Thursday, 28 November 2013

CHRONIC OBSTRUCTIVE PULMONARY DISEASE






Chronic obstructive pulmonary disease is a major global health problem. Cigarette smoking is the main cause, and is increasing in the developing world as a result of targeting by the tobacco industry. Air pollution, also aetiologically important, is also increasing, and there is a huge unmet need for effective drugs. Despite this, COPD has received relatively little attention compared with asthma.



Clinical features. 
The clinical picture starts with attacks of morning cough during the winter, and progresses to chronic cough with intermittent exacerbations, often initiated by a cold, when the sputum becomes purulent ('chronic bronchitis'). There is progressive breathlessness. Some patients have a reversible component of airflow obstruction identifiable by an improved FEV1 following a dose of bronchodilator. Pulmonary hypertension is a late complication, causing symptoms of heart failure (cor pulmonale). Exacerbations may be complicated by type 1 or type 2 respiratory failure (i.e. reduced PAo2 alone or with increased PAco2, respectively) requiring hospitalisation and intensive care. Tracheostomy and artificial ventilation, while prolonging survival, may serve only to return the patient to a miserable life.






Pathogenesis. 
There is small airways fibrosis, resulting in obstruction, and/or destruction of alveoli and of elastin fibres in the lung parenchyma. The latter features are hallmarks of emphysema, thought to be caused by proteases, including elastase, released during the inflammatory response. Small airways obstruction and emphysema vary independently of one another. The explanation for this variation is unknown. It is emphysema that causes respiratory failure, because it destroys the alveoli, impairing gas transfer. There is chronic inflammation, predominantly in small airways and lung parenchyma, characterised by increased numbers of macrophages, neutrophils, and T lymphocytes. The inflammatory mediators have not been as clearly defined as in asthma. Lipid mediators, inflammatory peptides, reactive oxygen and nitrogen species, chemokines, cytokines and growth factors are all implicated.




Principles of treatment. 
 Stopping smoking  slows the progress of COPD. Patients should be immunised against influenza and Pneumococcus, because superimposed infections with these organisms are potentially lethal. Glucocorticoids are generally ineffective, in contrast to asthma, but a trial of glucocorticoid treatment is worthwhile because asthma may coexist with COPD and have been overlooked. This contrast with asthma is puzzling, because in both diseases multiple inflammatory genes are activated, which might be expected to be turned off by glucocorticoids. Inflammatory gene activation results from acetylation of nuclear histones around which DNA is wound. Acetylation opens up the chromatin structure, allowing gene transcription and synthesis of inflammatory proteins to proceed. HDAC is a key molecule in suppressing production of proinflammatory cytokines. Corticosteroids recruit HDAC to activated genes, reversing acetylation and switching off inflammatory gene transcription. There is a link between the severity of COPD (but not of asthma) and reduced HDAC activity in lung tissue , furthermore, HDAC activity is inhibited by smoking-related oxidative stress, which may explain the lack of effectiveness of glucocorticoids in COPD.








Long-acting bronchodilators have been a worthwhile if modest advance in the treatment of COPD, but do not deal with the underlying inflammation. No currently licensed treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. Several new treatments that target the inflammatory process are in clinical development (Barnes & Stockley, 2005). Some, such as chemokine antagonists, are directed against the influx of inflammatory cells into the airways and lung parenchyma, whereas others target inflammatory cytokines such as TNF-α. PDE IV inhibitors (e.g. roflumilast; Rabe et al., 2005) show some promise. Other drugs that inhibit cell signalling  include inhibitors of p38 mitogen-activated protein kinase, nuclear factor κB and phosphoinositide-3 kinase-γ. More specific approaches are to give antioxidants, inhibitors of inducible NO synthase and leukotriene B4 antagonists. Other treatments have the potential to combat mucus hypersecretion, and there is a search for serine proteinase and matrix metalloproteinase inhibitors to prevent lung destruction and the development of emphysema.




Specific aspects of treatment. 
 Short- and long-acting inhaled bronchodilators can provide useful palliation in patients with a reversible component. The main short-acting drugs are ipratropium and salbutamol ; long-acting drugs include tiotropium  and salmeterol or formoterol . Theophylline can be given by mouth but is of uncertain benefit. Its respiratory stimulant effect may be useful for patients who tend to retain CO2. Other respiratory stimulants (e.g. doxapram; are sometimes used briefly in acute respiratory failure (e.g. postoperatively) but have largely been replaced by ventilatory support (intermittent positive-pressure ventilation).



Long-term oxygen therapy administered at home prolongs life in patients with severe disease and hypoxaemia (at least if they refrain from smoking-an oxygen fire is not a pleasant way to go, especially for one's neighbours!).





Acute exacerbations. 
Acute exacerbations of COPD are treated with inhaled O2 in a concentration (initially, at least) of only 24% O2, i.e. only just above atmospheric O2 concentration (approximately 20%). The need for caution is because of the risk of precipitating CO2 retention as a consequence of terminating the hypoxic drive to respiration. Blood gases and tissue oxygen saturation are monitored, and inspired O2 subsequently adjusted accordingly. Broad-spectrum antibiotics (e.g. cefuroxime; including activity against Haemophilus influenzae are used if there is evidence of infection. Inhaled bronchodilators may provide some symptomatic improvement.



A systemically active glucocorticoid (intravenous hydrocortisone or oral prednisolone) is also administered routinely, although efficacy is modest. Inhaled steroids do not influence the progressive decline in lung function in patients with COPD, but do improve the quality of life, probably as a result of a modest reduction in hospital admissions.