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Pulmonary vascular remodelling is a characteristic sign in different lung disorders. Vascular endothelial growth factor (VEGF) is a key mediator in vascular remodelling. The objective was to study the role of VEGF on fibroblast activity, such as extracellular matrix (ECM) synthesis, migration and proliferative capacity and to study if VEGF is affected in different lung disorders. Studies were performed in human lung fibroblasts (HFL-1) and primary distal fibroblasts cultures from control subjects, patients with COPD (GOLD IV) and patients with bronchiolitis obliterans syndrome (BOS). Lung fibroblasts were stimulated with TGF-b1. VEGF165 synthesis was measured in the cell culture medium. Changes in synthesis of the ECM proteins proteoglycans and procollagen I, proliferation rate and migration were analysed after stimulations with VEGF165 (1-10000 pg/ml). TGF-β1 significantly enhanced VEGF synthesis in all cell types. There were no differences in VEGF synthesis between fibroblasts from control subjects and COPD patients, whereas patients with BOS had a higher VEGF synthesis (p In conclusion, VEGF is promoting specific ECM synthesis and fibroblast activation. VEGF may have a crucial role in the interplay between fibroblasts and other cells in vascular remodelling processes in the distal lung.

Background: Chronic obstructive pulmonary disease (COPD) begins with inhomogeneous peripheral lung pathology for which the cheapest and simplest method of recognition is volumetric capnography. Aim: To evaluate the capnographic Lung Inhomogeneity index (LINHI) for diagnostics of COPD. Method: Volumetric capnography for a single breath at rest was analysed over a volume segment starting at appearance of CO2 and covering a volume of 15 % of predicted TLC. LINHI was defind as the grey area above the curve of the healthy subject divided by the area of the rectangle, i.e. 5x15 (Fig. 1A). Material: 12 non-smokers and 54 subjects with COPD GOLD 1-4 performed volumetric capnography, body plethysmography/spirometry, impulse oscillometry, DLCO test and N2 washout (ventilation heterogenity in the acinar airways). Results: LINHI continuously increased from healthy subjects to COPD of increasing severity. (Figure 1B). It correlated to N2 washout (0.72***), FEV1%predicted (-0.74***), DLCO%predicted (-0.75***) and FEV1/FVC (-0.55***). Conclusion: LINHI reflects inefectiveness of CO2 elimination caused by inhomogeniety of lung function and could identify COPD patients with increasing stages. LINHI offers an easy, effortless and cost valuable complement and in some situations, as it is easy to perform, even a good alternative to spirometry.

Introduction/Aim: Results from the recent one-year FLAME study demonstrated superior efficacy of IND/GLY over SFC in reducing the annual rate of moderate and severe exacerbations in COPD patients with moderate to very severe airflow limitation and ≥1 exacerbation in the preceding year. This economic evaluation aims to determine whether this clinical effect translates into health economic benefits using a cost-effectiveness analysis from the Swedish payer’s perspective.Methods: A previously published and validated patient-level simulation model was updated with population and clinical data from the FLAME study and exacerbation and maintenance cost data from the real-world retrospective ARCTIC Swedish cohort study (n=18,586). Both direct costs and benefits were analyzed over various time horizons and were discounted at 3% per annum. Here, we present results for the time horizon of 3 years.Results: IND/GLY was associated with lower total direct costs and better outcomes compared with SFC over the time horizon of 3 years. Results showed that the use of IND/GLY over SFC resulted in an incremental gain in 0.008 quality-adjusted life-years and 0.005 life-years with cost savings of €732 per patient. The average number of moderate and severe exacerbations per patient was predicted lower with the use of IND/GLY compared with SFC at 3 years (1.98 vs. 2.39).Conclusion: This cost-effectiveness analysis showed that treatment with IND/GLY is more effective and less costly compared to treatment with SFC in Swedish COPD patients with moderate to very severe airflow limitation and ≥1 exacerbation in the preceding year.

Heterogeneity of asthma and difficulty in achieving optimal control are the major challenges in the management of asthma. To help attain the best possible clinical outcomes in patients with asthma, several guidelines provide recommendations for patients who will require a referral to a specialist. Such referrals can help in clearing the uncertainty from the initial diagnosis, provide tailored treatment options to patients with persistent symptoms and offer the patients access to health care providers with expertise in the management of the asthma; thus, specialist referrals have a substantial impact on disease prognosis and the patient’s health status. Hurdles in implementing these recommendations include lack of their dissemination among health care providers and nonadherence to these guidelines; these hurdles considerably limit the implementation of specialist referrals, eventually affecting the rate of referrals. In this review, recommendations for specialist referrals from several key international and national asthma guidelines and other relevant published literature are evaluated. Furthermore, we highlight why referrals are not happening, how this can be improved, and ultimately, what should be done in the specialist setting, based on existing evidence in published literature.

Introduction: Systemic corticosteroids are anti-inflammatory agents with dexamethasone among the most potent in the class. Within (respiratory) allergy, systemic corticosteroids are usually applied in medical emergencies. In these situations, patients may experience physical or logistic problems taking tablets. To fulfil a practical unmet need for outpatients, Dexa ODF, an oral dissolvable film containing dexamethasone, was developed.Objectives: We compared the safety, tolerability and pharmacokinetics (PK) of Dexa ODF with Fortecortin tablets in healthy subjects.Methods: Thirty subjects participated in this open label, two-way, cross-over study, consisting of two treatment visits separated by 5-10 days. On both treatment visits, subjects randomly received one single dose of Dexa ODF (one strip; 8 mg dexamethasone) or one single dose of Fortecortin (two 4 mg tablets). Safety evaluations and blood sampling for PK were conducted until 48 h post-dose and bioequivalence analysis was performed on AUC(0-t), AUC(0-8) and Cmax.Results: All subjects were dosed. Forty-five adverse events (AEs) were reported by 17 subjects and approximately 50% were deemed ` possibly treatment related' (14 on Dexa ODF; 12 on Fortecortin) with no significant difference between treatments. For all three bioequivalence parameters the 90% CIs were within the acceptance limits of bioequivalence (0.8; 1.25).Conclusion: We demonstrated good tolerability and bioequivalence of Dexa ODF (8 mg dexamethasone) compared to Fortecortin tablets (2 x 4 mg dexamethasone). Dexa ODF is currently under development as an innovative treatment for use within respiratory and allergic conditions, including emergencies.

Background This study assessed the cost-effectiveness of indacaterol/glycopyrronium (IND/GLY) versus salmeterol/fluticasone (SFC) in chronic obstructive pulmonary disease (COPD) patients with moderate to very severe airflow limitation and ≥1 exacerbation in the preceding year. Methods A previously published and validated patient-level simulation model was adapted using clinical data from the FLAME trial and real-world cost data from the ARCTIC study. Costs (total monetary costs comprising drug, maintenance, exacerbation, and pneumonia costs) and health outcomes (life-years (LYs), quality-adjusted life-years (QALYs)) were projected over various time horizons (1, 5, 10 years, and lifetime) from the Swedish payer’s perspective and were discounted at 3% annually. Uncertainty in model input values was studied through one-way and probabilistic sensitivity analyses. Subgroup analyses were also performed. Results IND/GLY was associated with lower costs and better outcomes compared with SFC over all the analysed time horizons. Use of IND/GLY resulted in additional 0.192 LYs and 0.134 QALYs with cost savings of €1211 compared with SFC over lifetime. The net monetary benefit (NMB) was estimated to be €8560 based on a willingness-to-pay threshold of €55,000/QALY. The NMB was higher in the following subgroups: severe (GOLD 3), high risk and more symptoms (GOLD D), females, and current smokers. Conclusion IND/GLY is a cost-effective treatment compared with SFC in COPD patients with mMRC dyspnea grade ≥ 2, moderate to very severe airflow limitation, and ≥1 exacerbation in the preceding year. Electronic supplementary material The online version of this article (10.1186/s12931-017-0688-5) contains supplementary material, which is available to authorized users.

BACKGROUND: The respiratory epithelium is a major site for disease interaction with inhaled allergens. Additional to IgE-dependent effects, allergens contain proteases that may stimulate human bronchial epithelial cells (HBECs) through protease-activated receptors, causing the release of mediators important in driving Th2 mediated immune responses.OBJECTIVE: We aimed to investigate if different allergens induce metabolite DAMPs such as ATP and uric acid (UA) release in HBECs.METHODS: HBECs (BEAS-2B cell line) was exposed to different allergen extracts; house dust mite (HDM), Alternaria alternata, Artemisia vulgaris and Betula pendula and UA, ATP, IL-8 and IL-33 release were measured. Allergen extracts were heat-inactivated or pre-incubated with serine (AEBSF) or cysteine (E64) protease inhibitor to study involvement of protease activity in ATP, UA and IL-8 release. HDM-induced release of UA was studied in a mouse model of allergic inflammation.RESULTS: All allergens caused dose-dependent rapid release of ATP and IL-8, but only HDM induced UA release from HBECs. HDM also caused release of UA in vivo in our mouse model of allergic inflammation. ATP release by all four allergen extracts was significantly reduced by heat-inactivation and by serine protease inhibitors. Similarly, the HDM induced UA release was also abrogated by heat-inactivation of HDM extract and dependent on serine proteases. Furthermore, allergen-induced IL-8 mRNA expression was inhibited by serine protease inhibitors.CONCLUSIONS AND CLINICAL RELEVANCE: ATP was released by all four allergens in HBECs supporting the role of ATP involvement in asthma pathology. However, HDM stands out by its capacity to cause UA release, which is of interest in view of the proposed role of UA in early initiation of allergic asthma. Although serine proteases may be involved in the activity of all the studied allergens, further work is warranted to explain differences between HDM and the other three allergens regarding effects on UA release. This article is protected by copyright. All rights reserved. (Less)

Background: It has been observed that mice lacking the sulfatase modifying factor (Sumf1) developed an emphysema-like phenotype. However, it is unknown if SUMF1 may play a role in Chronic Obstructive Pulmonary Disease (COPD) in humans. The aim was to investigate if the expression and genetic regulation of SUMF1 differs between smokers with and without COPD. Methods: SUMF1 mRNA was investigated in sputum cells and whole blood from controls and COPD patients (all current or former smokers). Expression quantitative trait loci (eQTL) analysis was used to investigate if single nucleotide polymorphisms (SNPs) in SUMF1 were significantly associated with SUMF1 expression. The association of SUMF1 SNPs with COPD was examined in a population based cohort, Lifelines. SUMF1 mRNA from sputum cells, lung tissue, and lung fibroblasts, as well as lung function parameters, were investigated in relation to genotype. Results: Certain splice variants of SUMF1 showed a relatively high expression in lung tissue compared to many other tissues. SUMF1 Splice variant 2 and 3 showed lower levels in sputum cells from COPD patients as compared to controls. Twelve SNPs were found significant by eQTL analysis and overlapped with the array used for genotyping of Lifelines. We found alterations in mRNA expression in sputum cells and lung fibroblasts associated with SNP rs11915920 (top hit in eQTL), which validated the results of the lung tissue eQTL analysis. Of the twelve SNPs, two SNPs, rs793391 and rs308739, were found to be associated with COPD in Lifelines. The SNP rs793391 was also confirmed to be associated with lung function changes. Conclusions: We show that SUMF1 expression is affected in COPD patients compared to controls, and that SNPs in SUMF1 are associated with an increased risk of COPD. Certain COPD-associated SNPs have effects on either SUMF1 gene expression or on lung function. Collectively, this study shows that SUMF1 is associated with an increased risk of developing COPD.

It is well recognized that atopic sensitization is an important risk factor for asthma, both in adults and in children. However, the role of allergy in severe asthma is still under debate. The term 'Severe Asthma' encompasses a highly heterogeneous group of patients who require treatment on steps 4-5 of GINA guidelines to prevent their asthma from becoming 'uncontrolled', or whose disease remains 'uncontrolled' despite this therapy. Epidemiological studies on emergency room visits and hospital admissions for asthma suggest the important role of allergy in asthma exacerbations. In addition, allergic asthma in childhood is often associated with severe asthma in adulthood. A strong association exists between asthma exacerbations and respiratory viral infections, and interaction between viruses and allergy further increases the risk of asthma exacerbations. Furthermore, fungal allergy has been shown to play an important role in severe asthma. Other contributing factors include smoking, pollution and work-related exposures. The 'Allergy and Asthma Severity' EAACI Task Force examined the current evidence and produced this position document on the role of allergy in severe asthma.

Rationale: Symptom relief is a key treatment goal in patients with chronic obstructive pulmonary disease (COPD). However, there are limited data available on the response to bronchodilator therapy in patients at low risk of exacerbations with different levels of symptom severity. This study compared treatment responses in patients with a range of symptom severities as indicated by baseline COPD assessment test (CAT) scores. Methods: The 24-week EMAX trial evaluated the benefits of umeclidinium/vilanterol versus umeclidinium or salmeterol in symptomatic patients at low exacerbation risk who were not receiving inhaled corticosteroids. This analysis assessed lung function, symptoms, health status, and short-term deterioration outcomes in subgroups defined by a baseline CAT score [Results: Of the intent-to-treat population ( n = 2425), 56% and 44% had baseline CAT scores of Conclusions: Patients with symptomatic COPD benefit similarly from dual bronchodilator treatment with umeclidinium/vilanterol. Fractional polynomial analyses demonstrated the greatest treatment differences favouring dual therapy in patients with a CAT score

Jonas Jögi,1 Hanna Markstad,2 Ellen Tufvesson,3 Leif Bjermer,3 Marika Bajc1 1Department of Clinical Physiology and Nuclear Medicine, 2Department of Radiology, 3Department of Respiratory Medicine and Allergology, Skåne University Hospital and Lund University, Lund, Sweden Abstract: Ventilation/perfusion (V/P) single-photon emission computed tomography (SPECT) is recognized as a diagnostic method with potential beyond the diagnosis of pulmonary embolism. V/P SPECT identifies functional impairment in diseases such as heart failure (HF), pneumonia, and chronic obstructive pulmonary disease (COPD). The development of hybrid SPECT/computed tomography (CT) systems, combining functional with morphological imaging through the addition of low-dose CT (LDCT), may be useful in COPD, as these patients are prone to lung cancer and other comorbidities. The aim of this study was to investigate the added value of LDCT among healthy smokers and patients with stable COPD, when examined with V/P SPECT/CT hybrid imaging. Sixty-nine subjects, 55 with COPD (GOLD I–IV) and 14 apparently healthy smokers, were examined with V/P SPECT and LDCT hybrid imaging. Spirometry was used to verify COPD grade. Only one apparently healthy smoker and three COPD patients had a normal or nearly normal V/P SPECT. All other patients showed various degrees of airway obstruction, even when spirometry was normal. The same interpretation was reached on both modalities in 39% of the patients. LDCT made V/P SPECT interpretation more certain in 9% of the patients and, in 52%, LDCT provided additional diagnoses. LDCT better characterized the type of emphysema in 12 patients. In 19 cases, tumor-suspected changes were reported. Three of these 19 patients (ie, 4.3% of all subjects) were in the end confirmed to have lung cancer. The majority of LDCT findings were not regarded as clinically significant. V/P SPECT identified perfusion patterns consistent with decompensated left ventricular HF in 14 COPD patients. In 16 patients (23%), perfusion defects were observed. HF and perfusion defects were not recognized with LDCT. In COPD patients and long-time smokers, hybrid imaging had added value compared to V/P SPECT alone, by identifying patients with lung malignancy and more clearly identifying emphysema. V/P SPECT visualizes comorbidities to COPD not seen with LDCT, such as pulmonary embolism and left ventricular HF. Keywords: lung, lung cancer, V/P SPECT, ventilation/perfusion, single-photon emission computed tomography, computed tomography

Item does not contain fulltext BACKGROUND: Inhaled therapy is the cornerstone of pharmacotherapy in patients with asthma and chronic obstructive pulmonary disease (COPD). Appropriate inhalation device selection is as important as drug choice but device-specific guidance appears to be lacking. METHODS: To quantify the level of inhalation-device recommendations in clinical guidelines, a review was conducted by hand-searching national and international asthma and COPD guidelines (Global Initiative for Asthma [GINA] and Global initiative for chronic Obstructive Lung Disease [GOLD] guidelines) and an international guideline on device selection (the American College of Chest Physicians/American College of Asthma, Allergy, and Immunology [ACCP/ACAAI]). For each guideline, the number of pages, tables/figures and references relating to inhalation devices was identified. RESULTS: GINA and GOLD guidelines contain very little inhalation device-specific guidance beyond recommendations for demonstrating and testing correct inhalation technique

SummaryAsthma is often difficult to control and it is likely that not all patients are optimally treated.This study aimed to explore asthma control in adults receiving fixed dose combination (FDC) therapy. Control of asthma was assessed using the mannitol challenge test as a monitoring tool to see if this would give additional information compared to the asthma control test (ACT). The study was an open-label, prospective study on 98 adults prescribed with FDC therapies for at least three months.74 patients considered that their asthma was well controlled. However, 60 patients had a positive mannitol challenge test (PD15

Introduction: This study aimed to investigate the dose-response and pharmacology of a range of single doses of nebulised ensifentrine (RPL554), an inhaled dual phosphodiesterase (PDE) 3/4 inhibitor in patients with asthma. Methods: In this randomised, placebo-controlled, double-blind crossover study, patients received single nebulised doses of ensifentrine 0.4, 1.5, 6 and 24 mg, salbutamol 2.5 and 7.5 mg, and placebo. Eligible patients were adults with asthma, pre-bronchodilator forced expiratory volume in 1 s (FEV1) 60–90% predicted and ≥1.5 L, with post-salbutamol FEV1 increase ≥15%. The co-primary objectives were peak and average FEV1 over 12 h for ensifentrine vs placebo and salbutamol. Secondary endpoints included: peak and average systolic and diastolic blood pressure, pulse rate and ECG heart rate; and safety and tolerability (adverse events [AEs], and serum potassium). ClinicalTrials.gov: NCT02427165. Results: A total of 29 patients were randomised, with 25 (89%) completing the study. For the two co-primary endpoints there was a clear ensifentrine dose-response relationship, with all treatments superior to placebo (p < 0.001). There was no relationship between the ensifentrine dose and AE incidence or blood pressure. Ensifentrine 0.4, 1.5 and 6 mg had significantly lower effects than both salbutamol doses on pulse and heart rates. Ensifentrine did not impact potassium, whereas there was a was a dose-related reduction for salbutamol. Inhalation of ensifentrine resulted in a dose-related increase in plasma exposure. Conclusions: Single-dose ensifentrine demonstrated dose-dependent bronchodilation, and was as effective as a therapeutic dose of nebulised salbutamol. All ensifentrine doses were similarly well tolerated, and did not show the characteristic β2-agonist systemic adverse effects.

International audience; Despite the use of effective medications to control asthma, severe exacerbations in asthma are still a major health risk and require urgent action on the part of the patient and physician to prevent a serious outcome such as hospitalisation or death. Moreover, severe exacerbations are associated with substantial huge healthcare costs, and psychological burden including anxiety and fear for patients and their families. The European Academy of Allergy and Clinical Immunology (EAACI) and the European Respiratory Society (ERS) set up a Task Force (TF) to search for a clear definition of severe exacerbations and to also define research questions and priorities. The statement includes comments from patients who were members of the TF.

Background: It has been suggested that exhaled breath temperature (EBT) is increased in asthmatic subjects. Objectives: Our aim was to investigate EBT in asthmatics compared to healthy controls before and after eucapnic voluntary hyperventilation (EVH) and a methacholine challenge test (MCT). Methods: A total of 26 asthmatics and 29 healthy controls were included. Forced expiratory volume in 1 s (FEV1), EBT and oral, axillary and auricular temperatures were measured before and after EVH and MCT. Results: FEV1 % predicted (%p) was significantly lower in asthmatic subjects compared to healthy controls at all time points. EBT was significantly increased in all subjects 15-30 min after EVH and 5-45 min after MCT. Oral temperature displayed a similar pattern of increase, in contrast to axillary and auricular temperature, and correlated with EBT before and after both of the challenge tests. EBT after 5 min correlated with the largest drop in FEV1%p after EVH in asthmatic subjects. No significant differences or changes in EBT were found when comparing asthmatics to healthy controls before or after any of the tests. Conclusions: EBT is increased after both EVH and MCT, possibly reflecting a vascular response. This is related to both the fall in FEV1 and to oral temperature, suggesting an effect on the whole respiratory tract including the oral cavity. No differences in EBT are seen between asthmatics and healthy controls, indicating that the increase in EBT is mainly physiological rather than pathophysiological.

SummaryAirway epithelial injury is regarded as a key contributing factor to the pathogenesis of exercise-induced bronchoconstriction (EIB) in athletes. The concentration of the pneumoprotein club cell (Clara cell) CC16 in urine has been found to be a non-invasive marker for hyperpnoea-induced airway epithelial perturbation. Exercise-hyperpnoea induces mechanical, thermal and osmotic stress to the airways. We investigated whether osmotic stress alone causes airway epithelial perturbation in athletes with suspected EIB. Twenty-four recreational summer sports athletes who reported respiratory symptoms on exertion performed a standard eucapnic voluntary hyperpnoea test with dry air and a mannitol test (osmotic challenge) on separate days. Median urinary CC16 increased from 120 to 310 ρg μmol creatinine−1 after dry air hyperpnoea (P = 0.002) and from 90 to 191 ρg μmol creatinine−1 after mannitol (P = 0.021). There was no difference in urinary CC16 concentration between athletes who did or did not bronchoconstrict after dry air hyperpnoea or mannitol. We conclude that, in recreational summer sports athletes with respiratory symptoms, osmotic stress per se to the airway epithelium induces a rise in urinary excretion of CC16. This suggests that hyperosmolarity of the airway surface lining perturbs the airway epithelium in symptomatic athletes.

Pressure on healthcare budgets is increasing, while at the same time patent protection for many branded inhaled medications has expired, leading to the development and growing availability of generic inhaled medicines. Generic inhaled drugs are therapeutically equivalent to original branded options but may differ in their formulation and inhalation device. This new situation raises questions about the potential impact of switching from branded to generic drug/inhaler combination products in patients with asthma or COPD, with or without their consent, in countries where this is permitted. Inhalation devices, particularly dry powder inhalers, vary markedly in their design, method of operation and drug delivery to the lungs. Current guidelines stress the importance of training patients how to use their inhalers but offer little or no guidance on how this should be achieved. Non-adherence to therapy and incorrect inhaler usage are recognised as major factors in poorly or uncontrolled asthma and COPD and switching patients to a different inhaler device may exacerbate these problems, particularly in patients who disagree to switch. Where switching is permitted or mandatory, adequate patient instruction and follow-up monitoring should be provided routinely.

Recognition of asthma as a heterogeneous disease revealed different potential molecular targets and urged the development of targeted, customized treatment modalities. Evidence was provided for different inflammatory subsets of asthma and more recently, further refined to T helper (Th)2-high and Th2-low subphenotypes with different responsiveness to standard and targeted pharmacotherapy. Given these differences in immunology and pathophysiology, proof of concept studies of novel treatment modalities for asthma should be performed in adequate, well-defined phenotypes. In this review, we describe both existing and novel biomarkers of Th2-inflammation in asthma that can be applied to classify asthma subphenotypes in clinical studies and for treatment monitoring.

Background This placebo-controlled study assessed the effects of the once-daily inhaled corticosteroid (ICS) fluticasone furoate (FF) and long-acting beta2-agonist (LABA) vilanterol (VI) on early and late asthmatic responses (EAR/LAR) and airway hyper-responsiveness (AHR). Methods Patients (n = 27) were randomized to FF (100 μg), VI (25 μg), FF/VI (100/25 μg), and placebo for 21 days (four periods). Allergen challenge was performed 1 h post-dose on day 21. AHR was assessed on day 22 using methacholine. Results Allergen challenge caused an early change (0–2 h) in minimum forced expiratory volume in 1 s (FEV1) of −1.091 l (95% CI: −1.344; −0.837) following placebo therapy; changes were −0.955 l (−1.209; −0.702), −0.826 l (−1.070; −0.581), and −0.614 l (−0.858; −0.370) following VI, FF, or FF/VI therapy, respectively. Treatment differences were significant for all comparisons between therapies. Mean changes in 0–2 h %FEV1 were as follows: −28.05 (placebo), −23.10 (VI), −22.33 (FF), and −16.10 (FF/VI). Following placebo, the late change (4–10 h) in weighted mean FEV1 was −0.466 l (−0.589; −0.343) and −0.298 l (−0.415; −0.181) after VI, and was +0.018 l with both FF/VI (−0.089; 0.124) and FF (−0.089; 0.125). Treatment differences were significant for all comparisons between therapies except FF/VI vs FF. Mean changes in 4–10 h %FEV1 were as follows: −21.08 (placebo), −14.30 (VI), −5.02 (FF), and −5.83 (FF/VI). AHR 24 h after allergen challenge was significantly reduced with FF/VI and FF vs placebo, and FF/VI was superior to either component. Conclusion Combined treatment with FF/VI provides additive protection from the EAR relative to its components, significant protection over VI alone from the LAR, and confers sustained protection from hyper-responsiveness 24 h post-dose.

Exacerbations in chronic obstructive pulmonary disease (COPD) reduce quality of life and are associated with a more rapid deterioration of the disease. It is desirable to predict an oncoming exacerbation before it occurs. The aim of the present study was to identify biomarkers that may predict a forthcoming exacerbation.Forty-three patients with COPD in their stable state were included and followed up monthly until exacerbation, or for a maximum of 6 months. The patients come for an extra visit (prior to a scheduled visit) when exacerbated. The patients completed the questionnaires CCQ and MRC. Exhaled breath condensate (EBC) was collected followed by spirometry, impulse oscillometry, and sputum induction.Twenty-five patients had an exacerbation within the 6-month period. Leukotriene B4 in sputum was the only biomarker that was increased at the visit prior to exacerbation compared to at the stable phase (p = 0.05). There also was a tendency for a similar but not significant increase in the sputum levels of 8-isoprostane, myeloperoxidase activity, and interleukin-8, as well as additional increases during exacerbation. Sputum purulence was not increased until exacerbation (p = 0.02). In contrast, none of the inflammatory biomarkers in EBC, the quality-of-life questionnaire score, CRP, spirometric parameters, or impulse oscillometry parameters were increased at the visit prior to exacerbation compared to the values at the stable phase.Sputum biomarkers, especially leukotriene B4, could be used as predictors of a forthcoming exacerbation and worsening of COPD. This would be of great value for the patient, who may be a subject for early treatment and thereby avoid a progression of the disease.

A Good Practice is a practice that works well, produces good results, and is recommended as a model. MACVIA-ARIA Sentinel Network (MASK), the new Allergic Rhinitis and its Impact on Asthma (ARIA) initiative, is an example of a Good Practice focusing on the implementation of multi-sectoral care pathways using emerging technologies with real life data in rhinitis and asthma multi-morbidity. The European Union Joint Action on Chronic Diseases and Promoting Healthy Ageing across the Life Cycle (JA-CHRODIS) has developed a checklist of 28 items for the evaluation of Good Practices. SUNFRAIL (Reference Sites Network for Prevention and Care of Frailty and Chronic Conditions in community dwelling persons of EU Countries), a European Union project, assessed whether MASK is in line with the 28 items of JA-CHRODIS. A short summary was proposed for each item and 18 experts, all members of ARIA and SUNFRAIL from 12 countries, assessed the 28 items using a Survey Monkey-based questionnaire. A visual analogue scale (VAS) from 0 (strongly disagree) to 100 (strongly agree) was used. Agreement equal or over 75% was observed for 14 items (50%). MASK is following the JA-CHRODIS recommendations for the evaluation of Good Practices., MACVIA-France., info:eu-repo/semantics/publishedVersion

Background Elite athletes, independent of sport, have increased risk of developing asthma, but little is known about sex difference among adolescent athletes. Objective To investigate and compare sex-related differences according to symptoms and treatment of asthma, allergy, and health among elite athletes and a reference group. Methods Adolescent elite swimmers (n = 101), tennis players (n = 86), and a reference group (n = 1,628) responded to a questionnaire about respiratory symptoms, allergy, health behavior, psychosomatic symptoms, self- esteem, and well-being. The athletes performed a mannitol provocation and a sport-specific exercise provocation. Atopy was assessed by skin prick tests, and fractional exhaled nitric oxide was measured. Results The females reported more asthma symptoms than the males in both the reference group (29.1% vs 22.3%) and the athlete group (56.4% vs 40.2%). However, no significant differences were found in physician-diagnosed asthma or treatment with inhaled corticosteroids. More female athletes had a positive mannitol provocation result (48.7% vs 35.8% in male athletes), and more female swimmers had a positive exercise provocation result (15.1% vs 7.7% in male swimmers). The females in all groups had more psychosomatic symptoms compared with the respective males, and the males in the reference group reported higher self-esteem and felt more well-being compared with the reference group females. Conclusion Overall, we found a higher prevalence of asthma symptoms in the females. However, the frequency of physician-diagnosed asthma and the prescription of inhaled corticosteroids were the same in both sexes. This finding demonstrates an insufficient diagnosis of asthma in females.

Contains fulltext : 169715.pdf (Publisher’s version ) (Open Access) Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant deposition of extracellular matrix (ECM) constituents, including glycosaminoglycans (GAGs), that may play a role in remodelling processes by influencing critical mediators such as growth factors. We hypothesize that GAGs may be altered in IPF and that this contribute to create a pro-fibrotic environment. The aim of this study was therefore to examine the fine structure of heparan sulfate (HS), chondroitin/dermatan sulfate (CS/DS) and hyaluronan (HA) in lung samples from IPF patients and from control subjects. GAGs in lung samples from severe IPF patients and donor lungs were analyzed with HPLC. HS was assessed by immunohistochemistry and collagen was quantified as hydroxyproline content. The total amount of HS, CS/DS and HA was increased in IPF lungs but there was no significant difference in the total collagen content. We found a relative increase in total sulfation of HS due to increment of 2-O, 6-O and N-sulfation and a higher proportion of sulfation in CS/DS. Highly sulfated HS was located in the border zone between denser areas and more normal looking alveolar parenchyma in basement membranes of blood vessels and airways, that were immuno-positive for perlecan, as well as on the cell surface of spindle-shaped cells in the alveolar interstitium. These findings show for the first time that both the amount and structure of glycosaminoglycans are altered in IPF. These changes may contribute to the tissue remodelling in IPF by altering growth factor retention and activity, creating a pro-fibrotic ECM landscape.

To resist infections, robust defense mechanisms of the airways are essential. Retinoic acid promotes differentiation and maintains the phenotypic characteristics of bronchial epithelium. In addition, it induces the expression of the antibacterial growth factor midkine (MK). In the present study, we explored the expression and antibacterial activity of MK in an airway context. MK was detected in bronchial epithelial cells of large airways and type 2 pneumocytes of normal lungs by immunohistochemistry. Immunoelectron microscopy revealed a surface-associated distribution, both on the ciliated apical and basolateral sides, and MK was detected in sputum obtained from healthy individuals by ELISA. In vitro, MK killed the common respiratory pathogen Streptococcus pneumoniae at below micromolar concentrations, an activity retained in the presence of sodium chloride at physiological concentrations. The MK molecule consists of two domains with three anti-parallel β-sheets and a COOH-terminal tail. Although both the NH2- and COOH-terminal domains alone showed antibacterial activity, the COOH-terminal domain including the tail region possessed higher bactericidal activity, i.e. in the order of the holoprotein. Retinoic acid-induced differentiation of primary bronchial epithelial cells, using an air-liquid interface system, revealed bactericidal activity in the apical airway surface liquid, an activity that was reduced after immunoprecipitation of MK. This study shows that airway epithelial cells of large airways and alveoli have a constitutive production of MK that is part of the bactericidal activity present in the air surface liquid, at least in vitro, and may thus be an important part of this arm of airway host defense.

Involvement of pulmonary vascular remodelling is a characteristic sign in COPD. Vascular mediators such as vascular endothelial growth factor (VEGF) and prostacyclin may regulate fibroblast activity. The objective was to study the synthesis of VEGF and interactions with prostacyclin and transforming growth factor (TGF)-βPrimary distal lung fibroblast cultures were established from healthy individuals and from COPD patients (GOLD stage IV). Lung fibroblasts were stimulated with the prostacyclin analogue iloprost and the profibrotic stimuli TGF-βIloprost and TGF-βVEGF is synthesized in high amounts by distal lung fibroblasts and may have a crucial role in ongoing vascular remodelling processes in the distal lung compartments.

To demonstrate therapeutic equivalence of terbutaline via two different TurbuhalerIn this double-blind, double-dummy, multicentre, single-dose, 4-way crossover study, patients with stable mild-to-moderate asthma (FEV60 patients (mean age 31.1 years [range:18-64]; mean FEVBronchoprotection using a standardised methacholine challenge model proved to be an effective design to elucidate therapeutic equivalence between devices in patients with mild-to-moderate asthma. The findings indicate that patients may switch from one type of Turbuhaler2014-001457-16. CLINICALTRIALS.NCT02322788.

Introduction: The ENERGITO ® study demonstrated superior lung function with long-acting muscarinic antagonist (LAMA) tiotropium + long-acting β 2 -agonist (LABA) olodaterol (T+O) compared to inhaled corticosteroid (ICS) fluticasone + LABA salmeterol (F+S) in patients with COPD. Aim: To investigate if lung-function benefits of T+O compared to F+S were affected by prior ICS, LAMA or LABA treatment in ENERGITO ® . Methods: In ENERGITO ® (1237.11, NCT01969721; Phase IIIb, randomised, double-blind, double-dummy, four-period crossover), patients with moderate to severe COPD received once-daily T+O 2.5/5 or 5/5 µg and twice-daily F+S 250/50 or 500/50 µg for 6 weeks. A post hoc analysis evaluated FEV 1 AUC 0–12 and AUC 0–24 responses in patients with or without LAMA, LABA or ICS therapy at screening. We describe results comparing T+O 5/5 µg to both doses of F+S. Results: 229 patients were enrolled and treated: 123 received prior LAMA, 141 LABA, 109 ICS. T+O significantly improved FEV 1 AUC 0–12 and AUC 0–24 responses in patients with or without prior LAMA, LABA or ICS therapy compared to F+S (Table). Conclusions: In ENERGITO ® , patients with moderate or severe COPD showed improved lung function with T+O compared to F+S regardless of prior treatment. T+O is a better choice than LABA/ICS to optimise lung function when initiating maintenance treatment. Funding: Boehringer Ingelheim.

Background: Novel therapies targeting raised eosinophil counts improve asthma control, but the inappropriate use of these treatments in patients with poor adherence to standard therapy is a concern. Aim: To determine if poor adherence to ICS therapy explains poor asthma control in patients with raised blood eosinophils. Methods: Historical, observational, cohort study using clinical practice data of UK patients with asthma, aged ≥18 years, with ≥1 year ICS therapy (GINA steps 3 and 4). Patient records with increased (>0.4x10 9 /L) or normal eosinophil levels (≤0.4x10 9 /L) were analysed by demographic and clinical characteristics, and adherence to ICS. Descriptive statistics were reported as number (%) of patients with exacerbations and with controlled asthma. Results: Patients had a median eosinophil count of 0.5x10 9 /L and mean % predicted peak expiratory flow of 78%. Overall, 1,031 (14%) of 7,195 patients had increased blood eosinophil counts (mean age 60 years [SD 15.8]; 42% male). Of patients with increased blood eosinophil levels, 38% had good adherence to ICS therapy, yet 74% of them remained uncontrolled. Patients with ≥1 exacerbation were more adherent to prescribed therapy than patients with no history of exacerbations (30% vs 16%; p Conclusion: Poor adherence to ICS therapy does not explain poor asthma control in patients with increased blood eosinophils. Novel therapies might be considered for patients who do not respond to traditional ICS controller treatment despite good adherence.

RPL554 has bronchodilator, bronchoprotective, & anti-inflammatory effects. We investigated the dose-ranging effects & safety of a nebulized suspension formulation of RPL554 vs salbutamol (Salb) & placebo (PBO) in 29 mild-moderate asthmatics. This was a randomized double-blind, PBO controlled, 7 way cross-over study. Each patient received 4 doses of RPL554 (0.4mg-24mg), Salb (2.5mg, 7.5mg) & PBO separated by 3-14 days. FEV 1 FVC, safety & pharmacokinetic evaluations up to 12h post-dose were performed. RPL554 produced a similar degree of bronchodilation to a maximal dose of Salb (Fig 1). RPL554 was well tolerated. Occurrence of systemic AEs was more frequent in patients treated with Salb vs RPL554; tremor (37.5% vs 1.9%), hypokalemia (5.4% vs 0) & palpitations (12.5% vs 0.9%). There was an increase in peak heart rate only for the highest dose of RPL554 24 mg (6.4 bpm), however this was less than for Salb 2.5 mg (9.0 bpm) & Salb 7.5 mg (21.8 bpm). There were no SAEs or AEs leading to discontinuation. In summary, RPL554 caused a dose dependent bronchodilation with comparable magnitude to a maximal dose of Salb, but with fewer systemic side effects. RPL554 represents a well tolerated first in class compound with bronchodilator & anti-inflammatory effects in a single molecule making it a very exciting novel treatment for obstructive lung diseases. Fig 1 Average FEV1

Many lung-transplanted (LTx) patients develop obliterative bronchiolitis (OB) with deposition of extracellular matrix, accompanied by fibrocyte infiltration and increased lumen of vessels. In this study we hypothesize that fibrocytes, VEGF and prostacyclin (PGI2) are involved in remodelling processes after LTx. We investigated TGF-β activated peripheral fibroblast phenotypes regarding production of VEGF 165 /PGI2. Fibrocytes and fibroblast phenotypes were identified by prolyl4-hydroxylase (p4OH), CD45, VEGFR2 or PGIR. VEGF production from fibroblasts after LTx significantly decreased 3mo after LTx compared to healthy controls (p

Background: The mesenchymal stromal cells (MSC) are potent candidates for cell therapies, due to their immune-regulatory and regenerative properties. In most clinical trials bone marrow-derived MSC have been used, also for treatment of various pulmonary diseases. Bone marrow-derived MSC play an important role within the bone marrow, by providing and maintaining a functioning niche for the hematopoiesis. The functional role of lung-resident MSC, on the other hand, is still unknown. Exploring the proteins produced by lung-derived MSC might improve our understanding of the functional role of MSC within the lung. Therefore, we aimed to characterize the proteins produced by lung-derived MSC and to compare those findings to the proteins produced by MSC isolated from bone marrow. Methods: Proteins within the cell-layer and the conditioned medium of MSC isolated from lung biopsies and bone marrow aspirates were characterized using mass spectrometry-based quantitative proteomics. Results: Our results indicate that MSC isolated from lung biopsies and bone marrow aspirates are prominent producers of extracellular matrix proteins. Furthermore, these analyses revealed differences between lung- and bone marrow-derived MSC, both regarding proteins identified in the cell layer and within the conditioned medium. Conclusions: Lung-derived MSC are prominent extracellular matrix producers, and our results indicate that lung- and bone marrow-derived MSC produce different protein profiles.

Piotr Kuna,1 Leif Bjermer,2 Göran Tornling3,4 1Department of Internal Medicine, Asthma and Allergy, Barlicki University Hospital, Medical University of Łódz, Łódz, Poland; 2Department of Respiratory Medicine and Allergology, Skane University Hospital, Lund University, 3AstraZeneca Research and Development, Molndal, 4Respiratory Medicine Unit, Department of Medicine Solna and CMM, Karolinska Institute and Karolinska University Hospital, Solna, Sweden Background: Chemoattractant receptor-homologous molecule expressed on T helper type 2 (Th2) cell (CRTh2) receptor antagonists is being investigated for asthma.Objectives: The aim of this study was to assess the effects of the CRTh2 receptor antagonist, AZD1981 (with/without inhaled corticosteroids [ICSs]), on lung function and asthma control.Patients and methods: Adults aged 18–60years were enrolled in two randomized, placebo-controlled, parallel-group trials (protocol number: D9830C00003 [study 1, n=209] and protocol number: D9830C00004 [study 2, n=510]). In study 1, patients with stable asthma (forced expiratory volume in 1second [FEV1]: 65%-110%) were withdrawn from ICS (

Mesenchymal stromal cells (MSC) are multipotent cells with regenerative and immune-modulatory properties. Therefore, MSC have been proposed as a potential cell-therapy for bronchiolitis obliterans syndrome (BOS). On the other hand, there are publications demonstrating that MSC might be involved in the development of BOS. Despite limited knowledge regarding the functional role of tissue-resident lung-MSC, several clinical trials have been performed using MSC, particularly bone marrow (BM)-derived MSC, for various lung diseases. We aimed to compare lung-MSC with the well-characterized BM-MSC. Furthermore, MSC isolated from lung-transplanted patients with BOS were compared to patients without BOS. Our study show that lung-MSCs are smaller, possess a higher colony-forming capacity and have a different cytokine profile compared to BM-MSC. Utilizing gene expression profiling, 89 genes including lung-specific FOXF1 and HOXB5 were found to be significantly different between BM-MSC and lung-MSC. No significant differences in cytokine secretion or gene expression were found between MSC isolated from BOS patients compared recipients without BOS. These data demonstrate that lung-resident MSC possess lung-specific properties. Furthermore, these results show that MSC isolated from lung-transplanted patients with BOS do not have an altered phenotype compared to MSC isolated from good outcome recipients.

Background As lung function declines rapidly in the early stages of chronic obstructive pulmonary disease (COPD), the effects of bronchodilators in patients with moderate disease and those who have not previously received maintenance therapy are of interest. OTEMTO® 1 and 2 were two replicate, 12-week, Phase III studies investigating the benefit of tiotropium + olodaterol on lung function and quality of life in patients with moderate to severe disease. Post hoc analyses were performed to assess the benefits for patients according to disease severity and treatment history. Methods Four subgroup analyses were performed: Global initiative for chronic Obstructive Lung Disease (GOLD) 2/3, GOLD A/B/C/D, treatment naive/not treatment naive and receiving inhaled corticosteroids (ICS) at baseline/not receiving ICS at baseline. Primary end points were change in forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h response, change in trough FEV1 and St George’s Respiratory Questionnaire (SGRQ) total score. Transition Dyspnoea Index (TDI) focal score was a secondary end point, and SGRQ and TDI responder analyses were further end points; all were assessed at 12 weeks. Results In all subgroups, patients receiving tiotropium + olodaterol responded better overall than those receiving tiotropium monotherapy. Improvements with tiotropium + olodaterol over placebo or tiotropium monotherapy were noted across GOLD 2/3 and GOLD A/B/C/D; however, improvements in SGRQ total score were most evident in the GOLD B subgroup. Moreover, lung-function outcomes were generally greater in those patients who had been receiving previous long-acting bronchodilator and/or ICS maintenance treatment. Conclusions These data suggest that tiotropium + olodaterol should be considered as a treatment option in patients with moderate COPD who are initiating maintenance therapy, as well as those with more severe disease. Trial registration ClinicalTrials.gov: NCT01964352 and NCT02006732. Electronic supplementary material The online version of this article (doi:10.1186/s12931-016-0387-7) contains supplementary material, which is available to authorized users.

Rhinovirus infection is a major cause of chronic obstructive pulmonary disease (COPD) exacerbations and may contribute to the development into severe stages of COPD. The macrolide antibiotic azithromycin may exert anti-viral actions and has been reported to reduce exacerbations in COPD. However, little is known about its anti-viral actions on bronchial epithelial cells at clinically relevant concentrations. Primary bronchial epithelial cells from COPD donors and healthy individuals were treated continuously with azithromycin starting 24 h before infection with rhinovirus RV16. Expression of interferons, RIG-I like helicases, pro-inflammatory cytokines and viral load were analysed. Azithromycin transiently increased expression of IFNβ and IFNλ1 and RIG-I like helicases in un-infected COPD cells. Further, azithromycin augmented RV16-induced expression of interferons and RIG-I like helicases in COPD cells but not in healthy epithelial cells. Azithromycin also decreased viral load. However, it only modestly altered RV16-induced pro-inflammatory cytokine expression. Adding budesonide did not reduce interferon-inducing effects of azithromycin. Possibly by inducing expression of RIG-I like helicases, azithromycin increased rhinovirus-induced expression of interferons in COPD but not in healthy bronchial epithelium. These effects would reduce bronchial viral load, supporting azithromycin’s emerging role in prevention of exacerbations of COPD.

Kai-Michael Beeh,1 Eric Derom,2 José Echave-Sustaeta,3 Lars Grönke,4 Alan Hamilton,5 Dongmei Zhai,6 Leif Bjermer71Insaf GmbH Institut für Atemwegsforschung, Wiesbaden, Germany; 2Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium; 3Servicio de Neumología, Hospital Universitario Quirón, Madrid, Spain; 4Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; 5Boehringer Ingelheim, Burlington, ON, Canada; 6InVentiv Health Clinical, Wilmington, DE, USA; 7Department of Respiratory Medicine and Allergology, Lund University, Lund, SwedenBackground: Tiotropium + olodaterol has demonstrated improvements beyond lung function benefits in a large Phase III clinical program as a once-daily maintenance treatment for COPD and may be a potential option for the initiation of maintenance treatment in COPD. Despite guideline recommendations that combined long-acting β2-agonists and inhaled corticosteroids should only be used in individuals at high risk of exacerbation, there is substantial use in individuals at lower risk. This raises the question of the comparative effectiveness of this combination as maintenance treatment in this group compared to other combination regimens.Objective: The study aimed to assess the effect on lung function of once-daily tiotropium + olodaterol versus twice-daily salmeterol + fluticasone propionate in all participants with Global initiative for chronic Obstructive Lung Disease 2 or 3 (moderate to severe) COPD.Methods: This was a randomized, double-blind, double-dummy, four-treatment, complete crossover study in which participants received once-daily tiotropium + olodaterol (5/5µg and 2.5/5µg) via Respimat® and twice-daily salmeterol + fluticasone propionate (50/500µg and 50/250µg) via Accuhaler® for 6weeks. The primary end point was change in forced expiratory volume in 1second (FEV1) area under the curve from 0hour to 12hours (AUC0–12) relative to the baseline after 6weeks.Results: Tiotropium + olodaterol 5/5µg and 2.5/5µg demonstrated statistically significant improvements in FEV1 AUC0–12 compared to salmeterol + fluticasone propionate (improvements from baseline were 317mL and 295mL with tiotropium + olodaterol 5/5µg and 2.5/5µg, and 188mL and 192mL with salmeterol + fluticasone propionate 50/500µg and 50/250µg, respectively). Tiotropium + olodaterol was superior to salmeterol + fluticasone propionate in lung function secondary end points, including FEV1 area under the curve from 0hour to 24hours (AUC0–24).Conclusion: Once-daily tiotropium + olodaterol in participants with moderate-to-severe COPD provided superior lung function improvements to twice-daily salmeterol + fluticasone propionate. Dual bronchodilation can be considered to optimize lung function in individuals requiring maintenance treatment for COPD. Keywords: COPD, maintenance treatment, lung function, tiotropium, FEV1, inhaled corticosteroid

Background and purpose: Statin treatment may ameliorate viral infection-induced exacerbations of chronic obstructive pulmonary disease (COPD), which exhibit Th2-type bronchial inflammation. Thymic stromal lymphopoietin (TSLP), a hub cytokine switching on Th2-inflammation, is overproduced in viral and dsRNA-stimulated bronchial epithelial cells from COPD donors. Hence, TSLP may be causally involved in exacerbations. This study tests our hypothesis that simvastatin may inhibit dsRNA-induced TSLP. Experimental approach: Epithelial cells, obtained by bronchoscopy from COPD (n=7) and smoker control (n=8) donors, were grown and stimulated with viral infection and danger signal surrogate, dsRNA (10 µg·mL(-1) ). Cells were treated with simvastatin (0.2-5 µg·mL(-1) ), with or without mevalonate (13-26 µg·mL(-1) ), or dexamethasone (1 µg·mL(-1) ) prior to dsRNA. Cytokine expression and production, and transcription factor (IRF3 and NF-κB) activation were determined. Key results: dsRNA induced TSLP, TNFα, CXCL8, and IFNβ. TSLP was overproduced in dsRNA-exposed COPD cells compared to control. Simvastatin, concentration-dependently, but not dexamethasone, inhibited dsRNA-induced TSLP. Unexpectedly, simvastatin acted independent of mevalonate and did not affect dsRNA-induced NF-κB activation nor did it reduce production of TNFα and CXCL8. Instead, simvastatin inhibited dsRNA-induced IRF3 phosphorylation and generation of IFNβ. Conclusions and implications: Independent of mevalonate and NF-κB, previously acknowledged anti-inflammatory mechanisms of pleiotropic statins, simvastatin selectively inhibited dsRNA-induced IRF3 activation and production of TSLP and IFNβ in COPD epithelium. These data provide novel insight into epithelial generation of TSLP and suggest paths to be exploited in drug discovery aimed at inhibiting TSLP-induced pulmonary immunopathology.

Background Current guidelines recommend tailoring of asthma management according to disease control, which is largely defined by increased symptoms and deterioration in lung function. These features do not reflect the severity nor the type of the asthmatic airway inflammation. Fractional exhaled nitric oxide (FENO) is a simple, non-invasive and cost-effective online test applicable in both adults and children. In addition to symptoms and lung function measurements, FENO reflects airway eosinophilia and hence allows online assessment of the corticosteroid-sensitive T helper 2 type airway inflammation in asthmatic patients. FENO can thus be applied to aid asthma diagnosis and treatment monitoring both in clinical practice and for research purposes. Objectives The scope of this review is to provide an overview of the most important clinical studies using FENO in asthma management and to summarise the implications of FENO measurements in clinical practice. Results and Conclusion In several studies, FENO measurements provided additional information on aspects of asthma including phenotyping, corticosteroid-responsiveness and disease control. Thus, if correctly applied and interpreted, FENO can aid asthma diagnosis, identify patients at risk of exacerbation and support customized treatment decisions. A simple and reliable tool to quantify peripheral nitric oxide will further aid to identify patients with small airways inflammation.

Thymic stromal lymphopoietin (TSLP), an immunomodulating potentially disease-inducing cytokine, is overproduced in TLR3-stimulated bronchial epithelial cells from asthmatic donors whereas production of antiviral IFNβ is deficient. It is of therapeutic interest that capsazepine inhibits epithelial TSLP and relaxes human small airways with similar potencies. However, it is not known if other capsazepine-like compounds share such dual actions. This study explores epithelial anti-TSLP and anti-IFNβ effects of capsazepine and novel capsazepine-like bronchorelaxants. We used primary bronchial epithelial cells from asthmatic and chronic obstructive pulmonary disease (COPD) donors, and human small airways dissected from surgically removed lungs. Seven novel capsazepinoids were about 10 times, and one compound (RES187) >30 times, more potent than capsazepine as relaxants of LTD(4)-contracted small airways. TLR3-induced TSLP, TNFα, CXCL8, and IFNβ mRNA and protein levels were dose-dependently and non-selectively inhibited by capsazepine, equally in cells from asthmatic and COPD donors. The novel compounds, except RES187, reduced TSLP and IFNβ but none are more potent than capsazepine. Only capsazepine consistently inhibited TNFα and CXCL8 production and attenuated TLR3-induced epithelial NF-κB signalling. Hence, the present compounds did not separate between inhibition of TLR3-induced epithelial TSLP and IFNβ, but all compounds, except capsazepine, did separate between the bronchorelaxant and the epithelial immune effects. We conclude that similar mechanisms may be involved in capsazepine-like inhibition of TLR3-induced epithelial TSLP and IFNβ and that these are distinct from mechanisms involved in relaxation of small airways by these compounds.

Introduction: Respiratory allergic disorders like rhinitis and asthma are common conditions that not only affect target organs, but complicate the daily life of affected children and adolescents. Objectives: The aim of this study was to investigate the QoL (Quality of Life) in children with grass pollen allergy in and out of grass pollen season. Methods: We used the Pediatric Allergic Disease Quality of Life Questionnaire (PADQLQ), a disease specific questionnaire including both asthma and rhinitis symptoms. We also used the DISABKIDS questionnaire, a generic questionnaire covering non-organ specific effects of disease. Results: 98 children 7-18 years old with grass pollen allergy were included. 89 children (91%) completed the study. The QoL was significantly decreased during pollen season assessed both with DISABKIDS and PADQLQ. The correlation between the questionnaires was 0.73. Not only the physical domain score (p=0.00093) but also the emotional domain score (p=0.034) was significantly lowered. Children with multiple manifestations (asthma and rhinitis) had lower QoL than children with rhinitis alone (p= 0.01). Multiple regression analysis showed a highly significant impact on QoL for symptoms from nose, eyes and lungs. They were equally important (standardized coefficient 047, 0.47 and 0.46 respectively). Conclusion: The quality of life in children and adolescents with respiratory allergy deteriorates during pollen season. This was shown both with generic (DISABKIDS) and disease specific instrument (PADQLQ). © 2012 Blackwell Publishing Ltd.

Background: Bronchodilator therapy is central to the symptomatic management of chronic obstructive pulmonary disease (COPD), and treatment with short-acting bronchodilators is recommended in patients with mild COPD. Objective: This study aimed to evaluate the onset of effect of single-dose formoterol 9 μg versus single-dose salmeterol 50 μg in patients with moderate COPD. Methods: In this multicentre, double-blind, double-dummy, placebo-controlled, three-way single-dose crossover study, patients ≥40 years of age with moderate COPD were randomized to single-dose formoterol 9 μg via Turbuhaler® plus placebo via Diskus®, single-dose salmeterol 50 μg via Diskus® plus placebo via Turbuhaler® or placebo via Turbuhaler® and Diskus® (washout period 2–7 days). Terbutaline 0.5 mg/actuation via Turbuhaler® was used as reliever medication throughout. The primary endpoint was forced expiratory volume in 1 second (FEV1) at 5 minutes post-dose. Secondary endpoints included proportion of patients achieving ≥12% increase in FEV1 at 5 minutes post-dose. Results: 109 patients were randomized, and 108 completed the study. The increase in FEV1 5 minutes post-dose versus pre-dose was 7.2% for formoterol, 4.1% for salmeterol and 0.7% for placebo, and significantly greater for formoterol versus salmeterol (ratio of treatment effects: 1.030; 95% CI 1.008, 1.052; p = 0.009), for formoterol versus placebo (1.064, 95% CI 1.041, 1.087; p < 0.001) and for salmeterol versus placebo (1.033, 95% CI 1.011, 1.056; p = 0.003). The proportions of patients with ≥12% increase in FEV1 5 minutes post-dose were 23.1%, 9.2% and 6.4% for formoterol, salmeterol and placebo, respectively; this was statistically significantly larger after formoterol than salmeterol (p = 0.008) or placebo (p < 0.001). All treatments were well tolerated. Conclusion: In COPD patients, formoterol 9 μg has an onset of bronchodilatory effect that is more rapid than salmeterol 50 μg based on FEV1 at 5 minutes post-dose.

The aim of the study was to investigate the prevalence of asthma with or without exercise induced symptoms among elite and elite aspiring swimmers and to compare sport specific exercise provocation with mannitol provocation. METHODS: 101 adolescent swimmers were investigated with mannitol provocation and sport specific exercise challenge test. Mannitol positivity was defined as either direct FEV(1) PD15 (ordinary criteria) or as β(2)-reversibility ≥15% after challenge (extended criteria). A direct positive exercise test was defined as a drop in FEV(1) of 10% (ordinary criteria) or a difference in FEV of ≥15% either spontaneous, variability, or with β2-agonist, reversibility (extended criteria). RESULTS: We found a high prevalence of mannitol and/or exercise positivity. Twenty-six swimmers were mannitol direct positive and 14 were direct exercise positive using ordinary criteria. Using extended criteria 43 were mannitol positive and 24 were exercise positive. When including reversibility and variability to define a positive test the sensitivity for current asthma with or without exercise induced symptoms increased while the specificity remained roughly unchanged. Direct positivity for mannitol and exercise poorly overlapped using ordinary criteria but improved using extended criteria. CONCLUSION: We found a high prevalence of asthma among elite swimmers. The use of variability and reversibility (liability) as additional criteria to define a positive test provided to our mind relevant information and should be considered.