[Development of two questionnaires for the assessment of knowledge and self-management in patients with chronic-obstructive pulmonary disease (COPD)]. / Entwicklung zweier Fragebögen zum Krankheitswissen und Umgang mit der Erkrankung für Patienten mit chronisch-obstruktiver Lungenerkrankung (COPD).

INTRODUCTION: As with other chronic diseases, the course of chronic obstructive pulmonary disease (COPD) can be expected to be positively influenced if patients are well informed about their disease and undertake appropriate self-management. Assessments of the level of knowledge and management that are comparable should benefit from structured, systematically developed questionnaires. These, however, have not been published in Germany. METHODS: A total of 310 patients with COPD were recruited from three pneumological practices and one hospital to develop the questionnaires. Based on statistical criteria and content assessments by medical specialists, two questionnaires on knowledge (17 questions) and self-management (25 questions) were developed by selecting and modifying questions from published studies and training programs. In addition, two short versions with 5 and 3 questions were created to enable a quick assessment of the patients' knowledge and self-management. All questionnaires also included a visual analogue scale for self-assessment of knowledge and self-management. The statistical procedures for systematically guided selection comprised correlation and regression analyses. RESULTS: The questionnaires revealed considerable knowledge deficits in many patients and remarkably unsystematic, incoherent knowledge. The extent of this knowledge was negatively correlated with higher age and positively correlated with participation in training programs; this also applied to self-management. Correlations between the answers to the knowledge questions were higher in patients who had participated in training programs. The visual analogue scales for self-assessment of knowledge and management always correlated with the total number of correct answers. DISCUSSION: The questionnaires on knowledge and self-management in patients with COPD could be used in outpatient settings, including by non-medical staff, in order to quickly identify and correct deficits or as a reason to recommend training programs. The short versions and the analogue scales for self-assessment can give at least first hints. Potentially, training programs should focus more on promoting the coherence of knowledge through better understanding, as this presumably favors long-term knowledge. Older patients and those with a low level of education appear to be particularly in need of specially adapted training programs.

Minimal clinically important difference for impulse oscillometry in adults with asthma.

BACKGROUND: Impulse oscillometry (IOS) allows an effort-independent evaluation of small airway function in asthma. Unfortunately, well-determined minimal clinically important differences (MCIDs) for IOS measures are lacking. Here, we provide MCIDs for frequently used IOS measures, namely frequency dependence of resistance (FDR) and area of reactance (AX), in patients with asthma. METHODS: We performed IOS at baseline and 1 year later in adult patients with mild-to-severe asthma (n=235). In a two-step approach, we first applied a distribution-based method to statistically determine the MCID. Next, we validated the proposed MCID according to patient-reported outcome measures (PROMs): Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Questionnaire-7 (ACQ-7) and Asthma Control Test (ACT). We used multivariable analyses to investigate the proposed MCIDs as predictors for improvements in PROMs compared with the established MCID of forced expiratory volume in 1 s (FEV1). RESULTS: The proposed MCID was a decline of ≥0.06 kPa·L-1·s-1 and ≥0.65 kPa·L-1 for FDR and AX, respectively. Patients who had changes beyond the MCIDs for both FDR and AX showed greater improvements in all PROMs than those who had not. The mean improvements in PROMs were beyond the established MCIDs for ACQ-7 and AQLQ, and approximated the MCID for ACT. Multivariable analyses demonstrated the MCIDs for both FDR and AX as independent predictors for the MCIDs of all PROMs. The MCID for FDR was a stronger predictor of all PROMs than the MCID for FEV1. CONCLUSIONS: This study provides MCIDs for IOS-derived measures in adult patients with asthma and emphasises that small airway function is a distinguished end-point beyond the conventional measure of FEV1.

Connecting real-world digital mobility assessment to clinical outcomes for regulatory and clinical endorsement-the Mobilise-D study protocol.

BACKGROUND: The development of optimal strategies to treat impaired mobility related to ageing and chronic disease requires better ways to detect and measure it. Digital health technology, including body worn sensors, has the potential to directly and accurately capture real-world mobility. Mobilise-D consists of 34 partners from 13 countries who are working together to jointly develop and implement a digital mobility assessment solution to demonstrate that real-world digital mobility outcomes have the potential to provide a better, safer, and quicker way to assess, monitor, and predict the efficacy of new interventions on impaired mobility. The overarching objective of the study is to establish the clinical validity of digital outcomes in patient populations impacted by mobility challenges, and to support engagement with regulatory and health technology agencies towards acceptance of digital mobility assessment in regulatory and health technology assessment decisions. METHODS/DESIGN: The Mobilise-D clinical validation study is a longitudinal observational cohort study that will recruit 2400 participants from four clinical cohorts. The populations of the Innovative Medicine Initiative-Joint Undertaking represent neurodegenerative conditions (Parkinson's Disease), respiratory disease (Chronic Obstructive Pulmonary Disease), neuro-inflammatory disorder (Multiple Sclerosis), fall-related injuries, osteoporosis, sarcopenia, and frailty (Proximal Femoral Fracture). In total, 17 clinical sites in ten countries will recruit participants who will be evaluated every six months over a period of two years. A wide range of core and cohort specific outcome measures will be collected, spanning patient-reported, observer-reported, and clinician-reported outcomes as well as performance-based outcomes (physical measures and cognitive/mental measures). Daily-living mobility and physical capacity will be assessed directly using a wearable device. These four clinical cohorts were chosen to obtain generalizable clinical findings, including diverse clinical, cultural, geographical, and age representation. The disease cohorts include a broad and heterogeneous range of subject characteristics with varying chronic care needs, and represent different trajectories of mobility disability. DISCUSSION: The results of Mobilise-D will provide longitudinal data on the use of digital mobility outcomes to identify, stratify, and monitor disability. This will support the development of widespread, cost-effective access to optimal clinical mobility management through personalised healthcare. Further, Mobilise-D will provide evidence-based, direct measures which can be endorsed by regulatory agencies and health technology assessment bodies to quantify the impact of disease-modifying interventions on mobility. TRIAL REGISTRATION: ISRCTN12051706.

IgA+ memory B-cells are significantly increased in patients with asthma and small airway dysfunction.

BACKGROUND: Comprehensive studies investigated the role of T-cells in asthma which led to personalised treatment options targeting severe eosinophilic asthma. However, little is known about the contribution of B-cells to this chronic inflammatory disease. In this study we investigated the contribution of various B-cell populations to specific clinical features in asthma. METHODS: In the All Age Asthma Cohort (ALLIANCE), a subgroup of 154 adult asthma patients and 28 healthy controls were included for B-cell characterisation by flow cytometry. Questionnaires, lung function measurements, blood differential counts and allergy testing of participants were analysed together with comprehensive data on B-cells using association studies and multivariate linear models. RESULTS: Patients with severe asthma showed decreased immature B-cell populations while memory B-cells were significantly increased compared with both mild-moderate asthma patients and healthy controls. Furthermore, increased frequencies of IgA+ memory B-cells were associated with impaired lung function and specifically with parameters indicative for augmented resistance in the peripheral airways. Accordingly, asthma patients with small airway dysfunction (SAD) defined by impulse oscillometry showed increased frequencies of IgA+ memory B-cells, particularly in patients with mild-moderate asthma. Additionally, IgA+ memory B-cells significantly correlated with clinical features of SAD such as exacerbations. CONCLUSIONS: With this study we demonstrate for the first time a significant association of increased IgA+ memory B-cells with asthma and SAD, pointing towards future options for B-cell-directed strategies in preventing and treating asthma.

Longitudinal Impact of Sputum Inflammatory Phenotypes on Small Airway Dysfunction and Disease Outcomes in Asthma.

BACKGROUND: Little is known about the relationship between airway inflammatory phenotypes and some important asthma features such as small airway dysfunction (SAD). OBJECTIVE: To describe the longitudinal impact of airway inflammatory phenotypes on SAD and asthma outcomes. METHODS: We measured eosinophil and neutrophil counts in induced sputum at baseline and 1 year later to stratify 197 adult patients with asthma into 4 inflammatory phenotypes. We conducted a comprehensive assessment of lung function using spirometry, body plethysmography, impulse oscillometry, and inert gas single and multiple breath washouts. We compared lung function, asthma severity, exacerbation frequency, and symptom control between the phenotypes. We studied the longitudinal impact of persistent sputum inflammatory phenotypes and the change of sputum cell counts on lung function. RESULTS: Patients were stratified into eosinophilic (23%, n = 45), neutrophilic (33%, n = 62), mixed granulocytic (22%, n = 43), and paucigranulocytic (24%, n = 47) phenotypes. Patients with eosinophilic and mixed granulocytic asthma had higher rates of airflow obstruction and severe exacerbation as well as poorer symptom control than patients with paucigranulocytic asthma. All SAD measures were worse in patients with eosinophilic and mixed asthma than in those with paucigranulocytic asthma (all P values <.05). Eosinophilic asthma also indicated worse distal airflow obstruction, increased ventilation inhomogeneity (all P values <.05), and higher tendency for severe exacerbation (P = .07) than neutrophilic asthma. Longitudinally, persistent mixed granulocytic asthma was associated with the worst follow-up measures of SAD compared with persistent neutrophilic, persistent paucigranulocytic, or nonpersistent asthma phenotypes. In patients with stable forced expiratory volume in 1 second (FEV1), the mean increase in small airway resistance (R5-20) was greater in patients with persistent mixed granulocytic asthma (+103%) than in patients with persistent neutrophilic (+26%), P = .040, or persistent paucigranulocytic asthma (-41%), P = .028. Multivariate models adjusted for confounders and treatment with inhaled or oral corticosteroids or antieosinophilic biologics indicated that the change of sputum eosinophil rather than neutrophil counts is an independent predictor for the longitudinal change in FEV1, forced expiratory flow at 25% to 75% of forced vital capacity, specific effective airway resistance, residual lung volume, and lung clearance index. CONCLUSIONS: In asthma, airway eosinophilic inflammation is the main driver of lung function impairment and poor disease outcomes, which might also be aggravated by the coexistence of airway neutrophilia to confer a severe mixed granulocytic asthma phenotype. Persistent airway eosinophilia might be associated with dynamic SAD even in patients with stable FEV1.

T2-high asthma phenotypes across lifespan.

RATIONALE: In adults, personalised asthma treatment targets patients with type 2 (T2)-high and eosinophilic asthma phenotypes. It is unclear whether such classification is achievable in children. OBJECTIVES: To define T2-high asthma with easily accessible biomarkers and compare resulting phenotypes across all ages. METHODS: In the multicentre clinical All Age Asthma Cohort (ALLIANCE), 1125 participants (n=776 asthmatics, n=349 controls) were recruited and followed for 2 years (1 year in adults). Extensive clinical characterisation (questionnaires, blood differential count, allergy testing, lung function and sputum induction (in adults)) was performed at baseline and follow-ups. Interleukin (IL)-4, IL-5 and IL-13 were measured after stimulation of whole blood with lipopolysaccharide (LPS) or anti-CD3/CD28. MEASUREMENTS AND MAIN RESULTS: Based on blood eosinophil counts and allergen-specific serum IgE antibodies, patients were categorised into four mutually exclusive phenotypes: "atopy-only", "eosinophils-only", "T2-high" (eosinophilia + atopy) and "T2-low" (neither eosinophilia nor atopy). The T2-high phenotype was found across all ages, even in very young children in whom it persisted to a large degree even after 2 years of follow-up. T2-high asthma in adults was associated with childhood onset, suggesting early origins of this asthma phenotype. In both children and adults, the T2-high phenotype was characterised by excessive production of specific IgE to allergens (p<0.0001) and, from school age onwards, by increased production of IL-5 after anti-CD3/CD28 stimulation of whole blood. CONCLUSIONS: Using easily accessible biomarkers, patients with T2-high asthma can be identified across all ages delineating a distinct phenotype. These patients may benefit from therapy with biologicals even at a younger age.

The Relevance of Small Airway Dysfunction in Asthma with Nocturnal Symptoms.

RATIONALE: Small airway dysfunction (SAD) is a frequent feature of asthma that has been linked to disease severity and poor symptom control. However, little is known about the role of SAD in nocturnal asthma. OBJECTIVE: To study the association between the severity of SAD and frequency of nocturnal symptoms compared to conventional lung function testing. METHODS: We assessed the frequency of self-reported nocturnal symptoms through the asthma control test. We studied the impact of nocturnal asthma using the Asthma Quality of Life Questionnaire (AQLQ) and the Multidimensional Fatigue Inventory (MFI-20). We assessed the lung function using spirometry, body plethysmography, impulse oscillometry, single and multiple inert gas washout and measured markers of T2-inflammation (blood and sputum eosinophils; fractional exhaled nitric oxide (FeNo)). We stratified the patients according to the presence and frequency of nocturnal asthma. RESULTS: A total of 166 asthma patients were enrolled in the analysis. Eighty-seven patients (52%) reported to have nocturnal symptoms at least once in the last four weeks. The odds ratio of nocturnal asthma correlated with the severity of all non-spirometric measures of SAD, yet neither with airflow obstruction (FEV1 and FEV/FVC) nor with large airway resistance (R20). Patients with frequent nocturnal asthma (n = 29) had a numerical increase of T2 markers and more severe SAD, as indicated by all non-spirometric measures of SAD (all p-values < 0.05), worse overall asthma control, increased fatigue and reduced quality of life (all p-values < 0.01) compared to patients with infrequent nocturnal asthma (n = 58) or patients without nocturnal asthma (n = 79). We identified 63 patients without airflow obstruction, nearly 43% of them (n = 27) had nocturnal asthma. In this subgroup, only markers of air trapping and ventilation heterogeneity were significantly elevated and correlated with the frequency of nocturnal symptoms: LCI (Spearman's coefficient = -0.42, p < 0.001), RV% (-0.32, p = 0.02). CONCLUSION: SAD is closely associated to asthma with nocturnal symptoms. Spirometry might underestimate the broad spectrum of distal lung function impairments in this population of patients.

Raised sputum extracellular DNA confers lung function impairment and poor symptom control in an exacerbation-susceptible phenotype of neutrophilic asthma.

BACKGROUND: Extracellular DNA (e-DNA) and neutrophil extracellular traps (NETs) are linked to asthmatics airway inflammation. However, data demonstrating the characterization of airway inflammation associated with excessive e-DNA production and its impact on asthma outcomes are limited. OBJECTIVE: To characterize the airway inflammation associated with excessive e-DNA production and its association with asthma control, severe exacerbations and pulmonary function, particularly, air trapping and small airway dysfunction. METHODS: We measured e-DNA concentrations in induced sputum from 134 asthma patients and 28 healthy controls. We studied the correlation of e-DNA concentrations with sputum neutrophils, eosinophils and macrophages and the fractional exhaled nitric oxide (FeNO). Lung function was evaluated using spirometry, body plethysmography, impulse oscillometry and inert gas multiple breath washout. We stratified patients with asthma into low-DNA and high-DNA to compare lung function impairments and asthma outcomes. RESULTS: Patients with severe asthma had higher e-DNA concentration (54.2 ± 42.4 ng/µl) than patients with mild-moderate asthma (41.0 ± 44.1 ng/µl) or healthy controls (26.1 ± 16.5 ng/µl), (all p values < 0.05). E-DNA concentrations correlated directly with sputum neutrophils (R = 0.49, p < 0.0001) and negatively with sputum macrophages (R = - 0.36, p < 0.0001), but neither with sputum eosinophils (R = 0.10, p = 0.26), nor with FeNO (R = - 0.10, p = 0.22). We found that 29% of asthma patients (n = 39) had high e-DNA concentrations above the upper 95th percentile value in healthy controls (55.6 ng /µl). High-DNA was associated with broad lung function impairments including: airflow obstruction of the large (FEV1) and small airways (FEF50%, FEF25-75), increased air trapping (RV, RV/TLC), increased small airway resistance (R5-20, sReff), decreased lung elasticity (X5Hz) and increased ventilation heterogeneity (LCI), (all P values < 0.05). We also found that high e-DNA was associated with nearly three-fold greater risk of severe exacerbations (OR 2·93 [95% CI 1.2-7.5]; p = 0·012), worse asthma control test (p = 0.03), worse asthma control questionnaire scores (p = 0.01) and higher doses of inhaled corticosteroids (p = 0.026). CONCLUSION: Increased production of extracellular DNA in the airway characterizes a subset of neutrophilic asthma patients who have broad lung function impairments, poor symptom control and increased risk of severe exacerbations.

Small Airway Dysfunction Links Asthma Severity with Physical Activity and Symptom Control.

BACKGROUND: Little is known about the role of small airway dysfunction (SAD) and its complex relation with asthma control and physical activity (PA). OBJECTIVE: To investigate the interrelations among SAD, risk factors for asthma severity, symptom control, and PA. METHODS: We assessed SAD by impulse oscillometry and other sophisticated lung function measures including inert gas washout in adults with asthma (mild to moderate, n = 140; severe, n = 128) and 69 healthy controls from the All Age Asthma Cohort. We evaluated SAD prevalence and its interrelation with risk factors for asthma severity (older age, obesity, and smoking), type 2 inflammation (sputum and blood eosinophils, fractional exhaled nitric oxide), systemic inflammation (high-sensitivity C-reactive protein), asthma control (AC), and PA (accelerometer for 1 week). We applied a clinical model based on structural equation modeling that integrated causal pathways among these clinical variables. RESULTS: The prevalence of SAD ranged from 75% to 90% in patients with severe asthma and from 53% to 64% in mild to moderate asthma. Severe SAD was associated with poor AC and low PA. Structural equation modeling indicated that age, obesity, obesity-related systemic inflammation, T2 inflammation, and smoking are independent predictors of SAD. Small airway dysfunction was the main determinant factor of AC, which in turn affected PA. Obesity affected AC directly and through its contribution to SAD and low PA. In addition, PA had bidirectional associations with obesity, SAD, and AC. Structural equation modeling also indicated interrelations among distal airflow limitation, air trapping, and ventilation heterogeneity. CONCLUSIONS: Small airway dysfunction is a highly prevalent key feature of asthma that interrelates a spectrum of distal lung function abnormalities with risk factors for asthma severity, asthma control, and physical activity.

Influence of Cell Quality on Inflammatory Biomarkers in COPD Sputum Supernatant.

PURPOSE: We recently introduced a sputum cell quality score to rate how cell morphology, cellular debris and squamous cell contamination influence inflammatory cell identification during microscopic evaluation. However, sputum cell quality is generally not considered for the interpretation of sputum fluid phase biomarkers. Therefore, we compared the soluble protein concentrations between sputum samples with different cell quality. The impact of cell quality was compared to other factors potentially affecting soluble biomarker concentrations. METHODS: A comprehensive sputum dataset from 154 clinically stable COPD patients was used to analyse the differences and the variability of sputum supernatant concentrations for 23 proteins between low, medium, and high sputum cell quality samples. A model was developed and tested to compare the impact of different factors on sputum supernatant protein levels. RESULTS: Mean percentages of sputum macrophages, neutrophils, eosinophils, monocytes and lymphocytes showed no significant differences between low, medium and high cell quality levels. The mean percentage of squamous cells were lower, while total cell count/mL sputum and cell viability were significantly higher in sputum samples with higher cell quality. The concentrations of Interleukin-6, Interleukin-8 and Tumor Necrosis Factor Receptor 2 were significantly increased in sputum samples of higher cell quality. The variability of most protein concentrations declined with increasing cell quality levels. Sixteen proteins showed significantly negative correlations with the percentage of squamous cells. For 14 proteins we observed a positive correlation with cell number/mL sputum. Multiple regression analysis shows that generally less than 30% of the protein variability can be explained by the included factors. CONCLUSION: Sputum cell quality has a significant impact on some soluble biomarker concentrations in sputum supernatant. Sputum samples with low sputum cell quality show a higher variability of fluid phase proteins in comparison to medium and high sputum cell quality levels.

Persistent Uncontrolled Asthma: Long-Term Impact on Physical Activity and Body Composition.

RATIONALE: Asthma, obesity and physical activity (PA) are interrelated. However, longitudinal data with objective PA measures and direct assessment of body composition are still lacking. OBJECTIVE: To study the impact of symptom control on PA and body composition. METHODS: In a longitudinal cohort study of the German Center for Lung Research, we assessed the body composition of 233 asthma patients and 84 healthy controls using bioelectrical impedance analysis. PA (ie average daily steps and time of at least moderate activity, steps/min) was measured by accelerometry for one week. Asthma control was assessed by ACT score, ACQ-5 score and history of severe exacerbations. After two years of follow-up, we studied changes in physical activity and body composition in relation to asthma control. RESULTS: Patients with uncontrolled asthma had increased fat mass and decreased muscle mass compared to patients with controlled asthma or healthy controls. Both fat mass and muscle mass correlated better with asthma control than the body mass index (BMI). In multivariate regressions adjusted for age and sex, asthma control and physical activity were independent predictors of body composition (R2 = 0.61, p < 0.001). Persistent uncontrolled asthma patients (n=64) had lower physical activity at both baseline (6614 steps/118 min) and follow-up (6195/115). Despite having stable BMI, they also had significant muscle loss (-1.2%, -0.88 kg, p<0.01) and fat accumulation (+1%, +1.1 kg, p<0.01). By contrast, temporarily uncontrolled or controlled asthma patients had higher physical activity at baseline (8670/156) and follow -up (9058/153) with almost unchanged body composition. CONCLUSION: Persistent uncontrolled asthma is associated with sustained physical inactivity and adverse changes in body composition that might be overlooked by relying solely on BMI. Physical activity is an independent predictor of body composition and reliable long-term marker of symptom control.

Exploration of the sputum methylome and omics deconvolution by quadratic programming in molecular profiling of asthma and COPD: the road to sputum omics 2.0.

BACKGROUND: To date, most studies involving high-throughput analyses of sputum in asthma and COPD have focused on identifying transcriptomic signatures of disease. No whole-genome methylation analysis of sputum cells has been performed yet. In this context, the highly variable cellular composition of sputum has potential to confound the molecular analyses. METHODS: Whole-genome transcription (Agilent Human 4 × 44 k array) and methylation (Illumina 450 k BeadChip) analyses were performed on sputum samples of 9 asthmatics, 10 healthy and 10 COPD subjects. RNA integrity was checked by capillary electrophoresis and used to correct in silico for bias conferred by RNA degradation during biobank sample storage. Estimates of cell type-specific molecular profiles were derived via regression by quadratic programming based on sputum differential cell counts. All analyses were conducted using the open-source R/Bioconductor software framework. RESULTS: A linear regression step was found to perform well in removing RNA degradation-related bias among the main principal components of the gene expression data, increasing the number of genes detectable as differentially expressed in asthma and COPD sputa (compared to controls). We observed a strong influence of the cellular composition on the results of mixed-cell sputum analyses. Exemplarily, upregulated genes derived from mixed-cell data in asthma were dominated by genes predominantly expressed in eosinophils after deconvolution. The deconvolution, however, allowed to perform differential expression and methylation analyses on the level of individual cell types and, though we only analyzed a limited number of biological replicates, was found to provide good estimates compared to previously published data about gene expression in lung eosinophils in asthma. Analysis of the sputum methylome indicated presence of differential methylation in genomic regions of interest, e.g. mapping to a number of human leukocyte antigen (HLA) genes related to both major histocompatibility complex (MHC) class I and II molecules in asthma and COPD macrophages. Furthermore, we found the SMAD3 (SMAD family member 3) gene, among others, to lie within differentially methylated regions which has been previously reported in the context of asthma. CONCLUSIONS: In this methodology-oriented study, we show that methylation profiling can be easily integrated into sputum analysis workflows and exhibits a strong potential to contribute to the profiling and understanding of pulmonary inflammation. Wherever RNA degradation is of concern, in silico correction can be effective in improving both sensitivity and specificity of downstream analyses. We suggest that deconvolution methods should be integrated in sputum omics analysis workflows whenever possible in order to facilitate the unbiased discovery and interpretation of molecular patterns of inflammation.

Small airway dysfunction as predictor and marker for clinical response to biological therapy in severe eosinophilic asthma: a longitudinal observational study.

BACKGROUND: Anti-T2 biological therapies have proven to effectively reduce acute exacerbations and daily doses of oral steroids in severe eosinophilic asthma. Despite the remarkable clinical efficacy, there are usually only moderate improvements in airflow limitation, suggesting that other measures of lung function like small airway dysfunction (SAD) might better reflect the clinical response. We aimed to investigate if measures of small airway function would predict and correlate with the clinical response to anti-T2 therapy. METHODS: We studied data of patients who were previously included in the German prospective longitudinal All Age Asthma Cohort (ALLIANCE) that recruits asthma patients of all severity grades and inflammatory phenotypes. The selection criteria for this analysis were adult patients with severe eosinophilic asthma under treatment with anti-T2 biological agents. Asthma control was assessed by asthma control test (ACT) and number of severe exacerbations. Small airway function was assessed by the frequency dependence of resistance (FDR, R5-20)) derived from impulse oscillometry (IOS) and the mean forced expiratory flow between 25 and 75% of the forced vital capacity (FEF25-75). We also studied air trapping (RV and RV/TLC), blood eosinophils and FeNO. Patients were classified into responders and partial or non-responders. Clinical response was defined as at least 50% reduction in annualized severe exacerbations and daily oral steroid doses accompanied with a minimum increase of 3 points in the ACT score. We used a Receiver Operator Characteristic (ROC) to study the capacity of FDR in predicting clinical response compared to other clinical variable like blood eosinophils. We studied the correlation between FDR measures and clinical response, represented by the ACT score and number of exacerbations, using linear regressions. RESULTS: 20 patients were included (mean age, 59 ± 9 years; 60% female; mean body mass index (BMI), 27.6 ± 5.4 kg/m2; mean absolute blood eosinophils, 570 ± 389/µl; mean number of severe exacerbations 12 months prior to initiating the biological therapy, 5.0 ± 3; mean predicted FEV1, 76 ± 21%; mean predicted FDR, 224 ± 140%; mean daily prednisolone dose, 6.4 ± 4.9 mg; mean ACT score, 15 ± 5). Responders had significantly higher baseline FDR compared to partial or non-responders but similar FEV1, FEF25-75, RV and RV/TLC. ROC analysis showed that the combination of FDR and blood eosinophils had the best predictive capacity of the clinical response among all tested clinical markers (FeNO, FEV1, FDR, blood eosinophils) with an AUC of 85% [67-100%], (CI = 0.95, p = 0.01). Linear regressions indicated better associations between improvements in FDR and ACT score (R2 = 0.42, p = 0.001) than with FEV1 and ACT score (R2 = 0.25, p = 0.013). Likewise, we observed better associations between improvements in FDR and reduction of exacerbations (R2 = 0.41, p = 0.001) than with FEV1 (R2 = 0.20, p = 0.025). CONCLUSION: Our data suggest that severe SAD may represent a distinct phenotype of eosinophilic asthma that substantially improves under anti-T2 biological therapy. Measures of small airway function might be useful in selecting appropriate patients qualifying for anti-T2 biological therapy in addition to blood eosinophil count.

Impact of a Nurse-Led Advance Care Planning Intervention on Satisfaction, Health-Related Quality of Life, and Health Care Utilization Among Patients With Severe Respiratory Disease: A Randomized Patient-Preference Trial.

CONTEXT: Previous work has found that facilitated advance care planning (ACP) interventions are effective in increasing ACP uptake among patients with severe respiratory disease. OBJECTIVES: The objective of this study was to investigate whether a nurse-led, facilitated ACP intervention among participants with severe respiratory disease impacts self-reported or clinical outcomes. METHODS: A multicenter, open-label, patient-preference, randomized controlled trial of a nurse-led facilitated ACP intervention was performed. Outcome measures included self-report scales (health care satisfaction and EQ-5D-5L health-related quality of life at three- and six-month follow-up), 12-month mortality, and health care utilization during the final 90 days of life. RESULTS: One hundred forty-nine participants were recruited across two study settings (metropolitan tertiary hospital respiratory department and rural sites) and 106 were allocated to receive the ACP intervention. There was no effect of the intervention on satisfaction with health care, health-related quality of life, or 12-month mortality rates. Among those participants who died during the follow-up period (N = 54), those allocated to the ACP intervention had significantly fewer outpatient consultations (7.51 vs. 13.6, P < 0.001). There were no changes in emergency department attendances, total hospital admissions or length of stay, or home nursing visits. Among those allocated to the ACP intervention, there was a reduced length of stay in acute hospital settings (7.76 vs. 11.5 nights, P < 0.001) and increased length of stay in palliative hospital settings (5.54 vs. 2.08, P < 0.001) during the final 90 days of life. CONCLUSION: A facilitated ACP intervention among patients with severe respiratory disease did not have an impact on satisfaction, health-related quality of life, or 12-month mortality rate. Facilitated ACP may be associated with a different type of health care utilization during the end-of-life period.

Safety and efficacy of the human neutrophil elastase inhibitor BAY 85-8501 for the treatment of non-cystic fibrosis bronchiectasis: A randomized controlled trial.

BACKGROUND: There are only limited treatment options for patients with non-cystic fibrosis bronchiectasis (non-CF BE). Human neutrophil elastase (HNE) is a mediator of tissue destruction in non-CF BE. BAY 85-8501, a selective and reversible HNE inhibitor, could represent a new treatment option for this disease. METHODS: This was a phase 2a, randomized, placebo-controlled, double-blind, parallel-group study. The primary objective was to assess the safety and tolerability of 1 mg BAY 85-8501 once daily (OD) for 28 days compared with placebo in patients with non-CF BE. Secondary objectives were to investigate the effects of 4 weeks of treatment with BAY 85-8501 on health-related quality of life, pulmonary function, and inflammatory and tissue damage biomarkers in sputum, blood and/or urine, and to evaluate the pharmacokinetics of BAY 85-8501. RESULTS: Overall, 94 patients (mean age, 66 years; 53% male) were randomized (n = 47 per group), and 82 completed the study (BAY 85-8501, n = 37; placebo, n = 45). Treatment-emergent adverse events (TEAEs) occurred in 31 patients (66%) taking BAY 85-8501 and in 36 patients (77%) taking placebo, and were mostly mild or moderate. The serious TEAEs (BAY 85-8501, n = 3; placebo, n = 1) were not considered to be study-drug related. There were no changes in pulmonary function parameters from baseline to end of treatment, and health-related quality of life did not improve in any group. HNE activity in blood after zymosan challenge decreased significantly with BAY 85-8501 treatment (P = 0.0250 versus placebo). There were no significant differences in other biomarkers between treatment groups, with the exception of a small increase in interleukin-8 levels in sputum in the BAY 85-8501 group. Trough plasma concentrations of BAY 85-8501 plateaued after 2 weeks. CONCLUSIONS: 1 mg BAY 85-8501 OD had a favourable safety and tolerability profile when administered for 28 days to patients with non-CF BE. Further studies with a longer treatment duration are needed to evaluate the potential clinical efficacy in this study population.

Dual bronchodilation with tiotropium/olodaterol further reduces activity-related breathlessness versus tiotropium alone in COPD.

The 3-min constant speed shuttle test (CSST) was used to examine the effect of tiotropium/olodaterol compared with tiotropium at reducing activity-related breathlessness in patients with chronic obstructive pulmonary disease (COPD).This was a randomised, double-blind, two-period crossover study including COPD patients with moderate to severe pulmonary impairment, lung hyperinflation at rest and a Mahler Baseline Dyspnoea Index <8. Patients received 6 weeks of tiotropium/olodaterol 5/5 µg and tiotropium 5 µg in a randomised order with a 3-week washout period. The speed for the 3-min CSST was determined for each patient such that an intensity of breathing discomfort ≥4 ("somewhat severe") on the modified Borg scale was reached at the end of a completed 3-min CSST.After 6 weeks, there was a decrease in the intensity of breathlessness (Borg dyspnoea score) at the end of the 3-min CSST from baseline with both tiotropium (mean -0.968, 95% CI -1.238- -0.698; n=100) and tiotropium/olodaterol (mean -1.325, 95% CI -1.594- -1.056; n=101). The decrease in breathlessness was statistically significantly greater with tiotropium/olodaterol versus tiotropium (treatment difference -0.357, 95% CI -0.661- -0.053; p=0.0217).Tiotropium/olodaterol reduced activity-related breathlessness more than tiotropium in dyspnoeic patients with moderate to severe COPD exhibiting lung hyperinflation.

[The stepwise approach of COPD therapy]. / Stufentherapie der COPD.

The goal of pharmacologic therapy of stable chronic obstructive pulmonary disease (COPD) is to reduce symptoms, improve exercise intolerance and health-related quality of life, and to reduce exacerbations. Inhaled long-acting ß2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are equally effective for the symptomatic management of COPD. However, LAMAs are more effective than LABAs in the reduction of exacerbations. In patients with symptomatic COPD pharmacologic therapy is usually escalated using the fixed combination of LAMAs and LABAs (dual bronchodilation), which is also superior to LAMA monotherapy in the prevention of exacerbations. Adding inhaled corticosteroids (ICS) to LABA and LAMA (triple therapy) for a prevention of exacerbations results in a further reduction of exacerbations, especially in those patients with higher blood eosinophil counts. Non-pharmacologic management of COPD patients includes smoking cessation programs, vaccination, pulmonary rehabilitation, and strategies to improve or maintain their physical activity.