Background: Interleukin 5, an archetypal type 2 cytokine, is fundamental to eosinophilic airways disease, considered to signal the bone marrow to promote eosinophil progenitor maturation and increase levels of eosinophils in the circulation. Aim: To investigate the relationship between airway IL-5 concentrations and inflammatory phenotypes of severe asthma. Methods: Healthy volunteers and biologic naïve severe asthma patients were clinically characterised and had blood and induced sputum samples collected. Sputum was analysed for differential cell count and supernatant (PBS processed) proteins, measured by single plex ELISA. Eosinophilic asthma was defined as sputum eosinophils >2%. Between group comparisons were assessed by Kruskal Wallis and relationships between variables by spearman rank correlations. Results: 17 healthy controls, 53 non-eosinophilic and 26 eosinophilic patients with severe asthma participated in the study. In severe asthma, there were modest correlations between sputum IL-5 and sputum eosinophils (r = 0.519, p<0.001) and blood eosinophils (r=0.673, p<0.001). Those with severe eosinophilic asthma had significantly increased sputum eosinophils (8.2% [5.8,18.7]) and sputum IL-5 (11.6 ng/ml [2.1,18.9]), compared to those with non-eosinophilic asthma (both p<0.001). Though sputum eosinophil percentages in non-eosinophilic severe asthma (0.2% [0.0,1.0]) did not differ from in health (0.4% [0.0,0.8]), sputum IL-5 (0.2 ng/ml [0.1,0.9] was higher in this non-eosinophilic phenotype compared to that in healthy volunteers (0.0 ng/ml [0.0,0.0], p=0.002). Discussion: Despite high levels of steroid treatment, there is persistent IL-5 generation within the airways of severe asthma.

Introduction: Depression is a well-recognised comorbidity in SA associated with poorer disease control & quality of life (QOL) but it remains unclear whether this is the consequence of altered pathobiology. Method: We compared the clinical, physiological & biological characteristics of patients with & without depression (defined by HADS depression score ≥8) within WSAC, a large published cohort of well characterised patients fulfilling the ATS/ERS 2014 definition of SA. Results: Discussion: SA patients with depression report poorer disease control & QOL associated with a greater burden of co-morbidities including obesity, rhinosinusitis & reflux. However, no statistically significant differences were identified in their other clinical or physiological characteristics. Inflammatory phenotypes did not differ between the groups but those with depression were found to have significantly higher serum hs-CRP & sputum IL-6 levels (not seen when subdivided for BMI). There is a well-recognised association between inflammation & depression with elevated serum IL-6 levels previously reported. Our findings raise the possibility that depression influences the pathobiology of asthma & thus reflects a targetable trait.

Introduction: Identifying persistent T2 inflammation is vitally important in the management of SA, particularly in determining suitability for biologic therapies. Method: The Wessex Severe Asthma Cohort (WSAC) is a large published cohort of well characterised SA patients fulfilling the ATS/ERS 2014 definition of SA. We compared the clinical, physiological & biological characteristics of patients dependent upon the strength of their T2 signal. Results: Discussion: A strong T2 signal is associated with increased sinonasal comorbidity & lung function impairment alongside increased biological markers of the T2 inflammatory pathway. Patients with SA with an intermediate T2 signal suffer a similar burden of disease with high levels of co-morbidity, poor disease control, reduced quality of life & frequent severe exacerbations despite similar levels of ICS and maintenance OCS use. These patients currently fall outside of the treatment recommendations for anti-IL5 biologic therapies in the UK and thus reflect a significant unmet need.

Background: Sputum neutrophils are associated with poor disease outcome in asthma, yet there is a lack of a concordance for the definition of neutrophilia in asthma. Gaining an agreed definition of NA may guide clinical care Methods: Clinical data was collected from 138 non-eosinophilic asthma patients within the Wessex Severe Asthma Cohort Study. Data were split by two definitions of neutrophilia; >40% sputum neutrophils (1) and >61% sputum neutrophils (2). Differences in NA vs NNA were explored for each definition of neutrophilia using frequency statistics and Mann Whitney U analysis. Results: Conclusion: Sputum neutrophilia is associated with poor clinical outcome in asthma. Using a definition of >40% sputum neutrophils to define neutrophilia generates a more clinically distinct population of NA than a definition of >61% sputum neutrophils in our cohort. 1. Hastie, JACI 125(5): 1028-1036 e101 2. Simpson, Respirology 11(1): 54-61

Introduction: Maintenance OCS use in severe asthma (SA) is associated with significant side-effects and has the potential to mask the systemic type-2 inflammatory biomarker signal required for initiation of biologic therapies. Method: WSAC is a large published cohort of 342 well characterised SA patients fulfilling the ATS/ERS 2014 definition of SA undertaken prior to the widespread use of biologic treatments. We compared the clinical, physiological & biological characteristics of patients requiring & not requiring maintenance OCS. Results: Discussion: Maintenance OCS use is associated with a significantly greater burden of comorbidities, poorer quality of life & disease control with more frequent exacerbations & ITU admissions. Despite this no significant differences were identified in lung function, atopic status, inflammatory cell counts or the other extensive biological measures assessed in the cohort. 44% of patients on maintenance OCS showed no biomarker signal of T2 inflammation. 77% of those on maintenance OCS with a sputum eos ≥2% had a blood eos count ≥0.3x109/L whilst only 60% had a FeNO ≥25ppb (43% FeNO ≥50ppb) suggesting blood eos remains a useful biomarker of T2 inflammation.

Introduction: Exercise training is recommended for IPF patients but the optimum program and the mechanisms underlying improvements in exercise capacity are unknown. We tested feasibility of a HIIT in IPF. Methods: A single-centre study of IPF patients. An 8-week twice-weekly cycle-ergometer based HIIT was personalised using participants volume of oxygen consumption at anaerobic threshold (VO2AT) and peak (VO2peak) assessed by incremental CPET. Primary outcome was endurance time on constant load test at 75% VO2peak. Ethical approval obtained (REC 17/SC/0342). Results: Interim analysis of 11 patients. Baseline demographics as follows; males 82% with mean (SD) age 73.5years (6.8), FVC% 76.5 (13.4) and DLCO% 50.1 (15.8). Participants had significantly impaired exercise capacity at baseline with mean (SD) VO2peak of 12.3ml/kg/min (3.3) and VO2AT 8.3ml/kg/min (1.3). Participants had good adherence to HITT with mean of 15/16 sessions attended with no serious adverse events. HITT led to clinically meaningful improvement in mean endurance time [pre 8.3min vs post 16.8min difference 8.5min (95%CI 4.2-12.8) p<0.01] and 6min walk [pre 374m vs post 409m difference 35m (95%CI 0.6-69.4) p<0.05]. Significant increase was also observed in mean peak minute ventilation (peakVE) [pre 60.2L/min vs post 69.3L/min p=0.02]. However no change was observed in either VO2peak or VO2AT following HITT. Conclusion: A CPET derived HIIT was feasible in this cohort of IPF patients and led to significant improvement in endurance time and 6min walk. Increased peakVE following HITT suggests improved ventilatory mechanics may in part account for increased exercise test performance.

Introduction: There is evidence that obesity is linked to poor asthma control & airway inflammation; however the underlying pathobiological mechanisms are not well established. Methods: WSAC is a large published cohort of well characterised SA patients fulfilling the ATS/ERS 2014 definition of SA. We compared the clinical, physiological and biological characteristics of obese (BMI ≥30Kg/m2) & non-obese patients. Results: Discussion: The majority (76%) of obese SA patients were female but no other significant differences were identified in disease characteristics. Obese SA was associated with a significantly higher symptom burden & reduced quality of life with a higher incidence of other co-morbidities including diabetes & depression. Obese SA was associated with small airways dysfunction (measured by oscillometry) with less baseline or fixed airflow obstruction. Statistically significant differences were seen in the sputum inflammatory phenotypes (p=0.04) with significantly less T2 asthma in the obese group.

Introduction and objectives Exercise intervention may modulate the inflammation responsible for asthma, offering clinical benefit beyond functional improvement. Interval training is tolerated in asthmatics, and may also improve symptom control. This proof of concept study has recruited sub optimally controlled, untrained asthmatics to a 12-week Interval Training Programme to ascertain feasibility and safety, and effect on symptom control, airway and systemic inflammation, and physical fitness. Methods Participants completed thrice weekly 30-minute interval exercise training sessions for 12 weeks. The training intensities were prescribed based on oxygen uptake (VO2) at anaerobic threshold (AT) and peak exercise. Lung function, blood, exhaled breath, saliva, sputum and symptom questionnaires were sampled at baseline, 3, 6 and 12 weeks. Results Early results (n=6) suggest safety and tolerability, with improvement in symptom scores using the Asthma Control Questionnaire score (Friedman p=0.003) and Asthma Quality of Life Questionnaire score (Friedman p=0.02). This improvement in symptoms was associated with reductions in peripheral blood total white cell count (Friedman p=0.02), neutrophil count (Friedman p=0.04), eosinophil count (Friedman p=0.0017), and lymphocyte count (Friedman p=0.04). There was a significant improvement in pre-bronchodilator FVC (Friedman p=0.04) but not FEV1, with a trend for reduction in percentage bronchodilator reversibility (Wilcoxon signed rank p=0.09). The training intervention did not significantly improve physical fitness, assessed by VO2 at anaerobic threshold (Friedman p=0.37) or peak (Friedman p=0.15). BMI did not significantly change (Friedman p=0.18) and exhaled nitric oxide (FeNO) did not significantly improve (Friedman p=0.5). Conclusions This interim analysis suggests exercise intervention in sub optimally controlled asthma is tolerated and beneficial for symptom control, with associated improvement in inflammatory parameters and lung function. The stability of BMI suggests the improvements in inflammatory markers are not a result of reduced adipose tissue related systemic inflammation. The stability of FeNO and significant reductions in total white cell and neutrophil count suggest the improvement in symptoms and inflammation are not due to improved adherence to inhaled corticosteroids. Prescribed training programmes may provide a cost-effective, disease modifying treatment adjunct in poorly controlled asthma.

Background An abundance of neutrophils in sputum is associated with poor disease control1. In contrast to eosinophils, the role of neutrophils in asthma is poorly understood. Sputum neutrophil activity rather than proportions may provide a better insight into disease activity. Objective The purpose of this analysis was to explore the relationship between sputum markers of neutrophil activity, symptoms and lung function in asthma. Methods 23 mild asthma and 159 severe asthma patients recruited to the Wessex severe asthma cohort study underwent complex characterisation including spirometry, questionnaires and sputum induction. Sputum analysis included protein assays and differential cell counts. Myeloperoxidase (MPO) and Neutrophil Elastase (NE) were measured as markers of neutrophil activity using singleplex ELISA. Correlation analysis of lung function and asthma control with sputum measures were completed using Spearmans rho. Results Weak correlations were found between lung function and sputum measures. However, neutrophil activity had a stronger relationship with lung function than neutrophil proportion. Asthma control (ACQ6) had a very weak correlation with sputum neutrophil proportion but a weak significant relationship with markers of neutrophil activity. Conclusion Neutrophil activity in sputum is more reflective of lung function and asthma control than sputum neutrophil proportion in asthma. Markers of neutrophil activity, rather than neutrophils per se, may more accurately reflect the inflammatory processes in poorly controlled asthma. Reference Simpson JL, et al. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology 2006;11(1):54–61.

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

Background Asthma is now widely recognised to be a heterogeneous disease. The last two decades have seen the identification of a number of biological targets and development of various novel therapies. Despite this, asthma still represents a significant health and economic burden worldwide. Why some individuals should continue to suffer remains unclear. Methods The Wessex Asthma Cohort of Difficult Asthma (WATCH) is an ongoing ‘real-life’, prospective study of patients in the University Hospital Southampton Foundation Trust (UHSFT) Difficult Asthma service. Research data capture is aligned with the extensive clinical characterisation required of a commissioned National Health Service (NHS) Specialist Centre for Severe Asthma. Data acquisition includes detailed clinical, health and disease-related questionnaires, anthropometry, allergy and lung function testing, radiological imaging (in a small subset) and collection of biological samples (blood, urine and sputum). Prospective data are captured in parallel to clinical follow up appointments, with data entered into a bespoke database. Discussion The pragmatic ongoing nature of the WATCH study allows comprehensive assessment of the real world clinical spectrum seen in a Specialist Asthma Centre and allows a longitudinal perspective of deeply phenotyped patients. It is anticipated that the WATCH cohort would act as a vehicle for potential collaborative asthma studies and will build upon our understanding of mechanisms underlying difficult asthma.

Background: Small airways disease (SAD) is a central pathological process in COPD but there is no single gold standard measure with a number of lung function, CT and biological indices commonly used to determine it. Aims: To compare commonly used markers of SAD and demographics between frequent and infrequent COPD exacerbators and determine if any index differentiates these groups and provides insight into this phenotype. Methods: Twenty-six GOLD Stage I and II COPD subjects defined as either frequent exacerbators ( ≥ 2 exacerbations per year, n=11) and infrequent exacerbators (≤1 exacerbation per year, n=15) underwent Forced Oscillation Technique (R5-R19, AX), multiple breath nitrogen washout (Sacin), plethysmography (RV/TLC), spirometry (FEV1%, MEF25-75%), paired CT scans (MLD E/I), and bronchoscopy (bronchoalveolar lavage neutrophil % and eosinophils %). Results: Of the 12 indices compared, the only index that differentiated these groups was Sacin from multiple breath nitrogen washout which was higher in frequent exacerbators median (IQR), 0.42 (0.28) vs 0.25 (0.18), p=0.036. BAL neutrophil % was higher in frequent exacerbators median (IQR), 9.4 (25.40) vs 3.5 (7.75) with a trend towards significance (p=0.08). Conclusion: Increased ventilation heterogeneity (Sacin) may be a consequence of previous exacerbations or highlight a group of patients prone to exacerbations. This finding maybe associated with neutrophilic inflammation in the distal airways. Results should be confirmed in a larger prospective study to determine if Sacin would be a useful clinical measure of SAD and predicting exacerbation frequency in COPD.

Background: The UHSFT (Southampton, UK) Adult Regional Difficult Asthma Clinic receives referrals from a wide region. The majority of these patients come from the Wessex area, which is heterogeneous in terms of geography, urbanisation and deprivation. Deprivation has previously been linked to poor asthma outcomes, particularly in children and young adults. Aim: To assess the relationship between deprivation and disease characteristics and outcomes in patients in the WATCH cohort of Difficult Asthma, particularly in the under 40 age group. Methods: Patients were assigned to “most deprived”, “mid deprived” and “least deprived” according to the IMD (Index of Multiple Deprivation 2015) Rank of their home postcode. K Wallis and X2 statistical analyses were used to look for differences in clinical parameters between groups. Results: Patients from the most deprived tertiles were younger (p<0.05), had a higher BMI (p<0.001) and fewer never smokers (p<0.005). These patients also had lower FeNO (p<0.05) but higher ACQ6 scores (<0.005). When considering patients aged 18-40 only, we found no significant differences in demographics, ACQ6 or healthcare utilisation (hospitalisations or OCS courses in the past 12 months). Conclusions: Patients from the WATCH cohort are representative of a wide spectrum of deprivation. It is recognised that there are complex relationships between social economic status/deprivation and asthma outcomes. However, in contrast to previous studies, we find little influence of deprivation on asthma outcomes. This may reflect the fact that our cohort recruits exclusively from a regional asthma clinic, where patients are already under specialist care.

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, caused by emphysema and small airways disease (SAD). Computed tomography (CT) coupled with image analysis enables the quantification of these abnormalities; however, the optimum method for doing so has not been determined.Objectives: This study aims to compare two CT quantitative analysis techniques, disease probability measure (DPM) and parametric response mapping (PRM), and assess their relationship with specific physiological measures of SAD.Methods: Subjects with mild to moderate COPD, never smokers, and healthy ex-smokers were recruited. Each had airway oscillometry and multiple-breath nitrogen washout, measuring peripheral airway resistance, peripheral airway reactance, and acinar airway inhomogeneity. Subjects also had an inspiratory and expiratory chest CT, with DPM and PRM analysis performed by coregistering images and classifying each voxel as normal, emphysema, or nonemphysematous gas trapping related to SAD.Results: Thirty-eight subjects with COPD, 18 never smokers, and 23 healthy ex-smokers were recruited. There were strong associations between DPM and PRM analysis when measuring gas trapping (ρ = 0.87; P < 0.001) and emphysema (ρ = 0.99; P < 0.001). DPM assigned significantly more voxels as emphysema and gas trapped than PRM (P < 0.001). Both techniques showed significantly greater emphysema and gas trapping in subjects with COPD than in never smokers and ex-smokers (P < 0.001). All CT measures had significant associations with peripheral airway resistance and reactance, with disease probability measure of nonemphysematous gas trapping related to SAD having the strongest independent association with peripheral airway resistance (β = 0.42; P = 0.001) and peripheral airway reactance (β = 0.41; P = 0.001). Emphysema measures had the strongest associations with acinar airway inhomogeneity (β = 0.35-0.38).Conclusions: These results provide further validation for the use of DPM/PRM analysis in COPD by demonstrating significant relationships with specific physiological measures of SAD.

Background: Airway abnormalities are a key feature of COPD, although these are poorly characterised. In this study we used CT coupled with image analysis software to perform a detailed analysis of the large/intermediate airways in COPD. Methods: Subjects with mild-moderate COPD and controls each had an inspiratory chest CT. CT analysis was performed by VIDA Diagnostics using Apollo software. The airway tree was automatically segmented and labelled from the trachea to the sub-segmental bronchi. The total airway count (TAC) was measured by summing all airway segments from the segmented airway tree. In addition, cross-sectional airway area, airway wall area, lumen area and wall area % were measured in each of the third to eight generation airways. Results: 38 COPD subjects, 18 never and 23 ex-smokers were recruited. TAC was significantly reduced in COPD (218, IQR 131) compared to never (391, IQR 191) and healthy ex-smokers (374, IQR 203) (p<0.001). This reduction in airways in COPD subjects was seen throughout each of the five lobes and started relatively proximally in generation 5 airways. Airway area was significantly lower in COPD compared to controls in generations 5-8 (p<0.05). Wall area was reduced in COPD subjects in generations 5 and 7 (p<0.05). Lumen area was reduced in generations 4-8 in COPD subjects (p<0.05). Wall area % was significantly higher in all generations (p<0.05) apart from generation 7. No differences were seen in airway dimensions between ex and never smokers. Conclusion: Using CT image analysis, fewer and smaller airways were seen in COPD subjects compared to controls. The reasons for this is unclear, but may indicate an abnormal remodelling process occurring within the larger airways.

Background: Current tobacco smoking impairs asthma control and accelerates decline in lung function, however the underlying pathobiological mechanisms for this are not well established. Methods: This abstract compares the clinical, physiological and biological characteristics of current and never smokers within the Wessex Severe Asthma Cohort (WSAC). This is a large published cohort including 342 well characterised severe asthma patients fulfilling the ATS/ERS 2014 definition of severe asthma. Results: The table below shows a comparison between current and never smokers from the WSAC. Discussion: Severe asthmatics who are current smokers have significantly poorer asthma control and quality of life. However, no statistically significant differences were identified in the clinical or physiological characteristics between the groups. No differences were seen in sputum inflammatory cell counts and whilst current smokers had lower peripheral blood eosinophil counts overall the proportion of patients with eosinophilic asthma was similar. Sputum IL-5 and ECP were lower in current smokers but sputum IL-8 was significantly higher suggesting a different pathobiological mechanism of eosinophilia.

Introduction: Exercise intervention may modulate the inflammatory basis for asthma, offering clinical benefit beyond functional improvement. Interval training is tolerated in asthmatics, and may improve symptom control. Aims and Objectives: This proof of concept study has recruited poorly controlled asthmatics to a 12-week Interval Training Programme to ascertain if it is feasible and safe, improves symptom control, airway and systemic inflammation, and physical fitness. Methods: Participants were sampled at baseline and 3, 6 and 12 weeks of training. Results: Early results (n=7) suggest safety and tolerability, with improvement between baseline and week 3. Wilcoxon signed rank showed that Asthma Control Questionnaire score improved significantly (mdn=2 [IQR=1.8,2.3] vs mdn=1.63 [IQR=1.37,1.96], p=0.028). Asthma Quality of Life Questionnaire score improved significantly (mdn=4.97 [IQR=4.46,5.3] vs median 5.5 [IQR=5.09,5.84] p=0.018), but was not associated with improved physical fitness, assessed by VO2 at anaerobic threshold (mdn=10.1 [IQR=9.25,11.35] vs 9.7ml/kg/min [IQR=8.6,14]; p=0.46) and VO2peak (mdn= 21.30 [IQR=12.80,25.40] vs 22.8ml/kg/min [IQR=13.80,28.80]; p=0.86). There were no statistically significant improvements in FeNO (median=37.75 [IQR=27.63,66] vs median=36 [IQR=20,82], p=0.39) or peripheral blood eosinophilia (mdn=0.2 [IQR=0.2,0.38] vs mdn=0.3 [IQR=0.2,0.4], p=0.57). Conclusion: These interim data suggests even a short exercise intervention in poorly controlled asthma is tolerated and beneficial for symptom control, which may precede improvement in markers of inflammation. Prescribed training programmes may provide a cost-effective treatment adjunct in poorly controlled asthma.

Introduction Many asthmatics remain symptomatic despite optimized medical therapy. New treatments are needed that are scalable at minimal cost. Pulmonary rehabilitation is established in respiratory disease, and emerging data suggests that prescribed exercise intervention may modulate the immune and inflammatory basis for asthma, offering clinical benefit beyond functional capacity improvement. High-intensity interval training (HIIT) seems better tolerated in asthmatics than constant work-rate training, but HIIT with strength training has not been assessed in terms of immunomodulatory potential, and mechanistic work is needed to explain these responses to exercise. Methods This study will randomise ten suboptimally controlled asthma patients to a 12 week HIIT Structured Responsive Exercise Training Programme (SRETP) or SRETP with strength training, which allows adaptation of the programme as fitness improves. Participants will be assessed at 3, 6 and 12 weeks to ascertain if SRETP is feasible, safe and tolerable, improves symptom control, modifies airway and systemic inflammation, and physiology in asthmatic patients. An interim analysis of the first 5 patients is presented. Results Early results suggest safety and tolerability. Wilcoxon signed rank tests between Baseline and Week 3 showed that ACQ score improved significantly (median=2.00 [IQR=1.82–2.38] vs median=1.50 [IQR=1.00–1.83], p=0.043). There were no statistically significant improvements in airways inflammation as assessed by FeNO (median=44.50 [IQR=29.00–87.25] vs median=49 [IQR=21.25–92.50], p=0.686), peripheral blood eosinophilia (n=4, median=0.30 [IQR=0.20–0.50] vs median=0.35 [IQR=0.30–0.48], p=0.102), or aerobic fitness as assessed by VO2 at anaerobic threshold (AT) (n=4, median=10.90 [IQR=9.55–20.25] vs 11.00 ml/kg/min [IQR=9.48–22.35]; p=0.285) and VO2peak (n=4, median=21.80 [IQR=17.15–33.45] vs 23.00 ml/kg/min [IQR=15.73–35.68]; p=0.465) Conclusion This interim data suggests even a very short period of exercise intervention is tolerated and beneficial for symptom control in sub-optimally controlled asthma. Further data will allow assessment of whether this precedes improvement in markers of inflammation, and current results are due to early subclinical cellular improvements in inflammation, or whether symptoms improve independent of any reduction in inflammation. We aim to further investigate this response to exercise training in asthma in a fully powered, observational mechanistic study. Prescribed exercise training programmes may provide a cost-effective treatment adjunct for suboptimally controlled asthmatics.

Background: Small airways disease (SAD) is considered pivotal in the pathology of COPD. There are numerous publications describing physiological and Computed Tomography (CT) imaging markers to detect SAD. However, there is no agreed gold standard and limited understanding of the clinical associations of these measures to disease outcomes. Methods: We conducted a systematic review using Embase, Medline and Pubmed to explore the relationship between physiological and CT SAD measures in COPD (GOLD Stages 1-4). Furthermore, evidence linking these physiological measures with defined clinical outcomes such as health status, functional assessment and exacerbation frequency were summarised. Results: The search yielded 1160 abstracts of which 19 met the search criteria. Six studies examined physiological and CT measures while 13 publications identified physiological measures and clinical outcomes. Strong correlations were seen between CT and physiological measures of SAD. Varying associations between physiological measures and defined clinical outcomes were noted. Conclusions: Physiological and CT measures of SAD correlate and infer similar information. Physiological measures of SAD may offer valuable insight into clinical expression of the disease. A consensus on the standardisation and recommendation of tests to measure SAD is needed in order to better understand any clinical benefits of targeted drug therapy to the small airways.