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Issues in pulmonary function testing for the screening and diagnosis of chronic obstructive pulmonary disease.

The purpose of this review article is to provide an up-to-date summary on the current evidence for or against the use of lung function tests as screening and diagnostic tools for airflow obstruction in chronic obstructive pulmonary disease (COPD), and to consider the relevant issues in context.

RECENT FINDINGS: COPD is characterized by chronic respiratory symptoms and airflow limitation with only partial reversibility on lung function testing. However, screening on a population basis or of an enriched 'at-risk' subset like chronic smokers is not supported by findings from previous epidemiological studies, screening trials or in currently published clinical management guidelines by professional societies and review bodies. The definition of airflow obstruction and the classification of disease severity of COPD also differ slightly between guidelines and statements from different professional societies.

SUMMARY: Given the experience from previous screening trials and controversial classification of airflow obstruction by severity, it is impossible to have accurate screening results for COPD based on lung function tests alone. Clinical respiratory symptoms should be taken into consideration in terms of the diagnosis and management of COPD, as well as in any screening trial or programme that is to be attempted or implemented.

Early origins of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide and a significant challenge for adult physicians. However, there is a misconception that COPD is a disease of only adult smokers.

There is a growing body of evidence to support the hypothesis that chronic respiratory diseases such as COPD have their origins in early life. In particular, adverse maternal factors will interact with the environment in a susceptible host promoting altered lung growth and development antenatally and in early childhood. Subsequent lung injury and further gene-environment interactions may result in permanent lung injury manifest by airway obstruction predisposing to COPD.

This review will discuss the currently available data regarding risk factors in early life and their role in determining the COPD phenotype.

Efficacy and safety of 4 weeks' treatment with combined fluticasone furoate/vilanterol in a single inhaler given once daily in COPD: a placebo-controlled randomised trial.

Fluticasone furoate/vilanterol (FF/VI) is a novel once-daily (OD) inhaled corticosteroid/long-acting β(2) agonist combination in development for chronic obstructive pulmonary disease (COPD) and asthma.

Trial design A multicentre, randomised, double-blind, parallel-group, placebo-controlled study.

Methods : Participants were patients with moderate-to-severe COPD treated with placebo or FF/VI 400/25 μg OD for 4 weeks. Study objectives were to assess the safety and efficacy of FF/VI 400/25 μg OD administered for 4 weeks via a novel dry powder inhaler. Co-primary end points were change from baseline in weighted mean (wm) heart rate 0-4 h postdose at day 28 and the incidence of adverse events (AEs). Secondary end points included change from baseline in trough forced expiratory volume in one second (FEV(1)) (23-24 h postdose; day 29) and wm FEV(1) (0-4 h postdose; day 28). Patients were randomised to receive FF/VI 400/25 μg or placebo in a 2:1 ratio; all patients and investigators were blinded to active or placebo treatment.

Results : 60 patients (mean age 64 years) were randomised (FF/VI: n=40; placebo: n=20), and all contributed data to the analysis. Mean screening post-bronchodilator FEV(1) per cent predicted was comparable between groups (FF/VI: 58.5%; placebo: 60.1%). The wm heart rate 0-4 h postdose was similar between groups (difference: 0.6 beats per minute; 95% CI -3.9 to 5.1). More on-treatment AEs were reported in the FF/VI group (68%) compared with the placebo group (50%). The most common drug-related AEs in the FF/VI group were oral candidiasis (8%) and dysphonia (5%). There were no clinically relevant effects on laboratory values, including glucose and potassium, or on vital signs or ECGs/Holters. The FF/VI group had statistically greater improvements compared with placebo in trough FEV(1) (mean difference 183 ml) and 0-4 h postdose wm FEV(1) (mean difference 236 ml).

Conclusion : FF/VI has a good safety and tolerability profile and improves lung function compared with placebo in patients with COPD. Trial registration number clinical trials.gov-NCT00731822.

DNA damage as a molecular link in the pathogensis of copd in smokers.

In this study we investigated whether DNA double-strand breaks (DSBs) contribute to the pathogenesis of COPD.

We immunofluorescence-stained lung tissue samples obtained from COPD patients, asymptomatic smokers, and nonsmokers for markers of DSBs.The numbers of DSB foci (γH2AX, phosphorylated ATM substrate, and phosphorylated 53BP1 foci) per cell in alveolar type I cells, type II cells, and endothelial cells were higher in the COPD patients than in the asymptomatic smokers and nonsmokers. The lung tissue whose type II cells contained higher numbers of γH2AX foci per cell had higher percentages of type II cells that expressed p16, phosphorylated NFκB, and IL-6, and of alveolar wall cells that expressed active caspase-3. The type II cells that contained higher numbers of γH2AX foci per cell had higher rates of expression of p16, phosphorylated NFκB, and IL-6. Half of the alveolar wall cells that expressed active-caspase-3 contained γH2AX foci. Type II cells that stained positive for 8-OHdG contained a higher number of γH2AX foci per cell than the type II cells that stained negative.

In conclusion, DSBs at least in part caused by oxidative stress appear to contribute to the pathogenesis of COPD by inducing apoptosis, cell senescence, and proinflammatory responses.

Respiratory impairment and copd hospitalization in older persons--a competing risk analysis.

To evaluate, among older persons, the association between respiratory impairment and hospitalization for chronic obstructive pulmonary disease (COPD), based on spirometric Z-scores (Lambda-Mu-Sigma [LMS]) and a competing risk approach.

Using data on 3,563 white participants aged 65-80 years (Cardiovascular Health Study), we evaluated the association of LMS-defined respiratory impairment with incident COPD hospitalization and the competing outcome of death without COPD hospitalization, over a 5-year period. Respiratory impairment included airflow limitation (mild, moderate, and severe) and restrictive-pattern.Over a 5-year period, 276 (7.7%) participants had incident COPD hospitalization, whereas 296 (8.3%) died without COPD hospitalization.

The risk of COPD hospitalization was elevated more than 2-fold in LMS-defined mild and moderate airflow limitation and restrictive-pattern (adjusted hazard ratio [HR]: 2.25 [1.25, 4.05], 2.54 [1.53, 4.22], and 2.65 [1.82, 3.86], respectively), and more than 8-fold in LMS-defined severe airflow limitation (adjusted HR: 8.33 [6.24, 11.12]). Conversely, only LMS-defined restrictive-pattern was associated with the competing outcome of death without COPD hospitalization (adjusted HR: 1.68 [1.22, 2.32]).In white older persons, LMS-defined respiratory impairment is strongly associated with an increased risk of COPD hospitalization.

These results support the LMS method as a basis for defining respiratory impairment in older persons.

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