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Background: The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling., Objective: To report safety and efficacy results from enrolled participants with available data from CLAVIER., Methods: We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double-blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre-specified primary end-point was relative change in airway subepithelial eosinophils per mm 2 of basement membrane (cells/mm 2 ). Pre-specified secondary and exploratory outcomes included change in IL-13-associated biomarkers and measures of airway remodelling., Results: There was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm 2 in response to lebrikizumab (95% CI, -82.5%, 97.5%). As previously observed, FEV 1 increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21.5% after lebrikizumab treatment (95% CI, -32.9%, -10.2%), and fractional exhaled nitric oxide, CCL26 and SERPINB2 mRNA expression in bronchial tissues also reduced. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies., Conclusions & Clinical Relevance: We did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre-specified exploratory analyses, lebrikizumab treatment was associated with reduced degree of subepithelial fibrosis, a feature of airway remodelling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL-13 in airway pathobiology and suggest that neutralization of IL-13 may reduce asthmatic airway remodelling., Clinical Trial Registration: NCT02099656., (© 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Purpose: For exercise testing of COPD patients, a standard endurance test (ET) with constant workload is recommended. The test suffers from large inter-individual variability and need for large sample sizes in order to evaluate treatment effects., Methods: A new protocol for ET in COPD was designed. In contrast to the standard ET, the new ET involved an increasing workload in order to reduce the standard deviation of endurance time. Two new ETs were compared with the standard ET. In Study A, the new ET started at 75% of the patient's maximum workload (W MAX ) and increased stepwise with 3%/2 min until exhaustion. Study B started at 70% of W MAX and increased linearly with 1%/min., Results: In Study A, that included 15 patients, the standard deviation and range for endurance time and work capacity were narrower for the new versus the standard ET. However, the higher mean workload at end and the low mean work capacity relative to the standard ET indicated that the stepwise increase was too aggressive. In Study B, that included 18 patients, with a modified protocol, the averages for endurance time, workload at end and work capacity were similar for new and standard ET, while the standard deviations and ranges for endurance time and work capacity were kept more narrow in the new ET. The variances for endurance time were not equal between the standard ET and the two new ETs (p<0.05 for both according to Levene's test)., Conclusion: The new ET reduced the number of patients with extreme endurance times (short and long) compared to the standard test. The new test showed a significant lower variance for endurance time, which potentially can lead to fewer patients needed in comparative studies. The overall best results were observed with a low linear increase during endurance., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Tufvesson et al.)

As Covid-19 affects millions of people worldwide, the global health care will encounter an increasing burden of the aftermaths of the disease. Evidence shows that up to a fifth of the patients develop fibrotic tissue in the lung. The SARS outbreak in the early 2000 resulted in chronic pulmonary fibrosis in a subset (around 4%) of the patients, and correlated to reduced lung function and forced expiratory volume (FEV). The similarities between corona virus infections causing SARS and Covid-19 are striking, except that the novel coronavirus, SARS-CoV-2, has proven to have an even higher communicability. This would translate into a large number of patients seeking care for clinical signs of pulmonary fibrosis, given that the Covid-19 pandemic has up till now (Sept 2020) affected around 30 million people. The SARS-CoV-2 is dependent on binding to the angiotensin converting enzyme 2 (ACE2), which is part of the renin-angiotensin system (RAS). Downregulation of ACE2 upon virus binding disturbs downstream activities of RAS resulting in increased inflammation and development of fibrosis. The poor prognosis and risk of developing pulmonary fibrosis are therefore associated with the increased expression of ACE2 in risk groups, such as obesity, heart disorders and aging, conferring plenty of binding opportunity for the virus and subsequently the internalization of ACE2, thus devoiding the enzyme from acting counter-inflammatory and antifibrotic. Identifying pathways that are associated with Covid-19 severity that result in pulmonary fibrosis may enable early diagnosis and individualized treatment for these patients to prevent or reduce irreversible fibrotic damage to the lung., Competing Interests: There is no conflict of interest of any of the authors., (© 2020 The Authors.)

Background: Chronic rhinosinusitis (CRS) is a chronic inflammatory disease associated with a substantial personal and socioeconomic burden. Monitoring of patient-reported outcomes by mobile technology offers the possibility to better understand real-life burden of CRS., Methods: This study reports on the cross-sectional evaluation of data of 626 users of mySinusitisCoach (mSC), a mobile application for CRS patients. Patient characteristics of mSC users were analysed as well as the level of disease control based on VAS global rhinosinusitis symptom score and adapted EPOS criteria., Results: The mSC cohort represents a heterogeneous group of CRS patients with a diverse pattern of major symptoms. Approximately half of patients reported nasal polyps. 47.3% of all CRS patients were uncontrolled based on evaluation of VAS global rhinosinusitis symptom score compared to 40.9% based on adapted EPOS criteria. The impact of CRS on sleep quality and daily life activities was significantly higher in uncontrolled versus well-controlled patients. Half of patients had a history of FESS (functional endoscopic sinus surgery) and reported lower symptom severity compared to patients without a history of FESS, except for patients with a history of more than 3 procedures. Patients with a history of FESS reported higher VAS levels for impaired smell., Conclusion: Real-life data confirm the high disease burden in uncontrolled CRS patients, clearly impacting quality of life. Sinus surgery improves patient-reported outcomes, but not in patients with a history of more than 3 procedures. Mobile technology opens a new era of real-life monitoring, supporting the evolution of care towards precision medicine., (© 2020 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Introduction: Exercise-induced bronchoconstriction is due to osmotic stimulus of the airway epithelium and leads to a cascade of biomarker release from several inflammatory cells. Several type 2 (T2) mediators have been linked to exercise-induced bronchoconstriction, but the T2 response per se has not been described during exercise. The aim of this study was therefore to investigate T2 biomarkers in plasma and urine from subjects with asthma and healthy controls before and after an exercise challenge., Methods: Twenty-two subjects with mild asthma and 18 healthy controls performed an exercise challenge test on a treadmill, and fractional exhaled NO (FeNO) was measured at baseline. Blood and urine samples were collected repeatedly during 60 min after the test and Interleukin-13 (IL-13), thymus and activation-related chemokine (TARC), periostin and leukotrienes were measured., Results: Asthmatics and controls showed similar levels of IL-13, TARC, periostin and Cys-LT in plasma at baseline, and there were no differences in baseline levels between subjects with a negative and positive exercise challenge. After exercise, there was an overall increase in interleukin-13 (IL-13) in plasma in all subjects (p<0.001), with a peak at 10 min after the exercise challenge in both the asthmatic and control group. An increase in TARC in plasma was also seen (p<0.001), but only in the control subjects. In contrast, Cys-LT in plasma showed an overall decrease in all subjects (p<0.001), while periostin in plasma did not change. In conjunction with plasma, the level of IL-13 was increased in urine 30 min after the exercise challenge (p=0.002) and decreased again at 60 min (p=0.004). Similarly, leukotriene E 4 (LTE 4 ) was increased in urine samples, with a peak at 60 min and most pronounced in asthmatic subjects (p<0.001) but was seen also in controls (p=0.008)., Discussion: In conclusion, circulating levels of IL-13 are increased after exercise to the same extent in asthmatics and healthy control subjects, which indicates a physiological rather than a pathophysiological response. Also, the levels of TARC and leukotrienes were affected after exercise., Competing Interests: None of the authors have any conflicts of interest related to the manuscript content., (© 2020 Tufvesson et al.)

Background: Severe asthma exerts a disproportionately heavy burden on patients and health care. Due to the heterogeneity of the severe asthma population, many patients need to be evaluated to understand the clinical features and outcomes of severe asthma in order to facilitate personalised and targeted care. The International Severe Asthma Registry (ISAR) is a multi-country registry project initiated to aid in this endeavour., Methods: ISAR is a multi-disciplinary initiative benefitting from the combined experience of the ISAR Steering Committee (ISC; comprising 47 clinicians and researchers across 29 countries, who have a special interest and/or experience in severe asthma management or establishment and maintenance of severe asthma registries) in collaboration with scientists and experts in database management and communication. Patients (≥18 years old) receiving treatment according to the 2018 definitions of the Global Initiative for Asthma (GINA) Step 5 or uncontrolled on GINA Step 4 treatment will be included. Data will be collected on a core set of 95 variables identified using the Delphi method. Participating registries will agree to provide access to and share standardised anonymous patient-level data with ISAR. ISAR is a registered data source on the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. ISAR's collaborators include Optimum Patient Care, the Respiratory Effectiveness Group (REG) and AstraZeneca. ISAR is overseen by the ISC, REG, the Anonymised Data Ethics & Protocol Transparency Committee and the ISAR operational committee, ensuring the conduct of ethical, clinically relevant research that brings value to all key stakeholders., Conclusions: ISAR aims to offer a rich source of real-life data for scientific research to understand and improve disease burden, treatment patterns and patient outcomes in severe asthma. Furthermore, the registry will provide an international platform for research collaboration in respiratory medicine, with the overarching aim of improving primary and secondary care of adults with severe asthma globally.

Objective: A liquid mepolizumab formulation in a single-use prefilled syringe (PFS) is under development. We evaluated the usability of mepolizumab self-injected via PFS by patients with severe eosinophilic asthma (SEA), or their caregivers, in clinic and at home. Methods: This open-label, single-arm, Phase IIIa study included patients with SEA, aged ≥12 years, and receiving mepolizumab (100 mg subcutaneously) every 4 weeks for ≥12 weeks prior to screening. Patients with SEA not receiving mepolizumab at screening who met additional criteria were also included. Patients/caregivers self-administered mepolizumab (100 mg subcutaneously) via PFS every 4 weeks for 12 weeks. The first (Week 0) and third (Week 8) dose were observed in clinic; the second dose (Week 4) was unobserved at home. Primary and secondary endpoints were the proportion of patients who successfully self-administered their third and second doses, respectively. Injection success was determined by investigator/site staff. Patient experience, mepolizumab trough concentrations, blood eosinophil counts, and safety were also assessed. Results: Of the 56 patients/caregivers who self-administered ≥1 dose of mepolizumab, 55 completed the study. All patients were reported to have successfully self-administered their third mepolizumab dose in clinic ( N  = 55, 100%); this was further evidenced by trough concentrations/blood eosinophil counts. Most patients/caregivers found the PFS easy and convenient to use with 75% ( n  = 42) expressing little/no anxiety about using the device at home. Incidence of on-treatment drug-related adverse events was low (4%); none were fatal. Conclusions: Patients/caregivers successfully self-administered mepolizumab via the PFS both in clinic and at home, with no new safety concerns identified.

It is well-known that use of continuous systemic corticosteroids (SG) affects bone metabolism, bone mineral density (BMD), and ultimately increases the risk of osteoporosis. In patients with asthma, on the other hand, the effects of long-term high-dose inhaled corticosteroids (ICS) on BMD and risk of osteoporotic fractures is controversial. The reasons for this inconsistency could be explained by the fact that only few long-term studies investigating the effect of ICS in patients with asthma exist. The studies are characterized by different study designs and duration of ICS exposure, small study populations, and differences between the used ICS. The aim of this article is to unravel which factors, if any, that contribute to an increased risk of osteoporosis in patients with asthma and to summarize the evidence regarding adverse effects of ICS on bone metabolism, BMD and osteoporotic fractures in patients with asthma., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Spring and Summer 2020 are unique in that the challenges of care for those suffering from pollen allergy coincide with the COVID-19 pandemic. Several considerations are important to allow optimal care of allergic rhinitis (AR) and asthma and hence prevention of coronavirus spread through sneezing, rhinorrhoea, and coughing. This compact overview of recommendations by the EUFOREA expert teams on allergic airway diseases and allergen-specific immunotherapy (AIT) is based on investigation of the current COVID-19 literature in association with the key words above and shared clinical experience of the experts involved. It deals with similarities and differences between AR and coronavirus infection, specific recommendations for allergic disease care in the COVID-19 era, including guidance on AIT., (Crown Copyright © 2020 Published by Elsevier Inc. on behalf of World Allergy Organization.)

Although elevated blood or sputum eosinophils are present in many patients with COPD, uncertainties remain regarding the anatomical distribution pattern of lung-infiltrating eosinophils. Basophils have remained virtually unexplored in COPD. This study mapped tissue-infiltrating eosinophils, basophils and eosinophil-promoting immune mechanisms in COPD-affected lungs.Surgical lung tissue and biopsies from major anatomical compartments were obtained from COPD patients with severity grades Global Initiative for Chronic Obstructive Lung Disease stages I-IV; never-smokers/smokers served as controls. Automated immunohistochemistry and in situ hybridisation identified immune cells, the type 2 immunity marker GATA3 and eotaxins (CCL11, CCL24).Eosinophils and basophils were present in all anatomical compartments of COPD-affected lungs and increased significantly in very severe COPD. The eosinophilia was strikingly patchy, and focal eosinophil-rich microenvironments were spatially linked with GATA3 + cells, including type 2 helper T-cell lymphocytes and type 2 innate lymphoid cells. A similarly localised and interleukin-33/ST2-dependent eosinophilia was demonstrated in influenza-infected mice. Both mice and patients displayed spatially confined eotaxin signatures with CCL11 + fibroblasts and CCL24 + macrophages.In addition to identifying tissue basophilia as a novel feature of advanced COPD, the identification of spatially confined eosinophil-rich type 2 microenvironments represents a novel type of heterogeneity in the immunopathology of COPD that is likely to have implications for personalised treatment., Competing Interests: Conflict of interest: P. Jogdand has nothing to disclose. Conflict of interest: P. Siddhuraj has nothing to disclose. Conflict of interest: M. Mori has nothing to disclose. Conflict of interest: C. Sanden has nothing to disclose. Conflict of interest: J. Jönsson has nothing to disclose. Conflict of interest: A.F. Walls has nothing to disclose. Conflict of interest: J. Kearley is an employee of AstraZeneca (formerly MedImmune LLC) and has stock options in AstraZeneca. Conflict of interest: A.A. Humbles was an employee of AstraZeneca (formerly MedImmune LLC) at the time these analyses were conducted. Conflict of interest: R. Kolbeck was an employee of AstraZeneca (formerly MedImmune LLC) at the time these analyses were conducted. Conflict of interest: L. Bjermer has nothing to disclose. Conflict of interest: P. Newbold is an employee of AstraZeneca (formerly MedImmune LLC) and has stock options in AstraZeneca. Conflict of interest: J.S. Erjefält is founder (and stock owner) of Medetect AB, who received funding from AstraZeneca for conducting parts of the present study., (Copyright ©ERS 2020.)

Objectives: Chronic lung allograft dysfunction including Bronchiolitis obliterans syndrome (BOS) is common after lung transplantation. Histologically, BOS is recognized as fibrotic lesions with accumulated extracellular matrix (ECM) in small airways. Lung fibroblasts are major producers of ECM and vascular endothelial growth factor (VEGF). In this study we hypothesize that VEGF is involved in BOS development after lung transplantation., Methods: We investigated the effect of profibrotic transforming growth factor (TGF-β) on VEGF synthesis in lung fibroblasts isolated from distal lung tissue biopsies taken from patients at 3, 6 and 12 months after lung transplantation (n = 14). Co-expression of VEGF receptor (VEGFR) 2 and collagen marker prolyl4-hydroxylase (p4OH) were analyzed in lung tissue from patients with BOS (n = 11)., Results: VEGF synthesis from distal derived lung fibroblasts were significantly lower 3 months after lung transplantation (168.6 ± 133.7; n = 7) compared to non-transplanted subjects (451.8 ± 185.9; n = 9; p = 0.0033) and increased over time at 6 months (584.1 ± 264.9; n = 9; p = 0.0033) and 12 months (451.1 ± 207.5; n = 8; p = 0.0065) post transplantation. TGF-β significantly induced VEGF synthesis at all time points. At 12 months post transplantation there was significantly less VEGF synthesis after TGF-β stimulation in fibroblasts obtained from BOS patients (1170 ± 450.2; n = 4) compared to patients without any chronic rejection process (1980 ± 417.9; n = 4; p < 0.039). The numbers of cells expressing VEGFR2/p4OH were increased in patients with BOS (33.2 ± 10.9; n = 11) compared to control subjects (10.1 ± 9.9; n = 11; p < 0.001)., Conclusions: Our results support that changes in VEGF/VEGFR2 axis could be involved in BOS development and marker of poor outcome., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Exhaled breath temperature has been suggested to reflect airway inflammation, and it would be plausible to measure the peripheral airway temperature as a correlate to peripheral airway inflammation. This study aims to explore the relative peripheral airway temperature in patients with asthma, chronic obstructive pulmonary disease (COPD) or systemic sclerosis (SSc) compared to healthy controls, and relate to lung function and exhaled nitric oxide. Sixty-five subjects (16 asthmatics, 18 COPD patients, 17 SSc patients and 14 healthy subjects) performed fractional exhaled breath temperature measurements using a novel device, fractional exhaled NO measurements, spirometry, impulse oscillometry, body plethysmography and CO-diffusion capacity test. A significant overall difference among all the patient groups was seen in both the Tmax (= peak values of the entire exhalation) and T3max (= peak value of the last fraction of the exhaled volume). A significant difference in T3/T1 ratio (= the ratio of peripheral versus central air temperature) was found between asthmatic subjects and those with COPD or SSc. In addition, T1max (= temperature in the central), T3max (= peripheral airways) and the T3/T1ratio related to several volumetric measurements (both in absolute values and as percent predicted), such as vital capacity, total lung capacity, forced expiratory volume in 1 s, and diffusion capacity. The temperature ratio of the peripheral versus central airways was lower in patients with COPD or SSc compared to asthmatics, who in turn presented similar levels as the controls. There was also a large overlap between the groups. Overall, the airway temperatures were related to absolute lung volumes, and specifically, the peripheral temperature was related to the gas diffusion capacity (% predicted), suggesting a link to the vascular component., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Competing Interests: Conflict of interest: K. Geale reports research project funding from Novartis for the current work; personal fees for consultancy from Quantify Research, during the conduct of the study and outside the submitted work. Conflict of interest: H. Darabi reports research project funding from Novartis for the current work; personal fees for consultancy from Quantify Research, during the conduct of the study and outside the submitted work. Conflict of interest: M. Lindh reports research project funding from Novartis for the current work; personal fees for consultancy from Quantify Research, during the conduct of the study and outside the submitted work. Conflict of interest: H. Fues Wahl reports research project funding from Novartis for the current work; personal fees for consultancy from Quantify Research, during the conduct of the study and outside the submitted work. Conflict of interest: O. Ström reports research project funding from Novartis for the current work; personal fees for consultancy from Quantify Research, during the conduct of the study and outside the submitted work. Conflict of interest: H. Cao is an employee of Novartis Pharmaceutical Company. Conflict of interest: L.A. Alvares is an employee of Novartis. Conflict of interest: R. Dodge has nothing to disclose. Conflict of interest: E. Loefroth is an employee of Novartis. Conflict of interest: A. Altraja reports personal fees and travel and educational support from AstraZeneca, Berlin-Chemie Menarini, Boehringer Ingelheim, CSL Behring, Roche, Teva and Sanofi, grants, personal fees and travel and educational support from Chiesi (Norameda) and GlaxoSmithKline, personal fees and travel support from MSD, grants and personal fees from Bayer, travel and educational support from Actelion (Johnson and Johnson), personal fees from Shire Pharmaceuticals, outside the submitted work. Conflict of interest: V. Backer has nothing to disclose. Conflict of interest: H. Backman reports personal fees for lectures from AstraZeneca, outside the submitted work. Conflict of interest: L. Bjermer reports personal fees from AstraZeneca, Boehringer, Chiesi, GSK, Novartis, Teva and ALK, outside the submitted work. Conflict of interest: A. Bossios reports personal fees for advisory board work and/or lectures from AZ, Teva, GSK and Novartis, outside the submitted work. Conflict of interest: B. Bøgvald Aarli reports personal fees for lectures from Boehringer Ingelheim, Novartis, AstraZeneca, Chiesi and Alere, personal fees for consultancy from GlaxoSmithKline, and has stock in from KBB Medic AS, outside the submitted work. Conflict of interest: B. Dahlén reports personal fees for lectures and advisory board work from AstraZeneca, GSK, Teva, Sanofi and Novartis, outside the submitted work. Conflict of interest: O. Hilberg has nothing to disclose. Conflict of interest: C. Jansson has nothing to disclose. Conflict of interest: H. Kankaanranta reports grants, personal fees for lectures and consultancy, and non-financial support to attend meetings from AstraZeneca, personal fees for lectures and consultancy from Chiesi Pharma AB, Novartis and GlaxoSmithKline, personal fees for lectures and consultancy, and non-financial support to attend meetings from Boehringer Ingelheim and Orion Pharma, personal fees for lectures from Mundipharma, personal fees for consultancy from Sanofi Genzyme, outside the submitted work. Conflict of interest: J. Karjalainen reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mundipharma, Novartis, Orion Pharma and Teva, outside the submitted work. Conflict of interest: P. Kauppi reports personal fees for lectures from GSK, Teva and Novartis, personal fees for manuscript preparation from Fimea, personal fees for consultancy from Sanofi, outside the submitted work. Conflict of interest: M. Kilpeläinen has nothing to disclose. Conflict of interest: S. Lehmann reports data analysis and manuscript preparation support from Novartis, during the conduct of the study; personal fees for lectures from AstraZeneca, personal fees for manuscript preparation from Boehringer Ingelheim, outside the submitted work. Conflict of interest: L. Lehtimäki reports personal fees from AstraZeneca, Chiesi, GSK, Boehringer Ingelheim, MSD, Novartis, pi tlsb -.005wOrionPharma, ALK, Teva and Sanofi, outside the submitted work. Conflict of interest: B. Lundbäck reports grants from AstraZeneca, personal fees for lectures and advisory board work from AstraZeneca, Novartis, GSK and Sanofi, outside the submitted work. Conflict of interest: T. Sandström has nothing to disclose. Conflict of interest: C. Suppli. Ulrik has nothing to disclose. Conflict of interest: A. Sverrild has nothing to disclose. Conflict of interest: A. Viinanen has nothing to disclose. Conflict of interest: A. von Bülow has nothing to disclose. Conflict of interest: V. Yasinska has nothing to disclose. Conflict of interest: C. Porsbjerg reports grants and personal fees from AstraZeneca, GSK, Novartis, Sanofi and Teva, outside the submitted work.

Background: The BREATHE study is a cross-sectional study of real-life patients with asthma and/or COPD in Denmark and Sweden aiming to increase the knowledge across severities and combinations of obstructive airway disease. Design: Patients with suspicion of asthma and/or COPD and healthy controls were invited to participate in the study and had a standard evaluation performed consisting of questionnaires, physical examination, FeNO and lung function, mannitol provocation test, allergy test, and collection of sputum and blood samples. A subgroup of patients and healthy controls had a bronchoscopy performed with a collection of airway samples. Results: The study population consisted of 1403 patients with obstructive airway disease (859 with asthma, 271 with COPD, 126 with concurrent asthma and COPD, 147 with other), and 89 healthy controls (smokers and non-smokers). Of patients with asthma, 54% had moderate-to-severe disease and 46% had mild disease. In patients with COPD, 82% had groups A and B, whereas 18% had groups C and D classified disease. Patients with asthma more frequently had childhood asthma, atopic dermatitis, and allergic rhinitis, compared to patients with COPD, asthma + COPD and Other, whereas FeNO levels were higher in patients with asthma and asthma + COPD compared to COPD and Other (18 ppb and 16 ppb vs 12.5 ppb and 14 ppb, p  < 0.001). Patients with asthma, asthma + COPD and Other had higher sputum eosinophilia (1.5%, 1.5%, 1.2% vs 0.75%, respectively, p  < 0.001) but lower sputum neutrophilia (39.3, 43.5%, 40.8% vs 66.8%, p  < 0.001) compared to patients with COPD. Conclusions: The BREATHE study provides a unique database and biobank with clinical information and samples from 1403 real-life patients with asthma, COPD, and overlap representing different severities of the diseases. This research platform is highly relevant for disease phenotype- and biomarker studies aiming to describe a broad spectrum of obstructive airway diseases., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: In chronic obstructive pulmonary disease (COPD), both the time needed for patients to gain symptom improvement with long-acting bronchodilator therapy and whether an early response is predictive of a sustained response is unknown. This study aimed to investigate how quickly meaningful symptom responses are seen in patients with COPD with bronchodilator therapy and whether these responses are sustained., Methods: Early MAXimisation of bronchodilation for improving COPD stability (EMAX) was a 24-week, double-blind, double-dummy, parallel-group trial that randomised patients to umeclidinium/vilanterol (UMEC/VI), umeclidinium or salmeterol. Daily Evaluating Respiratory Symptoms in COPD (E-RS:COPD) score and rescue salbutamol use were captured via an electronic diary and analysed initially in 4-weekly periods. Post hoc analyses assessed change from baseline in daily E-RS:COPD score and rescue medication use weekly (Weeks 1-8), and association between E-RS:COPD responder status at Weeks 1-4 and later time points., Results: In the intent-to-treat population ( n  = 2425), reductions from baseline in E-RS:COPD scores and rescue medication use were apparent from Day 2 with all treatments. Treatment differences for UMEC/VI versus either monotherapy plateaued by Week 4-8 and were sustained at Weeks 21-24; improvements were consistently greater with UMEC/VI. For all treatments, most patients (60-85%) retained their Weeks 1-4 E-RS:COPD responder/non-responder status at Weeks 21-24. Among patients receiving UMEC/VI who were E-RS:COPD responders at Weeks 1-4, 70% were responders at Weeks 21-24., Conclusion: Patients with symptomatic COPD had greater potential for early symptom improvements with UMEC/VI versus either monotherapy. This benefit was generally maintained for 24 weeks. Early monitoring of treatment response can provide clinicians with an early indication of a patient's likely longer-term response to prescribed bronchodilator treatment and will facilitate appropriate early adjustments in care., Clinical Trial Registration: NCT03034915, 2016-002513-22 (EudraCT Number). The reviews of this paper are available via the supplemental material section.

A proportion of patients with severe asthma (SA) show poor responses to traditional asthma medications; however, it remains unknown why some patients remain persistently symptomatic. Our objective was to explore the use of laser-capture microdissection of specific epithelial structures combined with quantitative data-independent acquisition mass spectrometry to elucidate differences in protein composition in patients with SA with varying symptom control. Unbiased label-free quantitative proteome analyses were performed on laser-capture-microdissected areas of specific epithelial structures from patients with SA with varying degrees of symptom control. A total of 1993 stable SA and 1652 symptomatic SA proteins in normal epithelium and 1458 stable SA and 1647 symptomatic SA proteins in metaplastic epithelium were quantified. When comparing proteome profiles based on symptom control, 33 proteins in patients with stable SA (≥twofold change; P ≤ 0.05) and 13 proteins in patients with persistently symptomatic SA (≥twofold change; P ≤ 0.05) were enriched significantly. When comparing proteome profiles based on epithelial status, 21 proteins in normal epithelium (≥twofold change; P ≤ 0.05) and 6 proteins in metaplastic epithelium (≥twofold change; P ≤ 0.05) were enriched significantly. New treatment strategies are needed for patients with severe asthma and exploratory studies of unbiased nature such as this may help when searching for new mechanisms and potential targets involved in the disease pathology., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Novel therapies such as type 2 targeting biologics are emerging treatment options for patients with chronic inflammatory respiratory diseases, fulfilling the needs of severely uncontrolled patients. The majority of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and over half of patients with asthma show a type 2 inflammatory signature in sinonasal mucosa and/or lungs. Importantly, both chronic respiratory diseases are frequent comorbidities, ensuring alleviation of both upper and lower airway pathology by systemic biological therapy. Type 2-targeting biologics such as anti-IgE, anti-IL4Rα, anti-IL5, and anti-IL5Rα have entered the market for selected pheno/endotypes of asthma patients and may soon also become available for CRSwNP patients. Given the high prevalence of chronic respiratory diseases and the high cost associated with biologics, patient selection is crucial in order to implement such therapies into chronic respiratory disease care pathways. The European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) organized a multidisciplinary Expert Board Meeting to discuss the positioning of biologics into the care pathways for CRSwNP patients with and without comorbid asthma., (© 2019 The Authors Allergy Published by John Wiley & Sons Ltd.)

COPD and asthma exacerbations are commonly triggered by rhinovirus infection. Potentially promoting exacerbations, impaired anti-viral signaling and attenuated viral clearance have been observed in diseased bronchial epithelium. Oxidative stress is a feature of inflammation in asthma and COPD and is prominent during exacerbations. It is not known whether oxidative stress affects the anti-viral signaling capacity. Bronchial epithelial cells from asthmatic and COPD donors were infected with rhinovirus or treated with the oxidative stressor H 2 O 2 followed by exposure to the synthetic viral replication intermediate poly(I:C). Poly(I:C) was used to ascertain a constant infection-like burden. Gene and protein levels of antioxidants as well as anti-viral responses were measured 3 and 24 h post poly(I:C) exposure. Rhinovirus infection and poly(I:C) stimulation induced protein levels of the antioxidants SOD1 and SOD2. In asthmatic bronchial epithelial cells pre-treatment with H 2 O 2 dose-dependently decreased the antioxidant response to poly(I:C), suggesting exaggerated oxidative stress. Further, poly(I:C)-induced IFNβ gene expression was reduced after pre-treatment with H 2 O 2 . This epithelial effect was associated with a reduced expression of the pattern recognition receptors RIG-I, MDA5 and TLR3 both on gene and protein level. Pre-treatment with H 2 O 2 did not alter antioxidant responses in COPD bronchial epithelial cells and, more modestly than in asthma, reduced poly(I:C)-induced IFNβ gene expression. Knockdown of TLR3 but not RIG-I/MDA5 abrogated impairment of poly(I:C)-induced IFNβ gene expression by H 2 O 2 . We developed a method by which we could demonstrate that oxidative stress impairs anti-viral signaling in bronchial epithelial cells from asthmatic and COPD patients, most pronounced in asthma. The impairment apparently reflects reduced responsiveness of TLR3. These present findings shed light on molecular mechanisms potentially causing reduced interferon responses to rhinovirus infection at exacerbations in asthma and COPD. Together, our findings suggest a possible self-perpetuating vicious cycle underlying recurrent exacerbations, leading to an impaired anti-viral response, which in turn leads to viral-induced exacerbations, causing more airway inflammation., (Copyright © 2019 Menzel, Ramu, Calvén, Olejnicka, Sverrild, Porsbjerg, Tufvesson, Bjermer, Akbarshahi and Uller.)

Background : Maximum exercise workload (W MAX ) is today assessed as the first part of Cardiopulmonary Exercise testing. The W MAX test exposes patients with COPD, often having cardiovascular comorbidity, to risks. Our research project was initiated with the final aim to eliminate the W MAX test and replace this test with a predicted value of W MAX , based on a prediction algorithm of W MAX derived from multicentre studies. Methods : Baseline data (W MAX , demography, lung function parameters) from 850 COPD patients from four multicentre studies were collected and standardized. A prediction algorithm was prepared using Random Forest modelling. Predicted values of W MAX were used in a new W MAX test, which used a linear increase in order to reach the predicted W MAX within 8 min. The new W MAX test was compared with the standard stepwise W MAX test in a pilot study including 15 patients with mild/moderate COPD. Results : The best prediction algorithm of W MAX included age, sex, height, weight, and six lung function parameters. FEV 1 and DLCO were the most important predictors. The new W MAX test had a better correlation (R 2 = 0.84) between predicted and measured W MAX than the standard W MAX test (R 2 = 0.66), with slopes of 0.50 and 0.46, respectively. The results from the new W MAX test and the standard W MAX test correlated well. Conclusion : A prediction algorithm based on data from four large multicentre studies was used in a new W MAX test. The prediction algorithm provided reliable values of predicted W MAX . In comparison with the standard W MAX test, the new W MAX test provided similar overall results., (© 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: Prospective evidence is lacking regarding incremental benefits of long-acting dual- versus mono-bronchodilation in improving symptoms and preventing short-term disease worsening/treatment failure in low exacerbation risk patients with chronic obstructive pulmonary disease (COPD) not receiving inhaled corticosteroids., Methods: The 24-week, double-blind, double-dummy, parallel-group Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised patients at low exacerbation risk not receiving inhaled corticosteroids, to umeclidinium/vilanterol 62.5/25 μg once-daily, umeclidinium 62.5 μg once-daily or salmeterol 50 μg twice-daily. The primary endpoint was trough forced expiratory volume in 1 s (FEV 1 ) at Week 24. The study was also powered for the secondary endpoint of Transition Dyspnoea Index at Week 24. Other efficacy assessments included spirometry, symptoms, heath status and short-term disease worsening measured by the composite endpoint of clinically important deterioration using three definitions., Results: Change from baseline in trough FEV 1 at Week 24 was 66 mL (95% confidence interval [CI]: 43, 89) and 141 mL (95% CI: 118, 164) greater with umeclidinium/vilanterol versus umeclidinium and salmeterol, respectively (both p < 0.001). Umeclidinium/vilanterol demonstrated consistent improvements in Transition Dyspnoea Index versus both monotherapies at Week 24 (vs umeclidinium: 0.37 [95% CI: 0.06, 0.68], p = 0.018; vs salmeterol: 0.45 [95% CI: 0.15, 0.76], p = 0.004) and all other symptom measures at all time points. Regardless of the clinically important deterioration definition considered, umeclidinium/vilanterol significantly reduced the risk of a first clinically important deterioration compared with umeclidinium (by 16-25% [p < 0.01]) and salmeterol (by 26-41% [p < 0.001]). Safety profiles were similar between treatments., Conclusions: Umeclidinium/vilanterol consistently provides early and sustained improvements in lung function and symptoms and reduces the risk of deterioration/treatment failure versus umeclidinium or salmeterol in symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids. These findings suggest a potential for early use of dual bronchodilators to help optimise therapy in this patient group.

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 (FEV 1 ) 60-90% predicted and ≥1.5 L, with post-salbutamol FEV 1 increase ≥15%. The co-primary objectives were peak and average FEV 1 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 β 2 -agonist systemic adverse effects., (Copyright © 2019. Published by Elsevier Ltd.)

Inflammation, structural, and functional abnormalities within the airways are key features of asthma. Although these processes are well documented, their expression varies across the heterogeneous spectrum of asthma. Type 2 inflammatory responses are characterized by increased levels of eosinophils, FeNO, and type 2 cytokines in blood and/or airways. Presently, type 2 asthma is the best-defined endotype, typically found in patients with allergic asthma, but surprisingly also in nonallergic patients with (severe) asthma. The etiology of asthma with non-type 2 inflammation is less clear. During the past decade, targeted therapies, including biologicals and small molecules, have been increasingly integrated into treatment strategies of severe asthma. These treatments block specific inflammatory pathways or single mediators. Single or composite biomarkers help to identify patients who will benefit from these treatments. So far, only a few inflammatory biomarkers have been validated for clinical application. The European Academy of Allergy & Clinical Immunology Task Force on Biomarkers in Asthma was initiated to review different biomarker sampling methods and to investigate clinical applicability of new and existing inflammatory biomarkers (point-of-care) to support diagnosis, targeted treatment, and monitoring of severe asthma. Subsequently, we discuss existing and novel targeted therapies for asthma as well as applicable biomarkers., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

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 serious outcomes such as hospitalisation or death. Moreover, severe exacerbations are associated with substantial 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 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 task force., Competing Interests: Conflict of interest: A. Bourdin reports personal and institutional fees for advisory board work from AstraZeneca, Novartis, GSK, Boehringher Ingelheim, Chiesi, Actelion, Pfizer and Teva, outside the submitted work. Conflict of interest: L. Bjermer has nothing to disclose. Conflict of interest: C. Brightling reports grants and personal fees for consultancy from GlaxoSmithKline, AstraZeneca/Medimmune, Novartis, Chiesi, Roche/Genentech and Boehringer Inglheim, personal fees for consultancy from Vectura, Theravance, PreP, Gilead, Sanofi/Regeneron, Teva, Gossamer and 4DPharma, grants from Pfizer and Mologic, outside the submitted work. Conflict of interest: G.G. Brusselle reports personal fees for advisory board work and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva, personal fees for advisory board work from Sanofi, outside the submitted work. Conflict of interest: P. Chanez reports research grants and personal fees for consultancy, advisory board work and lectures from ALK, Almirall, Boehringer Ingelheim, GSK, AstraZeneca, Novartis, TEVA and Chiesi, grants from AMU, outside the submitted work. Conflict of interest: K.F. Chung has received honoraria for participating in advisory board meetings of GSK, AZ, Novartis, Merck, BI and TEVA regarding treatments for asthma and COPD, and has also been renumerated for speaking engagements. Conflict of interest: A. Custovic reports personal fees for consultancy from Novartis, Regeneron/Sanofi, Boehringer Ingelheim and Philips, personal fees for lectures from Thermo Fisher Scientific and Novartis, outside the submitted work. Conflict of interest: Z. Diamant reports personal fees from AstraZeneca and Sanofi-Genzyme, during the conduct of the study; personal fees from Aquilon, ALK, Boehringer Ingelheim, Gilead, Hal Allergy and MSD, outside the submitted work; and in addiction to academic affiliations, also works at a phase I/II unit performing clinical studies for different biotech and pharma companies. Conflict of interest: S. Diver has nothing to disclose. Conflict of interest: R. 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; in addition, is a co-founder and current consultant, and has shares in, Synairgen, a University of Southampton spin out company. Conflict of interest: D. Hamerlijnck has nothing to disclose. Conflict of interest: I. Horvath reports personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GSK, Novartis, CSL-Behring and Roche, outside the submitted work. Conflict of interest: S.L. Johnston reports personal fees for advisory board work from Therapeutic Frontiers and Virtus Respiratory Research, personal fees for consultancy from Myelo Therapeutics GmbH, Concert Pharmaceuticals, Bayer, Gerson Lehrman Group, resTORbio, Bioforce, Materia Medical Holdings, PrepBio Pharma, Pulmotect, Virion Health and Lallemand Pharma, personal and insititutional fees for consultancy from Synairgen, Novartis, Boehringer Ingelheim and Chiesi; and has received personal fees for the following patents planned, issued or pending: transgenic animal models of HRV with human ICAM-1 sequences (UK patent application number 02 167 29.4, and international patent application number PCT/EP2003/007939); anti-virus therapy for respiratory diseases (UK patent application number GB 0405634.7); interferon-beta for anti-virus therapy for respiratory diseases (international patent application number PCT/GB05/50031); interferon lambda therapy for the treatment of respiratory disease (UK patent application number 6779645.9, granted); induction of cross-reactive cellular response against rhinovirus antigens (European patent number 13305152), outside the submitted work. Conflict of interest: F. Kanniess reports personal fees for lectures and advisory board work from AstraZeneca, Novartis, Mundipharma and TEVA, outside the submitted work. Conflict of interest: N. Papadopoulos reports personal fees for advisory board work and lectures from Novartis, Nutricia, HAL, personal fees from Menarini/Faes Farma and Mylan/Meda, personal fees for lectures from Sanofi, Biomay, MSD, ASIT Biotech and Boehringer Ingelheim, personal fees for advisory board work from AstraZeneca and GSK, grants from Gerolymatos International SA and Capricare, outside the submitted work. Conflict of interest: A. Papi reports grants, personal fees for lectures, advisory board work and consultancy, and travel expenses reimbursement from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline and Teva, personal fees for advisory board work and consultancy from Sanofi/Regeneron, personal fees for lectures and travel expenses reimbursement from Zambon and Novartis, personal fees for lectures, advisory board work and consultancy, and travel expenses reimbursement from Mundipharma, personal fees for lectures and advisory board work, and travel expenses reimbursement Almirall, grants, personal fees for lectures and travel expenses reimbursement from Menarini, grants from Fondazione Maugeri, grants from Fondazione Chiesi Farmaceutici, outside the submitted work. Conflict of interest: R.J. Russell has nothing to disclose. Conflict of interest: D. Ryan reports personal fees for advisory board work from GSK and Trudell Medical, personal fees for advisory board work and lectures from AZ, personal fees for lectures from Mylan and Chiesi, personal fees for consultancy from Optimum Patient Care, outside the submitted work. Conflict of interest: K. Samitas has nothing to disclose. Conflict of interest: T. Tonia acts as ERS methodologist. Conflict of interest: E. Zervas reports personal fees consultancy and lectures from Astra, Bristol-Myers Squibb, Chiesi, GSK, Elpen, Merck, MSD, Novartis, Menarini and Pfizer, non-financial support for travel, accommodation and meeting expenses from Astra, Bristol-Myers Squibb, Galenica, Chiesi, Elpen, Novartis, Menarini and Roche, outside the submitted work. Conflict of interest: M. Gaga reports grants and personal fees from AZ, grants from BI, Elpen, Novartis and Menarini, personal fees from BMS, MSD, Chiesi and Pharmaten, outside the submitted work., (Copyright ©ERS 2019.)

Background: In all societies, the burden and cost of allergic and chronic respiratory diseases are increasing rapidly. Most economies are struggling to deliver modern health care effectively. There is a need to support the transformation of the health care system into integrated care with organizational health literacy., Main Body: As an example for chronic disease care, MASK (Mobile Airways Sentinel NetworK), a new project of the ARIA (Allergic Rhinitis and its Impact on Asthma) initiative, and POLLAR (Impact of Air POLLution on Asthma and Rhinitis, EIT Health), in collaboration with professional and patient organizations in the field of allergy and airway diseases, are proposing real-life ICPs centred around the patient with rhinitis, and using mHealth to monitor environmental exposure. Three aspects of care pathways are being developed: (i) Patient participation, health literacy and self-care through technology-assisted "patient activation", (ii) Implementation of care pathways by pharmacists and (iii) Next-generation guidelines assessing the recommendations of GRADE guidelines in rhinitis and asthma using real-world evidence (RWE) obtained through mobile technology. The EU and global political agendas are of great importance in supporting the digital transformation of health and care, and MASK has been recognized by DG Santé as a Good Practice in the field of digitally-enabled, integrated, person-centred care., Conclusion: In 20 years, ARIA has considerably evolved from the first multimorbidity guideline in respiratory diseases to the digital transformation of health and care with a strong political involvement., Competing Interests: Competing interestsDr. Ansotegui reports personal fees from Mundipharma, Roxall, Sanofi, MSD, Faes Farma, Hikma, UCB, Astra Zeneca, outside the submitted work. Dr. Bosnic-Anticevich reports grants from TEVA, personal fees from TEVA, Boehringer Ingelheim, AstraZeneca, Sanofi, Mylan, outside the submitted work. Dr. Bousquet reports personal fees and others from Chiesi, Cipla, Hikma, Menarini, Mundipharma, Mylan, Novartis, Sanofi-Aventis, Takeda, Teva, Uriach, others from Kyomed, outside the submitted work. Dr. Boulet reports and Disclosure of potential conflicts of interest—last 3 years. Research grants for participation to multicentre studies, AstraZeneca, Boston Scientific, GlaxoSmithKline, Hoffman La Roche, Novartis, Ono Pharma, Sanofi, Takeda. Support for research projects introduced by the investigator AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck, Takeda. Consulting and advisory boards Astra Zeneca, Novartis, Methapharm. Royalties Co-author of “Up-To-Date” (occupational asthma). Nonprofit grants for production of educational materials AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck Frosst, Novartis. Conference fees AstraZeneca, GlaxoSmithKline, Merck, Novartis. Support for participation in conferences and meetings Novartis, Takeda. Other participations Past president and Member of the Canadian Thoracic Society Respiratory Guidelines Committee; Chair of the Board of Directors of the Global Initiative for Asthma (GINA). Chair of Global Initiative for Asthma (GINA) Guidelines Dissemination and Implementation Committee; Laval University Chair on Knowledge Transfer, Prevention and Education in Respiratory and Cardiovascular Health; Member of scientific committees for the American College of Chest Physicians, American Thoracic Society, European Respiratory Society and the World Allergy Organization; 1st Vice-President of the Global Asthma Organization “InterAsma”. Dr. Casale reports grants and non-financial support from Stallergenes, outside the submitted work. Dr. Cruz reports grants and personal fees from GlaxoSmithKline, personal fees from Boehrinher Ingelheim, AstraZeneca, Novartis, Merk, Sharp & Dohme, MEDA Pharma, EUROFARMA, Sanofi Aventis, outside the submitted work. Dr. Ebisawa reports personal fees from DBV Technologies, Mylan EPD maruho, Shionogi & CO., Ltd., Kyorin Pharmaceutical Co., Ltd., Thermofisher Diagnostics, Pfizer, Beyer, Nippon Chemifar, Takeda Pharmaceutical Co., Ltd., MSD, outside the submitted work. Dr. Ivancevich reports personal fees from Euro Farma Argentina, Faes Farma, non-financial support from Laboratorios Casasco, outside the submitted work. Dr. Haahtela reports personal fees from Mundipharma, Novartis, and Orion Pharma, outside the submitted work. Dr. Klimek reports grants and personal fees from ALK Abelló, Denmark, Novartis, Switzerland, Allergopharma, Germany, Bionorica, Germany, GSK, Great Britain, Lofarma, Italy, personal fees from MEDA, Sweden, Boehringer Ingelheim, Germany, grants from Biomay, Austria, HAL, Netherlands, LETI, Spain, Roxall, Germany, Bencard, Great Britain, outside the submitted work. V.KV has received payment for consultancy from GSK and for lectures from StallergensGreer, Berlin-CHemie and sponsorship from MYLAN for in the following professional training: ARIA masterclass in allergic rhinitis participation. Dr. Larenas Linnemann reports personal fees from GSK, Astrazeneca, MEDA, Boehringer Ingelheim, Novartis, Grunenthal, UCB, Amstrong, Siegfried, DBV Technologies, MSD, Pfizer., grants from Sanofi, Astrazeneca, Novartis, UCB, GSK, TEVA, Chiesi, Boehringer Ingelheim, outside the submitted work. Dr. Mösges reports personal fees from ALK, grants from ASIT biotech, Leti, BitopAG, Hulka, Ursapharm, Optima; personal fees from allergopharma, Nuvo, Meda, Friulchem, Hexal, Servier, Bayer, Johnson & Johnson, Klosterfrau, GSK, MSD, FAES, Stada, UCB, Allergy Therapeutics; grants and personal fees from Bencard, Stallergenes; grants, personal fees and non-financial support from Lofarma; non-financial support from Roxall, Atmos, Bionorica, Otonomy, Ferrero; personal fees and non-financial support from Novartis; Dr. Okamoto reports personal fees from Eizai Co., Ltd., Shionogi Co., Ltd., Torii Co., Ltd., GSK, MSD, Kyowa Co., Ltd., grants and personal fees from Kyorin Co., Ltd., Tiho Co., Ltd., grants from Yakuruto Co., Ltd., Yamada Bee Farm, outside the submitted work. Dr. Papadopoulos reports grants from Gerolymatos, personal fees from Hal Allergy B.V., Novartis Pharma AG, Menarini, Hal Allergy B.V., outside the submitted work. Dr. Pépin reports grants from AIR LIQUIDE FOUNDATION, AGIR à dom, ASTRA ZENECA, FISHER & PAYKEL, MUTUALIA, PHILIPS, RESMED, VITALAIRE, other from AGIR à dom, ASTRA ZENECA, BOEHRINGER INGELHEIM, JAZZ PHARMACEUTICAL, NIGHT BALANCE, PHILIPS, RESMED, SEFAM, outside the submitted work. Dr. Pfaar reports grants and personal fees from ALK-Abelló, Allergopharma Stallergenes Greer, HAL Allergy Holding B.V./HAL Allergie GmbH, Bencard Allergie GmbH/Allergy Therapeutics, Lofarma, grants from Biomay, ASIT Biotech Tools S.A, Laboratorios LETI/LETI Pharma, Anergis S.A., grants from Nuvo, Circassia, Glaxo Smith Kline, personal fees from Novartis Pharma, MEDA Pharma, Mobile Chamber Experts (a GA2LEN Partner), Pohl-Boskamp, Indoor Biotechnologies, grants from, outside the submitted work. Dr. Todo-Bom reports grants and personal fees from Novartis, Mundipharma, GSK Teva Pharma, personal fees from AstraZeneca, grants from Leti, outside the submitted work. Dr. Tsiligianni reports advisory boards from Boehringer Ingelheim and Novartis and a grant from GSK, outside the submitted work. Dr. Wallace reports and Indicates that she is the co-chair of the Joint Task Force on Practice Parameters, a task force composed of 12 members of the American Academy of Allergy, Asthma, and Immunology and the American College of Allergy, Asthma, and Immunology. Dr. Waserman reports other from CSL Behring, Shire, AstraZeneca,Teva, Meda, Merck, outside the submitted work. Dr. Zuberbier reports and Organizational affiliations: Commitee member: WHO-Initiative “Allergic Rhinitis and Its Impact on Asthma” (ARIA). Member of the Board: German Society for Allergy and Clinical Immunology (DGAKI). Head: European Centre for Allergy Research Foundation (ECARF). Secretary General: Global Allergy and Asthma European Network (GA2LEN). Member: Committee on Allergy Diagnosis and Molecular Allergology, World Allergy Organization (WAO).

Rationale: Adults may exhibit characteristics of both asthma and chronic obstructive pulmonary disease (COPD), a situation recently described as asthma-COPD overlap (ACO). There is a paucity of information about ACO in primary care. Objectives: To estimate the prevalence and describe characteristics of individuals with ACO in primary care practices among patients currently diagnosed with asthma, COPD, or both; and to compare the prevalence and characteristics of ACO among the three source populations. Methods: The Respiratory Effectiveness Group conducted a cross-sectional study of individuals ≥40 years old and with ≥2 outpatient primary care visits over a 2-year period in the UK Optimum Patient Care Research Database. Patients were classified into one of three source populations based on diagnostic codes: 1 ) COPD only, 2 ) both asthma and COPD, or 3 ) asthma only. ACO was defined as the presence of all of the following 1 ) age ≥40 years, 2 ) current or former smoking, 3) post-bronchodilator airflow limitation (forced expiratory volume in 1 second/forced vital capacity <0.7), and 4 ) ≥12% and ≥200 ml reversibility in post-bronchodilator forced expiratory volume in 1 second. Results: Among 2,165 individuals (1,015 COPD only, 395 with both asthma and COPD, and 755 asthma only), the overall prevalence of ACO was 20% (95% confidence interval, 18-23%). Patients with ACO had a mean age of 70 years (standard deviation, 11 yr), 60% were men, 73% were former smokers (the rest were current smokers), and 66% were overweight or obese. Comorbid conditions were common in patients with ACO, including diabetes (53%), cardiovascular disease (36%), hypertension (30%), eczema (23%), and rhinitis (21%). The prevalence of ACO was higher in patients with a diagnosis of both asthma and COPD (32%) compared with a diagnosis of COPD only (20%; P  < 0.001) or asthma only (14%; P  < 0.001). Demographic and clinical characteristics of ACO varied across these three source populations. Conclusions: One in five individuals with a diagnosis of COPD, asthma, or both asthma and COPD in primary care settings have ACO based on the Respiratory Effectiveness Group ACO Working group criteria. The prevalence and characteristics of patients with ACO varies across the three source populations.

Background: Blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO) concentration are established biomarkers in asthma, associated particularly with the risk of exacerbations. We evaluated the relationship of BEC and FeNO as complementary and independent biomarkers of severe asthma exacerbations., Methods: This observational study included data from the Optimum Patient Care Research Database. Asthma patients (18-80 years) with valid continuous data for 1 year before FeNO reading, ≥ 1 inhaled corticosteroid prescription, and BEC recorded ≤ 5 years before FeNO reading were separated into cohorts. Categorisation 1 was based on the American Thoracic Society criteria for elevated FeNO concentration (high: ≥ 50 ppb; non-high: < 25 ppb) and BEC (high: ≥ 0.300 × 10 9 cells/L; non-high: < 0.300 × 10 9 cells/L). Categorisation 2 (FeNO concentration, high: ≥ 35 ppb; non-high: < 35 ppb) was based on prior research. Reference groups included patients with neither biomarker raised., Results: In categorisation 1, patients with either high FeNO or high BEC (n = 200) had a numerically greater exacerbation rate (unadjusted rate ratio, 1.31 [95% confidence interval: 0.97, 1.76]) compared with patients in the reference group. Combination of high FeNO and high BEC (n = 27) resulted in a significantly greater exacerbation rate (3.67 [1.49, 9.04]). Similarly, for categorisation 2, when both biomarkers were raised (n = 53), a significantly greater exacerbation rate was observed (1.72 [1.00, 2.93])., Conclusion: The combination of high FeNO and high BEC was associated with significantly increased severe exacerbation rates in the year preceding FeNO reading, suggesting that combining FeNO and BEC measurements in primary care may identify asthma patients at risk of exacerbations., Competing Interests: Competing interestsDP reports grants and/or personal fees from Aerocrine, AKL Research and Development Ltd., Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, the British Lung Foundation, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Merck, Mylan, Mundipharma, Napp, Novartis, Pfizer, Regeneron Pharmaceuticals, the Respiratory Effectiveness Group, Sanofi Genzyme, Skyepharma, Teva, Theravance, the UK National Health Service, Zentiva (Sanofi Generics); non-financial support from Efficacy and Mechanism Evaluation Programme and Health Technology Assessment, outside the submitted work; stock/stock options from AKL Research and Development Ltd.; and owns 74% of the social enterprise Optimum Patient Care Ltd. (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd. (Singapore). SB reports grants and personal fees from TEVA, personal fees from Boehringer Ingelheim, AstraZeneca, Sanofi, and Mylan, outside the submitted work. IP has received speaker’s honoraria for speaking at sponsored meetings from AstraZeneca, Boehringer Ingelheim, Aerocrine, Almirall, Novartis, Teva, Chiesi, and GlaxoSmithKline, and payments for organising educational events from AstraZeneca and Teva. He has received honoraria for attending advisory panels with Genentech, Regeneron, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Teva, Merck, Sanofi, Circassia, Chiesi, and Knopp. He has received sponsorship to attend international scientific meetings from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Teva, and Chiesi. He has received a grant from Chiesi to support a phase 2 clinical trial in Oxford. NR reports grants and personal fees from Boehringer Ingelheim, Novartis, Pfizer and personal fees from Teva, GlaxoSmithKline, AstraZeneca, Chiesi, Mundipharma, Cipla, Sanofi, Sandoz, 3 M, and Zambon. DH reports personal fees and/or non-financial support from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Pfizer, outside the submitted work. LB has nothing to disclose. OU has received grants and/or personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Aerocrine, GlaxoSmithKline, Napp, Mundipharma, Sandoz, Prosonix, Takeda, Zentiva, Edmond Pharma, Cipla, and Pearl Therapeutics. GB reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Sanofi, and Teva, outside the submitted work. SWM reports other from Observational and Pragmatic Research Institute Pte Ltd. (OPRI), outside the submitted work. He was employed by the OPRI at the time the analyses were conducted; OPRI has conducted paid research in respiratory disease on behalf of the following organisations in the past 5 years: Anaxys, AstraZeneca, Boehringer Ingelheim, British Lung Foundation, Chiesi, Circassia (formerly Aerocrine), GlaxoSmithKline, Harvey Walsh, Mapi, Morningside Healthcare, Mundipharma, Mylan (formerly Meda), Napp, Novartis, Orion, Plymouth University, Regeneron, Respiratory Effectiveness Group, Roche, Sanofi, Takeda, Teva, University of East Anglia, and Zentiva (a Sanofi company). SR was an employee of AstraZeneca at the time the analyses were conducted.

In idiopathic pulmonary fibrosis (IPF) structural properties of the extracellular matrix (ECM) are altered and influence cellular responses through cell-matrix interactions. Scaffolds (decellularized tissue) derived from subpleural healthy and IPF lungs were examined regarding biomechanical properties and ECM composition of proteins (the matrisome). Scaffolds were repopulated with healthy fibroblasts cultured under static stretch with heavy isotope amino acids (SILAC), to examine newly synthesized proteins over time. IPF scaffolds were characterized by increased tissue density, stiffness, ultimate force, and differential expressions of matrisome proteins compared to healthy scaffolds. Collagens, proteoglycans, and ECM glycoproteins were increased in IPF scaffolds, however while specific basement membrane (BM) proteins such as laminins and collagen IV were decreased, nidogen-2 was also increased. Findings were confirmed with histology, clearly showing a disorganized BM. Fibroblasts produced scaffold-specific proteins mimicking preexisting scaffold composition, where 11 out of 20 BM proteins were differentially expressed, along with increased periostin and proteoglycans production. We demonstrate how matrisome changes affect fibroblast activity using novel approaches to study temporal differences, where IPF scaffolds support a disorganized BM and upregulation of disease-associated proteins. These matrix-directed cellular responses emphasize the IPF matrisome and specifically the BM components as important factors for disease progression.

Background: The design of inhaler devices may potentially influence adherence/persistence and outcomes in asthma. Objective: The primary objective was to assess asthma control and any change in the quality of life in patients using an intuitive dry powder inhaler containing fluticasone propionate/salmeterol (AirFluSal ® Forspiro ® ) for the treatment of asthma in everyday practice. Methods: ASSURE was a multicenter, noninterventional, open-label, prospective study in patients with asthma, aged ≥12 years and treated with the Forspiro device in Denmark, Sweden and Norway. Patients' opinions of their asthma control were assessed by the Asthma Control Test (ACT) questionnaire and asthma-related quality of life by the Mini Asthma Quality of Life Questionnaire (miniAQLQ) at baseline and at two follow-up visits (approximately 4-8-week intervals). Results: Of 321 patients enrolled in the study, 299 received at least one dose of fluticasone propionate/salmeterol via the Forspiro device and 204 had evaluable data at the baseline visit and at least one later visit. Patients showed improvements in asthma control and quality of life during the study. The mean sum score of ACT increased from 18.0 (SD 4.5) at visit 1 to 19.9 (4.2) at visit 2 and 20.5 (4.3) at visit 3. Overall, 38.2% of patients improved by the minimal clinically important difference (MCID) of ≥3 points (45.6% among those with a baseline score below 23 [ie, not already well controlled]). The mean score on the miniAQLQ increased from 5.16 (SD 1.24) at visit 1 to 5.58 (SD 1.20) at visit 2 and 5.82 (SD 1.04) at visit 3. Overall, 42.6% of patients improved by the MCID of ≥0.5. Conclusion: This real-life study suggests that treatment with fluticasone propionate/salmeterol via the Forspiro device can improve asthma symptom control and quality of life., Competing Interests: Andreas Søderman is an employee of Sandoz AS. Spencer Jones is an employee of Sandoz International GmbH and holds stock in Novartis. Leif Bjermer reports honoraria from ALK, Airsonette, AstraZeneca, Boehringer, Chiesi, GlaxoSmithKline, Novartis, Teva, outside the submitted work. Olav Kåre Refvem reports personal fees from Boehringer-Ingelheim, outside the submitted work, and is the owner of Lungepraksis AS. The authors report no other conflicts of interest in this work.

Allergic rhinitis (AR) poses a global health problem and can be challenging to treat. Many of the current symptomatic treatments for AR have been available for decades, yet there has been little improvement in patient quality of life or symptom burden over the years. In this review, we ask why this might be and explore the pathophysiological gaps that exist within the various AR treatment classes. We focus on the benefits and drawbacks of different treatment options and delivery routes for AR treatments and consider how, given what is known about AR pathophysiology and symptomatology, patients may be offered more effective treatment options for rapid, effective, and sustained AR control. In particular, we consider how a new AR preparation, MP-AzeFlu (Dymista ® , Meda, Sweden), comprising a formulation of an intranasal antihistamine (azelastine hydrochloride), an intranasal corticosteroid (fluticasone propionate), and excipients delivered in a single spray, may offer benefits over and above single and multiple AR therapy options. We review the evidence in support of this treatment across the spectrum of AR disease. The concept of AR control is also reviewed within the context of new European Union and Contre les Maladies Chroniques pour un VIeillissement Actif-Allergic Rhinitis and its Impact on Asthma initiatives., Competing Interests: LB has received honoraria to participate in or give lectures for ALK, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Teva. MW, MH, and MCW declare that they have no competing interests.

Improving the lung function after experimental allergen challenge by blocking of mast cell (MC) mediators and the capability of MC mediators (including histamine, prostaglandin (PG) D2, and leukotriene (LT) C4) in induction of mucosal edema, bronchoconstriction, and mucus secretion provide evidence that MCs play a key role in pathophysiology of asthma. In asthma, the number of MCs increases in the airways and infiltration of MCs in a variety of anatomical sites including the epithelium, the submucosal glands, and the smooth muscle bundles occurs. MC localization within the ASM is accompanied with the hypertrophy and hyperplasia of the layer, and smooth muscle dysfunction that is mainly observed in forms of bronchial hyperresponsiveness, and variable airflow obstruction. Owing to the expression of a wide range of surface receptors and releasing various cytoplasmic mediators, MCs orchestrate the pathologic events of the disease. MC-released preformed mediators including chymase, tryptase, and histamine and de novo synthesized mediators such as PGD2, LTC4, and LTE4 in addition of cytokines mainly TGFβ1, TSLP, IL-33, IL-4, and IL-13 participate in pathogenesis of asthma. The release of MC mediators and MC/airway cell interactions during remodeling phase of asthma results in persistent cellular and structural changes in the airway wall mainly epithelial cell shedding, goblet cell hyperplasia, hypertrophy of ASM bundles, fibrosis in subepithelial region, abnormal deposition of extracellular matrix (ECM), increased tissue vascularity, and basement membrane thickening. We will review the current knowledge regarding the participation of MCs in each stage of asthma pathophysiology including the releasing mediators and their mechanism of action, expression of receptors by which they respond to stimuli, and finally the pharmaceutical products designed based on the strategy of blocking MC activation and mediator release.

Background: In atopic asthma, chronic Th2-biased inflammation is associated with an increased risk of pneumococcal infection. The anionic phosphoglycoprotein osteopontin (OPN) is highly expressed in asthma and has been ascribed several roles during inflammation. This study aimed to investigate whether OPN affects inflammation and vulnerability to pneumococcal infection in atopic asthma., Methods: House dust mite (HDM) extract was used to induce allergic airway inflammation in both wild-type (Spp1 +/+ ) and OPN knockout (Spp1 -/- ) C57BL/6J mice, and the airway was then infected with Streptococcus pneumoniae. Parameters reflecting inflammation, tissue injury, and bacterial burden were measured. In addition, samples from humans with allergic asthma were analyzed., Results: Both allergen challenge in individuals with allergic asthma and the intranasal instillation of HDM in mice resulted in increased OPN levels in bronchoalveolar lavage fluid (BALF). More immune cells (including alveolar macrophages, neutrophils, eosinophils, and lymphocytes) and higher levels of proinflammatory cytokines were found in Spp1 -/- mice than in Spp1 +/+ mice. Moreover, OPN-deficient mice exhibited increased levels of markers reflecting tissue injury. Upon infection with S. pneumoniae, Spp1 +/+ mice with allergic airway inflammation had a significantly lower bacterial burden in both BALF and lung tissue than did Spp1 -/- mice. Furthermore, Spp1 -/- mice had higher levels of cytokines and immune cells in BALF than did Spp1 +/+ mice., Conclusion: OPN reduces inflammation, decreases tissue injury, and reduces bacterial loads during concurrent pneumococcal infection and allergic airway inflammation in a murine model. These findings suggest that OPN significantly affects vulnerability to pneumococcal infection in atopic asthma., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Evidence from observational comparative effectiveness research (CER) is ranked below that from randomized controlled trials in traditional evidence hierarchies. However, asthma observational CER studies represent an important complementary evidence source answering different research questions and are particularly valuable in guiding clinical decision making in real-life patient and practice settings. Tools are required to assist in quality appraisal of observational CER to enable identification of and confidence in high-quality CER evidence to inform guideline development., Methods: The REal Life EVidence AssessmeNt Tool (RELEVANT) was developed through a step-wise approach. We conducted an iterative refinement of the tool based on Task Force member expertise and feedback from pilot testing the tool until reaching adequate inter-rater agreement percentages. Two distinct pilots were conducted-the first involving six members of the Respiratory Effectiveness Group (REG) and European Academy of Allergy and Clinical Immunology (EAACI) joint Task Force for quality appraisal of observational asthma CER; the second involving 22 members of REG and EAACI membership. The final tool consists of 21 quality sub-items distributed across seven methodology domains: Background, Design, Measures, Analysis, Results, Discussion/Interpretation, and Conflict of Interest. Eleven of these sub-items are considered critical and named "primary sub-items"., Results: Following the second pilot, RELEVANT showed inter-rater agreement ≥ 70% for 94% of all primary and 93% for all secondary sub-items tested across three rater groups. For observational CER to be classified as sufficiently high quality for future guideline consideration, all RELEVANT primary sub-items must be fulfilled. The ten secondary sub-items further qualify the relative strengths and weaknesses of the published CER evidence. RELEVANT could also be applicable to general quality appraisal of observational CER across other medical specialties., Conclusions: RELEVANT is the first quality checklist to assist in the appraisal of published observational CER developed through iterative feedback derived from pilot implementation and inter-rater agreement evaluation. Developed for a REG-EAACI Task Force quality appraisal of recent asthma CER, RELEVANT also has wider utility to support appraisal of CER literature in general (including pre-publication). It may also assist in manuscript development and in educating relevant stakeholders about key quality markers in observational CER., Competing Interests: JC -discloses prior Respiratory Effectiveness Group funding related to this study and has no other conflicts of interests to declare in association with this manuscript. RP has- no conflicts of interest to disclose. NP reports grants from Gerolymatos, personal fees from Hal Allergy B.V., personal fees from Novartis Pharma AG, personal fees from Menarini, personal fees from Hal Allergy B.V., personal fees from Mylan, outside the submitted work. JK has research funding from the U.S. National Institutes of Health and the U.S. Patient Centered Outcomes Research Institute paid to the University for investigator-initiated research. JK does not serve on advisory boards or have other potential conflicts of interest. GB has, within the last 5 years, received honoraria for lectures from AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva; he is a member of advisory boards for AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, Sanofi/Regeneron and Teva. AC and RP have no conflicts of interest to declare in relation to these papers. LB reports no perceived COI. MT nor any member of his close family has any shares in pharmaceutical companies. In the last 3 years he has received speaker’s honoraria for speaking at sponsored meetings or satellite symposia at conferences from the following companies marketing respiratory and allergy products: Aerocrine, GSK, Novartis. He has received honoraria for attending advisory panels with; Aerocrine, Boehringer Inglehiem, GSK, MSD, Novartis, Pfizer. He is a recent a member of the BTS SIGN Asthma guideline steering group and the NICE Asthma Diagnosis and Monitoring guideline development group. EVG reports grants and personal fees from ALK ABELLO, grants and personal fees from Bayer, grants and personal fees from BMS, grants and personal fees from GlaxoSmithKline, grants and personal fees from Merck Sharp and Dohme, personal fees from PELyon, outside the submitted work. MB reports grants from GlaxoSmithKline, TEVA, Chiesi, Genentech, outside the submitted work. JQ’s research group has received funding from The Health Foundation, MRC, Wellcome Trust, BLF, GSK, Insmed, AZ, Bayer and BI for other projects, none of which relate to this work. Dr Quint has received funds from AZ, GSK, Chiesi, Teva and BI for Advisory board participation or travel. DP has board membership with Aerocrine, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Mundipharma, Napp, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals; consultancy agreements with Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Napp, Novartis, Pfizer, Teva Pharmaceuticals, Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from Aerocrine, AKL Research and Development Ltd, AstraZeneca, Boehringer Ingelheim, British Lung Foundation, Chiesi, Mylan, Mundipharma, Napp, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, UK National Health Service, Zentiva (Sanofi Generics); payment for lectures/speaking engagements from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Merck, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, Skyepharma, Teva Pharmaceuticals; payment for manuscript preparation from Mundipharma, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from Aerocrine, AstraZeneca, Boehringer Ingelheim, Mundipharma, Napp, Novartis, Teva Pharmaceuticals; funding for patient enrolment or completion of research from Chiesi, Novartis, Teva Pharmaceuticals, Zentiva (Sanofi Generics); stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); and is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation programme, and Health Technology Assessment. NR reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from Novartis, personal fees from Teva, personal fees from GSK, personal fees from AstraZeneca, personal fees from Chiesi, personal fees from Mundipharma, personal fees from Cipla, grants and personal fees from Pfizer, personal fees from Sanofi, personal fees from Sandoz, personal fees from 3 M, personal fees from Zambon, outside the submitted work.

Introduction: A Task Force was commissioned jointly by the European Academy of Allergy and Clinical Immunology (EAACI) and the Respiratory Effectiveness Group (REG) to develop a quality assessment tool for real-life observational research to identify high-quality real-life asthma studies that could be considered within future guideline development., Methods: The resulting REal Life EVidence AssessmeNt Tool (RELEVANT) was achieved through an extensive analysis of existing initiatives in this area. The first version was piloted among 9 raters across 6 articles; the revised, interim, version underwent extensive testing by 22 reviewers from the EAACI membership and REG collaborator group, leading to further revisions and tool finalisation. RELEVANT was validated through an analysis of real-life effectiveness studies identified via systematic review of Medline and Embase databases and relating to topics for which real-life studies may offer valuable evidence complementary to that from randomised controlled trials. The topics were selected through a vote among Task Force members and related to the influence of adherence, smoking, inhaler device and particle size on asthma treatment effectiveness., Results: Although highlighting a general lack of high-quality real-life effectiveness observational research on these clinically important topics, the analysis provided insights into how identified observational studies might inform asthma guidelines developers and clinicians. Overall, RELEVANT appeared reliable and easy to use by expert reviewers., Conclusions: Using such quality appraisal tools is mandatory to assess whether specific observational real-life effectiveness studies can be used to inform guideline development and/or decision-making in clinical practice., Competing Interests: JC discloses prior Respiratory Effectiveness Group funding related to this study, but has no other conflicts of interests associated with this paper. NP reports grants from Gerolymatos, personal fees from Hal Allergy B.V., personal fees from Novartis Pharma AG, personal fees from Menarini, personal fees from Hal Allergy B.V., personal fees from Mylan, outside the submitted work. JK has research funding from the U.S. National Institutes of Health and the U.S. Patient Centered Outcomes Research Institute paid to the University for investigator-initiated research. JB does not serve on advisory boards or have other potential conflicts of interest. GB has, within the last 5 years, received honoraria for lectures from AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva; he is a member of advisory boards for AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, Sanofi/Regeneron and Teva. AC and GChave no conflicts of interest to declare in relation to this paper. LB has no perceived COI. MT nor any member of his close family has any shares in pharmaceutical companies. In the last 3 years he has received speaker’s honoraria for speaking at sponsored meetings or satellite symposia at conferences from the following companies marketing respiratory and allergy products: Aerocrine, GSK, Novartis. He has received honoraria for attending advisory panels with; Aerocrine, Boehringer Inglehiem, GSK, MSD, Novartis, Pfizer. He is a recent a member of the BTS SIGN Asthma guideline steering group and the NICE Asthma Diagnosis and Monitoring guideline development group. EVG reports grants and personal fees from ALK ABELLO, grants and personal fees from Bayer, grants and personal fees from BMS, grants and personal fees from GlaxoSmithKline, grants and personal fees from Merck Sharp and Dohme, personal fees from PELyon, outside the submitted work. MB reports grants from GlaxoSmithKline, TEVA, Chiesi, Genentech, outside the submitted work. JQ’sresearch group has received funding from The Health Foundation, MRC, Wellcome Trust, BLF, GSK, Insmed, AZ, Bayer and BI for other projects, none of which relate to this work. Dr Quint has received funds from AZ, GSK, Chiesi, Teva and BI for Advisory board participation or travel. DP has board membership with Aerocrine, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Mundipharma, Napp, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals; consultancy agreements with Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Napp, Novartis, Pfizer, Teva Pharmaceuticals, Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from Aerocrine, AKL Research and Development Ltd, AstraZeneca, Boehringer Ingelheim, British Lung Foundation, Chiesi, Mylan, Mundipharma, Napp, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, UK National Health Service, Zentiva (Sanofi Generics); payment for lectures/speaking engagements from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Merck, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, Skyepharma, Teva Pharmaceuticals; payment for manuscript preparation from Mundipharma, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from Aerocrine, AstraZeneca, Boehringer Ingelheim, Mundipharma, Napp, Novartis, Teva Pharmaceuticals; funding for patient enrolment or completion of research from Chiesi, Novartis, Teva Pharmaceuticals, Zentiva (Sanofi Generics); stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); and is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation programme, and Health Technology Assessment. NR - Dr. Roche reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from Novartis, personal fees from Teva, personal fees from GSK, personal fees from AstraZeneca, personal fees from Chiesi, personal fees from Mundipharma, personal fees from Cipla, grants and personal fees from Pfizer, personal fees from Sanofi, personal fees from Sandoz, personal fees from 3 M, personal fees from Zambon, outside the submitted work. The authors declare that they have no competing interests

Chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), together with their comorbidities, bear a significant burden on public health. Increased appreciation of molecular networks underlying inflammatory airway disease needs to be translated into new therapies for distinct phenotypes not controlled by current treatment regimens. On the other hand, development of new safe and effective therapies for such respiratory diseases is an arduous and expensive process. Antibody-based (biological) therapies are successful in treating certain respiratory conditions not controlled by standard therapies such as severe allergic and refractory eosinophilic severe asthma, while in other inflammatory respiratory diseases, such as COPD, biologicals are having a more limited impact. Small molecule drug (SMD)-based therapies represent an active field in pharmaceutical research and development. SMDs expand biologicals' therapeutic targets by reaching the intracellular compartment by delivery as either an oral or topically based formulation, offering both convenience and lower costs. Aim of this review was to compare and contrast the distinct pharmacological properties and clinical applications of SMDs- and antibody-based treatment strategies, their limitations and challenges, in order to highlight how they should be integrated for their optimal utilization and to fill the critical gaps in current treatment for these chronic inflammatory respiratory diseases., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Chronic obstructive pulmonary disease (COPD) is a leading cause of death world-wide. Recently, we showed that COPD is associated with gene polymorphisms in SUMF1, a master regulator of sulfatases. Sulfatases are involved in extracellular matrix remodeling and activated by SUMF1, but their role in the lung is poorly described. We aimed to examine how sulfatases are affected in the airways of patients with COPD compared to ever smokers and never smokers. We observed that mRNA expression of the sulfatases GALNS, GNS and IDS was increased, while protein expression of many sulfatases was decreased in COPD fibroblasts. Several sulfatases, including GALNS, IDS, and SGSH, showed increased activity in COPD fibroblasts. Examination of different sulfatases by immunofluorescence showed that IDS, ARSB, GNS and SGSH in fibroblasts were localized to sites other than their reported destination. Using a master panel from different organs, RNA expression of all sulfatases could be observed in lung tissue. Additionally, immunohistochemistry on lung biopsies indicated differing expression of sulfatases in COPD patients. In conclusion, mRNA, protein expression, sulfatase activity levels, and localization of sulfatases are altered in lung fibroblasts and lung tissue from COPD patients and may be mechanistically important in COPD pathogenesis. This could contribute to the understanding of the disease mechanism in COPD and in the long run, to lead to more individualized therapies.

Background: Allergen avoidance is important in allergic asthma management. Nocturnal treatment with Temperature-controlled Laminar Airflow (TLA; Airsonett ® ) has been shown to provide significant reduction of exposure to allergens in the breathing zone, leading to long-term reduction in airway inflammation and improvement in quality of life. Allergic asthma patients uncontrolled on GINA step 4 were found to benefit the most. A frequently asked question from clinicians and funders is related to time to onset (TTO) of improvements for patients using TLA., Methods: Asthma Quality of Life Questionnaire (AQLQ) scores were collected in a previous study. TTO of improvements in Quality of Life was analysed for difference (TLA-placebo) in Area-under-Curve using backwards deletion from 12, 9, 6, 3 down to 1 month for the AQLQ total score, the four individual domains and specifically the sleep question., Results: Patients with uncontrolled asthma on GINA step 4 (n = 87)) reported a statistically significant and clinically relevant (≥0.5 point) improvement in total AQLQ score (0.57; p = 0.009) after 3 months treatment for TLA over placebo. The shortest TTO was within 1 month for the environmental domain (0.68; p = 0.016) and the sleep question (0.771; p = 0.037). TTO for the emotional and symptom domains was 3 months (0.66; p = 0.020 and 0.64; p = 0.014 respectively) and for the activity domain 6 months (0.47; p = 0.036)., Conclusion: Nocturnal avoidance of allergens using TLA provided a statistically significant and clinically relevant improvement in total AQLQ score within 3 months in patients in the GINA 4 + ACT<18 group. Questions related to sleep quality may provide the first signal of response already within a month after commencing treatment., (Copyright © 2018. Published by Elsevier Ltd.)

There are three main types of inhalers, dry powder inhalers (DPI, single and multidose), metered dose inhalers (pMDI, spray, suspension and solution), and soft mist (SMI). There are major differences in inhalation technique and handling of the different inhaler types. Different inhalers are well suited for different patients and the choice of inhaler may be crucial for the treatment outcome. It is frequently observed that patients have poor inhaler technique and the use of different inhalers, in particular inhaler types, in the same patient increases the risk of handling errors. Careful instructions and follow up on inhaler technique at every visit to the health care center is of utmost importance. In treatment failure, change of inhaler may be considered before change of drugs or dosing. Change of inhaler as a result of a telephone prescriptions is unacceptable and must not happen.

Rationale: In symptomatic patients with COPD, the decision whether to initiate maintenance treatment with a single agent or a combination of long-acting bronchodilators remains unclear., Objective: To investigate whether baseline symptomatic status influences response to tiotropium/olodaterol treatment., Materials and Methods: Post hoc analysis of the randomized OTEMTO ® studies (NCT01964352; NCT02006732), in which patients with moderate-to-severe COPD received placebo, tiotropium 5 µg, tiotropium/olodaterol 2.5/5 µg, or tiotropium/olodaterol 5/5 µg once daily for 12 weeks via the Respimat ® inhaler (Boehringer Ingelheim, Ingelheim am Rhein, Germany). Impact of baseline symptomatic status (modified Medical Research Council [mMRC] score) on response to treatment with tiotropium/olodaterol 5/5 µg, tiotropium 5 µg, or placebo at Week 12 was assessed by St George's Respiratory Questionnaire (SGRQ) total score and response rate, transition dyspnea index (TDI) focal score and response rate, and trough forced expiratory volume in 1 second response., Results: Tiotropium/olodaterol improved SGRQ total scores and response rates compared with placebo and tiotropium for patients with baseline mMRC scores 0-1 and ≥2. For tiotropium/olodaterol vs tiotropium, greater improvements were observed for patients with mMRC ≥2 (SGRQ score adjusted mean treatment difference -3.44 [95% CI: -5.43, -1.46]; P =0.0007; SGRQ response rate ORs 2.09 [95% CI: 1.41, 3.10]; P =0.0002). Dyspnea, measured by TDI score, was consistently improved with tiotropium/olodaterol vs placebo for patients with mMRC scores 0-1 and ≥2 (adjusted mean treatment difference 1.63 [95% CI: 1.06, 2.20]; P <0.0001 and 1.60 [95% CI: 1.09, 2.10]; P <0.0001, respectively). In patients with mMRC scores 0-1 and ≥2, tiotropium/olodaterol consistently improved TDI response rate and lung function vs placebo and tiotropium., Conclusions: Patients with COPD with more severe baseline dyspnea appear to derive greater health status benefit with tiotropium/olodaterol compared with tiotropium alone., Competing Interests: Disclosure FJM reports grants from NHLBI during the conduct of the study, grants from National Institutes of Health, personal fees from Continuing Education, Forest Laboratories, GlaxoSmithKline, Nycomed/Takeda, AstraZeneca, Boehringer Ingelheim, Bellerophon Therapeutics (formerly Ikaria), Genentech, Novartis, Pearl, Roche, Sunovion, Theravance, CME Incite, Annenberg Center for Health Sciences at Eisenhower, Integritas, InThought, National Association for Continuing Education, Paradigm Medical Communications, LLC, PeerVoice, UpToDate, Haymarket Communications, Western Society of Allergy and Immunology, ProterixBio (formerly Bioscale), Unity Biotechnology, Concert Pharmaceuticals, Lucid, Methodist Hospital, Columbia University, Prime Healthcare Ltd, WebMD, PeerView Network, California Society of Allergy and Immunology, Chiesi, and Puerto Rico Thoracic Society, and advisory board participation for Janssen. RA reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline, and grants from Pearl Therapeutics. GTF reports consulting and advisory board fees from Boehringer Ingelheim, AstraZeneca, Pearl Therapeutics, Novartis, Forest, Sunovion, and Verona, consulting fees from Receptos, speaker fees from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Pearl Therapeutics, Forest, and Sunovion, and research grants from Boehringer Ingelheim, AstraZeneca, Pearl Therapeutics, Sunovion, Novartis, Theravance, Sanofi, Forest, and GlaxoSmithKline. LB reports advisory board participation or personal fees for lectures from ALK, Airsonett, AstraZeneca, Boehringer Ingelheim, Chiesi, Glaxo SmithKline, Novartis, Takeda, and Teva. FV is an employee of Boehringer Ingelheim. LG was an employee at the time of the conduct of the study, and is currently employed by CSL Behring. DS reports personal fees from Apellis, Cipla, Genentech, Peptinnovate, and Vectura (formerly Skyepharma), and grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Glenmark, Merck, Mundipharma, Novartis, Pfizer, Pulmatrix, Teva, Theravance, and Verona. The authors report no other conflicts of interest in this work.

Purpose of Review: In the past decades, cysteinyl leukotrienes (CysLTs) and prostaglandin D2 have been recognized as key mediators of asthma and comorbid conditions for their potent broncho-active and proinflammatory properties. However, both the development and initial positioning of small molecules targeting these lipid mediators [i.e., leukotriene-synthesis inhibitors, CysLT-antagonists, and chemoattractant receptor homologous molecule on T-helper2-cells (CRTH2) antagonists] experienced drawbacks by lacking adequate biomarkers to define potential responders., Recent Findings: New insights into the mechanisms of airway inflammation in asthma including the interaction of leukotrienes and prostanoids has uncovered potential therapeutic targets. Emerging application of biomarkers in more recent clinical studies helped identify responders to therapies targeting lipid mediators and demonstrated their clinical efficacy in distinct asthma phenotypes and endotypes., Summary: Interest in small molecules targeting lipid mediators in asthma and related conditions is emerging. Several clinical trials evaluating the efficacy and safety of CRTH2 (Prostaglandin D2 receptor 2) antagonists are ongoing. There is an urgent need for sensitive biomarkers to identify responders to such therapies and for monitoring of (long-term) effects. Furthermore, evaluation of effectiveness of combining different agents targeting lipid mediators or combining them with available or emerging biologics may uncover other potential benefits in certain asthma populations warranting future research.

Viral infections predispose to the development of childhood asthma, a disease associated with increased lung mast cells (MCs). This study investigated whether viral lower respiratory tract infections (LRTIs) can already evoke a MC response during childhood. Lung tissue from young children who died following LRTIs were processed for immunohistochemical identification of MCs. Children who died from nonrespiratory causes served as controls. MCs were examined in relation to sensitisation in infant mice exposed to allergen during influenza A infection. Increased numbers of MCs were observed in the alveolar parenchyma of children infected with LRTIs (median (range) 12.5 (0-78) MCs per mm 2 ) compared to controls (0.63 (0-4) MCs per mm 2 , p=0.0005). The alveolar MC expansion was associated with a higher proportion of CD34 + tryptase + progenitors (controls: 0% (0-1%); LRTIs: 0.9% (0-3%) CD34 + MCs (p=0.01)) and an increased expression of the vascular cell adhesion molecule (VCAM)-1 (controls: 0.2 (0.07-0.3); LRTIs: 0.3 (0.02-2) VCAM-1 per mm 2 (p=0.04)). Similarly, infant mice infected with H1N1 alone or together with house dust mite (HDM) developed an increase in alveolar MCs (saline: 0.4 (0.3-0.5); HDM: 0.6 (0.4-0.9); H1N1: 1.4 (0.4-2.0); HDM+H1N1: 2.2 (1.2-4.4) MCs per mm 2 (p<0.0001)). Alveolar MCs continued to increase and remained significantly higher into adulthood when exposed to H1N1+HDM (day 36: 2.2 (1.2-4.4); day 57: 4.6 (1.6-15) MCs per mm 2 (p=0.01)) but not when infected with H1N1 alone. Our data demonstrate that distal viral infections in young children evoke a rapid accumulation of alveolar MCs. Apart from revealing a novel immune response to distal infections, our data may have important implications for the link between viral infections during early childhood and subsequent asthma development., Competing Interests: Conflict of interest: C.K. Andersson has nothing to disclose. Conflict of interest: M. Shikhagaie has nothing to disclose. Conflict of interest: M. Mori has nothing to disclose. Conflict of interest: A. Al-Garawi has nothing to disclose. Conflict of interest: J.L. Reed has nothing to disclose. Conflict of interest: A.A. Humbles is an employee of and holds shares in MedImmune LLC. Conflict of interest: R. Welliver has nothing to disclose. Conflict of interest: T. Mauad has nothing to disclose. Conflict of interest: L. Bjermer has nothing to disclose. Conflict of interest: M. Jordana has nothing to disclose. Conflict of interest: J.S. Erjefält has nothing to disclose.

Background: Patients with asthma and elevated blood eosinophils are at increased risk of severe exacerbations. Management of these patients should consider nonadherence to inhaled corticosteroid (ICS) therapy as a factor for increased exacerbation risk., Objective: The objective of this study was to investigate whether poor adherence to ICS therapy explains the occurrence of asthma exacerbations in patients with elevated blood eosinophil levels., Methods: This historical cohort study identified patients within the Optimum Patient Care Research Database, aged 18 years or more, at Global Initiative for Asthma step 3 or 4, with 2 or more ICS prescriptions during the year before the clinical review. Patient characteristics and adherence (based on prescription refills and patient self-report) for ICS therapy were analyzed for those with elevated (>400 cells/μL) or normal (≤400 cells/μL) blood eosinophils., Results: We studied 7195 patients (66% female, mean age 60 years) with median eosinophil count of 200 cells/μL and found 81% to be not fully adherent to ICS therapy. A total of 1031 patients (14%) had elevated blood eosinophil counts (58% female, mean age 60 years), 83% of whom were not fully adherent to ICS. An increased proportion of adherent patients in the elevated blood eosinophil group had 2 or more exacerbations (14.0% vs 7.2%; P = .003) and uncontrolled asthma (73% vs 60.8%; P = .004) as compared with non-fully adherent patients., Conclusions: Approximately 1 in 7 patients had elevated eosinophils. Adherence to ICS therapy was not associated with decreased exacerbations for these patients. Additional therapy should be considered for these patients, such as biologics, which have been previously shown to improve control in severe uncontrolled eosinophilic asthma., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Remodeling of the extracellular matrix (ECM) is a common feature in lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Here, we applied a sequential tissue extraction strategy to describe disease-specific remodeling of human lung tissue in disease, using end-stages of COPD and IPF. Our strategy was based on quantitative comparison of the disease proteomes, with specific focus on the matrisome, using data-independent acquisition and targeted data analysis (SWATH-MS). Our work provides an in-depth proteomic characterization of human lung tissue during impaired tissue remodeling. In addition, we show important quantitative and qualitative effects of the solubility of matrisome proteins. COPD was characterized by a disease-specific increase in ECM regulators, metalloproteinase inhibitor 3 (TIMP3) and matrix metalloproteinase 28 (MMP-28), whereas for IPF, impairment in cell adhesion proteins, such as collagen VI and laminins, was most prominent. For both diseases, we identified increased levels of proteins involved in the regulation of endopeptidase activity, with several proteins belonging to the serpin family. The established human lung quantitative proteome inventory and the construction of a tissue-specific protein assay library provides a resource for future quantitative proteomic analyses of human lung tissues. SIGNIFICANCE: We present a sequential tissue extraction strategy to determine changes in extractability of matrisome proteins in end-stage COPD and IPF compared to healthy control tissue. Extensive quantitative analysis of the proteome changes of the disease states revealed altered solubility of matrisome proteins involved in ECM regulators and cell-ECM communication. The results highlight disease-specific remodeling mechanisms associated with COPD and IPF., (Copyright © 2018 Elsevier B.V. All rights reserved.)