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Introduction. Angiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system (RAS) that has been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). Enhancing ACE2 activity using GSK2586881, a recombinant form of human ACE2, could be beneficial in diseases such as ARDS but may blunt the hypoxic pulmonary vasoconstriction (HPV) response and potentially impact systemic and tissue oxygenation. This study aimed to evaluate the effect of GSK2586881 0.8 mg/kg on HPV response in healthy adult volunteers during exercise under hypoxic conditions. Methods. In this phase I, randomised, double-blind (sponsor open) study, GSK2586881 or placebo was administered as a single intravenous (IV) dose in a two-period crossover design. Treatment periods were separated by a washout period of 3-14 days. The primary endpoint was change from baseline in pulmonary artery systolic pressure (PASP) measured by echocardiography. Secondary endpoints included RAS peptides and oxygen saturation. Results. Seventeen adults aged 18-40 years were randomised to treatment. There were no clinically relevant differences (defined as a reduction of > 5 mmHg) in change from baseline in PASP between GSK2586881 and placebo. GSK2586881 was well tolerated, with no serious adverse events, no worsening of hypoxaemia and no evidence of immunogenicity. The study was terminated early after review of the data, which showed that the predefined success criteria had not been met. Following GSK2586881 administration, levels of the RAS peptide angiotensin II decreased while angiotensin (1-7) increased, as expected, indicating that GSK2586881 was pharmacologically active. Conclusions. A single IV dose of GSK2586881 0.8 mg/kg was well tolerated but did not impact the acute HPV response in healthy volunteers.

Background and Purpose: Human pharmacokinetic studies of lung-targeted drugs are typically limited to measurements of systemic plasma concentrations, which provide no direct information on lung target-site concentrations. We aimed to evaluate lung pharmacokinetics of commonly prescribed drugs by sampling different lung compartments after inhalation and oral administration. Experimental Approach: Healthy volunteers received single, sequential doses of either inhaled salbutamol, salmeterol and fluticasone propionate (n = 12), or oral salbutamol and propranolol (n = 6). Each participant underwent bronchoscopies and gave breath samples for analysis of particles in exhaled air at two points after drug administration (1 and 6, 2 and 9, 3 and 12, or 4 and 18 h). Lung samples were taken via bronchosorption, bronchial brush, mucosal biopsy and bronchoalveolar lavage during each bronchoscopy. Blood samples were taken during the 24 h after administration. Pharmacokinetic profiles were generated by combining data from multiple individuals, covering all sample timings. Key Results: Pharmacokinetic profiles were obtained for each drug in lung epithelial lining fluid, lung tissue and plasma. Inhalation of salbutamol resulted in approximately 100-fold higher concentrations in lung than in plasma. Salmeterol and fluticasone concentration ratios in lung versus plasma were higher still. Bronchosorption- and bronchoalveolar-lavage-generated profiles of inhaled drugs in epithelial lining fluid were comparable. For orally administered drugs, epithelial-lining-fluid concentrations were overestimated in bronchoalveolar-lavage-generated profiles. Conclusion and Implications: Combining pharmacokinetic data derived from several individuals and techniques sampling different lung compartments enabled generation of pharmacokinetic profiles for evaluation of lung targeting after inhaled and oral drug delivery.

© 2019 Background: Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy in prediction of treatment responses and a need for better understanding of the underlying mechanisms. Objective: We sought to identify molecular subphenotypes of asthma defined by proteomic signatures for improved stratification. Methods: Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyze the proteomes of sputum supernatants from 246 participants (206 asthmatic patients) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms. Results: Analysis of the sputum proteome resulted in 10 clusters (ie, proteotypes) based on similarity in proteomic features, representing discrete molecular subphenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined 3 of these as highly eosinophilic, 3 as highly neutrophilic, and 2 as highly atopic with relatively low granulocytic inflammation. For each of these 3 phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms. Conclusion: This study provides further stratification of asthma currently classified based on quantification of granulocytic inflammation and provided additional insight into their underlying mechanisms, which could become targets for novel therapies.

Gastro-oesophageal reflux disease (GORD) and obesity are associated with frequent exacerbations and poor quality of life in asthmatics. Multiple mechanisms have been proposed for the effect of obesity, including modification of inflammation affecting epithelial cell proliferation and wound repair, while the role of GORD is poorly understood and proton pump inhibitor (PPI) are of variable efficacy. GORD might exert a deleterious effect by inducing vagal reflex, neuroinflammation and directly ( via microaspiration) triggering airway inflammation. Studies of reflux in animal models and human bronchial epithelial cell culture show varying impact on inflammation and airway remodelling. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr PEROTIN has nothing to disclose. Conflict of interest: Dr Schofield has nothing to disclose. Conflict of interest: Dr Wilson has nothing to disclose. Conflict of interest: Dr Ward has nothing to disclose. Conflict of interest: Dr Brandsma has nothing to disclose. Conflict of interest: Dr Strazzeri has nothing to disclose. Conflict of interest: Dr Bansal has nothing to disclose. Conflict of interest: Dr Yang has nothing to disclose. Conflict of interest: Dr Rowe reports and a full time employee and shareholder of Janssen Pharmaceutical Companies of Johnson and Johnson. Conflict of interest: Miss Corfield has nothing to disclose. Conflict of interest: Dr Lutter has nothing to disclose. Conflict of interest: Prof. Shaw reports personal fees and non-financial support from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Novartis, personal fees from Teva, personal fees from Circassia, and a grant from GSK, outside the submitted work. Conflict of interest: Dr Bakke reports personal fees from GSK, AZ, Novartis andTeva, outside the submitted work. Conflict of interest: MC have no conflict of interest to disclose. Conflict of interest: Dr Dahlen has nothing to disclose. Conflict of interest: Dr Fowler reports personal fees and non-financial support from AstraZeneca, grants and personal fees from Boehringer Ingelheim, personal fees from Novartis, personal fees from Teva, outside the submitted work. Conflict of interest: Dr Horvath reports personal fees from Astra Zeneca, Boehringer Ingelheim, Novartis, CSL, Chiesi, Roche, GSK, Berlin-Chemie and Sandoz, outside the submitted work. Conflict of interest: Dr Howarth reports personal fees from GSK, outside the submitted work. Conflict of interest: Dr Krug has nothing to disclose. Conflict of interest: Dr Montuschi has nothing to disclose. Conflict of interest: Dr Sanak has nothing to disclose. Conflict of interest: Dr Sandstrom reports other monetary support from Boehringer Ingelheim, outside the submitted work. Conflict of interest: Dr Sun has nothing to disclose. Conflict of interest: Dr Pandis has nothing to disclose. Conflict of interest: Dr Auffray reports grants from Innovative Medicine Initiative, during the conduct of the study. Conflict of interest: Dr De Meulder reports grants from Innovative Medicine Initiative, during the conduct of the study. Conflict of interest: Ms. Lefaudeux reports grants from Innovative Medicine Initiative, grants from Innovative Medicine Initiative, during the conduct of the study. Conflict of interest: Dr Riley reports and I have shares in and I am employed by GSK. Conflict of interest: Dr Sousa has nothing to disclose. Conflict of interest: Dr Dahlen has nothing to disclose. Conflict of interest: Dr Adcock reports grants from EU-IMI, during the conduct of the study. Conflict of interest: KFC has received honoraria for participating in Advisory Board meetings of GSK, AZ, BI, Teva, Novartis and Merck regarding treatments for asthma and chronic obstructive pulmonary disease and has also been renumerated for speaking engagements. Conflict of interest: Dr Sterk reports grants from Innovative Medicines Initiative, during the conduct of the study. Conflict of interest: Dr Skipp has nothing to disclose. Conflict of interest: Dr Collins reports a patent application for use of a genetically modified Drosophila line carrying one or more mammalian genes associated with a chronic respiratory disease and uses to screen the impact of such genes. Conflict of interest: Dr Davies has nothing to disclose. Conflict of interest: Dr Djukanovic reports receiving fees for lectures at symposia organised by Novartis, AstraZeneca and TEVA, consultation for TEVA and Novartis as member of advisory boards, and participation in a scientific discussion about asthma organised by GlaxoSmithKline. He is a co-founder and current consultant, and has shares in Synairgen, a University of Southampton spin out company.

Background Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-‘omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-‘omics signatures of disease states. Methods The framework is divided into four major steps: dataset subsetting, feature filtering, ‘omics-based clustering and biomarker identification. Results We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-‘omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. Conclusions This framework will help health researchers plan and perform multi-‘omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine. Electronic supplementary material The online version of this article (10.1186/s12918-018-0556-z) contains supplementary material, which is available to authorized users.

Background: While ragweed (Ambrosia artemisiifolia) is a common plant and a major cause for allergic reactions in North America it has originally not been native to Europe. However, there have been reports of ragweed plants in Germany since approx. 150 years and today it can be considered native to Germany, especially in the southern regions. Due to climatic changes ragweed plants constantly spread to northern Germany. The aim of this study was to assess the prevalence of sensitization against ragweed pollen in a population of allergic patients at a clinical trial unit in Hannover, Northern Germany. Method: All patients with a history of allergic rhinitis, allergic asthma, or both, that received a skin prick test at the Fraunhofer Institute for Toxicology and Experimental Medicine in Hannover between 2009 and 2015 have been evaluated for a positive reaction to ragweed. The skin prick test was conducted according to the guidelines of the German Society of Allergology and Clinical Immunology (DGAKI) and consisted of a panel of 16 allergens, mainly pollen, including ragweed. Results: Between 2009 and 2015 a total of 666 patients with either allergic rhinitis (n = 452), allergic asthma (n = 14), or both (n = 200) have received a skin prick test. 178 patients (26.7%) showed a positive reaction to ragweed. The prevalence per year ranged from 17% to 39% with no increase over the years. Conclusion: Although ragweed is still not common in northern Germany there is a high rate of sensitization in the investigated population. An increase in the ratio of sensitization between 2009 and 2015 was not observed.

Background Asthma is a disease of varying severity and differing disease mechanisms. To date, studies aimed at stratifying asthma into clinically useful phenotypes have produced a number of phenotypes that have yet to be assessed for stability and to be validated in independent cohorts. The aim of this study was to define and validate, for the first time ever, clinically driven asthma phenotypes using two independent, severe asthma cohorts: ADEPT and U-BIOPRED. Methods Fuzzy partition-around-medoid clustering was performed on pre-specified data from the ADEPT participants (n = 156) and independently on data from a subset of U-BIOPRED asthma participants (n = 82) for whom the same variables were available. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and to a larger subset of the U-BIOPRED asthma dataset (n = 397). High and low type-2 inflammation phenotypes were defined as high or low Th2 activity, indicated by endobronchial biopsies gene expression changes downstream of IL-4 or IL-13. Results Four phenotypes were identified in the ADEPT (training) cohort, with distinct clinical and biomarker profiles. Phenotype 1 was “mild, good lung function, early onset”, with a low-inflammatory, predominantly Type-2, phenotype. Phenotype 2 had a “moderate, hyper-responsive, eosinophilic” phenotype, with moderate asthma control, mild airflow obstruction and predominant Type-2 inflammation. Phenotype 3 had a “mixed severity, predominantly fixed obstructive, non-eosinophilic and neutrophilic” phenotype, with moderate asthma control and low Type-2 inflammation. Phenotype 4 had a “severe uncontrolled, severe reversible obstruction, mixed granulocytic” phenotype, with moderate Type-2 inflammation. These phenotypes had good longitudinal stability in the ADEPT cohort. They were reproduced and demonstrated high classification probability in two subsets of the U-BIOPRED asthma cohort. Conclusions Focusing on the biology of the four clinical independently-validated easy-to-assess ADEPT asthma phenotypes will help understanding the unmet need and will aid in developing tailored therapies.

Background: Inhalant allergens may act as a trigger factor of atopic dermatitis (AD). In case reports and interventional studies on bronchial or nasal allergen provocation with inhalant allergens a deterioration of skin symptoms in a subgroup of AD patients has been described. Aside from this atopy patch tests (APT) with inhalant allergens revealed a high diagnostic specificity with regard to the patients' history. However, a diagnostic tool testing the clinical relevance of inhalant sensitization in patients with AD by provocation as near as possible to 'true life' conditions is not available. The aim of this single center, double-blind, placebo-controlled study was to assess the cutaneous reactions to grass pollen in adult patients suffering from AD with accompanying IgE-sensitization to grass pollen allergen. For this purpose, AD patients were exposed to grass pollen in an environmental challenge chamber (ECC). Method: On two consecutive days sensitized patients were challenged with either 4000 pollen grains/m3 of Dactylis glomerata pollen (verum) or clean air (placebo). Prior to the challenge, on each challenge day (Day 1 and 2) and also during a follow-up period (Day 3-5) the severity of AD was assessed by objective SCORAD (primary endpoint). Additionally, air-exposed and textile covered skin areas were separately scored by IGA and 'local SCORAD'. By 'local SCORAD' two representative target lesions - one textile covered and one air-exposed - in each patient were evaluated. As biomarker of the disease activity serum CCL17 levels were determined by ELISA. Results: In patients exposed to grass pollen a significantly higher increase in objective SCORAD from pre-challenge to postchallenge Day 3 in the verum group compared to the placebo group was observable (P = 0.010). Of note, a significant worsening of air-exposed rather than of textile covered skin occurred. A trend towards an increase of CCL17 serum levels in grass pollen exposed patients was obvious. Conclusion: By this proof-of-concept study, effects of an inhalant allergen on cutaneous symptoms in selected AD patients could clearly be demonstrated. Our results support the need for allergen avoidance as a preventive measure in these patients. Aerogen allergen challenge by means of an ECC might represent a useful procedure also for research on therapeutic agents in AD.

Background: An Environmental Challenge Chamber (ECC) is a useful tool to expose allergic patients to relevant allergens in a controlled indoor setting and to test antiallergic treatments.Hitherto, ECC studies with grass pollen are primarily conducted offseason to avoid potential confounders. Therefore, the aim of this prospective study was to investigate whether the therapeutic effect of a combination of cetirizine and pseudoephedrine in an ECC setting is equivalent when tested within and out of the grass pollen season. Methods: In a randomised, double blind study the effect of a combination of 10mg cetirizine and 120 mg pseudoephedrine versus placebo on nasal symptoms, nasal secretion, and nasal flow measured by rhinomanometry was investigated in 70 patients with seasonal allergic rhinitis. Subjects underwent four 6h pollen exposures with Dactylis glomerata pollen in an ECC with drug administration after 2 h. Two exposures were conducted within the pollen season and two out of the pollen season. Results: The active treatment significantly reduced nasal symptoms, nasal secretion, and nasal flow compared to placebo both within and out of the pollen season (Po 0.0001). Treatment effects on symptoms, nasal secretion, and nasal flow were not different between the seasons. (P40.2, P40.5 P40.6, respectively). Conclusion: An ECC can be used to test anti-allergic treatments both within and out of the grass pollen season.

Background: It is somewhat unclear how pollen allergens cause lower airway inflammation because pollen grains with a diameter of 30 mm are too large to reach the lower airways. One hypothesis is that lower airway inflammation is caused by allergen containing pollen starch granules which are released from the pollen grains and can easily enter the peripheral airways due to their smaller size. However, no data are available which have investigated the contribution of pollen starch granules to nasal symptoms and lower airway inflammation. Methods: In an 2 part cross over design 30 patients with allergic rhinitis and mild intermittent asthma underwent 4 h allergen challenges on two consecutive days in the Fraunhofer Environmental Challenge Chamber with either a normal and established mixture of pollen grains (4000 pollen/ m3) plus starch granules (app. 8000 granules/m3) or only starch granules (app. 8000 granules/m3). Prior to and during the challenges, the total nasal symptom score (TNSS), spirometry, nasal secretion weight, and nasal flow measured by rhinomanometry was determined. Furthermore the exhaled NO was measured prior to challenge and 24 h after the second challenge in each part. Results: The presence of pollen grains had a significant and considerable effect on increase in TNSS and secretion weight and on decline in nasal flow. Starch granules alone only had minimal effects on nasal symptoms. Challenges with starch granules alone increased exhaled NO. Pollen had no additional effect on exhaled NO. Conclusion: Pollen grains elicit nasal symptoms and starch granules trigger lower airway inflammation. This difference is probably caused by the different sizes of pollen grains and starch granules.