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Understanding how asthma biomarkers relate to gene expression signatures could help identify drivers of pathogenesis.This post hoc exploratory analysis of the phase II tralokinumab trial MESOS (ClinicalTrials.gov identifier NCT02449473) aimed to profile baseline airway inflammation in patients with moderate-to-severe asthma.The T2 and T17 gene expression signatures, 3-gene mean and 5-gene mean, were calculated through transcriptomic analysis of baseline bronchial brushing samples. Clustering analysis using these signatures identified 3 distinct inflammatory subgroups: T2Fractional exhaled nitric oxide (Feno) levels were highest for T2Feno level may be useful to differentiate patients with T2 or T17 gene expression. Elevated Feno levels are associated with high CST1 expression.

Background: Cough characteristics vary between patients, and this can impact clinical diagnosis and care. The purpose of part two of this state-of-the-art review is to update the American College of Chest Physicians (CHEST) 2006 guideline on global physiology and pathophysiology of cough. Study Design and Methods: A review of the literature was conducted using PubMed and MEDLINE databases from 1951 to 2019 using prespecified search terms. Results: We describe the demographics of typical patients with cough in the clinical setting, including how cough characteristics change across age. We summarize the effect of common clinical conditions impacting cough mechanics and the physical properties of mucus on airway clearance. Interpretation: This is the second of a two-part update to the 2006 CHEST cough guideline; it complements part one on basic phenomenology of cough by providing an extended clinical picture of cough along with the factors that alter cough mechanics and efficiency in patients. A greater understanding of the physiology and pathophysiology of cough will improve clinical management.

The purpose of this state-of-the-art review is to update the American College of Chest Physicians 2006 guideline on global physiology and pathophysiology of cough. A review of the literature was conducted using PubMed and MEDLINE databases from 1951 to 2019 and using prespecified search terms. We describe the basic phenomenology of cough patterns, behaviors, and morphological features. We update the understanding of mechanical and physiological characteristics of cough, adding a contemporary view of the types of cough and their associated behaviors and sensations. New information about acoustic characteristics is presented, and recent insights into cough triggers and the patient cough hypersensitivity phenotype are explored. Lastly, because the clinical assessment of patients largely focuses on the duration rather than morphological features of cough, we review the morphological features of cough that can be measured in the clinic. This is the first of a two-part update to the American College of Chest Physicians 2006 cough guideline; it provides a more global consideration of cough phenomenology, beyond simply the mechanical aspects of a cough. A greater understanding of the typical features of cough, and their variations, may allow a more informed interpretation of cough measurements and the clinical relevance for patients.

Background This is an update of the section on complications that are associated with coughing in the 2006 CHEST cough guidelines that addresses two aims: (1) to systematically identify and thematically categorize the diverse complications of cough by providing a guide for future studies and (2) to identify gaps in the literature for future research. Research Question What are the potential complications that are associated with the act of coughing that have been reported in infants, children, adolescents, and adults? Study Design and Methods A scoping review was performed with the use of PubMed and SCOPUS databases that were searched from their beginning until September 6, 2019. Results Two hundred forty-seven publications met our inclusion criteria. To these, we added 38 articles from the 2006 complications paper that were not identified in the literature search plus the paper itself for a final total of 286 publications that formed the basis of this review. Since 2006, three new categories of complications have been reported: ear, nose and throat; disease transmission; and laboratory testing. Multiple additional complications that fall outside of these three categories have also been identified and included in the following categories: cardiovascular, constitutional symptoms, dermatologic, GI, genitourinary, musculoskeletal, neurologic, ophthalmologic, psychosocial/quality of life, and respiratory. Not previously highlighted is that some of the complications led to serious morbidity that included death, especially in patients with comorbid conditions, and potentially resulted in harm to others when cough resulted in a motor vehicle accident. Interpretation Our work identified a large number of cough complications that we thematically categorized primarily by organ system so that future studies of each system or each complication can be conducted. The gap in the literature that future studies should address is to identify the frequency of the complications and the strength of their association with cough. Only then will one be able to describe the findings in a manner that allows specific recommendations for avoiding these complications. In the meantime, patients with cough should be evaluated and treated according to evidence-based guidelines to mitigate or prevent the myriad of potential complications that are associated with coughing.

Background Chronic cough due to chronic bronchitis (CB) causes significant impairment in quality of life, and effective treatment strategies are needed. We conducted a systematic review on the management of chronic cough due to CB to update the recommendations and suggestions of the American College of Chest Physicians (CHEST) 2006 guideline on this topic. Methods This systematic review asked three questions: (1) What are the clinical features of the history that suggest a patient's cough-phlegm syndrome is due to CB? (2) Can treatment of stable CB improve or eliminate chronic cough? (3) Can therapy that targets chronic cough due to CB prevent or reduce the occurrence of acute CB exacerbations? Studies of adult patients with CB were included and assessed for relevance and quality. Based on the systematic review, guideline suggestions were developed and voted on by using the CHEST organization methodology. Results The search strategy used an assortment of descriptors and assessments to identify studies of chronic cough due to CB. Conclusions The evidence supporting the management of chronic cough due to CB is limited overall and of low quality. This article provides guidance on treatment by presenting suggestions based on the best currently available evidence and identifies gaps in our knowledge and areas for future research.

Background Asthma and non-asthmatic eosinophilic bronchitis (NAEB) are among the commonest causes of chronic cough in adults. We sought to determine the role of non-invasive measurements of airway inflammation, including induced sputum and fractional exhaled nitric oxide, in the evaluation of cough associated with asthma, and what the best treatment is for cough due to asthma or NAEB. Methods We undertook three systematic reviews of randomized controlled trials and observational trials of adults and adolescents > 12 years of age with a chronic cough due to asthma or NAEB. Eligible studies were identified in MEDLINE, CENTRAL, and SCOPUS and assessed for relevance and quality. Guidelines were developed and voted upon using CHEST guideline methodology. Results Of the citations reviewed, 3/1,175, 53/656, and 6/134 were identified as being eligible for inclusion in the three systematic reviews, respectively. In contrast to established guidelines for asthma therapies in general and the inclusion in some guidelines for a role of biomarkers of airway inflammation to guide treatment in severe disease, the evidence of specific benefit related to the use of non-invasive biomarkers in patients with chronic cough due to asthma was weak. The best therapeutic option for cough in asthma or NAEB is inhaled corticosteroids followed by leukotriene receptor antagonism. Conclusions This guideline offers recommendations on the role of non-invasive measurements of airway inflammation and treatment for cough due to asthma or NAEB based on the available literature, and identifies gaps in knowledge and areas for future research.

Background Cough is one of the most common presenting symptoms to general practitioners. The objective of this article is to collate the pediatric components of the CHEST chronic cough guidelines that have recently updated the 2006 guidelines to assist general and specialist medical practitioners in the evaluation and management of children who present with chronic cough. Methods We reviewed all current CHEST Expert Cough Panel's statements and extracted recommendations and suggestions relating to children aged ≤ 14 years with chronic cough (> 4 weeks duration). Additionally, we undertook systematic reviews to update other sections we considered relevant and important. Results The eight recent CHEST guidelines relevant to children, based on systematic reviews, reported some high-quality evidence in the management of chronic cough in children (eg, use of algorithms and management of wet/productive cough using appropriate antibiotics). However, much evidence is still inadequate, particularly in the management of non-specific cough in the community. Conclusions The recommendations and suggestions related to the management of chronic cough in the pediatric age group have been based upon high-quality systematic reviews and are summarized in this article. Compared to the 2006 Cough Guidelines, there is now high-quality evidence for some aspects of the management of chronic cough in children. However, further studies particularly in primary health care are required.

Background Evidence for the diagnosis and management of cough due to acute bronchitis in immunocompetent adult outpatients was reviewed as an update to the 2006 "Chronic Cough Due to Acute Bronchitis: American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines." Methods Acute bronchitis was defined as an acute lower respiratory tract infection manifested predominantly by cough with or without sputum production, lasting no more than 3 weeks with no clinical or any recent radiographic evidence to suggest an alternative explanation. Two clinical population, intervention, comparison, outcome questions were addressed by systematic review in July 2017: (1) the role of investigations beyond the clinical assessment of patients presenting with suspected acute bronchitis, and (2) the efficacy and safety of prescribing medication for cough in acute bronchitis. An updated search was undertaken in May 2018. Results No eligible studies relevant to the first question were identified. For the second question, only one relevant study met eligibility criteria. This study found no difference in number of days with cough between patients treated with an antibiotic or an oral nonsteroidal antiinflammatory agent compared with placebo. Clinical suggestions and research recommendations were made based on the consensus opinion of the CHEST Expert Cough Panel. Conclusions The panelists suggested that no routine investigations be ordered and no routine medications be prescribed in immunocompetent adult outpatients first presenting with cough due to suspected acute bronchitis, until such investigations and treatments have been shown to be safe and effective at making cough less severe or resolve sooner. If the cough due to suspected acute bronchitis persists or worsens, a reassessment and consideration of targeted investigations should be considered.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous inflammatory airway disease. The epithelial-derived IL-33 and its receptor ST2 have been implicated in airway inflammation and infection. We aimed to determine whether astegolimab, a selective ST2 IgG2 monoclonal antibody, reduces exacerbations in COPD.COPD-ST2OP was a single-centre, randomised, double-blinded, placebo-controlled phase 2a trial in moderate-to-very severe COPD. Participants were randomly assigned (1:1) with a web-based system to received 490 mg subcutaneous astegolimab or subcutaneous placebo, every 4 weeks for 44 weeks. The primary endpoint was exacerbation rate assessed for 48 weeks assessed with a negative binomial count model in the intention-to-treat population, with prespecified subgroup analysis by baseline blood eosinophil count. The model was the number of exacerbations over the 48-week treatment period, with treatment group as a covariate. Safety was assessed in the whole study population until week 60. Secondary endpoints included Saint George's Respiratory Questionnaire for COPD (SGRQ-C), FEVThe exacerbation rate at 48 weeks in the intention-to-treat analysis was not significantly different between the astegolimab group (2·18 [95% CI 1·59 to 2·78]) and the placebo group (2·81 [2·05 to 3·58]; rate ratio 0·78 [95% CI 0·53 to 1·14]; p=0·19]). In the prespecified analysis stratifying patients by blood eosinophil count, patients with 170 or fewer cells per μL had 0·69 exacerbations (0·39 to 1·21), whereas those with more than 170 cells per μL had 0·83 exacerbations (0·49 to 1·40). For the secondary outcomes, the mean difference between the SGRQ-C in the astegolimab group versus placebo group was -3·3 (95% CI -6·4 to -0·2; p=0·039), and mean difference in FEVIn patients with moderate-to-very severe COPD, astegolimab did not significantly reduce exacerbation rate, but did improve health status compared with placebo.Funded by Genentech and National Institute for Health Research Biomedical Research Centres.

Background Whether gastroesophageal reflux (GER) or GER disease (GERD) causes chronic cough in children is controversial. Using the Population, Intervention, Comparison, Outcome (PICO) format, we undertook four systematic reviews. For children with chronic cough (> 4-weeks duration) and without underlying lung disease: (1) who do not have gastrointestinal GER symptoms, should empirical treatment for GERD be used? (2) with gastrointestinal GER symptoms, does treatment for GERD resolve the cough? (3) with or without gastrointestinal GER symptoms, what GER-based therapies should be used and for how long? (4) if GERD is suspected as the cause, what investigations and diagnostic criteria best determine GERD as the cause of the cough? Methods We used the CHEST Expert Cough Panel's protocol and American College of Chest Physicians (CHEST) methodological guidelines and GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework. Delphi methodology was used to obtain consensus. Results Few randomized controlled trials addressed the first two questions and none addressed the other two. The single meta-analysis (two randomized controlled trials) showed no significant difference between the groups (any intervention for GERD vs placebo for cough resolution; OR, 1.14; 95% CI, 0.45-2.93; P = .78). Proton pump inhibitors (vs placebo) caused increased serious adverse events. Qualitative data from existing CHEST cough systematic reviews were consistent with two international GERD guidelines. Conclusions The panelists endorsed that: (1) treatment(s) for GERD should not be used when there are no clinical features of GERD; and (2) pediatric GERD guidelines should be used to guide treatment and investigations.

Background The decision to treat a suspected case of pertussis with antibiotics is usually based on a clinical diagnosis rather than waiting for laboratory confirmation. The current guideline focuses on making the clinical diagnosis of pertussis-associated cough in adults and children. Methods The American College of Chest Physicians (CHEST) methodologic guidelines and the Grading of Recommendations, Assessment, Development, and Evaluation framework were used. The Expert Cough Panel based their recommendations on findings from a systematic review that was recently published on the topic; final grading was reached by consensus according to Delphi methodology. The systematic review was carried out to answer the Key Clinical Question: In patients presenting with cough, how can we most accurately diagnose from clinical features alone those who have pertussis-associated cough as opposed to other causes of cough? Results In adults, after pre-specified meta-analysis exclusions, pooled estimates of sensitivity and specificity were generated for only 4 clinical features: paroxysmal cough, post-tussive vomiting, inspiratory whooping, and absence of fever. Both paroxysmal cough and absence of fever had high sensitivity (93.2% [95% CI, 83.2-97.4] and 81.8% [95% CI, 72.2-88.7], respectively) and low specificity (20.6% [95% CI, 14.7-28.1] and 18.8% [95% CI, 8.1-37.9]). Inspiratory whooping and posttussive vomiting had a low sensitivity (32.5% [95% CI, 24.5-41.6] and 29.8% [95% CI, 18.0-45.2]) but high specificity (77.7% [95% CI, 73.1-81.7] and 79.5% [95% CI, 69.4-86.9]). In children, after pre-specified meta-analysis exclusions, pooled estimates of sensitivity and specificity were generated for only 1 clinical feature in children (0-18 years): posttussive vomiting. Posttussive vomiting in children was only moderately sensitive (60.0% [95% CI, 40.3-77.0]) and specific (66.0% [95% CI, 52.5-77.3]). Conclusions In adults with acute (

Background Patients commonly present to primary care services with upper and lower respiratory tract infections, and guidelines to help physicians investigate and treat acute cough due to suspected pneumonia and influenza are needed. Methods A systematic search was carried out with eight patient, intervention, comparison, outcome questions related to acute cough due to suspected pneumonia or influenza. Results There was a lack of randomized controlled trials in the setting of outpatients presenting with acute cough due to suspected pneumonia or influenza who were not hospitalized. Both clinical suggestions and research recommendations were made on the evidence available and CHEST Expert Cough Panel advice. Conclusions For outpatient adults with acute cough due to suspected pneumonia, we suggest the following clinical symptoms and signs are suggestive of pneumonia: cough; dyspnea; pleural pain; sweating, fevers, or shivers; aches and pains; temperature ≥ 38°C; tachypnea; and new and localizing chest examination signs. Those suspected of having pneumonia should undergo chest radiography to improve diagnostic accuracy. Although the measurement of C-reactive protein levels strengthens both the diagnosis and exclusion of pneumonia, there was no added benefit of measuring procalcitonin levels in this setting. We suggest that there is no need for routine microbiological testing. We suggest the use of empiric antibiotics according to local and national guidelines when pneumonia is suspected in settings in which imaging cannot be performed. Where there is no clinical or radiographic evidence of pneumonia, we do not suggest the routine use of antibiotics. There is insufficient evidence to make recommendations for or against specific nonantibiotic, symptomatic therapies. Finally, for outpatient adults with acute cough and suspected influenza, we suggest that initiating antiviral treatment (according to Centers for Disease Control and Prevention advice) within 48 hours of symptoms could be associated with decreased antibiotic use and hospitalization and improved outcomes.

Background: Bronchial Thermoplasty (BT) reduces exacerbations and improves asthma quality of life questionnaire (AQLQ) scores in asthma [1]. Studies have shown reductions in airway smooth muscle (ASM) mass and reticular basement membrane (RBM) thickness after BT, but are limited by small sample size. Aims: To investigate airway remodeling responses to BT, and compare these to clinical outcomes. Methods: Pre- and post-BT data was pooled for 99 patients at 7 centres. ASM mass and RBM thickness were measured on bronchial biopsies, and compared to clinical outcomes. Results: Mean (SD) age was 48.4 years (11.7) and BMI was 29.0 kg/m2 (6.4). Baseline FEV1 was 68.8% predicted (23.1) and blood eosinophils were 0.25x10-9/L (0.26). 59 of 99 patients were taking maintenance oral Prednisolone (mean dose 25.7mg). In response to BT, mean (SD) annual exacerbation rate decreased from 6.4 (5.5) to 1.1 (1.7) (p= Conclusion: ASM mass and RBM thickness reduce rapidly following BT, and effects persist beyond 1 year. The observed improvements in airway remodeling parameters are not related to improvements in clinical outcomes. Other bronchial mucosal changes or mechanisms may play a role in the clinical response to BT. Reference: 1) Castro et al, AJRCCM. 2010;181(2):116-24

Asthma and non-asthmatic eosinophilic bronchitis (NAEB) are among the commonest causes of chronic cough in adults. We sought to determine the role of non-invasive measurements of airway inflammation, including induced sputum and fractional exhaled nitric oxide, in the evaluation of cough associated with asthma, and what the best treatment is for cough due to asthma or NAEB.We undertook three systematic reviews of randomized controlled trials and observational trials of adults and adolescents12 years of age with a chronic cough due to asthma or NAEB. Eligible studies were identified in MEDLINE, CENTRAL, and SCOPUS and assessed for relevance and quality. Guidelines were developed and voted upon using CHEST guideline methodology.Of the citations reviewed, 3/1,175, 53/656, and 6/134 were identified as being eligible for inclusion in the three systematic reviews, respectively. In contrast to established guidelines for asthma therapies in general and the inclusion in some guidelines for a role of biomarkers of airway inflammation to guide treatment in severe disease, the evidence of specific benefit related to the use of non-invasive biomarkers in patients with chronic cough due to asthma was weak. The best therapeutic option for cough in asthma or NAEB is inhaled corticosteroids followed by leukotriene receptor antagonism.This guideline offers recommendations on the role of non-invasive measurements of airway inflammation and treatment for cough due to asthma or NAEB based on the available literature, and identifies gaps in knowledge and areas for future research.

Eosinophilic airway inflammation is observed in 30% to 50% of chronic cough sufferers. It is a common feature of asthma and upper airway cough syndrome, and it is required in the diagnosis of nonasthmatic eosinophilic bronchitis. Our understanding of the mechanisms underlying allergic and nonallergic eosinophilic inflammation have evolved tremendously in the last 2 decades, but the cause of this inflammation in any individual is often uncertain. Inhaled corticosteroids are the mainstay therapy for cough due to asthma or nonasthmatic eosinophilic bronchitis, and response is related to the presence of biomarkers of eosinophilic airway inflammation. In upper airway cough syndrome, nasal topical corticosteroids are beneficial in allergic rhinitis and chronic rhinosinusitis with polyposis. This review will describe the diagnosis, current and possible future treatments, and prognosis of chronic cough in adults with eosinophilic inflammation.

Asthma affects over 300 million people worldwide and is severe in 10% of sufferers. Severe asthma is associated with greater morbidity and mortality particularly as a consequence of frequent exacerbations. Advances in approaches to phenotype the heterogeneity of severe asthma has established the importance of eosinophilic inflammation and emerging new therapies are broadly designed to target T2-mediated eosinophilic inflammation with the aim to reduce exacerbation frequency. Here, we summarize the evidence that eosinophilic asthma is an important pheno(endo)type and identifies a group at risk of exacerbations; that established therapies reduce exacerbations, particularly in eosinophilic severe asthma; and discuss the role of mepolizumab, an IL-5 neutralising monoclonal antibody therapy, in reducing exacerbations in severe eosinophilic asthma compared to established and other emerging therapies.

Summary Background The role of interleukin 13 in airway inflammation and remodelling in asthma is unclear. Tralokinumab is a human monoclonal antibody that neutralises interleukin 13. We aimed to evaluate whether tralokinumab would have an effect on airway eosinophilic infiltration, blood and sputum eosinophil concentrations, eosinophil activation, and airway remodelling. Methods We did a multicentre, double-blind, randomised, placebo-controlled phase 2 trial at 15 centres across the UK, Denmark, and Canada. We enrolled participants of either sex aged 18–75 years with inadequately controlled moderate-to-severe asthma for 12 months or more, requiring treatment with inhaled corticosteroids at a stable dose. We randomly assigned participants (1:1) to receive tralokinumab (300 mg) or placebo by an interactive web-based system or voice response system. Participants and study personnel were masked to treatment allocation. Both tralokinumab and placebo were administered subcutaneously every 2 weeks. The primary outcome measure was change from baseline to week 12 in bronchial biopsy eosinophil count. Secondary outcome measures included change in blood and sputum eosinophil counts. Exploratory outcomes included fractional exhaled nitric oxide (FENO) and blood IgE concentrations. Safety analyses were carried out in all participants who received study drug. This trial is registered with ClinicalTrials.gov, number NCT02449473, and with the European Clinical Trials Database, EudraCT 2015-000857-19. Findings Between Sept 25, 2015, and June 21, 2017, 224 participants were enrolled and screened. Of these participants, 79 were randomly assigned to receive tralokinumab (n=39) or placebo (n=40). Tralokinumab did not significantly affect bronchial eosinophil count compared with placebo at week 12 (treatment effect ratio 1·43, 95% CI 0·63–3·27; p=0·39). Compared with placebo, tralokinumab did not significantly affect blood eosinophil count (treatment effect ratio 1·21, 95% CI 1·00–1·48; p=0·055) or sputum eosinophil count (0·57, 0·06–6·00; p=0·63), but FENO concentration (0·78, 0·63–0·96; p=0·023) and total blood IgE concentration (0·86, 0·77–0·97; p=0·014) were significantly reduced. 33 (85%) of 39 patients receiving tralokinumab and 32 (80%) of 40 receiving placebo reported at least one adverse event during the treatment period. No deaths in either treatment group were observed. Treatment-related adverse events occurred more frequently in the tralokinumab group than in the placebo group (11 [28%] of 39 vs seven [18%] of 40). Interpretation Tralokinumab did not significantly affect eosinophilic inflammation in bronchial submucosa, blood, or sputum compared with placebo, but did reduce FENO and IgE concentrations. These results suggest interleukin 13 is not crucial for eosinophilic airway inflammation control in moderate-to-severe asthma. Funding AstraZeneca.

Asthma is a common chronic inflammatory condition of the airways affecting over 300 million people world-wide. In 5%-10% of cases, it is severe, with disproportionate healthcare resource utilization including costs associated with frequent exacerbations and the long-term health effects of systemic steroids. Characterization of inflammatory pathways in severe asthma has led to the development of targeted biological and small molecule therapies which aim to achieve disease control while minimizing corticosteroid-associated morbidity. Herein, we review currently licensed agents and those in development, and speculate how drug therapy for severe asthma might evolve and impact on clinical outcomes in the near future.

Background: Bronchial Thermoplasty (BT) has been shown to improve asthma control and symptoms, and reduce exacerbation frequency and rescue medication use. Small studies have shown reduced airway smooth muscle (ASM) mass following BT, but understanding of the mechanism of action of BT is incomplete. Aims: To investigate the clinical, physiological and histological effects of BT in severe asthma. Methods: 34 severe asthma patients undergoing BT as part of clinical care were recruited from four UK centres. Asthma questionnaires and lung function were assessed before, 6 weeks after, and 6 months after treatment. 19 patients underwent endobronchial biopsy at the time of BT procedures, which were examined for ASM and epithelial changes. Results: ACQ6 and AQLQ improved significantly 6 weeks after BT (mean change -0.55, p=0.03; mean change 0.57, p=0.02 respectively), but this was not maintained at 6 months. Median (interquartile range IQR) ASM% reduced from 13.8% (7.7-16.9) at baseline to 5.8% (2.1-12.1) at first follow-up (p=0.03), although marginally increased to 6.6% (3.1-14.1) at second follow-up (p=0.1 baseline to second follow-up). Median (IQR) epithelial integrity improved from 28.9% (15.1-42.7) at baseline to 43.4% (28.8-52.7) at first follow-up (p=0.004), and was mostly maintained at 42.4% (16-68) at second follow-up (p=0.06 baseline to second follow-up). There was no change in lung function. Conclusion: BT improves ACQ6 and AQLQ over baseline in severe asthma but does not affect lung function. ASM% initially reduces in response to BT but subsequently increases again. Epithelial integrity increases following BT, and this effect is mostly maintained beyond the end of treatment.

The pathogenesis of asthma is complex and multi-faceted. Asthma patients have a diverse range of underlying dominant disease processes and pathways despite apparent similarities in clinical expression. Here, we present the current understanding of asthma pathogenesis. We discuss airway inflammation (both T2HIGH and T2LOW), airway hyperresponsiveness (AHR) and airways remodelling as four key factors in asthma pathogenesis, and also outline other contributory factors such as genetics and co-morbidities. Response to current asthma therapies also varies greatly, which is probably related to the inter-patient differences in pathogenesis. Here, we also summarize how our developing understanding of detailed pathological processes potentially translates into the targeted treatment options we require for optimal asthma management in the future.

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

IntroductionPatients presenting with acute undifferentiated breathlessness are commonly encountered in admissions units across the UK. Existing blood biomarkers have clinical utility in distinguishing patients with single organ pathologies but have poor discriminatory power in multifactorial presentations. Evaluation of volatile organic compounds (VOCs) in exhaled breath offers the potential to develop biomarkers of disease states that underpin acute cardiorespiratory breathlessness, owing to their proximity to the cardiorespiratory system. To date, there has been no systematic evaluation of VOC in acute cardiorespiratory breathlessness. The proposed study will seek to use both offline and online VOC technologies to evaluate the predictive value of VOC in identifying common conditions that present with acute cardiorespiratory breathlessness.Methods and analysisA prospective real-world observational study carried out across three acute admissions units within Leicestershire. Participants with self-reported acute breathlessness, with a confirmed primary diagnosis of either acute heart failure, community-acquired pneumonia and acute exacerbation of asthma or chronic obstructive pulmonary disease will be recruited within 24 hours of admission. Additionally, school-age children admitted with severe asthma will be evaluated. All participants will undergo breath sampling on admission and on recovery following discharge. A range of online technologies including: proton transfer reaction mass spectrometry, gas chromatography ion mobility spectrometry, atmospheric pressure chemical ionisation-mass spectrometry and offline technologies including gas chromatography mass spectroscopy and comprehensive two-dimensional gas chromatography-mass spectrometry will be used for VOC discovery and replication. For offline technologies, a standardised CE-marked breath sampling device (ReCIVA) will be used. All recruited participants will be characterised using existing blood biomarkers including C reactive protein, brain-derived natriuretic peptide, troponin-I and blood eosinophil levels and further evaluated using a range of standardised questionnaires, lung function testing, sputum cell counts and other diagnostic tests pertinent to acute disease.Ethics and disseminationThe National Research Ethics Service Committee East Midlands has approved the study protocol (REC number: 16/LO/1747). Integrated Research Approval System (IRAS) 198921. Findings will be presented at academic conferences and published in peer-reviewed scientific journals. Dissemination will be facilitated via a partnership with the East Midlands Academic Health Sciences Network and via interaction with all UK-funded Medical Research Council and Engineering and Physical Sciences Research Council molecular pathology nodes.Trial registration numberNCT03672994.

Chronic Obstructive Pulmonary Disease (COPD) is characterised by persistent airflow obstruction, airway inflammation and increased oxidative stress. The Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidases (NOX1-5 and DUOX1-2) are implicated in the generation of reactive oxygen species, but their role in COPD is uncertain. As part of the EvA study bronchial brushings were obtained from 279 COPD subjects and 215 healthy controls. Gene expression of the NOX isoforms was analysed; compared between COPD and health and multiple regression analyses of NOX expression and clinical, physiological, and quantitative (q)CT parameters were performed in COPD cases. Gene expression of NOX2, 4 and DUOX2 was increased significantly and NOX1 decreased in COPD compared to controls, whereas NOX5 and DUOX1 expression was not different between groups and NOX3 was not present. Multiple regression analyses identified independent associations between: NOX1 and DUOX2 with airflow obstruction (FEV1/FVC ratio) (β=0.006[0.003]; P=0.046 and β=-0.016[0.008]; P=0.035 respectively); NOX1 and NOX2 with airway inflammation (NOX1 with sputum neutrophil and eosinophil % β=0.004[0.002]; P=0.016 and β=-0.056[0.028]; P=0.047 and NOX2 with sputum eosinophils % β=0.004[0.002]; P=0.016); and NOX4 with body mass index (β=0.022[0.005]; P In conclusion, NOX1, 2 and 4, and DUOX2 are differentially expressed between COPD and health. Associations between these NOX isoforms and important clinical characteristics suggest a potential role for NOX in the pathogenesis of COPD.

Introduction: We surveyed adults who presented to respiratory and cardiology outpatients (OPD) or an acute clinical cardio-respiratory decisions unit (CDU) to inform service improvements for the diagnosis of unexplained breathlessness. Methods: We reviewed: 1) all referrals to cardiology and respiratory OPD - March 2015, 2) all admissions to CDU in 96 hours - July 2015. Results: 1) 63/174 referrals from primary care to OPD were for breathlessness: n=56 respiratory, n=2 to both specialities. 38 had unexplained symptoms prior to referral with 35% having ≤1 investigation. Mean time to diagnosis from referral was 16 weeks. There were no inter-speciality referrals. 2) 67/156 adult admissions were for breathlessness. 33/67 had unexplained symptoms, of which 17 were discharged within 24 hrs. Of the 33, 61% required simple investigations only and 50% had an EWS of ≤1 on arrival. The median [IQR] duration of breathlessness was 3 [1 - 14] days. Table 1 shows the diagnoses for each setting. Conclusions: Simple investigations are not fully utilized prior to OPD referral for breathlessness. The need for three different approaches to breathlessness services was identified: 1) a diagnostic pathway for primary care, 2) an ambulatory same day service and 3) an earlier diagnostic combined speciality OPD.

Four experiments were performed to determine the stimulus characteristics that favor the development of conditional stimulus control in the single reversal paradigm with pigeon subjects. In Experiment 1, pigeons were trained on a successive discrimination between tone frequencies ranging from 350 to 3500 Hz in a particular houselight context condition (houselight-on or -off). The subjects then were trained on the reversal of the tone discrimination in the alternative context. Subsequent tone-frequency generalization testing in the two contexts indicated that they had failed to gain conditional control over the pigeons’ discriminative performance. Such control was obtained in Experiment 2, in which the two problems were alternated daily for 32 sessions of training. The gradients then peaked at the appropriate S+ value in each context. In Experiment 3, the key colors (blue vs. red) served as contexts while pigeons learned a successive discrimination in which the discriminative cues were houselight-on versus houselight-off conditions. This was followed by a reversal of the discrimination in the alternative key-color context condition. The key colors were effective conditional cues in this situation. In a previous experiment (Thomas, McKelvie, & Mah, 1985), key color had been ineffective as a conditional cue when the discriminative cues were lines superimposed on the colored background. In Experiment 4, key color was effective when the color and lines were presented on a single key as in the earlier experiment, but were sequenced such that the onset of the key color preceded and then overlapped the presentation of the lines. We concluded that conditional discriminations are easiest for pigeons when visual cues are used, but the conditional and discriminative cues must be presented in such a way that they do not combine to form a psychological compound.