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[COPD and inflammation: Statement from a French expert group: Inflammation and remodelling mechanisms.]

The present study reviews the literature on inflammation and remodelling mechanisms in chronic obstructive pulmonary disease (COPD). The development of COPD is associated with chronic pulmonary inflammation. Immunity (innate or adaptive) plays a role in its onset and continuation.

Airways inflammation alters bronchial structure/function relations: increased bronchial wall thickness, increased bronchial smooth muscle tone, seromucosal gland hypersecretion and loss of elastic structures. Circulating markers of pulmonary inflammation indicate its systemic dissemination. Oxidative stress plays a major role in the onset and persistence of tissue abnormalities. The determinants of extra- and intra-cellular redox control are only partially known. Susceptibility genes, antioxidant system insufficiency and reduced levels of anti-age molecules and of histone deacetylation are also involved. The molecular and cellular targets of inflammation and remodelling are numerous and complex.

Currently, tools exist to limit inflammation in COPD but not to act on structural remodelling.

Reduced Heart Rate Variability in Patients with Chronic Obstructive Pulmonary Disease Independent of Anticholinergic or β-agonist Medications.

Reduced heart rate variability (HRV) is a predictor of poor outcome in several pathologies and in general population. Whether HRV is altered during normal daily activities or influenced by anticholinergic and β-adrenergic medications in chronic obstructive pulmonary disease (COPD) remains unknown.

Forty-one clinically stable COPD patients and 19 healthy controls matched for age, sex and smoking history underwent a 24-hour ambulatory ECG recording during normal daily activities. HRV was assessed by standardized temporal and spectral analysis.

COPD patients showed a reduced HRV (LF/HF ratio) compared with healthy controls (median [interquartile range]) during daytime (2.6 [1.5-3.8] vs. 3.5 [2.9-5.6]), nighttime (1.8 [1.1-4.3] vs. 4.2 [2.7-6.9]) as well as during the entire 24-hour (1.9 [1.5-3.4] vs. 3.9 [3.2-5.6]) recordings (all P < 0.005). There was no significant difference between the two groups in the time domain and in the low frequency or high frequency domain for the 24-hour period analysis. In COPD patients, the 24-hour LF/HF ratio positively correlated with forced expiratory volume in 1 second (FEV(1)) (r = 0.342, P = 0.028) and negatively correlated with age (r = -0.317, P = 0.044). In multiple regression analysis, LF/HF ratio was associated with FEV(1) (P = 0.05) but not with age (P = 0.08). There was no difference of HRV between patients using or not anticholinergic or β-agonist medications.

These results demonstrate that COPD patients have a reduced sympatho-vagal balance compared with healthy subjects. HRV correlates with disease severity and does not seem to be influenced by anticholinergic or adrenergic medications.

Cardiovascular Safety of QVA149, a Combination of Indacaterol and NVA237, in COPD Patients.

This study assessed the cardiovascular safety of QVA149, an inhaled, once daily, bronchodilator combination containing two 24-hour bronchodilators, the long-acting β(2)-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium (NVA237).

In this randomised, double-blind, placebo-controlled, parallel-group study, 257 patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) were randomised to receive QVA149 (indacaterol/NVA237) 600/100 μg, 300/100 μg or 150/100 μg, indacaterol 300 μg or placebo, once daily for 14 days.

The primary endpoint was change from baseline in 24-h mean heart rate versus placebo on Day 14. 255 patients were included in the safety analysis (mean age 63.8 years, 76.5% male, post-bronchodilator forced expiratory volume in one second [FEV(1)] 53.2% predicted, FEV(1)/FVC [forced vital capacity] 50.0%, mean 24-h heart rate 79.6 bpm). There were no clinically significant differences in the 24-h mean heart rate on Day 14 between the three doses of QVA149 and placebo or indacaterol. The confidence intervals of these treatment differences (contrasts) were within the pre-specified equivalence limit (-5 to 5 bpm).

No clinically relevant differences in QTc interval (Fridericia's) were observed between groups on Days 1, 7 and 14. Once-daily QVA149 was well tolerated in COPD patients with a cardiovascular safety profile and overall adverse event rates similar to placebo.

Addressing the Complexity of COPD.

Chronic obstructive pulmonary disease (COPD) is a complex disease at the clinical, cellular and molecular levels. However, its diagnosis, assessment and therapeutic management are based almost exclusively on the severity of airflow limitation. A better understanding of the multiple dimensions of COPD and its relationship to other diseases is very relevant and of high current interest.

Recent theoretical (scale-free networks), technological (high throughput technology, bio-computing) and analytical improvements (systems biology) provide tools capable of addressing the complexity of COPD. The information obtained from the integrated use of those techniques will be eventually incorporated into routine clinical practice.

This review summarizes our current knowledge in this area and offers an insight into the elements needed to progress towards an integrated, multi-level view of COPD based upon the novel scientific strategy of systems biology and its potential clinical derivative, P4 medicine (Personalized, Predictive, Preventive and Participatory).

Insights into chronic obstructive pulmonary disease patient attitudes on ventilatory support.

A large proportion of chronic obstructive pulmonary disease (COPD) patients do not actually discuss ventilation and other end-of-life issues in the stable state. Such discussions often occur during the exacerbation itself. There is a paucity of data regarding attitudes of COPD patients toward end-of-life attitudes in general and specifically concerning the area of ventilatory support.

RECENT FINDINGS: The majority of COPD patients feel end-of-life discussions are warranted in the stable state. Some studies have shown that increasing age and the presence of depression preclude patients from choosing life-sustaining treatment, whereas physicians were often inaccurate in judging patient preference for cardiopulmonary resuscitation and ventilation as they frequently underestimated patient quality of life. Patient information sheets and other tools may have a role as decision aids in end-of-life discussions.

SUMMARY: Physicians should consider the discussion of end-of-life issues preferably when patients are stable. Decision aids may prove to be a valuable adjunct in framing treatments such as mechanical ventilation.

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