BackgroundSmall airways dysfunction (SAD) in asthma is difficult to measure and a gold standard is lacking. The aim of this study was to develop a simple tool including items of the Small Airways Dysfunction Tool (SADT) questionnaire, basic patient characteristics and respiratory tests available depending on the clinical setting to predict SAD in asthma.MethodsThis study was based on the data of the multinational ATLANTIS (Assessment of Small Airways Involvement in Asthma) study including the earlier developed SADT questionnaire. Key SADT items together with clinical information were now used to build logistic regression models to predict SAD group (less likely or more likely to have SAD). Diagnostic ability of the models was expressed as area under the receiver operating characteristic curve (AUC) and positive likelihood ratio (LR+).ResultsSADT item 8, “I sometimes wheeze when I am sitting or lying quietly”, and the patient characteristics age, age at asthma diagnosis and body mass index could reasonably well detect SAD (AUC 0.74, LR+ 2.3). The diagnostic ability increased by adding spirometry (percentage predicted forced expiratory volume in 1 s: AUC 0.87, LR+ 5.0) and oscillometry (resistance difference between 5 and 20 Hz and reactance area: AUC 0.96, LR+ 12.8).ConclusionsIf access to respiratory tests is limited (e.g.primary care in many countries), patients with SAD could reasonably well be identified by asking about wheezing at rest and a few patient characteristics. In (advanced) hospital settings patients with SAD could be identified with considerably higher accuracy using spirometry and oscillometry.

Introduction: Small airways dysfunction (SAD) is an increasingly recognized aspect of asthma pathophysiology. Quantitative computed tomography (qCT) imaging of the lungs may provide additional insight into SAD in addition to physiological measurements. However, the relationship between qCT biomarkers, small airway physiology and clinical patient reported outcomes (PROs) is still poorly understood. Objectives: To determine whether a particular set of qCT imaging biomarkers are associated with physiological SAD markers and asthma PROs over 1 year. Methods: Data from the Assessment of Small Airways Involvement in Asthma (ATLANTIS) study, including 47 healthy and 278 asthmatic participants, were used. qCT markers capturing lung tissue deformation gradients, imaging lung volume and mean lung density were extracted. Leading variables of five radiomic signatures derived from factor analysis were evaluated as predictors of physiological SAD (R5-R20, Sacin, RV/TLC, FEF25-75) and PROs (ACQ, AQLQ, SAD questionnaire score, EuroQoL-5D-5L and asthma exacerbations) using mixed models. Results: The lung density gradient along the anterior-posterior axis was significantly associated with all four SAD markers of interest over the 1-year prospective follow-up, where reduced posterior ventilation suggests increased SAD. None of the qCT markers were significantly associated with clinically important changes in the PROs of interest. Conclusions: The selected qCT imaging biomarkers were associated with prospective SAD. The results underscore qCT as a potential screening tool for early, pre-symptomatic asthma. However, this would need to be tested in prospective studies.

Background: An extrafine formulation triple therapy combination of beclomethasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium bromide (GB) has been developed for the maintenance treatment of asthma and chronic obstructive pulmonary disease. This study used gamma scintigraphy to evaluate the intrapulmonary and extrapulmonary in vivo deposition of BDP/FF/GB, and the intrapulmonary regional distribution of the deposited formulation. Methods: This open-label uncontrolled nonrandomized single-dose study recruited 10 healthy volunteers and 9 patients with asthma. After a krypton-81m (81mKr) ventilation scan was conducted, subjects inhaled study drug (four inhalations of BDP/FF/GB 100/6/12.5 μg radiolabeled using technetium-99 m [99mTc]) through pressurized metered-dose inhaler, and a series of scintigraphic images were taken. The primary objective was to evaluate intrapulmonary drug deposition of BDP/FF/GB, determined as the percentage of nominal (i.e., metered) dose. Secondary endpoints included central/peripheral deposition ratio (C/P), and the standardized central/peripheral ratio (sC/P; 99mTc aerosol C/P/81mKr gas C/P). Results: All participants completed the study, with all scintigraphy procedures performed at one site. In patients with asthma, mean ± standard deviation intrapulmonary deposition was 25.50% ± 6.81%, not significantly different to that in healthy volunteers (22.74% ± 9.19%; p = 0.4715). Approximately half of the lung dose was deposited in the peripheral region of the lung (fraction deposited 0.52 ± 0.07 and 0.49 ± 0.06 in healthy volunteers and patients with asthma, respectively), resulting in C/P ratios of 0.94 ± 0.25 and 1.06 ± 0.25, respectively, with sC/P ratios of 1.80 ± 0.40 and 1.94 ± 0.38. Deposition patterns were similar in the two populations. BDP/FF/GB was well tolerated. Conclusions: This study confirmed that the extrafine particles delivered by BDP/FF/GB penetrate the peripheral areas of the lungs, with a similar proportion of particles deposited in the central and peripheral regions. Importantly, the deposition patterns were similar in healthy volunteers and patients with asthma, suggesting that disease characteristics are unlikely to impact drug deposition. Clinical Trial Registration number: NCT03795350.

Aims and Objectives: Delivery of therapeutic aerosols to peripheral airways is key in the treatment of asthma. We investigated the lung deposition and distribution of extra fine BDP/FF/GB inhalation solution delivered via a pressurised metered-dose inhaler (pMDI) in subjects with asthma and healthy volunteers. Methods: Subjects underwent gamma scintigraphy after 4 inhalations of technetium (99mTc) radiolabelled BDP/FF/GB, 100/6/12.5 mcg. After correcting for 99mTc decay, tissue attenuation and background radioactivity, total lung deposition was expressed as percent of nominal dose (DL%ND), and intra-pulmonary drug distribution (right lung only) as the fraction of 99mTc labelled aerosol and krypton (81mKr) gas in the central (C) and peripheral (P) regions of interest. The C/P ratio was calculated for the 99mTc aerosol and 81mKr gas and their ratio is referred to as standardised C/P (sC/P). Results: Nine asthmatics (6 males, FEV1 61 – 76 % predicted, 32-48 years) and 10 healthy subjects (6 males, FEV1 89 - 120 % predicted, 28-49 years) completed the study. No differences were observed in lung deposition and distribution parameters (Table): Conclusions: Lung deposition of extra fine BDP/FF/GB pMDI is comparable between healthy subjects and patients with mild-moderate asthma and is well dispersed across the central and peripheral lung regions.

Abstract Background A single-inhaler extrafine triple combination of beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) has been developed for maintenance therapy of chronic obstructive pulmonary disease (COPD). This study evaluated the efficacy and safety of BDP/FF/G in patients in three eastern Asian areas: China, Republic of Korea and Taiwan. Methods TRIVERSYTI was a double-blind, randomised, active-controlled, parallel-group study in patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) < 50% predicted, ≥ 1 exacerbation in the previous 12 months, and receiving inhaled maintenance medication. Patients received either extrafine BDP/FF/G 100/6/10 µg via pressurised metered-dose inhaler, or non-extrafine budesonide/formoterol (BUD/FF) 160/4.5 µg via dry-powder inhaler, both administered as two puffs twice-daily for 24 weeks. The co-primary objectives (analysed in the overall population) were to demonstrate superiority of BDP/FF/G over BUD/FF for change from baseline in pre-dose morning and 2-h post-dose FEV1 at Week 24 (these were analysed as key secondary objectives in the China subgroup). The rate of moderate/severe COPD exacerbations was a secondary endpoint. Results Of 708 patients randomised, 88.8% completed. BDP/FF/G was superior to BUD/FF for pre-dose and 2-h post-dose FEV1 at Week 24 [adjusted mean differences 62 (95% CI 38, 85) mL and 113 (87, 140) mL; both p < 0.001]. The annualised moderate/severe exacerbation rate was 43% lower with BDP/FF/G [rate ratio 0.57 (95% CI 0.42, 0.77); p < 0.001]. Adverse events were reported by 61.1% and 67.0% patients with BDP/FF/G and BUD/FF. Results were similar in the China subgroup. Conclusions In patients with COPD, FEV1 < 50% and an exacerbation history despite maintenance therapy, treatment with extrafine BDP/FF/G improved bronchodilation, and was more effective at preventing moderate/severe COPD exacerbations than BUD/FF. Trial registration CFDA CTR20160507 (registered 7 Nov 2016, http://www.chinadrugtrials.org.cn/index.html ).

Airway remodelling, which may include goblet cell hyperplasia / hypertrophy, changes in epithelial integrity, accumulation of extracellular matrix components, smooth muscle hypertrophy and thickening of the lamina reticularis, is a feature of severe asthma and contributes to the clinical phenotype.

Purpose: This study aimed to evaluate the non-inferiority of initiating extrafine beclometasone dipropionate/formoterol fumarate (BDP/FF) versus double bronchodilation (long-acting beta-agonists [LABA]/long-acting muscarinic antagonists [LAMA]) among patients with a history of chronic obstructive pulmonary disease (COPD) exacerbations. Patients and Methods: A historical cohort study was conducted using data from the UK's Optimum Patient Care Research Database. Patients with COPD >= 40 years at diagnosis were included if they initiated extrafine BDP/FF or any LABA/LAMA double therapy as a step-up from no maintenance therapy or monotherapy with inhaled corticosteroids (ICS), LAMA, or LABA and a history of >= 2 moderate/severe exacerbations in the previous two years. The primary outcome was exacerbation rate from therapy initiation until a relevant therapy change or end of follow-up. Secondary outcomes included rate of acute respiratory events, acute oral corticosteroids (OCS) courses, and antibiotic prescriptions with lower respiratory indication, modified Medical Research Council score (mMRC) >= 2, and time to first pneumonia diagnosis. The non-inferiority boundary was set at a relative difference of 15% on the ratio scale. Five potential treatment effect modifiers were investigated. Results: A total of 1735 patients initiated extrafine BDP/FF and 2450 patients initiated LABA/LAMA. The mean age was 70 years, 51% were male, 41% current smokers, and 85% had FEV1 <80% predicted. Extrafine BDP/FF showed non-inferiority to LABA/LAMA for rate of exacerbations (incidence rate ratio [IRR] = 1.01 [95% CI 0.94-1.09]), acute respiratory events (IRR = 0.98 [0.92-1.04]), acute OCS courses (IRR = 1.01 [0.91-1.11]), and antibiotic prescriptions (IRR = 0.99 [0.90-1.09]), but not for mMRC (OR = 0.93 [0.69-1.27]) or risk of pneumonia (HR = 0.50 [0.14-1.73]). None of the a priori defined effect modifier candidates affected the comparative effectiveness. Conclusion: This study found that stepping up to extrafine BDP/FF from no maintenance or monotherapy was not inferior to stepping up to double bronchodilation therapy in patients with a history of exacerbations.

PURPOSE:To identify optimal therapeutics and response parameters for small airways dysfunction evaluation is key in COPD.We explored whether a switch from non-extra fine to extra fine therapeutic particles may result in improved regional bronchodilation and ventilation due to enhanced peripheral drug deposition in patients with severe COPD using functional respiratory imaging (FRI). METHODS:This was a multi-center, open-label exploratory trial where patients with symptomatic severe COPD previously on a stable dose non-extra fine multi-inhaler triple therapy (MITT) with inhaled corticosteroid/long-acting b2 agonist (ICS/LABA) plus a long-acting muscarinic antagonist (LAMA) for $ 3 months were switched to single-inhaler extra fine triple therapy (SITT) with beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB 100/6/12.5mg) pressurized metered dose inhaler (pMDI) 2 inhalations bid for 24 weeks.Regional bronchodilation, e.g., changes in image-based specific inner airway volume (siVaw), and resistance (siRaw) were derived from low-dose computed tomography (CT) scans at total lung capacity (TLC) and functional residual capacity (FRC) at week 12 and 24.Regional lung deposition of ICS, LABAs and LAMAs was simulated as a function of age, height, disease severity, aerosol characteristics, and breathing pattern.Percent changes from baseline in FRI parameters, measured on a lobar basis, were assessed post-hoc using a linear mixed-model approach.The correlations between FRI indices and pulmonary function tests were determined using Spearman rank correlation coefficient.RESULTS: 21 patients were enrolled, 20 completed the study.Mean age was 63.4 years, FEV1 was 40.5% of predicted normal, 55% were current smokers, 50% were females and 70% showed predominant emphysema on the CT scan.At week 24, overall percent change from baseline was þ22.0%(p< 0.001) for siVaw, and -17.6% (p¼0.014) for siRaw at TLC. Change from baseline in SGRQ total score was inversely correlated to siVaw (r¼-0.470,p¼0.042) whereas change from baseline in FEV1 bore no correlation to either siVaw (r¼0.299,p¼0.214) or siRaw (r¼-0.349,p¼0.143).Switching from a non-extra fine MITT to extra fine BDP/FF/GB increased the peripheral lung deposition of ICS by 19.8 AE 3.8 %, LABA by 18.8 AE 3.4 % and LAMA by 13.2 AE 7.1 % of delivered dose, respectively.CONCLUSIONS: FRI signatures but not FEV1 capture the significant bronchodilation effect occurring after 24 weeks following switch from non-extra fine to extra fine inhaled triple therapy in patients with severe COPD.CLINICAL IMPLICATIONS: Switching to extra fine BDP/FF/GB pMDI results in enhanced regional ventilation to the small airways as assessed by CT surrogate ventilation maps

Objective: Several commercial and custom-made forced oscillation technique (FOT) devices are used to assess respiratory system impedance. The impulse oscillometry system (IOS) is a widespread device, which yields similar but not identical results to those provided by other FOT systems. Differences may be related to the forcing waveform, the device hardware, or the data processing algorithms. We evaluated the agreement between resistance (R-rs) and reactance (X-rs) measurements while alternating between different forcing waveforms and data processing algorithms.Approach: We performed pre- and post-bronchodilator measurements in 20 patients with respiratory complaints. We generated pulse waveforms using an IOS, and sinusoidal oscillations by replacing the IOS loudspeaker with customized loudspeaker providing a 5 Hz sinusoidal pressure signal. Pressure and flow were measured using the IOS sensors and breathing circuit. We developed a data processing algorithm compatible to both forcing signals. We also applied commercial IOS software during pulse waveform and a least mean square (lms) algorithm during sinusoidal waveform.Main results: The median (5th, 95th percentile) differences betweenR(rs)andX(rs)were (1) -0.35 (-2.49, 1.23) and 0.16 (-1.63, 3.07 cmH(2)O*s l(-1), when the same algorithm was used during pulse vs sinusoidal stimulus; (2) 0.34 (-2.33, 5.98) and 0.57 (-2.64, 6.09) cmH(2)O*s l(-1), when our algorithm and the IOS software were used during pulse waveform; and (3) 0.33 (-1.20, 6.05) and 0.25 (-4.94, 4.28) cmH(2)O*s l(-1)when the IOS software was used during pulse and the lms algorithm during sinusoidal waveforms.Significance: Both forcing signal and data processing contribute to differences in impedance values measured by different FOT devices.

SESSION TITLE: Obstructive Lung Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: The estimated overall prevalence of COPD in China in 2014–15 was 13.6% for people ≥ 40 years old, indicating a major public-health problem. COPD exacerbations are a major cause of death and are associated with significant medical expenditure. Strategies to appropriately treat COPD are needed urgently. Randomized clinical trials in Europe have shown triple therapy with extra-fine BDP/FF/GB pMDI to provide significant clinical benefits over tiotropium, BDP/FF and indacaterol/glycopyrronium. The efficacy and safety of this product in an East Asian population has not previously been evaluated. One of the aims of the TRIVERSYTI study was to compare BDP/FF/GB pMDI to the fixed combination inhaled corticosteroid/long-acting β2-agonist budesonide/formoterol fumarate (BUD/FF) dry powder inhaler (DPI) on moderate-to-severe exacerbations in patients from China, South Korea and Taiwan. METHODS: TRIVERSYTI was a phase III multicentre, randomized, double-blind, double-dummy, parallel group trial comparing a 24-week treatment with BDP/FF/GB pMDI (100/6/12.5 µg/actuation, 2 inhalations bid) to BUD/FF DPI (160/4.5 µg/inhalation, 2 inhalations bid) (Symbicort® Turbuhaler®). Enrolled patients were diagnosed with COPD, a post-bronchodilator FEV1/FVC ratio < 0.7 and FEV1 < 50% predicted, had a history of ≥1 exacerbation in the past year and had to be on stable single or dual inhaled maintenance COPD therapy for ≥2 months. Annualized rate of moderate-to-severe exacerbations and time to first event were tested as secondary efficacy endpoints. Treatment-emergent pneumonia was recorded. RESULTS: 614 patients were randomized and 545 completed the study. In comparison to BUD/FF, treatment with BDP/FF/GB resulted in a 40% reduction of moderate-to-severe COPD exacerbations (rate ratio [95% CI]: 0.600 [0.439; 0.819], p=0.001), with a 47% reduction considering Chinese participants only (rate ratio [95% CI]: 0.526 [0.371; 0.746], p<0.001). Delay in time to first moderate-to-severe exacerbation was observed in patients treated with BDP/FF/GB compared to BUD/FF (Hazard Ratio [95% CI]:0.561 [0.407; 0.772], p<0.001). In the overall safety population, the rate of pneumonia was 64.2 and 99.6 /1000 patient-years on BDP/FF/GB and BUD/FF, respectively. CONCLUSIONS: Treatment with extra-fine BDP/FF/GB pMDI provided a significant reduction of moderate-to-severe exacerbations with a numerically lower rate of pneumonia compared to BUD/FF DPI in patients with COPD, severe airflow limitation and history of exacerbations. CLINICAL IMPLICATIONS: Treatment of severe COPD with extra-fine BDP/FF/GB pMDI can help address a significant unmet medical need in East Asia and specifically in China. DISCLOSURES: Employee relationship with Chiesi Farmaceutici Please note: $1001 - $5000 Added 03/23/2020 by Simonetta BALDI, source=Web Response, value=Salary Employee relationship with Chiesi Farmaceutici, S.p.A. Please note: >$100000 Added 03/20/2020 by George Georges, source=Web Response, value=Salary Employee relationship with Chiesi S.A.S Please note: $20001 - $100000 Added 03/27/2020 by FREDERIQUE GRAPIN, source=Web Response, value=Salary Employee relationship with Chiesi Farmaceutici S.p.A Please note: $20001 - $100000 Added 03/23/2020 by Alessandro Guasconi, source=Web Response, value=Salary No relevant relationships by Kwan Ho Lee, source=Web Response No relevant relationships by Zhao Li, source=Admin input no disclosure on file for Huiping Li; Advisory Committee Member relationship with Aastrazeneca, Chiesi, GSK, TEVA, menarini, novartis, Please note: $20001 - $100000 Added 03/23/2020 by Alberto Papi, source=Web Response, value=Honoraria Removed 03/23/2020 by Alberto Papi, source=Web Response Advisory Committee Member relationship with Astrazeneca, Chiesi, GSK, TEVA Please note: $5001 - $20000 Added 03/23/2020 by Alberto Papi, source=Web Response, value=Honoraria Advisory Committee Member relationship with edmondpharma, zambon, sanofi, Please note: $5001 - $20000 Added 03/23/2020 by Alberto Papi, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with AZ, GSK, Chiesi NOVARTIs, BI, sanofi, Zambon Please note: $5001 - $20000 Added 03/23/2020 by Alberto Papi, source=Web Response, value=Honoraria Consultant relationship with AstraZeneca Please note: $20001 - $100000 Added 03/23/2020 by Dave Singh, source=Web Response, value=Consulting fee Consultant relationship with Chiesi Please note: $20001 - $100000 Added 03/23/2020 by Dave Singh, source=Web Response, value=Consulting fee Consultant relationship with Novartis Please note: $1001 - $5000 Added 03/23/2020 by Dave Singh, source=Web Response, value=Consulting fee Consultant relationship with Boehinger Please note: $5001 - $20000 Added 03/23/2020 by Dave Singh, source=Web Response, value=Consulting fee Consultant relationship with GSK Please note: $5001 - $20000 Added 03/23/2020 by Dave Singh, source=Web Response, value=Consulting fee Consultant relationship with Menaini Please note: $5001 - $20000 Added 03/23/2020 by Dave Singh, source=Web Response, value=Consulting fee Consultant relationship with Therevance Please note: $1001 - $5000 Added 03/23/2020 by Dave Singh, source=Web Response, value=Consulting fee Consultant relationship with Cipla Please note: $1001 - $5000 Added 03/23/2020 by Dave Singh, source=Web Response, value=Consulting fee Advisory Committee Member relationship with AstraZeneca Please note: $1001 - $5000 Added 04/07/2020 by Jin-Ping Zheng, source=Admin input, value=Consulting fee Advisory Committee Member relationship with Boehringer Ingelheim Please note: $1-$1000 Added 04/07/2020 by Jin-Ping Zheng, source=Admin input, value=Consulting fee

Background Small airways dysfunction (SAD) is well recognised in asthma, yet its role in the severity and control of asthma is unclear. This study aimed to assess which combination of biomarkers, physiological tests, and imaging markers best measure the presence and extent of SAD in patients with asthma. Methods In this baseline assessment of a multinational prospective cohort study (the Assessment of Small Airways Involvement in Asthma [ATLANTIS] study), we recruited participants with and without asthma (defined as Global Initiative for Asthma severity stages 1-5) from general practices, the databases of chest physicians, and advertisements at 29 centres across nine countries (Brazil, China, Germany, Italy, Spain, the Netherlands, the UK, the USA, and Canada). All participants were aged 18-65 years, and participants with asthma had received a clinical diagnosis of asthma more than 6 months ago that had been confirmed by a chest physician. This diagnosis required support by objective evidence at baseline or during the past 5 years, which could be: positive airway hyperresponsiveness to methacholine, positive reversibility (a change in FEV 1 >= 12% and >= 200 mL within 30 min) after treatment with 400 mu g of salbutamol in a metered-dose inhaler with or without a spacer, variability in peak expiratory flow of more than 20% (measured over 7 days), or documented reversibility after a cycle (eg, 4 weeks) of maintenance anti-asthma treatment. The inclusion criteria also required that patients had stable asthma on any previous regular asthma treatment (including so-called rescue beta 2-agonists alone) at a stable dose for more than 8 weeks before baseline and had smoked for a maximum of 10 pack-years in their lifetime. Control group participants were recruited by advertisements; these participants were aged 18-65 years, had no respiratory symptoms compatible with asthma or chronic obstructive pulmonary disease, normal spirometry, and normal airways responsiveness, and had smoked for a maximum of 10 pack-years. We assessed all participants with spirometry, body plethysmography, impulse oscillometry, multiple breath nitrogen washout, CT (in selected participants), and questionnaires about asthma control, asthma-related quality of life (both in participants with asthma only), and health status. We applied structural equation modelling in participants with asthma to assess the contribution of all physiological and CT variables to SAD, from which we defined clinical SAD and CT SAD scores. We then classified patients with asthma into SAD groups with model-based clustering, and we compared asthma severity, control, and health-care use during the past year by SAD score and by SAD group. This trial is registered with ClinicalTrials.gov, number NCT02123667. Findings Between June 30, 2014, and March 3, 2017, we recruited and evaluated 773 participants with asthma and 99 control participants. All physiological measures contributed to the clinical SAD model with the structural equation modelling analysis. The prevalence of SAD in asthma was dependent on the measure used; we found the lowest prevalence of SAD associated with acinar airway ventilation heterogeneity (S-acin), an outcome determined by multiple breath nitrogen washout that reflects ventilation heterogeneity in the most peripheral, pre-acinar or acinar airways. Impulse oscillometry and spirometry results, which were used to assess dysfunction of small-sized to mid-sized airways, contributed most to the clinical SAD score and differed between the two SAD groups. Participants in clinical SAD group 1 (n= 452) had milder SAD than group 2 and comparable multiple breath nitrogen washout S-acin to control participants. Participants in clinical SAD group 2 (n= 312) had abnormal physiological SAD results relative to group 1, particularly their impulse oscillometry and spirometry measurements, and group 2 participants also had more severe asthma (with regard to asthma control, treatments, exacerbations, and quality of life) than group 1. Clinical SAD scores were higher (indicating more severe SAD) in group 2 than group 1, and we found that these scores were related to asthma control, severity, and exacerbations. We found no correlation between clinical SAD and CT SAD scores. Interpretation SAD is a complex and silent signature of asthma that is likely to be directly or indirectly captured by combinations of physiological tests, such as spirometry, body plethysmography, impulse oscillometry, and multiple breath nitrogen washout. SAD is present across patients with all severities of asthma, but it is particularly prevalent in severe disease. The clinical classification of SAD into two groups (a milder and a more severe group) by use of impulse oscillometry and spirometry, which are easy to use, is meaningful given its association with GINA severity stages, asthma control, quality of life, and exacerbations. Copyright (c) 2019 Elsevier Ltd. All rights reserved.

BACKGROUND:There is a paucity of studies comparing asthma and chronic obstructive pulmonary disease (COPD) based on thoracic quantitative computed tomographic (QCT) parameters. OBJECTIVES:We sought to compare QCT parameters of airway remodeling, air trapping, and emphysema between asthmatic patients and patients with COPD and explore their relationship with airflow limitation. METHODS:Asthmatic patients (n = 171), patients with COPD (n = 81), and healthy subjects (n = 49) recruited from a single center underwent QCT and clinical characterization. RESULTS:Proximal airway percentage wall area (%WA) was significantly increased in asthmatic patients (62.5% [SD, 2.2]) and patients with COPD (62.7% [SD, 2.3]) compared with that in healthy control subjects (60.3% [SD, 2.2], P < .001). Air trapping measured based on mean lung density expiratory/inspiratory ratio was significantly increased in patients with COPD (mean, 0.922 [SD, 0.037]) and asthmatic patients (mean, 0.852 [SD, 0.061]) compared with that in healthy subjects (mean, 0.816 [SD, 0.066], P < .001). Emphysema assessed based on lung density measured by using Hounsfield units below which 15% of the voxels lie (Perc15) was a feature of COPD only (patients with COPD: mean, -964 [SD, 19.62] vs asthmatic patients: mean, -937 [SD, 22.7] and healthy subjects: mean, -937 [SD, 17.1], P < .001). Multiple regression analyses showed that the strongest predictor of lung function impairment in asthmatic patients was %WA, whereas in the COPD and asthma subgrouped with postbronchodilator FEV1 percent predicted value of less than 80%, it was air trapping. Factor analysis of QCT parameters in asthmatic patients and patients with COPD combined determined 3 components, with %WA, air trapping, and Perc15 values being the highest loading factors. Cluster analysis identified 3 clusters with mild, moderate, or severe lung function impairment with corresponding decreased lung density (Perc15 values) and increased air trapping. CONCLUSIONS:In asthmatic patients and patients with COPD, lung function impairment is strongly associated with air trapping, with a contribution from proximal airway narrowing in asthmatic patients.

Currently, imaging in asthma is confined to chest radiography and CT. The emergence of new imaging techniques and tremendous improvement of existing imaging methods, primarily due to technological advancement, has completely changed its research and clinical prospects. In research, imaging in asthma is now being employed to provide quantitative assessment of morphology, function and pathogenic processes at the molecular level. The unique ability of imaging for non-invasive, repeated, quantitative, and in vivo assessment of structure and function in asthma could lead to identification of 'imaging biomarkers' with potential as outcome measures in future clinical trials. Emerging imaging techniques and their utility in the research and clinical setting is discussed in this review.

Background Inspiratory resistive breathing (IRB) challenges affect respiratory muscle endurance in healthy individuals, which is considered to be an interleukin 6 (IL-6)–dependent mechanism. Whether nonpharmacological thermal therapies promote the endurance of loaded inspiratory muscles in chronic obstructive pulmonary disease (COPD) is unclear. The objectives of this study were to compare the effects of two thermal interventions on endurance time (ET) and plasma IL-6 concentration following an IRB challenge. Methods This study was a randomized, parallel-group, unblinded clinical trial in a single-center setting. Forty-two patients (aged 42–76 years) suffering from mild to severe COPD participated in this study. Both groups completed 12 sessions of the mud bath therapy (MBT) (n=22) or leisure thermal activity (LTA) (n=19) in a thermal spa center in Italy. Pre- and postintervention spirometry, maximum inspiratory pressure, and plasma mediators were obtained and ET and endurance oxygen expenditure (VO2Endur) were measured following IRB challenge at 40% of maximum inspiratory pressure. Results There was no difference in ΔIL-6 between the intervention groups. But, IRB challenge increased cytokine IL-6 plasma levels systematically. The effect size was small. A statistically significant treatment by IRB challenge effect existed in ET, which significantly increased in the MBT group (P=0.003). In analysis of covariance treatment by IRB challenge analysis with LnVO2Endur as the dependent variable, ΔIL-6 after intervention predicted LnVO2Endur in the MBT group, but not in the LTA group. Adverse events occurred in two individuals in the MBT group, but they were mainly transient. One patient in the LTA group dropped out. Conclusion MBT model improves ET upon a moderate IRB challenge, indicating the occurrence of a training effect. The LnVO2Endur/ΔIL-6 suggests a physiologic adaptive mechanism in respiratory muscles of COPD patients allocated to treatment. Both thermal interventions are safe.

Objectives To explore the mediating role of protein interleukin-6 (IL-6) on the relationship between forced expiratory volume in 1 second (FEV1) and 6-minute walk distance (6MWD) and, further, to determine whether status variables (such as age, sex, and body mass index [BMI]) operate as moderators of this mediation relationship. Design Moderated mediation model. Setting An inpatient pulmonary rehabilitation center in Italy. Participants All 153 patients involved in the screening of a randomized controlled clinical trial (ClinicalTrials.gov identifier: NCT01253941) were included in this study. All patients were Global initiative for chronic Obstructive Lung Disease (GOLD) stages I–IV and were aged 70.1±9.1 years. Measurements At run-in phase of the protocol, clinical and functional screening included BMI, fasting plasma levels of protein (IL-6), spirometry, and standardized 6-minute walking test, measured at the start of the respiratory rehabilitation program. Methods The size of the indirect effect of the initial variable (FEV1) upon the outcome variable (6MWD) through the intervening variable (IL-6) was computed and tested for statistical significance. Moderated mediation analyses were subsequently conducted with age, sex, and BMI. Results FEV1 averaged 53.4%±21.2%, and 6MWD 66.4%±41.3% of predicted. Median protein IL-6 was 6.68 pg/mL (interquartile range: 5.96). A bootstrapped mediation test supported the predicted indirect pathway (P=0.003). The indirect effect through IL-6 log units accounted for 17% of the total effect between FEV1 and 6MWD. Age functioned as a significant moderator of the mediational pattern. For individuals aged <70 years, the standardized indirect effect was significant (0.122, 95% confidence interval [CI]: 0.044–0.254, P=0.004), and for individuals >70 years it was not significant (0.04, 95% CI: –0.010 to 0.142, P=0.10). Conclusion This moderated mediation result based on concurrent data suggests, but does not prove, a causal role of systemic inflammatory syndrome on progression from functional impairment to “frailty” status and substantial disability in aging chronic obstructive pulmonary disease.

To explore the causative role of cytokine IL6 blood levels on the relationship between FEV 1 and 6 minute walking distance (6MWD), 153 patients (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages I–IV) underwent measurement of fasting plasma levels of IL6, together with pulmonary function tests, standardized six minute walking test, and EuroQoL 5D questionnaire at the start of respiratory rehabilitation program at our Institution. We hypothesized a mediation model were effect of the initial variable X (FEV 1 ) upon the outcome variable Y (6MWD) is caused by the intervening variable M (IL6). A four steps causal approach was used by conducting three separate regression analyses. Out of 153 patients (120 males) 54, 28, 34, 37 were in GOLD stage I, II, III, and respectively IV. Mean age was 69,7±9,0 years. Mean FEV 1 averaged 54,3±23,5% of predicted, and 6MWD 295,6±135,7 meters (66,4±41,3% of predicted). Median cytokine IL6 was 6,68 (IQR: 5.87). Raw correlation coefficients for association of 6MWD on FEV 1 was: 0,518, of IL6, in log units, on FEV 1 : -0,283, and of 6MWD on IL6, in log units, -0,447, (p 1 upon walking performance decline by a systemic immune activation biomarker stands for a underlying pathological process that makes up heterogeneity of the syndrome of COPD, and might enable tailoring rehabilitation strategies to individual patients.

The effects of full lung inflation on respiratory conductance (Grs) and reactance (Xrs) were measured in 15 subjects with moderate to severe chronic obstructive pulmonary disease (COPD) and 11 matched healthy control subjects. Airway distensibility was estimated from the ratio of the difference of Grs between functional residual capacity and total lung capacity to the relevant changes in lung volume (ΔGrs/ΔVl) or transpulmonary pressure (ΔGrs/ΔPtp). Similar analysis was applied to Xrs to estimate lung volume recruitment (ΔXrs/ΔVl or ΔXrs/ΔPtp). The extent of emphysema in COPD subjects was estimated from the percentage of low attenuation area (LAA) at high-resolution computed tomography. At baseline, ΔGrs/ΔVl and ΔXrs/ΔVl were significantly less in COPD than control subjects, indicating less distensibility and volume recruitment in the former. In COPD, ΔGrs/ΔPtp and ΔXrs/ΔPtp were uncorrelated with LAA but correlated with 1-s forced expiratory volume and with each other. After albuterol, both ΔGrs/ΔPtp and ΔGrs/ΔVl became significantly and negatively correlated with LAA, while ΔXrs/ΔPtp and ΔXrs/ΔVl decreased significantly independently of LAA. Moreover, ΔGrs/ΔPtp and ΔXrs/ΔPtp with lung inflation were no longer correlated with each other, suggesting that airway distensibility and volume recruitment were affected differently by airway smooth muscle tone. Assuming that Grs mainly reflects airway caliber and Xrs the number of ventilated lung units, we conclude that airway smooth muscle contributes to airway stiffness and ventilation inhomogeneities in COPD subjects with prevailing bronchitis but only to the latter in those with more emphysema. We suggest that changes of airway distensibility and volume recruitment with a bronchodilator may be useful for disease phenotyping.

BACKGROUND:Fat-free mass (FFM) depletion marks the imbalance between tissue protein synthesis and breakdown in chronic obstructive pulmonary disease (COPD). To date, the role of essential amino acid supplementation (EAAs) in FFM repletion has not been fully acknowledged. A pilot study was undertaken in patients attending pulmonary rehabilitation. METHODS:28 COPD patients with dynamic weight loss > 5% over the last 6 months were randomized to receive EAAs embedded in a 12-week rehabilitation program (EAAs group n = 14), or to the same program without supplementation (C group n = 14). Primary outcome measures were changes in body weight and FFM, using dual X-ray absorptiometry (DEXA). RESULTS:At the 12th week, a body weight increment occurred in 92% and 15% of patients in the EAAs and C group, respectively, with an average increase of 3.8 +/- 2.6 kg (P = 0.0002) and -0.1 +/- 1.1 kg (P = 0.81), respectively. A FFM increment occurred in 69% and 15% of EAAs and C patients, respectively, with an average increase of 1.5 +/- 2.6 kg (P = 0.05) and -0.1 +/- 2.3 kg (P = 0.94), respectively. In the EAAs group, FFM change was significantly related to fasting insulin (r(2) 0.68, P < 0.0005), C-reactive protein (C-RP) (r(2) = 0.46, P < 0.01), and oxygen extraction tension (PaO(2x)) (r(2) = 0.46, P < 0.01) at end of treatment. These three variables were highly correlated in both groups (r > 0.7, P < 0.005 in all tests). CONCLUSIONS:Changes in FFM promoted by EAAs are related to cellular energy and tissue oxygen availability in depleted COPD. Insulin, C-RP, and PaO(2x) must be regarded as clinical markers of an amino acid-stimulated signaling to FFM accretion.

BACKGROUND:Arterial oxygen tension, oxygen delivery to tissue, and systemic inflammation are recognized as pivotal factors in the progression of chronic obstructive pulmonary disease (COPD). However, interconnections between systemic inflammation and tissue oxygen availability are scantly investigated. Tissue oxygen availability depends on arterial PaO2, oxygen concentration, hemoglobin oxygen affinity (P50), and hemoglobin oxygen binding capacity (ceHb). As the integrated changes of those indices are summarized by oxygen extraction tension (PaO2x), the objective of this study was to explore the association between C-reactive protein (CRP) blood levels and either PaO2x or each of its determinants, in stable COPD.MATERIALS AND METHODS:Blood CRP and oxygen status of arterial blood were measured at rest while breathing room air in 44 moderate to severe stable COPD patients. PaO2x was calculated along the shape of oxygen binding curve as the oxygen tension resulting from removal of 2.3 mmol of oxygen per liter of blood. Multiple linear regression analysis was performed with PaO2, ceHb, and P50 as independent variables, and CRP as the dependent variable, adjusting for age and sex. The analysis was repeated using PaO2x as a sole independent variable.RESULTS:Multiple linear regression analysis indicated that ceHb, PaO2, and P50, were significant and independent predictors of CRP (R2 = 0.52, p < 0.0001). PaO2x alone was an even stronger predictor of CRP (R2 = 0.62, p < 0.0001).CONCLUSIONS:These findings indicate that physiological determinants of tissue oxygen availability are independently associated with CRP blood levels. Thus, improvement of tissue oxygen availability is a central therapeutic option to modulate the severity of systemic inflammatory processes in patients with COPD.