Differential regulation of PD-1 and its ligands in allergic asthma.

BACKGROUND: Targeting PD-1/PD-1 ligand signalling is an established treatment option for cancer. The role of these molecules in allergic asthma has been investigated in several mouse studies yielding conflicting results. However, human studies investigating the expression and regulation of PD-1 and its ligands in allergic inflammation are lacking. OBJECTIVE: To analyse the expression and regulation of PD-1 and its ligands in human allergic asthma. METHODS: The well-established human asthma model of segmental allergen challenge (SAC) was used to analyse the regulation of PD-1 and its ligands PD-L1 and PD-L2 on T lymphocytes and dendritic cells by flow cytometry. The impact of immunoglobulin E (IgE)-mediated signalling on PD-L1 expression was analysed on isolated plasmacytoid dendritic cells (pDCs). RESULTS: PD-1 expression by blood CD4+ T cells was negatively associated with total and specific (against the allergen used for provocation) IgE serum concentrations. Twenty-four hours after SAC, a small decrease in endobronchial PD-1+ CD4+ T cells was accompanied by an increase in PD-L1 expression on endobronchial myeloid dendritic cells (mDCs) and pDCs. The PD-L1 up-regulation on pDCs was not induced by IgE-mediated mechanisms. In contrast, PD-L2 was only detected on endobronchial mDCs and was significantly down-regulated 24 hours after SAC. CONCLUSION AND CLINICAL RELEVANCE: This study shows, for the first time, an association of a low PD-1 expression by circulating CD4+ T cells with high total and specific (against the allergen used for provocation) IgE concentrations in allergic asthma. In addition, we demonstrate a differential regulation of PD-1 ligands on endobronchial DCs after allergen challenge which may favour Th2 inflammation. Therefore, modulating PD-1 ligand-mediated pathways might be a promising target in allergic asthma.

Vitamin D binding protein and vitamin D in human allergen-induced endobronchial inflammation.

Allergic asthma is a chronic disease of the airways associated with airway hyperresponsiveness, a variable degree of airflow obstruction, airway remodelling and a characteristic airway inflammation. Factors of the vitamin D axis, which include vitamin D metabolites and vitamin D binding protein (VDBP), have been linked to asthma, but only few data exist about their regulation in the lung during acute allergen-induced airway inflammation. Therefore, we analysed the regulation of factors of the vitamin D axis during the early- and late-phase reaction of allergic asthma. Fifteen patients with mild allergic asthma underwent segmental allergen challenge. VDBP was analysed in bronchoalveolar lavage fluid (BALF) and serum using the enzyme-linked immunosorbent assay (ELISA) technique. 25-hydroxyvitamin D(3)[25(OH)D(3)] and 1,25-dihydroxyvitamin D(3)[1,25(OH)(2)D(3)] were analysed by a commercial laboratory using the liquid chromatography-mass spectrometry (LC/MS) technique. VDBP (median 2·3, range 0·2-7·1 µg/ml), 25(OH)D(3) (median 0·060, range < 0·002-3·210 ng/ml) and 1,25(OH)(2)D(3) (median < 0·1, range < 0·1-2·8 pg/ml) were significantly elevated in BALF 24 h but not 10 min after allergen challenge. After correction for plasma leakage using the plasma marker protein albumin, VDBP and 25(OH)D(3) were still increased significantly while 1,25(OH)(2)D(3) was not. VDBP and 25(OH)D(3) were correlated with each other and with the inflammatory response 24 h after allergen challenge. Serum concentrations of all three factors were not influenced by allergen challenge. In conclusion, we report a significant increase in VDBP and 25(OH)D(3) in human BALF 24 h after allergen challenge, suggesting a role for these factors in the asthmatic late-phase reaction.

[Health care of asthma patients in combination therapy with ICS and LABA - An analysis of statutory health insurance data]. / Versorgung von Asthmapatienten mit Kombinationstherapie aus ICS und LABA - Eine GKV-Daten-Analyse.

The study indicates the patient-centered care of patients with asthma with fixed-dose combination therapy (with three different combinations) regarding the claims-data of several sickness funds. The identified patients were grouped according to their fixed-dose combination, their course of treatment and the number of treatment days with the possibility of two puffs per day. The effects of the corresponding group, their course of treatment and the number of days with two puffs on duration and costs of hospitalisations were evaluated. 47.9 % of the 16 312 insured patients were supplied for only a maximum of 6 out of 24 months with two puffs per day with an ICS/LABA fixed-dose combination. Only 8.3 % received at least two puffs per day for the whole period of investigation. The results may explain the insufficient asthma control found in other studies and serve as basis for further investigations concerning patient centered care. The true reasons for the observed undertreatment remain speculative. The author's recommendations for daily practice are to remain vigilant about activities to measure and manage patient's adherence and their degree of compliance with the medical guidelines.

IL-33 is a mediator rather than a trigger of the acute allergic response in humans.

BACKGROUND: IL-33 enhances FcεRI-induced mediator release in human basophils without inducing degranulation itself. In contrast, studies in mice suggested that in the presence of high IgE levels, IL-33 triggers degranulation and anaphylaxis of similar severity as specific allergen. Consistent with this view, sera of atopic patients contain elevated levels of IL-33 after anaphylaxis. In this study, we determined whether IL-33 is potentially anaphylactogenic in humans with high IgE levels by regulating exocytosis independent of FcεRI cross-linking. Furthermore, we investigated whether IL-33 is released upon allergen provocation in vivo. METHODS: In subjects with high serum IgE levels, we measured IL-33-induced histamine/LTC4 in vitro, CD63 translocation ex vivo, and responsiveness of mast cells in vivo by skin prick test (SPT). In asthma patients, release of IL-33 and its correlation with early (tryptase)- and late-phase markers (IL-13 levels, eosinophil numbers) of the allergic response were assessed in bronchoalveolar lavage fluids (BALFs) after allergen challenge. RESULTS: IL-33 itself does not trigger basophil degranulation in vitro and ex vivo, even in subjects with high serum IgE levels, and negative SPTs demonstrate that skin mast cells do not degranulate in response to IL-33. However, in response to allergen challenge, IL-33 is rapidly released into BALFs at levels that do not correlate with other immediate- and late-phase parameters. CONCLUSION: IL-33 is unlikely an independent trigger of anaphylaxis even in subjects with high IgE levels. However, the rapid release of IL-33 upon allergen provocation in vivo supports its role as a mediator of immediate allergic responses.

Prescription of inhalers in asthma and COPD: towards a rational, rapid and effective approach.

Inhaled medication is the cornerstone of the pharmacological treatment of patients with asthma and COPD. The major two classes of inhaled medication include corticosteroids (ICS) and bronchodilators. There is a wide diversity in molecules in both classes. Moreover, there is a wide variation in delivery systems. The correct use of inhalers is not granted and patients often incur in many mistakes when using pMDIs and DPIs, despite repeated instructions. A better matching between patient and device could be accomplished if the physician is aware of: (1) the patient characteristics (disease, severity, fluctuation in airflow obstruction, etc); (2) what class of medication is indicated; (3) where in the lung the medication should be delivered; and, (4) how this can be best achieved by a given device in this specific patient. We focus on the prescription of pMDIs and DPIs at the GP office or at the outpatient clinic of the hospital, and we propose an evidence based approach enabling the caregiver to make a rational choice in only a few minutes by just considering the following four simple questions: Who?, What? Where? and How? (the so-called 3W-H approach).

Plasmacytoid dendritic cells in allergic asthma and the role of inhaled corticosteroid treatment.

BACKGROUND: Plasmacytoid dendritic cells (pDCs) infiltrate sites of acute Th2-dominant inflammation, but their role in allergic asthma remains unclear. OBJECTIVE: To characterize circulating pDCs from patients with allergic asthma outside their respective allergen season. METHODS: Adhesion molecules, co-stimulatory molecules, immunoglobulin receptors and chemokine receptors were quantified on blood pDCs from 20 patients with allergic asthma and 18 healthy controls using flow cytometry. In addition, IL-6-, TNF-α- and IFN-α-secretion were analysed after stimulating isolated pDCs with TLR7- and TLR9-ligands. RESULTS: Plasmacytoid dendritic cells from patients with allergic asthma showed an increased expression of chemokine receptors involved in inflamed tissue homing such as CCR2, CCR4, CCR9, CCR10, CXCR2, CXCR5 and CXCR6, while the expression of the lymph node homing receptor CXCR3 was down-regulated. In addition, these pDCs exhibited a higher expression of activation markers and Th2-associated molecules such as CD40, CD62L, CD64 and FcεRIα. In contrast, TLR7-mediated IL-6-, TNF-α- and IFN-α-secretion was significantly reduced in pDCs from patients with asthma. The TLR9-mediated cytokine response was only suppressed in those patients who were treated with inhaled corticosteroids (ICS) during previous allergen seasons. The same effect was observed for CD54 and OX40L expression. CONCLUSIONS: We report an increased expression of activation markers, and Th2-associated molecules, and an increased migratory potential of circulating pDCs in allergic asthma. These changes are accompanied by a reduced TLR7-mediated cytokine response. In addition, our results suggest a longterm impact of ICS treatment on the characteristics of circulating pDCs.

Untangling asthma phenotypes and endotypes.

Asthma phenotypes have been developed to address the complexities of the disease. However, owing to a lack of longitudinal studies, little is known about the onset as well as the stability of phenotypes. Distinguishing phenotypes with regard to the severity or duration of the disease is essential. A phenotype covers the clinically relevant properties of the disease, but does not show the direct relationship to disease etiology and pathophysiology. Different pathogenetic mechanisms might cause similar asthma symptoms and might be operant in a certain phenotype. These putative mechanisms are addressed by the term 'endotype'. Classification of asthma based on endotypes provides advantages for epidemiological, genetic, and drug-related studies. A successful definition of endotypes should link key pathogenic mechanisms with the asthma phenotype. Thus, the identification of corresponding molecular biomarkers for individual pathogenic mechanism underlying phenotypes or subgroups within a phenotype is important. Whether newly defined asthma endotypes predict the individual course of asthma has to be validated in longitudinal studies. The accurate endotyping reflects natural history of asthma and should help to predict treatment response. Thus, understanding asthma endotypes might be useful in clinical practice.

[Hypertrophic pulmonary osteoarthropathy as a cue for NSCLC: four cases in the light of the current literature]. / Das Marie-Bamberger-Syndrom als Fingerzeig auf ein NSCLC: vier Fälle im Lichte der aktuellen Literatur.

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.

Impact of ocular symptoms on quality of life (QoL), work productivity and resource utilisation in allergic rhinitis patients--an observational, cross sectional study in four countries in Europe.

OBJECTIVE: It is hypothesised that the presence of ocular, in addition to nasal, symptoms among patients with allergic rhinitis (AR) results in poorer quality of life, reduced work productivity and increased resource utilisation. This study investigated the impact on quality of life, burden of illness and healthcare resources among 1640 AR patients. METHODS: Data were drawn from an observational cross-sectional study of consulting patients undertaken in May/June 2008 in four European countries. Doctors provided records for the next four to five patients presenting with AR who filled out a self-completion survey which included the Work Productivity and Activity Impairment Allergic Specific Questionnaire (WPAI:AS), the Mini Rhinoconjunctivitis Quality of Life Questionnaire (RQOLQ) and the Pittsburgh Sleep Quality Index (PSQI). Propensity scoring allied to regression-type analysis was used to assess the extra burden associated with ocular symptoms utilising two comparison groups (patients with nasal-only symptoms versus those with nasal and ocular symptoms). The analysis controlled for differences between the groups on confounding variables age, gender, smoking status and co-morbidities. The analysis was conducted twice, once controlling for differences between the groups in nasal severity and once without, recognising that it is not clear whether or not increased nasal severity symptoms are naturally associated with ocular symptoms. The severity of ocular symptoms as opposed to their presence alone was also assessed on outcome measures using regression type methods. RESULTS: A total of 1009 patient records met the inclusion criteria, of whom 69% presented with both ocular and nasal symptoms. The results show that the presence of ocular symptoms reduces quality of life, reduces work productivity and increases resource utilisation irrespective of whether differences in severity of nasal symptoms are accounted for between the comparison groups. Patients with nasal and ocular symptoms require more healthcare consultations. All work-related domains were statistically different, with the presence of ocular symptoms associated with greater impact on work hours missed and impairment while working. For each of the above this was the case regardless of whether or not adjustment was made for nasal severity (both p < 0.05). Patients with nasal and ocular symptoms also record an additional half a day more time off work in the last 3 months as a result of AR (nasal severity unadjusted or adjusted, both p < 0.05). Clinically meaningful differences were found in overall quality of life score as represented by RQLQ, with a mean score increase of 0.6 (nasal severity unadjusted) and 0.5 (nasal severity adjusted) associated with the presence of ocular symptoms (both p < 0.05). With regard to sleep quality, the presence of ocular symptoms was associated with a mean increase in PSQI of 1 when no adjustment was made for nasal severity (p < 0.05). When nasal severity was adjusted for, no significant difference was observed. Similarly, for the number of prescribed medications, when no adjustment was made for nasal severity, patients with ocular symptoms were observed to receive a significantly higher number of AR drugs (+0.19, p < 0.05) whereas with nasal severity adjusted for the difference was +0.17 which was not significant. In addition, with the exception of the number of AR drugs prescribed, for all outcome variables, the severity of ocular symptoms, and not just their presence, had a detrimental impact on the outcome. LIMITATIONS: Since patients were recruited via the physician, the study aim was to represent the consulting population. In addition, it cannot be fully excluded that the likelihood for an individual patient to complete a questionnaire is influenced by differences in patient typology compared with those patients who chose not to complete. Given the geographical dispersion of the sample patients, it may be reasonable to assume possible differences in the intensity of the AR season based on latitude. CONCLUSION: The added presence of ocular symptoms in AR patients suffering with nasal symptoms deteriorates patients' quality of life, leads to greater lost productivity and places higher burden on resource utilisation. Studies are therefore needed to test whether treatment options that address ocular in addition to nasal symptoms will improve quality of life and reduce both direct and indirect resource use associated with AR.

The purinergic receptor P2Y2 receptor mediates chemotaxis of dendritic cells and eosinophils in allergic lung inflammation.

BACKGROUND: Extracellular ATP contributes to the pathogenesis of asthma via signalling at purinergic receptors. However, the precise purinergic receptors subtypes mediating the pro-asthmatic effects of ATP have not been identified, yet. METHODS: In vivo studies were performed using the OVA-alum model. Functional expression of the P2Y(2) purinergic receptor subtype on human monocyte-derived dendritic cells and eosinophils was investigated using real-time PCR, migration assays, and production of reactive oxygen species. RESULTS: Compared to wild-type animals P2Y(2) -/- mice showed reduced allergic airway inflammation which can be explained by defective migration of blood myeloid DCs towards ATP in vitro and in vivo, whereas the influence of ATP on maturation and cytokine production was not changed. Additionally, ATP failed to induce migration of bone marrow-derived eosinophils from P2Y(2) R-deficient animals. The relevance of our findings for humans was confirmed in functional studies with human monocyte-derived DCs and eosinophils. Interestingly, stimulation of human DCs derived from allergic individuals with house dust mite allergen induced functional up-regulation of the P2Y(2) R subtype. Furthermore, eosinophils isolated from asthmatic individuals expressed higher levels of P2Y(2) R compared to healthy controls. This was of functional relevance as these eosinophils were more sensitive to ATP-induced migration and production of reactive oxygen metabolites. CONCLUSIONS: In summary, P2Y(2) R appears to be involved in asthmatic airway inflammation by mediating ATP-triggered migration of mDCs and eosinophils, as well as reactive oxygen species production. Together our data suggest that targeting P2Y(2) R might be a therapeutic option for the treatment of asthma.

[Asthma - historical development, current status and perspectives]. / Asthma - Geschichtliche Entwicklung, Status quo und Ausblick.

Asthma is not a new disease. It is one of the most common chronic disorders affecting approximately 4-5  % of adults and more than 10 % of children in Germany. This turns asthma into one of the most prevalent chronic disorders. Over the last century ideas about its pathogenesis have changed many times. While around one hundred years ago asthma was often considered a neurotic disease, changes in airway smooth muscle, mast cell accumulation and activation or specific mediators such as platelet-activating factor have since been incriminated in its pathogenesis. Eosinophils, cytokines and T-lymphocytes were favourites some time later. Nowadays, - and this is unlikely to be the end of the story - asthma is considered as a complex disorder of the adaptive immune system. Therapeutic approaches have changed dramatically, too. While until about 30 years ago asthma was still considered a Smooth muscle disorder, recurrent attacks of asthma which required frequent, mostly nocturnal interventions, status asthmaticus, or the necessity of mechanical, invasive ventilation have markedly decreased. In view of the asthma epidemic in recent years, this development suggests that current treatments are at least partially effective. In spite of this patients with asthma are often only moderately well controlled with considerable morbidity from the disease as well as its treatment. Thus, despite recent advances in diagnosis and treatment, asthma is still not a trivial disease and future attempts at improving the care of those affected are warranted. The developments of the past 100 years as well as a careful look into the future are presented in this review.

[Aspirin-Intolerance-Syndrom : a common and interdisciplinary disease]. / Analgetikaintoleranz : Ein häufiges, interdisziplinäres Krankheitsbild.

The full clinical picture of aspirin intolerance - the association of aspirin-induced bronchial asthma, aspirin sensitivity and nasal polyps - has been described as Morbus Widal or later as the "Samter triad". Today the term Aspirin-exacerbated respiratory disease (AERD) is preferred to account for the progressive nature of this inflammatory airway condition with its unrelenting course even in the absence of non steroidal anti-inflammatory drugs (NSAID). This acquired idiosyncrasy appears to be related to an abnormal arachidonic acid metabolism. Epidemiological data suggests that 10% of all asthmatics do react with life-threatening asthma-attacks after the ingestion of aspirin (ASA) or other NSAID. Some asthmatics with nasal polyposis have been reported to suffer from aspirin intolerance. Although the exact mechanism is still unclear, it is unlikely that the pathogenesis is IgE-mediated. Patients often report chronic nasal obstruction, hyposmia, chronic rhinorrhoea, orbital edema and urticaria with flushing after the ingestion of NSAID. While a typical history and endoscopic findings can be suggestive of AERD, a definite diagnosis relies on appropriate challenge tests. AERD is often refractory to standard asthma treatment with systemic and inhaled steroids, ß(2)-agonists, leukotrien-antagonists. Adaptive desactivation can induce a reversible tolerance to NSAID which also leads to an improvement in signs and symptoms of the underlying AERD.

Functional expression of granzyme B in human plasmacytoid dendritic cells: a role in allergic inflammation.

BACKGROUND: Plasmacytoid dendritic cells (pDCs) are involved in a variety of immune functions. However, the expression of cytotoxic granule proteins like granzymes and perforin in human pDCs is still poorly understood. OBJECTIVE: The aim of this study was to systematically analyse the expression and regulation of cytotoxic granule proteins in human pDCs. METHODS: The expression of cytotoxic proteins was analysed by RT-PCR, flow cytometry, and fluorescence microscopy. The functional expression of these proteins was confirmed in a flow-cytometry-based cytotoxicity assay using K562 cells as targets. In order to analyse the regulation of pDC-derived cytotoxic proteins in infectious and allergic diseases, human pDCs were analysed after stimulation with toll-like receptor (TLR)7/9 ligands and in the human asthma model of segmental allergen challenge. RESULTS: Granzyme B (GrB), but not the granzymes A, H, K, M or perforin, was specifically expressed by human pDCs and this GrB expression was up-regulated by IL-3 stimulation. In addition, IL-3-stimulated pDCs were found to kill K562 cells in a GrB- and caspase-dependent manner. TLR7/9 ligands significantly suppressed GrB expression in pDCs. In contrast, there was an up-regulation of GrB in endobronchial pDCs 24 h after allergen challenge, and this was accompanied by enhanced GrB concentrations in bronchoalveolar lavage fluid. CONCLUSION: We report the selective expression of GrB in human pDCs and show for the first time pDC-mediated GrB- and caspase-dependent cytotoxicity against target cells. In addition, the regulation of GrB expression was investigated in vitro and in vivo providing an evidence for a specific role of pDC-derived GrB in allergic inflammation.

sCD14 in bronchoalveolar lavage 18, 42 and 162 hours after segmental allergen provocation.

Lipopolysaccharides (LPS) have been associated with a protective role in the development of asthma while higher levels of endotoxin have been linked with more severe asthma. LPS recruit neutrophils and eosinophils and activate macrophages via the CD14 receptor. The soluble CD 14 receptor (sCD14) has been found in bronchoalveolar lavage fluid in different diseases including allergic asthma. To elucidate the kinetics and the regulation of sCD14 concentrations in BAL in asthma, 18 patients with allergic asthma underwent segmental allergen challenge at different time points (10 min, 18, 42 and 162 h). In addition, CD14(+) peripheral blood mononuclear cell (PBMC-CD14(+)) cultures from seven allergic and seven non-allergic subjects were stimulated with LPS, leukotrien D(4) (LTD(4)), a combination of LPS and LTD(4), IL-17 and LTD(4) in presence of the leukotriene-receptor antagonist (LTRA) Montelukast for 6, 12 and 24 h. sCD14 concentrations in BAL and the supernatants were measured by ELISA. sCD14 concentrations in BAL were significantly increased 18 h after allergen challenge and peaked at 42 h. At 162 h, concentrations had returned to baseline levels. In PBMC-CD14(+) cultures, sCD14 levels increased significantly 24 h after stimulation with LTD(4) and Montelukast was able to block LTD(4)-induced stimulation. Allergen challenge leads to a significant increase in sCD14 concentrations in BAL and might modulate the allergen-induced inflammation. In addition, LTD(4) might play a role in the release of sCD14, and it could be speculated that sCD14 reduction by LTRA might contribute to the mechanisms of LTRA in the treatment of allergic asthma.

Acute effects of tobacco smoke on human airway dendritic cells in vivo.

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.

Persistence with asthma treatment is low in Germany especially for controller medication - a population based study of 483,051 patients.

BACKGROUND: The objective of the present analysis was to evaluate treatment patterns and persistence with treatment of an unselected patient population with a diagnosis of asthma. METHODS: The database of the Bavarian statutory health insurance physician's association (Kassenärztliche Vereinigung) covering 83% of the population was analyzed for an index period from April 2005 to March 2006. Defined daily doses (DDDs) were used to quantify treatment persistence. Results were compared with recent guidelines. RESULTS: The prevalence of physician diagnosed asthma in Bavaria was 4.8% in females and 4.5% in males; only 61.4% of these patients (of a total of n = 483,051) received any anti-asthmatic pharmacotherapy; 68.3% received medical care from their general practitioner, and 8.3% from a pulmonologist alone. Most patients (65.1%) received no more than 90 DDDs of controller medication in the index period of 365 days, only about 1% received medication for the complete index period. Long- (40.1%) and short-acting beta(2)-agonists (65.6%) were used more frequently than inhaled corticosteroids (ICS). 52.8% of asthma patients were treated in accordance with guidelines. CONCLUSIONS: Persistence of asthma patients with medical treatment is low, especially for controller medication. The discrepancy between current knowledge, guidelines and clinical practice is substantial and may question the value of current guidelines for the treatment of patients with asthma in ambulatory care. In addition, the results of this study cast doubt on the impact of contemporary treatment on the decline of asthma mortality seen in recent years in Germany.

[Asthma--a small airway disease: concepts and evidence]. / Asthma--eine Erkrankung der kleinen Atemwege: Konzept und Evidenz.

Inflammatoric processes in the large airways have traditionally been considered to be very important. But as new studies show inflammation and structural alteration also take place in the peripheral airways. Meanwhile it is highly evident that asthma is related to all areas of the lung--to the large and even the small airways. But the inflammation of the small airways is not sufficiently diagnostically detected. FEV(1) and PEF reflect the participation of the small airways only partially. New findings about inflammation and remodelling in the small airways underline the need of therapies reaching all parts of the lung. A combined therapy with ICS and LABA seem to have the capability to improve efficacy and safety, especially when very fine formulations are chosen.

Adverse effects of salmeterol in asthma: a neuronal perspective.

BACKGROUND: Regular use of inhaled beta(2)-agonists has been associated with a paradoxical loss of asthma control and a deterioration of airway hyper-responsiveness, but the underlying mechanism is unknown. The neurotrophin brain-derived neurotrophic factor (BDNF) has recently been identified as a mediator of airway hyper-responsiveness in asthma. METHODS: Eighteen patients with mild allergic asthma who did not use any regular antiasthmatic therapy inhaled the long-acting beta(2)-agonist salmeterol for 2 weeks followed by 2 weeks of combination therapy with salmeterol and the corticosteroid fluticasone. Airway responsiveness to histamine and BDNF concentrations in blood were assessed prior to entry, after 14 days of salmeterol therapy and after 14 days of combination therapy. In a separate experiment, salmeterol effects on BDNF release by human peripheral blood mononuclear cells were assessed. RESULTS: Monotherapy with salmeterol significantly increased BDNF concentrations in serum and platelets. This increase was abolished by the addition of fluticasone to the treatment. The findings were confirmed in vitro: salmeterol increased the release of BDNF by mononuclear cells, and this was inhibited by co-incubation with fluticasone. Increased BDNF concentrations in serum and platelets correlated with the deterioration of airway hyper-responsiveness following salmeterol monotherapy. In contrast, there was no association between beta(2)-receptor polymorphisms and changes in airway responsiveness. CONCLUSION: Increased BDNF concentrations may underly the adverse effects of salmeterol monotherapy on airway responsiveness in asthma. TRIAL REGISTRATION NUMBER: NCT00736801.