Randomised controlled trial of adjunctive inspiratory muscle training for patients with COPD.

BACKGROUND: This study aimed to investigate whether adjunctive inspiratory muscle training (IMT) can enhance the well-established benefits of pulmonary rehabilitation (PR) in patients with COPD. METHODS: 219 patients with COPD (FEV1: 42%±16% predicted) with inspiratory muscle weakness (PImax: 51±15 cm H2O) were randomised into an intervention group (IMT+PR; n=110) or a control group (Sham-IMT+PR; n=109) in this double-blind, multicentre randomised controlled trial between February 2012 and October 2016 (ClinicalTrials.gov NCT01397396). Improvement in 6 min walking distance (6MWD) was a priori defined as the primary outcome. Prespecified secondary outcomes included respiratory muscle function and endurance cycling time. FINDINGS: No significant differences between the intervention group (n=89) and the control group (n=85) in improvements in 6MWD were observed (0.3 m, 95% CI -13 to 14, p=0.967). Patients who completed assessments in the intervention group achieved larger gains in inspiratory muscle strength (effect size: 1.07, p<0.001) and endurance (effect size: 0.79, p<0.001) than patients in the control group. 75 s additional improvement in endurance cycling time (95% CI 1 to 149, p=0.048) and significant reductions in Borg dyspnoea score at isotime during the cycling test (95% CI -1.5 to -0.01, p=0.049) were observed in the intervention group. INTERPRETATION: Improvements in respiratory muscle function after adjunctive IMT did not translate into additional improvements in 6MWD (primary outcome). Additional gains in endurance time and reductions in symptoms of dyspnoea were observed during an endurance cycling test (secondary outcome) TRIAL REGISTRATION NUMBER: NCT01397396; Results.

Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report. GOLD Executive Summary.

This Executive Summary of the Global Strategy for the Diagnosis, Management, and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 report focuses primarily on the revised and novel parts of the document. The most significant changes include: (1) the assessment of chronic obstructive pulmonary disease has been refined to separate the spirometric assessment from symptom evaluation. ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations; (2) for each of the groups A to D, escalation strategies for pharmacologic treatments are proposed; (3) the concept of deescalation of therapy is introduced in the treatment assessment scheme; (4) nonpharmacologic therapies are comprehensively presented; and (5) the importance of comorbid conditions in managing chronic obstructive pulmonary disease is reviewed.

Teamwork and Adherence to Recommendations Explain the Effect of a Care Pathway on Reduced 30-day Readmission for Patients with a COPD Exacerbation.

This study aimed to increase our understanding of processes that underlie the effect of care pathway implementation on reduced 30-day readmission rate. Adherence to evidence-based recommendations, teamwork and burnout have previously been identified as potential mechanisms in this association. We conducted a secondary data analysis of 257 patients admitted with chronic obstructive pulmonary disease exacerbation and 284 team members caring for these patients in 19 Belgian, Italian and Portuguese hospitals. Clinical measures included 30-day readmission and adherence to a specific set of five care activities. Teamwork measures included team climate for innovation, level of organized care and burnout (emotional exhaustion, level of competence and mental detachment). Care pathway implementation was significantly associated with better adherence and reduced 30-day readmission. Better adherence and higher level of competence were also related to reduced 30-day readmission. Only better adherence fully mediated the association between care pathway implementation and reduced 30-day readmission. Better team climate for innovation and level of organized care, although both improved after care pathway implementation, did not show any explanatory mechanisms in the association between care pathway implementation and reduced 30-day readmission. Implementation of a care pathway had an impact on clinical and team indicators. To reduce 30-day readmission rates, in the development and implementation of a care pathway, hospitals should measure adherence to evidence-based recommendations during the whole process, as this can give information regarding the success of implementation.

Withdrawal of inhaled glucocorticoids and exacerbations of COPD.

BACKGROUND: Treatment with inhaled glucocorticoids in combination with long-acting bronchodilators is recommended in patients with frequent exacerbations of severe chronic obstructive pulmonary disease (COPD). However, the benefit of inhaled glucocorticoids in addition to two long-acting bronchodilators has not been fully explored. METHODS: In this 12-month, double-blind, parallel-group study, 2485 patients with a history of exacerbation of COPD received triple therapy consisting of tiotropium (at a dose of 18 µg once daily), salmeterol (50 µg twice daily), and the inhaled glucocorticoid fluticasone propionate (500 µg twice daily) during a 6-week run-in period. Patients were then randomly assigned to continued triple therapy or withdrawal of fluticasone in three steps over a 12-week period. The primary end point was the time to the first moderate or severe COPD exacerbation. Spirometric findings, health status, and dyspnea were also monitored. RESULTS: As compared with continued glucocorticoid use, glucocorticoid withdrawal met the prespecified noninferiority criterion of 1.20 for the upper limit of the 95% confidence interval (CI) with respect to the first moderate or severe COPD exacerbation (hazard ratio, 1.06; 95% CI, 0.94 to 1.19). At week 18, when glucocorticoid withdrawal was complete, the adjusted mean reduction from baseline in the trough forced expiratory volume in 1 second was 38 ml greater in the glucocorticoid-withdrawal group than in the glucocorticoid-continuation group (P<0.001); a similar between-group difference (43 ml) was seen at week 52 (P=0.001). No change in dyspnea and minor changes in health status occurred in the glucocorticoid-withdrawal group. CONCLUSIONS: In patients with severe COPD receiving tiotropium plus salmeterol, the risk of moderate or severe exacerbations was similar among those who discontinued inhaled glucocorticoids and those who continued glucocorticoid therapy. However, there was a greater decrease in lung function during the final step of glucocorticoid withdrawal. (Funded by Boehringer Ingelheim Pharma; WISDOM ClinicalTrials.gov number, NCT00975195.).

Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary.

This Executive Summary of the Global Strategy for the Diagnosis, Management, and Prevention of COPD (GOLD) 2017 Report focuses primarily on the revised and novel parts of the document. The most significant changes include: 1) the assessment of chronic obstructive pulmonary disease has been refined to separate the spirometric assessment from symptom evaluation. ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations; 2) for each of the groups A to D, escalation strategies for pharmacological treatments are proposed; 3) the concept of de-escalation of therapy is introduced in the treatment assessment scheme; 4) nonpharmacologic therapies are comprehensively presented and; 5) the importance of comorbid conditions in managing COPD is reviewed.

A simple algorithm for the identification of clinical COPD phenotypes.

This study aimed to identify simple rules for allocating chronic obstructive pulmonary disease (COPD) patients to clinical phenotypes identified by cluster analyses.Data from 2409 COPD patients of French/Belgian COPD cohorts were analysed using cluster analysis resulting in the identification of subgroups, for which clinical relevance was determined by comparing 3-year all-cause mortality. Classification and regression trees (CARTs) were used to develop an algorithm for allocating patients to these subgroups. This algorithm was tested in 3651 patients from the COPD Cohorts Collaborative International Assessment (3CIA) initiative.Cluster analysis identified five subgroups of COPD patients with different clinical characteristics (especially regarding severity of respiratory disease and the presence of cardiovascular comorbidities and diabetes). The CART-based algorithm indicated that the variables relevant for patient grouping differed markedly between patients with isolated respiratory disease (FEV1, dyspnoea grade) and those with multi-morbidity (dyspnoea grade, age, FEV1 and body mass index). Application of this algorithm to the 3CIA cohorts confirmed that it identified subgroups of patients with different clinical characteristics, mortality rates (median, from 4% to 27%) and age at death (median, from 68 to 76 years).A simple algorithm, integrating respiratory characteristics and comorbidities, allowed the identification of clinically relevant COPD phenotypes.

Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary.

This Executive Summary of the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 Report focuses primarily on the revised and novel parts of the document. The most significant changes include: (i) the assessment of chronic obstructive pulmonary disease has been refined to separate the spirometric assessment from symptom evaluation. ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations; (ii) for each of the groups A to D, escalation strategies for pharmacological treatments are proposed; (iii) the concept of de-escalation of therapy is introduced in the treatment assessment scheme; (iv)non-pharmacological therapies are comprehensively presented and (v) the importance of co-morbid conditions in managing COPD is reviewed.

Automated Interpretation of Pulmonary Function Tests in Adults with Respiratory Complaints.

BACKGROUND: The use of pulmonary function tests is primarily based on expert opinion and international guidelines. Current interpretation strategies are using predefined cutoffs for the description of a typical pattern. OBJECTIVES: We aimed to explore the predicted disease outcome based on the American Thoracic Society/European Respiratory Society (ATS/ERS) interpreting strategy. Subsequently, we investigated whether an unbiased machine learning framework integrating lung function with clinical variables may provide alternative decision trees resulting in a more accurate diagnosis. METHODS: Our study included data from 968 subjects admitted for the first time to a pulmonary practice. The final clinical diagnosis was based on the combination of complete pulmonary function with the investigations that were decided at the physician's discretion. Clinical diagnoses were separated into 10 different groups and validated by an expert panel. RESULTS: The ATS/ERS algorithm resulted in a correct diagnostic label in 38% of the subjects. Chronic obstructive pulmonary disease (COPD) was detected with an acceptable accuracy (74%), whereas all other diseases were poorly identified. The new data-based decision tree improved the general accuracy to 68% after 10-fold cross-validation when detecting the most common lung diseases, with a significantly higher positive predictive value and sensitivity for COPD, asthma, interstitial lung disease, and neuromuscular disorder (83/78, 66/82, 52/59, and 100/54%, respectively). CONCLUSIONS: Our data show that the current algorithms for lung function interpretation can be improved by a computer-based choice of lung function and clinical variables and their decision-making thresholds.

Morphometric Analysis of Explant Lungs in Cystic Fibrosis.

RATIONALE: After repeated cycles of lung infection and inflammation, patients with cystic fibrosis (CF) evolve to respiratory insufficiency. Although histology and imaging have provided descriptive information, a thorough morphometric analysis of end-stage CF lung disease is lacking. OBJECTIVES: To quantify the involvement of small and large airways in end-stage CF. METHODS: Multidetector computed tomography (MDCT) and micro-CT were applied to 11 air-inflated CF explanted lungs and 7 control lungs to measure, count, and describe the airway and parenchymal abnormalities in end-stage CF lungs. Selected abnormalities were further investigated with thin section histology. MEASUREMENTS AND MAIN RESULTS: On MDCT, CF explanted lungs showed an increased median (interquartile range) number (631 [511-710] vs. 344 [277-349]; P = 0.003) and size of visible airways (cumulative airway diameter 217 cm [209-250] vs. 91 cm [80-105]; P < 0.001) compared with controls. Airway obstruction was seen, starting from generation 6 and increasing to 40 to 50% of airways from generation 9 onward. Micro-CT showed that the total number of terminal bronchioles was decreased (2.9/ml [2.6-4.4] vs. 5.3/ml [4.8-5.7]; P < 0.001); 49% were obstructed, and the cross-sectional area of the open terminal bronchioles was reduced (0.093 mm(2) [0.084-0.123] vs. 0.179 mm(2) [0.140-0.196]; P < 0.001). On micro-CT, 41% of the obstructed airways reopened more distally. This remodeling was confirmed on histological analysis. Parenchymal changes were also seen, mostly in a patchy and peribronchiolar distribution. CONCLUSIONS: Extensive changes of dilatation and obstruction in nearly all airway generations were observed in end-stage CF lung disease.

An International Study of Adherence to Guidelines for Patients Hospitalised with a COPD Exacerbation.

Guideline adherence rates for the treatment of chronic obstructive pulmonary disease (COPD) exacerbation are low. The aim of this study is to perform an importance-performance analysis as an approach for prioritisation of interventions by linking guidelines adherence rates to expert consensus rates for the in-hospital management of COPD exacerbation. We illustrate the relevance of such approach by describing variation in guideline adherence across indicators and hospitals. A secondary data analysis of patients with an acute COPD exacerbation admitted to Belgian, Italian and Portuguese hospitals was performed. Twenty-one process indicators were used to describe adherence to guidelines from patient record reviews. Expert consensus on the importance for follow-up of these 21 indicators was derived from a previous Delphi study. Three of the twenty-one indicators had high level of expert consensus and a high level of adherence. Eleven of the twenty-one indicators had high level of expert consensus but a low level of adherence. For none of the 378 patients included in this study were all process indicators adhered to, patients received 41.0% of the recommended care on average, and only 34.1% of the patients received 50% or more of the care they should receive. There was also a large variation within and between hospitals regarding the care received. This study confirms the findings of previous studies, indicating that COPD exacerbations are largely undertreated. Importance-performance analysis provides a decision-making tool for prioritising indicators. All hospitals in this study would benefit from having in place a quality framework for systematic follow-up of these indicators.

Evaluation of the effects of olodaterol on exercise endurance in patients with chronic obstructive pulmonary disease: results from two 6-week crossover studies.

BACKGROUND: Two replicate, double-blind, placebo-controlled, 6-week crossover studies assessed the effect of the once-daily long-acting ß2-agonist olodaterol 5 µg and 10 µg on constant work-rate cycle endurance in patients with moderate to very severe chronic obstructive pulmonary disease. METHODS: Patients received placebo, olodaterol 5 µg once daily (QD) and olodaterol 10 µg QD in a randomised order for 6 weeks each, with a 2-week washout period in between. The primary end point was change in endurance time during constant work-rate cycle ergometry to symptom limitation at 75 % maximal work capacity after 6 weeks of treatment (2 h post-dose), based on log10-transformed data. Key secondary end points were inspiratory capacity at isotime and intensity of breathing discomfort at isotime. RESULTS: 151 and 157 patients were randomised and treated in Studies 1222.37 and 1222.38, respectively, with 147 and 154 being included in the full analysis sets. Mean endurance time at week 6 was increased compared to placebo by 14.0 % (Study 1222.37; p < 0.001) and 11.8 % (Study 1222.38; p < 0.01) with olodaterol 5 µg, and by 13.8 % (Study 1222.37; p < 0.001) and 10.5 % (Study 1222.38; p < 0.01) with olodaterol 10 µg. Inspiratory capacity at isotime increased with olodaterol 5 µg (Study 1222.37, 0.182 L, p < 0.0001; Study 1222.38, 0.084 L, p < 0.05) and 10 µg (Study 1222.37, 0.174 L; Study 1222.38, 0.166 L; both studies, p < 0.0001), and breathing discomfort was significantly reduced in Study 1222.37 (olodaterol 5 µg, 0.77 Borg units, p < 0.001; olodaterol 10 µg, 0.63 Borg units, p < 0.01) but not Study 1222.38. CONCLUSIONS: These studies provide further characterisation of the efficacy of olodaterol, showing that improvements in airflow (forced expiratory volume in 1 s) are associated with increases in inspiratory capacity and improvements in exercise endurance time. TRIAL REGISTRATIONS: NCT01040130 (1222.37) and NCT01040793 (1222.38).

Defining a COPD composite safety endpoint for demonstrating efficacy in clinical trials: results from the randomized, placebo-controlled UPLIFT® trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) clinical trials evaluating hard endpoints (mortality, hospitalized exacerbations) require a large number of subjects and prolonged observational periods. We hypothesized that a composite endpoint of respiratory outcomes (CERO) can help evaluate safety and benefit in COPD trials. METHODS: Retrospective analysis of 5992 patients enrolled in the 4-year UPLIFT® trial, a randomized trial of tiotropium versus placebo in patients with moderate-to-severe COPD. Patients were permitted to continue using their usual COPD medications except for other anticholinergics. The CERO included deaths, respiratory failure, hospitalized exacerbations, and trial dropout due to COPD worsening. The incidence rates (IRs) per 100 patient-years and risk ratios (RRs and 95 % CI) were determined at years 1 to 4. The effect of treatments on CERO was similarly assessed. A power analysis helped calculate the sample size needed to achieve outcome differences between treatments. RESULTS: The CERO IRs at years 1 to 4 for tiotropium versus placebo were 16, 13, 11, and 11, and 21, 16, 14, and 13, respectively. The RRs of CERO between tiotropium and placebo at the same time points were: RR-year 0.76 (0.67, 0.86), 0.80 (0.72, 0.88), 0.81 (0.74, 0.89), and 0.84 (0.77, 0.92). Using the IRs and RRs, the sample size (alpha = 0.05 two-sided, 90 % power) for studies of 1, 2, 3, and 4 years would be 1546, 1392, 1216, and 1504 per treatment group, respectively, with 575, 810, 930, 1383 required events, respectively, for hypothetical, event-driven studies. CONCLUSIONS: A composite endpoint incorporating relatively infrequent serious or significant COPD-related safety outcomes could be useful in clinical trials. In UPLIFT®, CERO events were significantly reduced in patients receiving tiotropium compared with placebo. TRIAL REGISTRATION: NCT00144339 .

An Official American Thoracic Society/European Respiratory Society Statement: Research questions in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this Official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. METHODS: Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarized, and then salient knowledge gaps were identified. RESULTS: Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. CONCLUSIONS: Great strides have been made in the diagnosis, assessment, and management of COPD as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS Research Statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centered outcomes.

DNA methylation profiling of non-small cell lung cancer reveals a COPD-driven immune-related signature.

INTRODUCTION: Non-small cell lung cancer (NSCLC) is a heterogeneous disorder consisting of distinct molecular subtypes each characterised by specific genetic and epigenetic profiles. Here, we aimed to identify novel NSCLC subtypes based on genome-wide methylation data, assess their relationship with smoking behaviour, age, COPD, emphysema and tumour histopathology, and identify the molecular pathways underlying each subtype. METHODS: Methylation profiling was performed on 49 pairs of tumour and adjacent lung tissue using Illumina 450 K arrays. Transcriptome sequencing was performed using Illumina HiSeq2000 and validated using expression data from The Cancer Genome Atlas (TCGA). Tumour immune cell infiltration was investigated by immunohistochemistry. RESULTS: Unsupervised hierarchical clustering of tumour methylation data revealed two subgroups characterised by a significant association between cluster membership and presence of COPD (p=0.024). Ontology analysis of genes containing differentially methylated CpGs (false discovery rate, FDR-adjusted p<0.05) revealed that immune genes were strongly enriched in COPD tumours, but not in non-COPD tumours. This COPD-specific immune signature was attributable to methylation changes in immune genes expressed either by tumour cells or tumour-infiltrating immune cells. No such differences were observed in adjacent tissue. Transcriptome profiling similarly revealed that genes involved in the immune response were differentially expressed in COPD tumours (FDR-adjusted p<0.05), an observation that was independently replicated using TCGA data. Immunohistochemistry validated these findings, revealing fewer CD4-positive T lymphocytes in tumours derived from patients with COPD. CONCLUSIONS: Lung tumours of patients with COPD differ from those of patients without COPD, with differentially methylated and expressed genes being mainly involved in the immune response.

An official American Thoracic Society/European Respiratory Society statement: research questions in COPD.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) research statement is to describe evidence related to diagnosis, assessment and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS research statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centred outcomes.

Cardiac safety of tiotropium in patients with cardiac events: a retrospective analysis of the UPLIFT® trial.

BACKGROUND: Tiotropium is an anticholinergic bronchodilator for symptom relief and reducing exacerbations with an established safety profile in patients with chronic obstructive pulmonary disease (COPD). Using data from the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) study, we re-evaluated the safety of tiotropium HandiHaler® in patients who experienced recent myocardial infarction (MI), heart failure or unstable rhythm disorder during the study. METHODS: A post-hoc analysis of all-cause mortality and serious cardiac adverse events (cardiac SAEs), including cardiac deaths and death unknown, was conducted in patients who had experienced cardiac arrhythmia, MI or cardiac failure during UPLIFT® and who completed the study. Descriptive analyses were performed. RESULTS: Most patients experiencing cardiac events, for which they would have been excluded at baseline, remained in the trial. Kaplan-Meier analyses revealed a trend to later occurrence of cardiac SAEs with tiotropium HandiHaler® versus placebo. Patients who experienced a cardiac event and continued in UPLIFT® were not found to be at subsequently increased risk of all-cause mortality or cardiac SAEs with tiotropium treatment. Evaluation of deaths by major adverse cardiac events composite endpoints also showed that patients treated with tiotropium were not at increased risk of mortality or cardiac SAEs compared with placebo. CONCLUSIONS: Risk of cardiac events, mortality or SAEs was not increased by tiotropium in patients experiencing cardiac events for which they would have been excluded at study baseline. The findings support the cardiac safety of tiotropium HandiHaler® in patients with COPD.

Airways resistance and specific conductance for the diagnosis of obstructive airways diseases.

BACKGROUND: Airway resistance (RAW) and specific airway conductance (sGAW) are measures that reflect the patency of airways. Little is known of the variability of these measures between different lung diseases. This study investigated the contribution of RAW and sGAW to a diagnosis of obstructive airways disease and their role in differentiating asthma from COPD. METHODS: 976 subjects admitted for the first time to a pulmonary practice in Belgium were included. Clinical diagnoses were based on complete pulmonary function tests and supported by investigations of physicians' discretion. 651 subjects had a final diagnosis of obstructive diseases, 168 had another respiratory disease and 157 subjects had no respiratory disease (healthy controls). RESULTS: RAW and sGAW were significantly different (p < 0.0001) between obstructive and other groups. Abnormal RAW and sGAW were found in 39 % and 18 % of the population, respectively, in which 81 % and 90 % had diagnosed airway obstruction. Multiple regression revealed sGAW to be a significant and independent predictor of an obstructive disorder. To differentiate asthma from COPD, RAW was found to be more relevant and statistically significant. In asthma patients with normal FEV1/FVC ratio, both RAW and sGAW were more specific than sensitive diagnostic tests in differentiating asthma from healthy subjects. CONCLUSIONS: RAW and sGAW are significant factors that contribute to the diagnosis and differentiation of obstructive airways diseases.

Using dynamics of forced expiration to identify COPD where conventional criteria for the FEV1 /FVC ratio do not match.

BACKGROUND AND OBJECTIVE: The definition of chronic obstructive pulmonary disease (COPD) based on a fixed forced expiratory volume in 1 s (FEV1 )/forced vital capacity (FVC) ratio or on the lower limits of FEV1 /FVC of a healthy reference population is the subject of continuous debate. We explored whether dynamics of forced expiratory flow decline on spirometry can identify subjects with and without COPD when the two key diagnostic criteria are discordant. METHODS: Four hundred twenty-three individuals with a history of ≥15 pack-years smoking had pulmonary function measurements conducted. A second-order input-output model was used to describe the dynamics of the forced expiration. The capability of the model parameters to predict presence of disease was explored with a support vector machine classifier. In the discordant individuals, newly classified subjects were validated by other pulmonary function tests. RESULTS: In the non-discordant subjects (n = 370), the second-order model was able to confirm a diagnosis of COPD in 95% of subjects (n = 351). In the discordant individuals (n = 53), the classification by dynamic flow analysis found 28 patients to be healthy whereas 25 patients were still classified as COPD. Hyperinflation, increased airways resistance and reduced dynamic volumes were observed in the newly identified COPD group of discordant subjects. When using non-spirometry-based pulmonary function criteria as a standard for correct diagnoses in the individual discordant subjects, the model allocated 68% (n = 36) of the discordant to a correct diagnosis. CONCLUSIONS: Expiratory flow dynamics can detect airflow limitation and indicate the presence of COPD. In discordant subjects, our methodology allows a better identification of subjects with or without characteristics of COPD.

Minimal clinically important differences in pharmacological trials.

The concept of a minimal clinically important difference (MCID) is well established. Here, we review the evidence base and methods used to define MCIDs as well as their strengths and limitations. Most MCIDs in chronic obstructive pulmonary disease (COPD) are empirically derived estimates applying to populations of patients. Validated MCIDs are available for many commonly used outcomes in COPD, including lung function (100 ml for trough FEV1), dyspnea (improvement of ≥ 1 unit in the Transition Dyspnea Index total score or 5 units in the University of California, San Diego Shortness of Breath Questionnaire), health status (reduction of 4 units in the St George's Respiratory Questionnaire total score), and exercise capacity (47.5 m for the incremental shuttle walking test, 45-85 s for the endurance shuttle walking test, and 46-105 s for constant-load cycling endurance tests), but there is currently no validated MCID for exacerbations. In a clinical trial setting, many factors, including study duration, withdrawal rate, baseline severity, and Hawthorne effects, can influence the measured treatment effect and determine whether it reaches the MCID. We also address recent challenges presented by clinical trials that compare active treatments and suggest that MCIDs should be used to identify the additional proportion of patients who benefit, for example, when one drug is replaced by another or when a second drug is added to a first. We propose the term "minimum worthwhile incremental advantage" to describe this parameter.

Risk factors and comorbidities in the preclinical stages of chronic obstructive pulmonary disease.

RATIONALE: There is little information about comorbidities and their risk factors in the preclinical stages of chronic obstructive pulmonary disease (COPD). OBJECTIVES: This study aims to investigate the prevalence of premorbid risk factors and comorbid diseases and its association with daily physical activity in subjects detected with COPD by spirometry screening. METHODS: Sixty subjects with preclinical COPD (63 ± 6 yr; 68% [n = 41] male) were compared with 60 smoking control subjects (62 ± 7 yr; 70% [n = 42] male) and 60 never-smoking control subjects (62 ± 6 yr; 57% [n = 34] male). Comorbidities (cardiovascular, metabolic, and musculoskeletal disease) and daily physical activity (by multisensor activity monitor) were measured objectively. MEASUREMENTS AND MAIN RESULTS: The prevalence of premorbid risk factors and comorbid diseases was significantly higher in preclinical COPD compared with age-matched never-smoking control subjects, but was similar to smoking control subjects not suffering from COPD. In preclinical COPD and smoking control subjects, the combination of cardiovascular disease and musculoskeletal disease was the most prevalent (15% [n = 9] and 12% [n = 7], respectively). In a multivariate logistic regression analysis, physical inactivity and smoking were found to be independent risk factors for having greater than or equal to two comorbidities. CONCLUSIONS: Premorbid risk factors and comorbid diseases were more prevalent in the preclinical stages of COPD and smokers without COPD. Physical inactivity and smoking were more strongly associated with the presence of comorbidities compared with airflow obstruction. Clinical trial registered with www.clinicaltrials.gov (NCT 01314807).