Paul Albert

Bronchodilator responsiveness as a phenotypic characteristic of established chronic obstructive pulmonary disease

Background Bronchodilator responsiveness is a potential phenotypic characteristic of chronic obstructive pulmonary disease (COPD). We studied whether change in lung function after a bronchodilator is abnormal in COPD, whether stable responder subgroups can be identified, and whether these subgroups experience different clinical outcomes. Methods 1831 patients with COPD, 285 smoking (SC) and 228 non-smoking (NSC) controls from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort. Spirometric reversibility to 400 μg inhaled salbutamol was assessed on four occasions over 1 year. Results Forced expiratory volume in 1 s (FEV1) increase after salbutamol was similar in SC (mean 0.14 litres (SD 0.15)) and COPD (0.12 litres (0.15)) and was significantly greater than NSC (0.08 litres (0.14)). Reversibility status varied with repeated testing in parallel with the day-to-day variation in pre-bronchodilator FEV1, which was similar in control subjects and patients with COPD. Absolute FEV1 change decreased by Global initiative for chronic Obstructive Lung Disease (GOLD) stage in patients with COPD (GOLD II, mean 0.16 litres (SD 0.17); III, 0.10 litres (0.13); IV, 0.05 litres (0.08) as did chances of being classified as reversible. CT-defined emphysema was weakly related to the absolute change in FEV1 post salbutamol. Consistently reversible patients (n=227) did not differ in mortality, hospitalisation or exacerbation experience from irreversible patients when allowing for differences in baseline FEV1. Limitations Reversibility only assessed with salbutamol and defined by FEV1 criteria. The COPD population was older than the control populations. Conclusions Post-salbutamol FEV1 change is similar in patients with COPD and smoking controls but is influenced by baseline lung function and the presence of emphysema. Bronchodilator reversibility status varies temporally and does not distinguish clinically relevant outcomes, making it an unreliable phenotype. Clinical trial registration number NCT00292552 (http://ClinicalTrials.gov).

Qualitative aspects of breathlessness in health and disease

Background: Patients with respiratory disease use many different expressions to describe the sensation they experience as breathlessness. Although previous analyses have identified multiple dimensions of breathlessness, there is little agreement about their number and nature. This study has applied a novel approach, principal component analysis (PCA), to understanding descriptions of breathlessness in health and disease and extracting representative components. Methods: 202 patients (asthma n = 60, chronic obstructive pulmonary disease n = 65, interstitial lung disease n = 41, idiopathic hyperventilation n = 36) and 30 healthy volunteers were studied. All subjects performed spirometry and gave binary responses to 45 descriptions recalling their experience of breathlessness at the end of exercise; patients repeated this for resting breathlessness. PCA identified response patterns in the questionnaire data and extracted discriminatory components. Component scores were calculated for each individual using the regression method. Results: PCA identified six distinct components of breathlessness on exercise, explaining 62.8% of the variance: (1) air hunger, (2) affective, (3) nociceptive, (4) regulation, (5) attention and (6) miscellaneous qualities. Rest components explaining 63.1% of variance were (1) affective, (2) air hunger, (3) nociceptive, (4) wheeze, (5) regulation and (6) miscellaneous. Components identified on exercise differed significantly between disease groups and controls and were related to percentage predicted forced vital capacity. Conclusion: This analysis suggests that air hunger is the dominant sensation during exercise, while affective distress characterises resting breathlessness in patients with a range of respiratory disorders including idiopathic hyperventilation where lung mechanics are normal. This suggests that common mechanisms operate in qualitative aspects of breathlessness.

Bronchodilator reversibility in chronic obstructive pulmonary disease: use and limitations

The change in forced expiratory volume in 1 s (FEV1) after administration of a short-acting bronchodilator has been widely used to identify patients with chronic obstructive pulmonary disease (COPD) who have a potentially different disease course and response to treatment. Despite the apparent simplicity of the test, it is difficult to interpret or rely on. Test performance is affected by the day of testing, the severity of baseline lung-function impairment, and the number of drugs given to test. Recent data suggest that the response to bronchodilators is not enhanced in patients with COPD and does not predict clinical outcomes. In this Review we will discuss the insight that studies of bronchodilator reversibility have provided into the nature of the COPD, and how the abnormal physiology seen in patients with this disorder can be interpreted.

Risk of Misdiagnosis, Health-Related Quality of Life, and BMI in Patients Who Are Overweight With Doctor-Diagnosed Asthma

BACKGROUND Obesity and asthma both cause breathlessness, and there is a risk of misdiagnosis of asthma in patients who are obese. Impaired health-related quality of life (HRQoL) and increased BMI increase physician attendance rates, increasing this risk. We explored the possibility of misdiagnosis and the relationship between BMI, HRQoL, and other traditional measures of asthma severity in subjects who were obese with a doctors diagnosis of asthma. METHODS Data were obtained from subjects who were overweight with physician-diagnosed asthma screened as part of another study, including bronchial provocative concentration of methacholine to produce a 20% fall in FEV(1) (PC(20)) or reversibility to bronchodilators, HRQoL measured using generic (Short Form-36 [SF-36]) and disease-specific (St. George Respiratory Questionnaire and Impact of Weight on Quality of Life-Lite) questionnaires. The fraction of exhaled nitric oxide (Feno), height, weight, and atopic status were also recorded. RESULTS Of 91 subjects (mean BMI, 38 kg/m(2); mean FEV(1)%, 85.8%; mean FEV(1)/FVC, 70.0%; mean Feno, 25.1 parts per billion taking a mean chlorofluorocarbon-beclomethasone-equivalent dose of 1,273.5 μg/d), 36.3% had no bronchial hyperresponsiveness (possible misclassification of asthma diagnosis.) The BMI and HRQoL were significantly related: The St. George Respiratory Questionnaire total (r = 0.33, P < .001), SF-36 physical health subtotal (r = -0.42, P < .001), SF-36 mental health subtotal (r = -0.39, P < .001), and Impact of Weight on Quality of Life-Lite total (r = 0.51, P < .001) showed no relationship to airways inflammation and bronchial reactivity. There was no significant difference in quality-of-life scores in subjects with or without bronchial hyperreactivity. CONCLUSIONS We found evidence of misdiagnosis of asthma in subjects who were obese. The BMI in subjects who were obese and had asthma negatively correlates with the HRQoL, which may relate to the diagnostic uncertainty and requires further exploration. TRIAL REGISTRY ISRCTN Register; No.: 54432221; URL: www.controlled-trials.com/isrctn.

The effect of posture on asynchronous chest wall movement in COPD

Chronic obstructive pulmonary disease (COPD) patients often show asynchronous movement of the lower rib cage during spontaneous quiet breathing and exercise. We speculated that varying body position from seated to supine would influence rib cage asynchrony by changing the configuration of the respiratory muscles. Twenty-three severe COPD patients (forced expiratory volume in 1 s = 32.5 ± 7.0% predicted) and 12 healthy age-matched controls were studied. Measurements of the phase shift between upper and lower rib cage and between upper rib cage and abdomen were performed with opto-electronic plethysmography during quiet breathing in the seated and supine position. Changes in diaphragm zone of apposition were measured by ultrasounds. Control subjects showed no compartmental asynchronous movement, whether seated or supine. In 13 COPD patients, rib cage asynchrony was noticed in the seated posture. This asynchrony disappeared in the supine posture. In COPD, upper rib cage and abdomen were synchronous when seated, but a strong asynchrony was found in supine. The relationships between changes in diaphragm zone of apposition and volume variations of chest wall compartments supported these findings. Rib cage paradox was noticed in approximately one-half of the COPD patients while seated, but was not related to impaired diaphragm motion. In the supine posture, the rib cage paradox disappeared, suggesting that, in this posture, diaphragm mechanics improves. In conclusion, changing body position induces important differences in the chest wall behavior in COPD patients.

Drugs (including oxygen) in severe COPD

Access to comprehensive guidelines on the management of chronic obstructive pulmonary disease (COPD) is now available, and several treatment goals of therapy have been identified from these guidelines, which have since been studied in clinical trials. Drug therapy is a key component of an individual patient’s management plan, particularly in more severe disease. During the past few years, a number of new drug treatments have become available, although these are not always appropriately prescribed; this is particularly the case for oxygen. For patients with a history of exacerbations, there is good evidence for the use of inhaled long-acting anticholinergic agents or combined inhaled steroids and long-acting β-agonists. Evidence for prophylactic antibiotics and antioxidant agents is lacking. Nutritional and calorie supplementation have not been shown to improve exercise capacity. Statins may improve outcomes in COPD, but prospective trials are needed to confirm this. The evidence for the use of long-term oxygen therapy in hypoxaemic patients is robust. Ambulatory oxygen improves exercise capacity, but whether it is used appropriately is in doubt. Overall, short burst oxygen therapy does not offer a benefit and therefore cannot be recommended.

Identifying Physical Activity Profiles in COPD Patients Using Topic Models

With the growing amount of physical activity (PA) measures, the need for methods and algorithms that automatically analyze and interpret unannotated data increases. In this paper, PA is seen as a combination of multimodal constructs that can cooccur in different ways and proportions during the day. The design of a methodology able to integrate and analyze them is discussed, and its operation is illustrated by applying it to a dataset comprising data from COPD patients and healthy subjects acquired in daily life. The method encompasses different stages. The first stage is a completely automated method of labeling low-level multimodal PA measures. The information contained in the PA labels are further structured using topic modeling techniques, a machine learning method from the text processing community. The topic modeling discovers the main themes that pervade a large set of data. In our case, topic models discover PA routines that are active in the assessed days of the subjects under study. Applying the designed algorithm to our data provides new learnings and insights. As expected, the algorithm discovers that PA routines for COPD patients and healthy subjects are substantially different regarding their composition and moments in time in which transitions occur. Furthermore, it shows consistent trends relating to disease severity as measured by standard clinical practice.

Pharmacological Therapy: Inhaled Corticosteroids

Inhaled corticosteroids have a more favourable safety profile than oral corticosteroids. Inhaled corticosteroids do not consistently modify inflammatory cell numbers in sputum or the airway wall of COPD patients. Inhaled corticosteroids produce small improvements in lung function with significantly better health status and exacerbation frequency than patients not so treated. The change in the number of exacerbations largely drives the improvement in exacerbation frequency. The effects of inhaled corticosteroids on the rate of decline of lung function remain controversial. Despite their symptomatic benefits inhaled corticosteroids alone do not modify the risk of dying from COPD. Bone and eye side effects are not increased in frequency in inhaled corticosteroid users but clinically diagnosed pneumonia is. Inhaled corticosteroids are not recommended for use as monotherapy in COPD but significantly increase clinical benefits when used together with long-acting beta-agonists and this includes a reduction in the risk of dying.