Evidence generation for the clinical impact of myCOPD in patients with mild, moderate and newly diagnosed COPD: a randomised controlled trial.

Self-management interventions in COPD aim to improve patients' knowledge, skills and confidence to make correct decisions, thus improving health status and outcomes. myCOPD is a web-based self-management app known to improve inhaler use and exercise capacity in individuals with more severe COPD. We explored the impact of myCOPD in patients with mild-moderate or recently diagnosed COPD through a 12-week, open-label, parallel-group, randomised controlled trial of myCOPD compared with usual care. The co-primary outcomes were between-group differences in mean COPD assessment test (CAT) score at 90 days and critical inhaler errors. Key secondary outcomes were app usage and patient activation measurement (PAM) score. Sixty patients were randomised (29 myCOPD, 31 usual care). Groups were balanced for forced expiratory volume in 1 s (FEV1 % pred) but there was baseline imbalance between groups for exacerbation frequency and CAT score. There was no significant adjusted mean difference in CAT score at study completion, -1.27 (95% CI -4.47-1.92, p=0.44) lower in myCOPD. However, an increase in app use was associated with greater CAT score improvement. The odds of ≥1 critical inhaler error was lower in the myCOPD arm (adjusted OR 0.30 (95% CI 0.09-1.06, p=0.061)). The adjusted odds ratio for being in a higher PAM level at 90 days was 1.65 (95% CI 0.46-5.85) in favour of myCOPD. The small sample size and phenotypic difference between groups limited our ability to demonstrate statistically significant evidence of benefit beyond inhaler technique. However, our findings provide important insights into associations between increased app use and clinically meaningful benefit warranting further study in real world settings.

COPD phenotype description using principal components analysis.

BACKGROUND: Airway inflammation in COPD can be measured using biomarkers such as induced sputum and Fe(NO). This study set out to explore the heterogeneity of COPD using biomarkers of airway and systemic inflammation and pulmonary function by principal components analysis (PCA). SUBJECTS AND METHODS: In 127 COPD patients (mean FEV1 61%), pulmonary function, Fe(NO), plasma CRP and TNF-alpha, sputum differential cell counts and sputum IL8 (pg/ml) were measured. Principal components analysis as well as multivariate analysis was performed. RESULTS: PCA identified four main components (% variance): (1) sputum neutrophil cell count and supernatant IL8 and plasma TNF-alpha (20.2%), (2) Sputum eosinophils % and Fe(NO) (18.2%), (3) Bronchodilator reversibility, FEV1 and IC (15.1%) and (4) CRP (11.4%). These results were confirmed by linear regression multivariate analyses which showed strong associations between the variables within components 1 and 2. CONCLUSION: COPD is a multi dimensional disease. Unrelated components of disease were identified, including neutrophilic airway inflammation which was associated with systemic inflammation, and sputum eosinophils which were related to increased Fe(NO). We confirm dissociation between airway inflammation and lung function in this cohort of patients.

The repeatability of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein in COPD patients over one year.

BACKGROUND: Many of the systemic manifestations of chronic obstructive pulmonary disease (COPD) are mediated through increased systemic levels of inflammatory proteins. We assessed the long term repeatability of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP) over one year and examined the relationships between these systemic markers in COPD. METHODS: Fifty-eight stable COPD patients completed a baseline and one-year visit. Serum IL-6, plasma CRP, and plasma TNF-alpha were measured. Repeatability was expressed by intraclass correlation coefficient (R(i)) and the Bland-Altman method. Pearson correlations were used to determine the relationships between the systemic markers at both visits. RESULTS: There was moderate repeatability with a very high degree of statistical significance (p

Impulse oscillometry in COPD: identification of measurements related to airway obstruction, airway conductance and lung volumes.

BACKGROUND: Impulse oscillometry system (IOS) assesses pulmonary resistance and reactance. We set out to investigate which IOS measurements are related to airflow obstruction, airway conductance and lung volumes in chronic obstructive pulmonary disease (COPD). METHODS: Ninety-four COPD patients were recruited and 58 agreed to follow up after 1 year. IOS measurements (R5, R20, X5 & Fres), body plethysmography (sGaw, FRC, TLC, RV & IC) and spirometry (FEV(1)) were performed. Pearson or Spearman correlation determined the relationships between IOS and other measurements. RESULTS: R5, X5 and Fres were all significantly associated (p<0.05) with FEV(1), sGaw, TLC, RV and IC. However, R20 was not related to any of these measurements except for RV. The strongest associations were observed between FEV(1) and the reactance measurements X5 (r=0.48) and Fres (r=-0.44), and sGaw with X5 (r=0.47) and Fres (r=0.51). The r values for the associations with TLC and IC were all <0.25. There was no statistically significant change in the FEV(1), R5, X5 or Fres after 1 year, but R20 significantly increased over the year. The changes in R5 and R20 did not significantly correlate with the changes in FEV(1). In contrast, X5 changes were significantly related to FEV(1) changes over 1 year (r=-0.27, p=0.05), while for Fres changes there was a trend to statistical significance (p=0.08). CONCLUSIONS: IOS reactance measurements are more closely related than resistance measurements to other pulmonary function measurements in COPD patients. The IOS reactance measurements appear to be indicative of changes in pulmonary compliance caused by airflow obstruction.

Non-invasive biomarkers and pulmonary function in smokers.

Limited information exists regarding measurement, reproducibility and interrelationships of non-invasive biomarkers in smokers. We compared exhaled breath condensate (EBC) leukotriene B4 (LTB4) and 8-isoprostane, exhaled nitric oxide, induced sputum, spirometry, plethysmography, impulse oscillometry and methacholine reactivity in 18 smokers and 10 non-smokers. We assessed the relationships between these measurements and within-subject reproducibility of EBC biomarkers in smokers. Compared to non-smokers, smokers had significantly lower MMEF % predicted (mean 64.1 vs 77.7, p = 0.003), FEV1/FVC (mean 76.2 vs 79.8 p = 0.05), specific conductance (geometric mean 1.2 vs 1.6, p = 0.02), higher resonant frequency (mean 15.5 vs 9.9, p = 0.01) and higher EBC 8-isoprostane (geometric mean 49.9 vs 8.9 pg/ml p = 0.001). Median EBC pH values were similar, but a subgroup of smokers had airway acidification (pH < 7.2) not observed in non-smokers. Smokers had predominant sputum neutrophilia (mean 68.5%). Repeated EBC measurements showed no significant differences between group means, but Bland Altman analysis showed large individual variability. EBC 8-isoprostane correlated with EBC LTB4 (r = 0.78, p = 0.0001). Sputum supernatant IL-8 correlated with total neutrophil count per gram of sputum (r = 0.52, p = 0.04) and with EBC pH (r = -0.59, p = 0.02). In conclusion, smokers had evidence of small airway dysfunction, increased airway resistance, reduced lung compliance, airway neutrophilia and oxidative stress.

The reproducibility of adenosine monophosphate bronchial challenges in mild, steroid-naive asthmatics.

AIMS: Repeated adenosine monophosphate (AMP) challenges are used to assess drug efficacy in clinical trials of mild, steroid-naive asthmatics. Refractoriness has been reported after repeated challenges over short intervals. This study evaluated possible tachyphylaxis after repeated AMP challenges at 12 and 24 h in mild, steroid-naive asthmatics. METHODS: This was an open, three-way crossover study. Twenty-six steroid-naive asthmatic subjects were randomized to the following AMP challenge regimens separated by 7-14 days: (A) challenge at 08.00 h, repeated 24 h later; (B) challenge at 08.00 h, repeated 12 and 24 h later; (C) challenge at 20.00 h, repeated 12 h later. Comparisons within day were assessed using 90% confidence intervals (CIs). Non-inferiority approach taken with 1 doubling concentration (DC) as a clinically relevant difference. RESULTS: Regimen A: Significant increase in AMP reactivity at 24 h. Mean DC difference was 0.6 (90% CI 0.24, 0.96). Regimen B: No evidence of difference between AMP reactivity at 08.00 h and a repeated challenge 12 h later. Repeated challenge at 24 h caused a significant increase in provocation concentration (PC)(20) compared with 12 h (mean DC difference 0.48, 90% CI 0.02, 0.95) and 0 h (mean DC difference 0.82, 90% CI 0.49, 1.14 - the upper CI exceeds the criteria of 1 DC). Challenge regimen C: No difference between challenges; mean DC difference of 0.28 (90% CI -0.2, 0.76). CONCLUSION: The small decline in AMP reactivity during repeated challenges was not consistently observed, and was small compared with the known effects of inhaled drugs.

Cognitive behavior therapy for depression? Choose horses for courses.

OBJECTIVE: Although cognitive behavior therapy is a widely accepted treatment for depression, the problematic nature of efficacy studies is insufficiently recognized. METHOD: The authors reviewed original studies and quantitative analyses on the use of cognitive behavior therapy for depression. RESULTS: The authors suggested that claims for cognitive behavior therapy's efficacy on depression have been overstated, questioned whether its efficacy fits within its theoretical underpinning, and argued against viewing cognitive behavior therapy as a universal rather than a targeted strategy. CONCLUSIONS: Although cognitive behavior therapy may act more by its nonspecific therapeutic ingredients, the authors argued that by testing cognitive behavior therapy's efficacy in heterogeneous study groups, rather than in specific subgroups, failure to differentiate it from control therapies may have been ensured.

The development of a six-item daily self-report measure assessing identified depressive domains.

BACKGROUND: There is debate as to whether any anti-depressant strategy acts more rapidly than any other, while 'improvement' in overall depression severity reflects a summation of individual domains that may individually show differing trajectories. We developed a brief self-report measure of depression's constituent constructs to allow such issues to be examined. METHODS: A 25-item measure was prepared and completed daily by depressed patients until they had evidenced distinct improvement. RESULTS: Factor analyses favoured a six-factor structure, with constructs labelled depression, irritability, brooding, poor concentration, insomnia and anxiety. Scores on those constructs were differentially associated with overall depression severity as measured on the clinician-rated Hamilton measure, arguing for their potential utility. LIMITATIONS: The original data set was small while the measure's utility will only emerge in application studies. CONCLUSIONS: The six-item measure is appended and several possible application studies noted. In particular, we favour its evaluation in studies examining the impact and time to onset of differing antidepressant strategies on differing depressive sub-types.

Atypical depression: a reappraisal.

OBJECTIVE: The study evaluated the DSM-IV definition of the atypical features specifier for a major depressive episode in major depressive disorder. METHOD: Nonpsychotic patients with major depressive disorder were assessed to determine if the DSM-IV model and decision rules for the atypical features specifier for a major depressive episode could be supported. RESULTS: The five clinical features of the DSM-IV atypical features specifier for a major depressive episode showed weak internal consistency, and the mandatory criterion A feature of mood reactivity did not show specificity in relation to any of the four criterion B accessory symptoms. The more severe the depression, the less likely the patient was to report criterion A and hence to meet criteria for the atypical features specifier. Remodeling the five features favored the personality style descriptor of interpersonal rejection sensitivity as an alternate primary feature. A reformulated model also suggested lifetime panic disorder and social phobia as higher-order determinants of atypical features in major depressive disorder. Additional analyses of criteria suggested that interpersonal rejection sensitivity and leaden paralysis had a phenomenological base in anxiety, that mood reactivity was linked with irritability, and that neither weight gain nor hypersomnia were clearly aligned with anxiety or depression, raising questions about their status as symptoms. CONCLUSIONS: The current definition and modeling of the DSM-IV atypical features specifier for a major depressive episode in major depressive disorder appears problematic. As suggested by earlier descriptions of atypical depression, certain expressions of anxiety may have primacy, and some clinical features associated with the DSM-IV model may be adaptive homeostatic responses rather than pathological symptoms.