Many patients with chronic obstructive pulmonary disease (COPD) also suffer from other disorders that are considered to be comorbidities and that may have a major impact on morbidity and mortality.

So far, it is not clear if these diseases in the context of COPD need specific drugs or if patients diagnosed with COPD should receive certain medications to prevent the development of systemic effects of COPD. Cachexia may be caused by many contributing factors and thus may prove to be very difficult to reverse. For the treatment of osteoporosis in patients with COPD, treatment recommendations have been published.

COPD is associated with reduced systemic levels of vitamin D, which has not only calcemic, but also extracalcemic effects that may play a role in the development of COPD and its consequences. Available evidence suggests that statins have a high potential, although definitive studies have not been published yet. Physical inactivity may be a major cause for systemic inflammation. In turn, exercise training may be an effective form of therapy.

Although smoking cessation is very effective, it is not successful in the majority of cases.

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Airway remodelling is a collective term for changes in the amount or organisation of the cellular and molecular constituents of the airway wall. Remodelling occurs in and is associated with the pathophysiology of airways diseases including asthma and chronic obstructive pulmonary disease.

The remodelling that occurs in these diseases exhibits both shared and distinct features. Remodelling is generally considered to be deleterious to airway function but recent studies also indicate potential protective effects. However, the true impact of different aspects of the remodelling process on lung function, both negative and positive, is poorly understood. In addition, the genetic susceptibility and processes by which environmental insults drive the cell and molecular events which result in airway remodelling and the potential for therapeutic reversibility are also incompletely understood.

The last 10-15 years has seen the development of animal models of airway remodelling which have been refined and modified as new factors such as exacerbations and early life influences have been recognised as being of importance. In addition, invertebrate models have been put forward and complex in vitro culture systems and lung slice preparations developed. In parallel, imaging technology has developed to an extent where it is feasible using a combination of techniques to image structural components, cells and proteins in the airway wall as well as to analyse biological processes, cell and receptor activation non-invasively over time.

The integration of data from in vivo and in vitro models together with use of imaging techniques in man and animals should allow validation of models, further our understanding of the pathophysiology of airway remodelling and potentially improve predictive accuracy for the translation of novel therapeutic agents into the clinic.

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In the 19th Century, Cheyne and Stokes independently reported cycles of respiration in patients with heart failure, beginning with apnea, followed by a few breaths. However Cheyne-Stokes respiration (C-SR) can also occur in healthy individuals with sleep, and was demonstrated in 1908 with voluntary hyperventilation, followed by apnea that Haldane blamed on hypoxia, subsequently called post-hyperventilation apnea.

Additional theories explaining C-SR did not appear until 1954, based on control theory, specifically a feed-back regulator controlling CO(2). This certainly describes control of normal respiration, but to produce an unstable state such as C-SR requires either a very long transit time (3½min) or an increase of the controller gain (13 times), physiologically improbable. There is general agreement that apnea initiates C-SR but that has not been well explained except for post-hyperventilation apnea, and that explanation is not compatible with a study by Nielsen and Smith in 1951. They plotted the effects of diminished oxygen on ventilation (V) in relation to CO(2) (Fig. 1). They found that the slope of V/CO(2) (gain) increased with hypoxia, but it flattened at a moderate CO(2) level and had nointercept with zero (apnea). It is also incompatible with our published findings in 1975 that showed that apnea did not occur until an extreme level of hypoxia occurred (the PO(2) fell below 10mmHg), followed shortly by gasping. Much milder hypoxia underlies most cases of C-SR, when hypoxic drive replaces the normal CO(2)-based respiratory drive, in a failsafe role. I hypothesize that the cause of apnea is a brief interruption of hypoxic drive caused by a pulse of oxygen from a stronger than average breath, such as a sigh. The rapidity of onset of apnea in response to a pulse of oxygen, reflects the large pressure gradient for oxygen from air to lung with each breath, in contrast to CO(2). With apnea, there is a gradual fall in oxygen, resulting in a resumption of hypoxic drive, and the cycle of C-SR continues until the next large breath.

This novel theory, that a pulse of oxygen interrupts hypoxic drive to cause the initiating apnea of C-SR, is compatible with the known causes of C-SR: onset of sleep, mild hypoxia with congestive heart failure, and neurologic disorders. It is also compatible with factors known to abolish C-SR: waking, oxygen supplementation, and drugs that increase alertness such as caffeine.

Testing of the hypothesis would require beat by beat recording of respiration, and arterial oxygen with a response time fast enough to demonstrate the rapid suppression of hypoxic drive. Alternatively, using a different theoretical approach such as limit-cycle oscillators instead of control theory.

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COPD treatment begins with smoking cessation and influenza and pneumococcal vaccines. Bronchodilators are indicated when dyspnea on exertion is reported (usually, FEV1 < 80% predicted). On-demand short-acting agents are chosen when dyspnea is intermittent, daily long-acting agents are administered once dyspnea occurs in daily life activities. In all cases, anticholinergics and beta2 agonists can be associated when one class is not sufficiently effective.

In patients with FEV1 < 50% predicted (budesonide-formoterol) or 60% predicted (fluticasone-salmeterol), repeated exacerbations and symptoms despite maintenance bronchodilators, fixed associations are indicated. When a handicap persists on pharmacological treatment, respiratory rehabilitation centered on education and exercise training has to be proposed. Care for COPD has to integrate treatment of comorbidities such as cardio-vascular diseases, anxiety-depression, malnutrition, muscle dysfunction, osteoporosis, anemia ...

Ongoing research aims at identifying new therapeutic targets, focusing on inflammation, remodeling, protease-antiprotease balance, oxidative stress, lung regeneration/repair and mucus production.

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