlled asthma despite good adherence and trigger avoidance. These strategies serve primarily to reduce or completely avoid long-term oral corticosteroid therapy. A number of these options have already been implemented in practice or will soon be authorized for the treatment of asthma, while others still need to prove their clinical practicability, safety and efficacy. The present article provides an overview of the broad spectrum of novel inhaled, oral, systemic, and invasive treatment strategies for asthma.

Multidimensional chromatography based on two-dimensional high performance liquid chromatography on-line coupled to gas chromatography (on-line HPLC-HPLC-GC) enables the separate analysis of saturated, monounsaturated and aromatic hydrocarbons in packaging materials like polyolefins or paperboard and their migrates into foods. Since normal-phase HPLC on silica gel did not preseparate saturated from monounsaturated hydrocarbons, a separation step on a normal-phase HPLC column treated in the laboratory with an optimized amount of silver nitrate was added. The preparation of this HPLC column and the instrumental set-up are described, followed by examples showing the potential of the method. In a preliminary investigation of 11 polyolefin granulates for food contact up to 40% monounsaturated hydrocarbons among the oligomers C16-35 were determined., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The present study examines deformation bands in calcareous arkosic sands. The investigated units can be considered as an equivalent to the Matzen field in the Vienna Basin (Austria), which is one of the most productive oil reservoirs in central Europe. The outcrop exposes carbonate-free and carbonatic sediments of Badenian age separated by a normal fault. Carbonatic sediments in the hanging wall of the normal fault develop dilation bands with minor shear displacements (< 2 mm), whereas carbonate-free sediments in the footwall develop cataclastic shear bands with up to 70 cm displacement. The cataclastic shear bands show a permeability reduction up to 3 orders of magnitude and strong baffling effects in the vadose zone. Carbonatic dilation bands show a permeability reduction of 1-2 orders of magnitude and no baffling structures. We distinguished two types of deformation bands in the carbonatic units, which differ in deformation mechanisms, distribution and composition. Full-cemented bands form as dilation bands with an intense syn-kinematic calcite cementation, whereas the younger loose-cemented bands are dilatant shear bands cemented by patchy calcite and clay minerals. All analyzed bands are characterized by a porosity and permeability reduction caused by grain fracturing and cementation. The changed petrophysical properties and especially the porosity evolution are closely related to diagenetic processes driven by varying pore fluids in different diagenetic environments. The deformation band evolution and sealing capacity is controlled by the initial host rock composition.

Background: Dendritic cells (DCs) control immunity and play a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the expression of function-associated surface molecules on circulating DCs in COPD is unknown., Methods: Four-colour flow cytometry was used to compare blood DC surface molecules of 54 patients with COPD (median age: 59 years; median FEV1: 38% predicted, median CAT score: 24) with two age-matched control groups with normal lung function: 21 current smokers and 21 never-smokers., Results: Concentrations of plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) and the mDC/pDC ratio did not differ between the groups. The increased expression of BDCA-1, BDCA-3, CD86 and CCR5 on mDCs in patients with COPD did not significantly differ from smokers with normal lung function. In contrast, COPD was specifically characterised by a decreased expression of the anti-inflammatory co-stimulatory molecule PD-L1 on pDCs and an increased expression of the pro-inflammatory co-stimulatory molecule OX40 ligand (OX40L) on mDCs. These changes were not confined to patients with elevated systemic inflammation markers (leukocytes, c-reactive protein, interleukin-6, fibrinogen). The ratio of OX40L to PD-L1 expression (OX40L/PD-L1 ratio), a quantitative measure of imbalanced DC co-stimulation, correlated with the severity of pulmonary emphysema in patients with COPD., Conclusion: An imbalance of DC co-stimulation might contribute to the pathogenesis of COPD.

Background: A minority of patients with asthma have uncontrolled or partially controlled asthma despite intensive treatment. These patients present a special challenge because of the extensive diagnostic evaluation that they need, insufficient evidence regarding personalized treatments, and their high consumption of health-care resources., Methods: The definition, diagnosis, and treatment of severe asthma are presented on the basis of a selective literature review and the authors' clinical experience., Results: Severe asthma is present, by definition, when adequate control of asthma cannot be achieved by high-dose treatment with inhaled cortico - steroids and additional controllers (long-acting inhaled beta 2 agonists, montelukast, and/or theophylline) or by oral corticosteroid treatment (for at least six months per year), or is lost when the treatment is reduced. Before any further treatments are evaluated, differential diagnoses of asthma should be ruled out, comorbidities should be treated, persistent triggers should be eliminated, and patient adherence should be optimized. Moreover, pulmonary rehabilitation is recommended in order to stabilize asthma over the long term and reduce absences from school or work. The additional drugs that can be used include tiotropium, omalizumab (for IgE-mediated asthma), and azithromycin (for non-eosinophilic asthma). Antibodies against interleukin-5 or its receptor will probably be approved soon for the treatment of severe eosinophilic asthma., Conclusion: The diagnosis and treatment of severe asthma is time consuming and requires special experience. There is a need for competent treatment centers, continuing medical education, and research on the prevalence of severe asthma.

Background: Myeloid dendritic cells (DCs) are increased in the airway wall of patients with chronic obstructive pulmonary disease (COPD), and postulated to play a crucial role in COPD. However, DC phenotypes in COPD are poorly understood., Methods: Function-associated surface molecules on bronchoalveolar lavage fluid (BALF) DCs were analyzed using flow cytometry in current smokers with COPD, in former smokers with COPD and in never-smoking controls., Results: Myeloid DCs of current smokers with COPD displayed a significantly increased expression of receptors for antigen recognition such as BDCA-1 or Langerin, as compared with never-smoking controls. In contrast, former smokers with COPD displayed a significantly decreased expression of these receptors, as compared with never-smoking controls. A significantly reduced expression of the maturation marker CD83 on myeloid DCs was found in current smokers with COPD, but not in former smokers with COPD. The chemokine receptor CCR5 on myeloid DCs, which is also important for the uptake and procession of microbial antigens, was strongly reduced in all patients with COPD, independently of the smoking status., Conclusion: COPD is characterized by a strongly reduced CCR5 expression on myeloid DCs in the airway lumen, which might hamper DC interactions with microbial antigens. Further studies are needed to better understand the role of CCR5 in the pathophysiology and microbiology of COPD.

For many years, pathogenetic concepts and the results of clinical trials supported the view that anti-IgE treatment is specifically effective in allergic asthma. However, there is now growing clinical and mechanistic evidence suggesting that treatment with the anti-IgE antibody omalizumab can be effective in patients with intrinsic asthma. Therefore, large and well-controlled clinical trials with anti-IgE are urgently warranted in patients with intrinsic asthma. In addition, there is a need to find new biomarkers which can identify patients with asthma who respond to anti-IgE treatment.

Medical care for allergic patients in Germany is decreasing, although the prevalence of allergic disorders continues to rise. This article describes the magnitude and the causes of this paradox. In addition, the consequences of this phenomenon for respiratory medicine and for the diagnosis and therapy of asthma are discussed., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Myeloid Dendritic cells are key drivers of inflammation in smoke-related lung diseases, whereas plasmacytoid DCs play a crucial role in the defense against infections. Effects of inhaled corticosteroids (ICS) on airway DCs in smokers are unknown., Methods: In this randomized, double-blind, placebo-controlled clinical trial, 45 active cigarette smokers inhaled placebo, fluticasone or fluticasone plus salmeterol twice daily for 4 weeks. Bronchoalveolar lavage fluid DCs were analyzed using four-color flow cytometry before and after the inhalation period. In addition, fluticasone effects were tested on T-cell proliferation in co-cultures with blood myeloid DCs from smokers., Results: Inhalation of fluticasone plus salmeterol, but not fluticasone alone or placebo, reduced endobronchial concentrations of myeloid DCs (median decrease: 24%), macrophages (median decrease: 26%) and neutrophils (median decrease: 76%). In contrast, fluticasone reduced plasmacytoid DC concentrations independently of salmeterol. There were no changes in the expression of function-associated surface molecules on myeloid DC (such as CD1a, Langerin, BDCA-1, CD83 or CCR5) in all groups after treatment. Fluticasone (either alone or in combination with salmeterol) suppressed T-cell proliferation in co-cultures with blood myeloid DCs from smokers., Conclusions: Resistance to ICS monotherapy in smokers might in part be due to lacking effects on airway myeloid DCs, whereas the increased risk for infections during ICS therapy could be attributable to a reduction in plasmacytoid DCs. Combination therapy of fluticasone with salmeterol is associated with a reduction in airway myeloid DCs, but also airway macrophages and neutrophils., Trial Registration: Registered at ClinicalTrials.gov (identifier: NCT00908362) and the European Clinical Trial Database, EudraCT (identifier: 2009-009459-40).

Background: Chronic Obstructive Pulmonary Disease (COPD) is characterised by complex inflammatory, neuronal and fibrotic changes. Brain-derived Neurotrophic Factor (BDNF) is a key regulator of neuronal plasticity, whereas Transforming Growth Factor-β1 (TGF-β1) plays a crucial role in tissue repair and emphysema pathogenesis. Both mediators are stored in platelets and released from platelets in inflammatory conditions and during serum preparation. In patients with asthma, it was previously shown that elevated serum BDNF concentrations correlate with disease severity, whereas TGF-β1 concentrations were normal., Methods: In the present study, 63 patients with stable COPD (spirometric GOLD stages 2-4) and 17 age- and comorbidity-matched controls were studied. Lung function, smoking history, medication, platelet concentrations in peripheral blood and serum concentrations of BDNF, TGF-β1 and Serotonin (5-HT) were assessed in all participants., Results: Serum levels of both BDNF and TGF-β1 (but not concentrations of platelets in peripheral blood) were significantly elevated in all stages of COPD as compared to controls. Highest BDNF concentrations were found in spirometric GOLD stage 3, whereas highest TGF-β1 serum levels were found in spirometric GOLD stage 4. There were specific, stage-dependent correlations of these mediators with lung function parameters of the patients., Conclusions: Taken together, we show that, in contrast to asthma, COPD is characterised by elevated concentrations of both BDNF and TGF-β1 in serum. The stage-dependent association with lung function supports the hypothesis that these platelet mediators may play a role in the pathogenesis of COPD.

Airway hyperresponsiveness (AHR) is the most characteristic clinical feature of asthma. The pathogenesis of AHR in asthma is characterized by a variety of epithelial, microbial, and inflammatory triggers on one hand and abnormalities of effector structures in the airways such as smooth muscle cells, blood vessels, and nerves on the other hand. Obesity is increasingly recognized as an important additional factor in the diagnosis and the pathogenesis of AHR in asthma. It is important to note that structural changes in the asthmatic airway can persist in the absence of inflammation. This may be one reason for the observation that potent new antiinflammatory drugs for the treatment of asthma have only little impact on AHR. New therapeutic strategies are, therefore, needed to modulate structural and functional changes in the airways, especially in patients with treatment-resistant severe asthma., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Dendritic cells (DCs) play a crucial role in the initiation of immune responses against infectious particles and tumor cells; however, the impact of age, anthropometric parameters, and gender on the number and the expression of function-associated molecules of human DCs is poorly understood. In this study, blood DCs of 50 volunteers (19-84 years old) with no acute or chronic inflammatory diseases were examined using 4-color flow cytometry. Increasing age was associated with a decrease in blood plasmacytoid, but not myeloid DCs and a selective decrease in Toll-like receptor 9 (TLR9) expression by plasmacytoid DCs. In contrast, gender and body mass index did not impact the number of DC subsets or the expression of function-associated DC molecules. Thus, we demonstrate that age has a selective impact on plasmacytoid DCs and their TLR9 expression. This may contribute to an increased susceptibility to infections and tumors with increasing age., (Copyright © 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Hypertrophic pulmonary osteoarthropathy (often referred to as Marie-Bamberger syndrome) occurs in 1 - 5 % of all patients with non-small cell lung cancer (NSCLC) as a paraneoplastic syndrome. The complete syndrome is characterised by clubbing of the fingers and toes (often without hypoxia) and pain in the joints and tubular bones. On the basis of four clinical cases, this article shows that this syndrome can precede tumour-specific symptoms and that it is still often overlooked by physicians. An early suspicion of this syndrome is of great clinical value because it can lead to a diagnosis of NSCLC at an earlier tumour stage. In addition to the case reports, the current literature on hypertrophic pulmonary osteoarthropathy is reviewed in this article, with special reference to pathogenetic concepts und to therapeutic options., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Dendritic cells (DCs) play a key role in the host defence against inhaled pathogens. However, the phenotype of blood DCs in patients with acute respiratory infections is unknown., Objective: To investigate the number and the expression of function-associated molecules of blood DCs in patients with acute infectious pneumonia., Methods: Sixteen patients with acute pneumonia and 19 controls without pneumonia were included in the study. The number as well as the expression of function-associated molecules of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) were analysed in peripheral blood using four-colour flow cytometry., Results: Elevated concentrations of procalcitonin (median: 0.55 ng/ml) and the rapid response to antibiotic treatment suggested a bacterial origin of the pneumonia in the patients. Total mDC (median: 27% of the controls) and pDC counts (median: 53% of the controls) were markedly reduced in patients with pneumonia, as compared to the controls. Percentages of blood mDCs, but not pDCs, were negatively correlated with serum concentrations of C-reactive protein. Patients with pneumonia were characterised by a significantly increased expression of Fc gamma receptors (CD32 and CD64) on mDCs and the Toll-like receptor 9 (TLR9) on pDCs., Conclusions: Circulating DCs are markedly reduced in patients with pneumonia, and characterised by an up-regulation of molecules recognising pathogen-associated molecular patterns and opsonised antigens., (Copyright © 2011 S. Karger AG, Basel.)

Anti-platelet treatment is a key therapeutic intervention in patients with cerebrovascular diseases. However, there is no information on its impact on the release of Brain-derived neurotrophic factor (BDNF), which is stored in large amounts in human platelets and essential for neuronal protection and repair. Here, we show that a single oral dose of clopidogrel, but not aspirin, significantly reduced the release of BDNF from platelets in healthy volunteers. These data point, for the first time, to possible differential effects of anti-platelet regimens on neuronal function in patients with cerebrovascular disorders., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Extracellular ATP is up-regulated in the airways of patients with chronic obstructive pulmonary disease, and may contribute to the pathogenesis of the disease. However, the precise mechanisms are poorly understood. Our objective was to investigate the functional role of the ATP receptor P2X(7) in the pathogenesis of cigarette smoke (CS)-induced lung inflammation and emphysema in vivo. Expression of the P2X(7) receptor (P2X(7)R) was measured in lung tissue und immune cells of mice with CS-induced lung inflammation. In a series of experiments using P2X(7) antagonists and genetically engineered mice, the functional role of the P2X(7)R in CS-induced lung inflammation was explored. CS-induced inflammation was associated with an up-regulation of the P2X(7)R on blood and airway neutrophils, alveolar macrophages, and in whole lung tissue. Selective intrapulmonary inhibition of the P2X(7)R reduced CS-induced lung inflammation and prevented the development of emphysema. Accordingly, P2X(7)R knockout mice showed a reduced pulmonary inflammation after acute CS exposure. Experiments with P2X(7)R chimera animals revealed that immune cell P2X(7)R expression plays an important role in CS-induced lung inflammation and emphysema. Extracellular ATP contributes to the development of CS-induced lung inflammation and emphysema via activation of the P2X(7)R. Inhibition of this receptor may be a new therapeutic target for the treatment of chronic obstructive pulmonary disease.

Background: Modulation of T-cell differentiation, which is controlled by dendritic cells (DCs), plays a crucial role in specific immunotherapy (SIT). However, the number and the characteristics of blood DCs before and during immunotherapy are unknown., Objective: To analyze the number and the characteristics of blood DC subsets in patients with Hymenoptera venom allergy before and after initiation of SIT., Methods: In this clinical trial (NCT00947908), blood myeloid and plasmacytoid DCs were analyzed in 20 patients with Hymenoptera venom allergy (bee or wasp venom) by using 4-color flow cytometry at 3 time points: directly before SIT, and 52 hours and 12 months after initiation of SIT. In addition, 20 age-matched and sex-matched controls were examined., Results: In patients with Hymenoptera venom allergy, the number of plasmacytoid DCs before SIT was comparable to that of controls. Plasmacytoid DCs decreased markedly 52 hours after initiation of SIT and returned to control levels after 12 months of treatment. Myeloid DCs were elevated in patients with Hymenoptera venom allergy before, during, and after the first 12 months of SIT. In addition, there were changes in the expression of function-associated surface molecules on myeloid DCs (such as Fc γ receptor 2 and Toll-like receptor 2) during SIT., Conclusion: Numbers of blood myeloid DCs are elevated in patients with Hymenoptera venom allergy, and there are specific changes in the expression of function-associated surface molecules on these cells during SIT. Numbers of plasmacytoid DCs in blood are profoundly but are only transiently decreased after initiation of SIT., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Extracellular ATP acts as a "danger signal" and can induce inflammation by binding to purinergic receptors. Chronic obstructive pulmonary disease is one of the most common inflammatory diseases associated with cigarette smoke inhalation, but the underlying mechanisms are incompletely understood. In this study, we show that endogenous pulmonary ATP levels are increased in a mouse model of smoke-induced acute lung inflammation and emphysema. ATP neutralization or nonspecific P2R-blockade markedly reduced smoke-induced lung inflammation and emphysema. We detected an upregulation the purinergic receptors subtypes on neutrophils (e.g., P2Y2R), macrophages, and lung tissue from animals with smoke-induced lung inflammation. By using P2Y(2)R deficient ((-/-)) animals, we show that ATP induces the recruitment of blood neutrophils to the lungs via P2Y(2)R. Moreover, P2Y(2)R deficient animals had a reduced pulmonary inflammation following acute smoke-exposure. A series of experiments with P2Y(2)R(-/-) and wild type chimera animals revealed that P2Y(2)R expression on hematopoietic cell plays the pivotal role in the observed effect. We demonstrate, for the first time, that endogenous ATP contributes to smoke-induced lung inflammation and then development of emphysema via activation of the purinergic receptor subtypes, such as P2Y(2)R.

Airway dendritic cells (DCs) play a key role in smoke-related lung diseases; however, the acute effects of tobacco smoke on human airway DCs in vivo are unknown. A total of 16 smokers underwent bronchoalveolar lavage at two time-points: directly after a 4-h period of nonsmoking (no smoke exposure); and directly after a 4-h period during which eight cigarettes were smoked (acute smoke exposure). Using flow cytometry, myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), as well as function-associated surface molecules on mDCs, were analysed in bronchoalveolar lavage fluid (BALF) and in blood. The numbers of macrophages, lymphocytes, neutrophils, eosinophils and pDCs were unchanged in BALF following acute smoke exposure, as compared to no smoke exposure. In contrast, there was a strong increase in mDC number in BALF and a concomitant decrease in mDC number in blood following acute smoke exposure. In addition, acute smoke exposure led to an increase in the expression of the surface molecules blood dendritic cell antigen 1 and 4 and a decrease in the expression of the lung homing receptor, CC chemokine receptor 5, on mDCs in BALF. Acute tobacco smoke inhalation results in an immediate and selective recruitment of mDCs into human airways, which might reflect the very early reaction of the adaptive immune system to smoke exposure.

Rationale: Extracellular ATP promotes inflammation, but its role in chronic obstructive pulmonary disease (COPD) is unknown., Objectives: To analyze the expression of ATP and its functional consequences in never-smokers, asymptomatic smokers, and patients with COPD., Methods: ATP was quantified in bronchoalveolar lavage fluid (BALF) of never-smokers, asymptomatic smokers, and patients with COPD of different severity. The expression of specific ATP (purinergic) receptors was measured in airway macrophages and blood neutrophils from control subjects and patients with COPD. The release of mediators by macrophages and neutrophils and neutrophil chemotaxis was assessed after ATP stimulation., Measurements and Main Results: Chronic smokers had elevated ATP concentrations in BALF compared with never-smokers. Acute smoke exposure led to a further increase in endobronchial ATP concentrations. Highest ATP concentrations in BALF were present in smokers and ex-smokers with COPD. In patients with COPD, BALF ATP concentrations correlated negatively with lung function and positively with BALF neutrophil counts. ATP induced a stronger chemotaxis and a stronger elastase release in blood neutrophils from patients with COPD, as compared with control subjects. In addition, airway macrophages from patients with COPD responded with an increased secretion of proinflammatory and tissue-degrading mediators after ATP stimulation. These findings were accompanied by an up-regulation of specific purinergic receptors in blood neutrophils and airway macrophages of patients with COPD., Conclusions: COPD is characterized by a strong and persistent up-regulation of extracellular ATP in the airways. Extracellular ATP appears to contribute to the pathogenesis of COPD by promoting inflammation and tissue degradation.

Airway dendritic cells (DCs) control pulmonary immune responses to inhaled particles. However, the profile of function-associated surface molecules on airway DCs in smokers is unknown. In this study, function-associated surface molecules were analyzed using four-color flow cytometry on myeloid DCs (mDCs) in bronchoalveolar lavage fluid (BALF) of cigarette smokers and never-smokers. Furthermore, the lung function was assessed directly before bronchoscopy in all participants. There was a 7-fold increase in total cell numbers in BALF of smokers, as compared with never-smokers. The percentage of mDCs among BALF cells and the expression of the maturation marker CD83 on mDCs did not differ between smokers and never-smokers. However, there was a strong increase in the expression of Langerin and CD1a (markers of Langerhans cells) on mDCs of smokers. Furthermore, mDCs of smokers were characterized by an increased expression of antigen presentation markers such as CD80 and CD86. By contrast, mDCs of smokers displayed a decreased expression of the lymph node homing receptor CCR7, as compared with mDCs of never-smokers. Decreased expression of CCR7 on mDCs, but not any of the other surface molecules studied, was specifically associated with airway obstruction and pulmonary hyperinflation in smokers. In conclusion, our data suggest that smoking affects the expression profile of function-associated surface molecules on airway mDCs. We provide the first evidence that a reduced CCR7 expression on airway mDCs is associated with airflow limitation in smokers.

Background: Segmental allergen challenge is widely used to study mechanisms of human allergic asthma. Despite the relatively large dissemination, limited information is available about the safety of this method., Objective: Observational, retrospective study to report the adverse events of segmental allergen challenge in a large group of volunteers with asthma., Methods: In total, 78 cases from several studies performed between 1994 and 2007 were pooled for this analysis. Volunteers underwent allergen challenge using either a fixed dose of allergen (7 cases) or an individually standardized allergen dose defined by an inhaled allergen test before the challenge (71 cases). A subgroup of 13 volunteers underwent repeated challenges, with more than 6 months between the challenges., Results: With a fixed dose instilled during bronchoscopy, 43% of the participants developed wheezing and coughing, requiring 2-6 puffs of a ss(2)-agonist after segmental allergen challenge. In volunteers with individually standardized doses, a ss(2)-agonist was required in only 19% of the cases. No severe adverse events occurred in all cases studied. Volunteers who underwent repeated challenges did not develop more adverse events than those who underwent 1 challenge., Conclusions: Segmental allergen challenge is a safe tool to study the mechanisms of human allergic asthma, even when repeated challenges are performed in the same patient. It is associated with only a few, tolerable adverse events, especially when the dose of allergen is standardized individually.

Enhanced bronchial responsiveness during and following lower respiratory tract infections is a major clinical problem, but its pathogenesis is poorly understood. Brain-derived neurotrophic factor (BDNF), which can be released by platelets and leukocytes, has been identified as a mediator of bronchial hyperresponsiveness. It is unknown whether the release of BDNF is altered during lower respiratory tract infections of the adult. In this clinical pilot study, 16 patients (35-80 years old) with the diagnosis of an acute bacterial lower respiratory tract infection and elevated serum concentrations of c-reactive protein (>100 microg/ml) and procalcitonin (>0.1 ng/ml) were examined on admission to the hospital and 1 week after antibiotic treatment. Sixteen age- and sex-matched controls were examined in the same time period. BDNF concentrations in serum and platelets, but not in plasma, were markedly reduced in patients on the day of admission (median <25% of the controls). Analysis of the platelet marker serotonin (5-HT) suggested that the decrease of platelet BDNF is part of a non-specific release of platelet-derived mediators in this condition. Clinical improvement was accompanied by a restoration of serum and platelet BDNF concentrations which returned to control levels after 1 week of treatment. Cell culture experiments revealed that bacterial lipopolysaccharide (LPS) enhanced the release of BDNF by peripheral blood mononuclear cells of the patients at both time points. In conclusion, these data suggest that lower respiratory tract infections might be associated with an augmented release of BDNF by platelets and mononuclear cells.

Neurotrophins, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are potent modulators of neuronal and immune function, and have been implicated recently in diseases associated with pregnancy. In contrast to serum BDNF, which is reportedly suppressed in the perinatal period, regulation of NGF in the perinatal period is unknown. In this study, serum NGF concentrations were measured in 40 pregnant (follow-up: 30th and 37th week of gestation, 1 week and 8 weeks after childbirth) and 40 non-pregnant women. Maternal NGF serum levels did not differ significantly from controls (median: 7.6 pg NGF/ml serum) neither before nor after childbirth, although there was a trend towards increased NGF concentrations at the 37th week of gestation (median: 12.5 pg NGF/ml serum) and 1 week after childbirth (median: 11.6 pg NGF/ml serum). There was no association of maternal NGF with 17beta-estradiol, progesterone, dehydroepiandrosterone sulfate (DHEAS) and cortisol concentrations in maternal serum, or maternal depression, as measured by the Edinburgh Postnatal Depression Scale (EPDS). In the non-pregnant control group, NGF serum concentrations were negatively correlated with the number of days since the first day of the menstrual cycle (r=-0.32, p<0.05). In conclusion, NGF is not altered during normal pregnancy on a systemic level. In addition, NGF displays a different regulation compared with BDNF during the menstrual cycle.

Background: Although the timing of allergen-induced bronchoconstriction is well defined, there is little information about the kinetics of allergen-induced leukocyte infiltration in asthma and its comparability between human and animal models of asthma., Objective: To investigate systematically allergen-induced leukocyte infiltration into the airway lumen in human and experimental asthma by using bronchoalveolar lavage., Methods: Patients with allergic asthma were lavaged at different time points as long as 1 week after segmental allergen challenge. Allergen-sensitized mice were lavaged as long as 3 weeks after allergen challenge. Differential cell counts, lymphocyte subsets, and cytokines were assessed in bronchoalveolar lavage fluid., Results: In both models, neutrophil infiltration was a relatively early event (maximum: 18 hours after challenge). In contrast, eosinophil infiltration peaked 42 hours (human model) to 4 days (mouse model) after allergen challenge, paralleled by an IL-5 peak in this period. There were elevated macrophage counts over a period of several days after allergen challenge in both models. Lymphocytes (predominantly CD4+ T cells) peaked 18 hours after challenge in the human model, but not until 2 weeks after challenge in the murine model., Conclusion: Early neutrophil accumulation (within hours after challenge) and delayed eosinophil accumulation (within days after challenge) in the airway lumen are common features of allergen-induced airway inflammation, whereas lymphocyte kinetics are dependent on the asthma model., Clinical Implications: Similarities in the infiltration kinetics of granulocytes after allergen challenge suggest a common role for these cells in asthma, whereas the presumed orchestration of allergic inflammation by lymphocytes appears to differ between the models.

There is growing evidence that target-derived neurotrophins regulate the function of visceral neurons after birth. However, the postnatal profile of neurotrophin supply from internal organs is poorly described. In this study, we compared neurotrophin concentrations in lysates of murine peripheral target tissues (lung, heart, liver, colon, spleen, thymus, kidney and urinary bladder) at different time points after birth. In most organs, there was a decrease of neurotrophin concentrations in the first weeks after birth. In contrast, there were characteristic increases of specific neurotrophins during adolescence or adulthood. These increases were found for nerve growth factor (NGF) in the heart, thymus, kidney and liver, for brain-derived neurotrophic factor (BDNF) in the lung, and for neurotrophin-3 (NT-3) in the colon. In conclusion, we show that neurotrophins display a very differential and dynamic profile in internal organs after birth.

Background: Patients with obstructive sleep apnoea syndrome (OSAS) often display persistent cognitive dysfunction despite effective treatment with continuous positive airway pressure (CPAP). Brain-derived neurotrophic factor (BDNF) is a key mediator of memory and cognition, but its regulation in OSAS and during CPAP treatment is unknown., Methods: Serum and plasma BDNF concentrations, BDNF secretion by peripheral blood mononuclear cells, and overnight polysomnography were evaluated in 17 men with newly diagnosed OSAS (as defined by a respiratory disturbance index of >10/hour with >70% obstructive events and corresponding daytime symptoms) and 12 healthy control men. In the patients all the parameters were monitored after 1 night and 3 months of CPAP treatment., Results: There was no significant difference in baseline serum BDNF, plasma BDNF, or spontaneous BDNF secretion by peripheral blood mononuclear cells between untreated patients and controls. After 1 night of CPAP treatment there was a steep fall in median serum BDNF (from 18.0 ng/ml to 4.1 ng/ml) and plasma BDNF (from 58.7 pg/ml to 22.0 pg/ml) concentrations. Following 3 months of treatment BDNF concentrations did not return to baseline. In contrast, BDNF secretion was not suppressed by CPAP treatment., Conclusions: Patients with untreated OSAS have normal serum and plasma BDNF levels. CPAP treatment is associated with a rapid decrease in serum and plasma BDNF levels which may reflect enhanced neuronal demand for BDNF in this condition.

In the present study, we demonstrated a significant reduction of B lymphocytes in the blood, spleen and bone marrow of BDNF deficient mice. The observed developmental block in bone marrow B cell development was linked specifically to the Pre-BII stage. B lymphocytes express the BDNF receptors p75NTR and TrkB(gp95), while no BDNF expression was found. However, a strong BDNF expression was demonstrated in bone marrow stromal cells. An increase of intracellular free calcium [Ca2+]i in B lymphocytes after BDNF application confirms a direct responsiveness of B lymphocytes to BDNF. In conclusion, these results suggest a role of BDNF for normal B lymphocyte development through paracrine effects in the bone marrow.

Activated macrophages have been shown to produce brain-derived neurotrophic factor (BDNF) in diseases such as multiple sclerosis (MS) or allergic bronchial asthma (BA). However, there is little data on BDNF regulation in these cells. We demonstrate that unstimulated human peripheral blood monocytes, but not lymphocytes, constitutively secrete BDNF. IL-6 and TNF-alpha specifically enhanced BDNF secretion in monocytes, whereas typical Th1- and Th2-cytokines did not show any effect. None of the cytokines induced BDNF secretion in T- or B-cells. Thus, our data provide evidence that IL-6 and TNF-alpha represent a specific link between monocyte infiltration and neuronal changes in inflammatory diseases.

Brain-derived neurotrophic factor (BDNF), a key mediator of neuronal plasticity, contributes to airway obstruction and hyperresponsiveness in a model of allergic asthma. BDNF is stored in human platelets and circulates in human plasma, but the significance of BDNF in this compartment is poorly understood. We investigated the relationship between platelet and plasma BDNF levels and pulmonary function in a cohort of 26 adult patients with recently diagnosed allergic asthma. BDNF levels in serum, platelets, and plasma were significantly increased in participants with asthma, as compared with 26 age- and sex-matched control subjects. In steroid-naive patients, but not in patients using inhaled corticosteroids, enhanced platelet BDNF levels correlated with parameters of airway obstruction and airway hyperresponsiveness to histamine. Experiments with activated peripheral blood mononuclear cells revealed that corticosteroids such as fluticasone effectively suppress BDNF secretion. In conclusion, we demonstrate that enhanced platelet BDNF is associated with airflow limitation and airway hyperresponsiveness in asthma. In addition, we provide evidence that corticosteroids suppress BDNF production by activated immune cells.