COPD IS NOT ASTHMA
COPD is different from asthma. Although both diseases involve airflow inflammation, the causes differ. The inflammatory cells, the mediators, the inflammatory consequences and the affected sites are all different. Hence, the response to treatment is also different. Yet, unfortunately, most patients with COPD are treated as if they have poorly responsive asthma.
COPD is characterised by a neutrophilic inflammation in the respiratory tract. There is no airway hyper-responsiveness and COPD patients do not show any marked response to steroids. On the other hand, asthma is characterised by an eosinophilic inflammation.
Airway hyper-responsiveness is the key physiological abnormality in asthma. As most asthma patients respond to steroids, inhaled steroids are recommended as the mainstay of treatment for all patients with persistent asthma symptoms.
However, there are some patients who have features of both diseases. They are described as having wheezy bronchitis and can be considered to have two different diseases at the same time.
Mechanisms of COPD: The mechanisms that cause airflow limitation in COPD are different from those in asthma. Three mechanisms contribute to airflow limitation in COPD (Fig 1).

- The first is the disruption of alveolar attachments of small airways. Normally alveolar attachments prevent the airways from closing during expiration. When patients develop emphysema, the airway attachments are destroyed and the airways close more readily.
- The second mechanism, which is particularly important in the early stages of the disease, is the narrowing of the airway wall itself. This is a result of inflammation that leads to fibrosis of small airways. This condition is known as chronic obstructive bronchitis.
- The third mechanism is mucus hypersecretion, which fills the lumen of small airways to restrict airflow.

CLOSER LOOK AT THE CELLULAR MECHANISMS AND MEDIATORS
Cigarette smoke and other irritants activate alveolar macrophages to release tumour necrosis factor (TNF - alpha). This in turn activates other macrophages and the epithelial cells to produce interleukin 8 (IL-8).
IL-8 attracts neutrophils into the lungs. Neutrophils produce their own IL-8 leading to chronic neutrophilic inflammation. These macrophages and neutrophils release proteases (like neutrophil elastase) that destroy the alveolar wall leading to emphysema and mucus hypersecretion. Normally, this would be prevented by endogenous protease inhibitors such as alpha1-antitrypsin. But in some COPD patients these inhibitors may be deficient. These inflammatory cells also release factors that attract CD8 lymphocytes (cytotoxic T-lymphocytes). These lymphocytes have the capacity to destroy alveolar walls, thereby further contributing to emphysema.
An important feature of COPD is oxidative stress. This is due to increased production of reactive oxygen species generated by inflammatory cells such as macrophages and neutrophils in the lungs.
The damaging effects of oxidants in the lungs
- They activate a transcription factor called NF-kappa B, which switches on the production of TNF and IL-8 leading to neutrophil recruitment.
- They damage antiproteases and therefore accelerate the progression of emphysema.
- They increase mucus secretion, plasma leakage, and broncho-constriction.
It is therefore is logical to treat COPD patients with antioxidants. Unfortunately, dietary vitamin C and N-acetylcysteine are very weak antioxidants. These are not potent enough to neutralize the high level of oxidative stress in the lungs of COPD patients. So there is a need to develop more potent antioxidants.

WHY DO SOME SMOKERS DEVELOP COPD?
In people who do not smoke, the lung function declines steadily from the age of 25. It is now known that this is due to the loss of elastin with time. It is exactly the same process that leads to wrinkling of the skin with age. Most people who smoke follow exactly the same decline as normal people. But some people have a more rapid decline. These are called susceptible smokers and account for 10 to 20% of smokers
(Fig. 2). These are the people who develop COPD. As the decline accelerates, a point is reached when around 50 percent of the lung function is lost. This leads to shortness of breath on exertion and other symptoms. The disease inevitably progresses, leading to disability and premature death.
Stopping smoking is the only strategy available to reduce the progression of the disease and is therefore a very important part of management particularly in the early phase of the disease.
Stopping smoking early, before symptoms develop, normalises the rate of decline in lung function. However, there is little recovery if one stops smoking after symptoms are manifest.

THERAPEUTIC AND PHARMACOLOGICAL APPROACHES TO COPD
Role of bronchodilators
When COPD patients develop symptoms, bronchodilators offer the only beneficial drug therapy option. Bronchodilators reduce the hyperinflation typical of COPD. This decreases dyspnoea and increases exercise tolerance.
In asthma, the b2-agonists are more effective than anticholinergic drugs like ipratropium bromide. By contrast, in COPD, the anticholinergic drugs are more effective than the b2-agonists. In asthma, the bronchoconstrictive mechanisms are triggered by mediators (like histamine and leukotrienes), which can be reversed by b2-agonists. In COPD there are no such mediators and the cholinergic tone is greater. However, studies report an additive effect between b2-agonists and anticholinergics. A combination of ipratropium bromide four times a day with a long-acting b2-agonist such as salmeterol twice a day is the best way to treat most patients of COPD.
Role of mucolytic drugs
Previously mucolytic drugs were used to reduce the viscosity of mucus and thereby to help clear the airways. However, a recent meta-analysis has found a small but significant benefit in reducing exacerbations.
Role of theophylline in COPD
Low dose theophylline has been studied in patients with moderately severe COPD. There was a significant reduction in neutrophils in the sputum, a significant fall and an improvement in diaphragmatic contractility.
Role of steroids in COPD
The last group of drugs used in COPD are inhaled steroids but their use is controversial. Response to steroids is diagnostic of asthma. However, in COPD, steroids do not result in any major improvement. If there is an improvement in a patient who has COPD, then the patient most likely has asthma too and must be treated as if the two diseases coexist.
However, some surprising new data has shown that combination inhalers (combining a long-acting beta2-agonist and a corticosteroid) show a much better improvement in lung function in COPD patients too. The symptoms are only slightly reduced by inhaled steroids, with a slightly bigger effect seen with only a long-acting beta2-agonist. Together they have a much greater effect. It is not clear why this occurs, and if there is a molecular interaction between these two drugs.
Role of pulmonary rehabilitation
The only other treatment, which has been shown to be effective in COPD, is pulmonary rehabilitation, which involves physiotherapy, education about good nutrition and an exercise program. This approach has been shown to reduce symptoms, improve quality of life and, very importantly, reduce hospital admissions.

Smoking out tomorrow's therapies for COPD
Several novel treatments are under development. These include IL-8 and TNF-alpha antagonists that inhibit the mediators that recruit neutrophils. There are drugs that suppress the cytotoxic T-cells that may be causing emphysema. There are also drugs such as phosphodiester inhibitors (PDE4) that inhibit the neutrophilic inflammation in COPD (Table I).

The most important development, however, has been the discovery of a very long-acting inhaled anticholinergic drug called tiotropium bromide. This drug is suitable for once daily administration. The molecule itself is somewhat similar to ipratropium bromide but its duration of action is markedly greater. It also improves the quality of life, reduces exacerbations and is well tolerated.

CONCLUSION
COPD is an extremely common and rather neglected disease that presents a major challenge to global health.
Bronchodilators are the main stay of treatment. Inhaled steroids are largely ineffective, but the fixed combination inhalation of a long acting 2agonist and corticosteroids is more effective.
None of the treatments available is able to slow the progression of the disease As there is a very active inflammatory destructive process in COPD, there is a concerted effort to develop new drugs that will control the underlying inflammatory processes.