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Chronic Obstructive Pulmonary Disease (COPD) is a term describing chronic bronchitis, emphysema or small airways disease. COPD is a long term inflammatory respiratory condition resulting in airflow obstruction. Recent theories suggest that COPD is a disease of accelerated lung aging resulting from oxidative stress; this is based on the manifestation of shortened lymphocyte telomeres and reduced antiaging molecules such as histone deacetylases in patients with COPD1. (PUT SOMETHING ABOUT HOW BIG COPD IS)
The risk of developing COPD is said to be related to the 'total burden of inhaled particles'2. The aetiology of COPD typically spans tobacco smoking, occupational causes and genetics.
Tobacco smoking is the best known cause of COPD; this includes cigars, cigarettes, pipes and various other cultural practices such as hookah smoking; however, not all smokers develop COPD. The age at which the person started smoking, the amount they smoke each day, in addition to how long they have smoked for are all important indicators for the risk of COPD. In England the adult smoking prevalence is estimated at 24%3 - a growing cause for concern based upon the relevance to COPD. In England, 87% of COPD deaths in men and 84% of COPD deaths in women are attributed to smoking4. The commonly quoted figure of 13% of deaths in smokers caused by COPD5 is misleading as the incidence of COPD in smokers is much greater. The risk of death from COPD increases 13 fold in smokers compared to non smokers6. Passive smoking is attributed to COPD, which is significant but causes a small number of deaths7.
In occupations where there is exposure to vapours, gas, dust or fumes there is an increased incidence of COPD7. Coal miners, construction workers, and individuals involved in the transport and cotton industry are typically at an increased risk of COPD8. Cadmium9 and Silica10 are agents which have good evidence for cause of COPD. The Zutphen study concluded that occupational exposure in men had a relative risk of 1.48 for COPD11. Although this risk may seem large, it is not as significant as the link between smoking and COPD. General air pollution is also a risk factor for COPD, confirmed by 'The Air Pollution and Health: a European Approach project'12.
1-Antitrypsin is an enzyme made by the liver which blocks neutrophil elastase (a digestive enzyme of lung tissue), thus protecting the lung parenchyma. 1-Antitrypsin (AATD) deficiency is a disorder of genetic homozygotic origin characterized by reduced levels of functional 1-Antitrypsin leaving the lung tissue exposed to neutrophil elastase during infection13. AATD is a known cause of familial emphysema14.
The key indicators of COPD are dyspnoea, chronic cough, chronic sputum production and history of exposure to key factors2. COPD patients have symptoms of dyspnoea (laboured or difficult breathing15) on exertion or at rest. The chronic cough and sputum production usually lasts in excess of three months in two consecutive years to be considered as chronic bronchitis-a component of COPD16. In addition to this, other symptoms can be shortness of breath, wheezing, chest tightness and fatigue17. Acute exacerbations of COPD present with a worsening of these symptoms in addition to reduced exercise tolerance, tachypnoea (shortness of breath), possible cyanosis (high levels of deoxygenated haemoglobin) and peripheral oedema17. COPD is a chronic progressive disease indicating that these symptoms become worse over time even with the best medical care2.
Very severe COPD can develop into respiratory failure. There are two extreme patterns of respiratory failure. One is the 'pink puffer' (emphysematous type18), someone who has dyspnoea but not resting cyanosis. The other is nicknamed the 'blue bloater' (bronchitic type18); a patient with cyanosis at rest, corpulmonale and oedema17. Corpulmonale is a condition of right ventricular hypertrophy as a result of the COPD.
When a patient presents with the key indicators of COPD, diagnosis of the disease should be a strong consideration. The most common form of confirming this diagnosis is by spirometry. In the UK the National Institute for Health and Clinical Excellence (NICE) recommends the use of the European Respiratory Society (ERS) 1993 Spirometry predicted normal values19. It is recommended that a bronchiodilator is also used for the diagnosis and assessment of severity of COPD by spirometry. The patients' spirometry result is compared to the predicted value for their height and age allowing COPD diagnosis. Often under-diagnosis occurs in the elderly using this method, and the ERS 1993 values are not applicable to some populations such as Asians20.
The best known and internationally recognised criteria for COPD are that from Global Initiative for Chronic Obstructive Lung Disease (GOLD). The lung function test results can be graded by the GOLD criteria into different categories of severity of COPD. The figure below indicates the different stages of COPD and the treatment indicated in each stage.
The forced expiratory volume in one second (FEV1) is the maximum volume of air (in Litres at body temperature and ambient pressure) one can expel from their lungs in one second. The forced vital capacity (FVC) is the maximum volume of air one can expel from their lungs upon expiration. The FEV1/FVC is the Forced Expiratory Ratio if below the normal value of 0.75-0.9 helps to ascertain an obstructive pulmonary defect such as COPD17.
Figure 1: Gold criteria and treatment
Further testing can be done; the extent of breathlessness can be measured using the Medical Research Council Dyspnoea Scale. A chest radiograph such as Computer Tomography can be used to rule out differential diagnoses. A full blood count test can be administered to exclude the differential diagnoses of anaemia. Cyanosis can be detected by pulse oximetry, and an Electrocardiogram can show indications of Cor Pulmonale20.
Figure 2: COPD histopathologyChronic bronchitis is characterised by goblet cell hypertrophy, chronic mucosal inflammation, bronchospasm, and increased mucus secretion17 (figure 2). As the disease progresses to its latter stages the bronchi themselves exhibit inflammation with pus in the lumen21. There is an inverse relationship between FEV1 decline in COPD and eosinophils, neutrophils and CD8+ T lymphocyte accumulation in the respiratory tract22. Infiltration of the epithelium by neutrophils is seen throughout the bronchial tree, along with Eosinophil accumulation in the lamina propria23. Widespread scarring and remodelling follows the inflammation resulting in thickened airway walls resulting in lumen narrowing particularly affecting the small airways.
Changes in the epithelial morphology are seen (squamous metaplasia), coupled with sub epithelial fibrosis causing exacerbation of airflow limitation21.
Senile emphysema can be defined as the naturally occurring physiological aging of a lung characterised by inflammation and structural changes leading to deterioration in pulmonary function24. Senile emphysema can be differentiated from the emphysematous lung by the lack of alveolar wall damage25. Centri-acinar (or centrilobular) is the most frequent of emphysema; this begins in the respiratory bronchioles, rarely affecting the alveolar portions of the lungs. Panacinar emphysema, another major form of emphysema associated with AATD affects the entire acinar structure. Emphysema is characterised by permanent 'dilation and destruction' of lung parenchyma distal to the terminal bronchiole21. Loss of elastin results in reduced lung elastic recoil. This loss of recoil aids the collapse of airways which is exacerbated by a loss of interstitial supporting tissue. The collapse of airways causes air to get trapped and hyperinflate alveoli resulting in (bullae) 17.
In COPD, emphysema and chronic bronchitis often co-exist resulting in various functional consequences. Loss of lung recoil causes elevated total lung capacity, functional residual capacity and residual volume. Ventilation-Perfusion mismatching occurs because of mucus blocking smaller airways (chronic bronchitis effect) and loss of recoil (emphysema effect). Ventilation-Perfusion mismatching results in a reduced partial pressure of oxygen in arterial blood, hence tachypnoea seen in the 'Pink Puffer'. Carbon dioxide content is unaffected due to the tachypnoea facilitating excretion at a rate to suffice the central chemoreceptor (responsible for 80% 17of the ventilatory response), which is receptive to carbon dioxide and not oxygen17. However, failure to maintain the ventilatory response results in central chemoreceptor insensitivity to high carbon dioxide levels. This results in a hypoxaemic, oedematous, cyanosed state seen in the 'blue bloater' COPD patient. Commonly these patients experience polycythaemia to counteract the hypoxaemia21.
COPD is not curable but the progression of the disease can be slowed with effective management. Treatment aims to alleviate chronic symptoms and prevent acute exacerbations. The first and foremost management is to reduce the risk factors to COPD-the cause of the disease. Smoking cessation is the most important factor to slow the progression of COPD in smokers. Smoking is the only intervention that can slow the progression of the COPD. There is a large amount of help one can get when deciding to quite smoking; examples include behavioural therapy, and pharmacological intervention (nicotinic replacement therapy or bupropion26). The government pushes education, training and public campaigns to raise awareness of smoking too26.
Oral corticosteroids such as prednisolone courses can be prescribed for acute exacerbations of COPD, but with a small effect, theoretically working by inflammatory reductions. Sometimes COPD patients may not be able to stop taking these corticosteroids after the acute exacerbation is over, resulting in use for 'maintenance' 27. Long term use of oral corticosteroids is not encouraged and should be kept at a minimum dose due to the risks of osteoporosis. Inhaled corticosteroids are not encouraged or licensed for use alone in COPD treatment. Studies have shown that inhaled corticosteroids do not reduce inflammation judged by sputum analysis28. Corticosteroids are generally not used in COPD patients due to insensitivity causing a very poor response. Only 25% of patients will show a response to this treatment17.
There are various ways of preventing acute exacerbations. Pneumococcal and influenza vaccinations can help to reduce respiratory infections. Staying away from cold weather aids this in addition to reducing bronchospasm (and the resulting breathlessness) by staying warmer. Prompt treatment with an antibiotic course will shorten the acute exacerbation of COPD21.
Bronchodilators are commonly used in the management of COPD delivered by inhalers or nebulisers. β2 adrenergic receptor agonists relax smooth muscle, dilating the bronchial pathways in the lung. Short acting β2 agonist salbutamol is often used, improving lung function, dyspnoea, and exercise limitation 27. Muscarinic receptor antagonists can be used to relax smooth muscle by blocking parasympathetic bronchial constriction. Short term ipatropium can be used; this is combined with β2 agonism for the greatest effect. When short acting bronchodilators are ineffective, long-acting β2 agonists such as salmeterol27, and longer term muscarinic antagonists such as Tiotropium are used in conjuction for greatest effects. There are adverse cardiovascular outcomes associated with bronchodilators29.
Theophylline is a type of xanthine which acts by inhibiting phosphodiesterase. This inhibition potentiates cyclic AMP production in the lung, thus inducing smooth muscle relaxation. In addition to this it causes mast cell stabilisation and reduces eosinophil survival. The effects upon spirometry are negligible, but it can improve blood gasses and exercise tolerance17. Theophylline has recently been shown to potentiate the action of corticosteroids, thus being more effective when co-administered30. In the UK theophylline is only used after the unsuccessful use of bronchodilators29.
The importance of pulmonary rehabilitation is underplayed. This is a multidisciplinary programme aimed at exercise for patients with COPD. The programme is tailored to suit the individual based on the severity of their impairment. The programme aims to increase exercise tolerance and build accessory respiratory muscle strength. Ultimately it aims to improve the physical and psychosocial aspects of a COPD patient's life.
Oxygen therapy can be used in acute exacerbations of COPD and end-stage COPD. It aims to prolong the life of patients with a resting daytime hypoxaemia, helping to slow the rate of progression of cor pulmonale. The more oxygen is typically used, the better the outcomes, however this is controversial in AATD. Oxygen therapy can be helpful overnight and during exercise17. COPD is a chronic disease which cannot be cured making it terminal in its latter stages. As a result the importance of palliative care as part of management cannot be underestimated.
In COPD sufferers with a forced expiratory volume 1 (FEV1) less that 0.8L, there is a yearly mortality rate of 25%17. Patients with complications such as ongoing infections, hypercapnia, cor pulmonale, or even those who still smoke have a significantly worse prognosis. COPD patients die from complications such as respiratory failure, pneumonias or cardiac arrhythmias, not COPD itself17. COPD is accountable for over 70% of respiratory disease mortality31. It is the 6th greatest cause of mortality in the UK31. The prevalence of COPD is estimated at 3.7 million people in the UK22. In 2009 it was estimated that 428 men and 288 women per million population died1. The international prevalence of stage 2 COPD or higher is estimated at 10.1%32. In Europe alone the direct cost of COPD is 38.6 billion Euros33. COPD is the thirteenth leading cause of burden of disease in terms of disability, weighing in at 30.2 million disability-adjusted-life-years (DALYs) 34. It is expected that by 2020 that COPD will be the fifth leading cause of burden of disease in terms of disability35.
COPD does not just manifest itself through the lungs; there are also systemic effects of the disease. Weight loss is gradually seen, which worsens the prognosis of the disease. Peripheral muscle dysfunction and general weakness exacerbates exercise intolerance; osteoporosis and atherosclerosis are also other complications36
Firure 3: A diagram showing the changing rates of mortality for the highest ranking diseases from 1970 to 2002 in the USACOPD is a complex disease which has various co-morbidities. The most significant co-morbidities are cardiovascular events; the increase in relative risk of cardiac arrhythmia is 2.4 for COPD sufferers37. Similarly heart failure and ischaemic heart disease are much more common in the COPD population than the general population. COPD patients are 1.3 times more prone to affective disorders than the general population37. Other co-morbidities include diabetes mellitus, osteoporosis, and malignant pulmonary neoplasms.
From figure 3 we can see the changing rates of mortality in certain diseases. Since 1970 the deaths as a result of COPD have doubled. Cardiovascular disease and accident mortality has rapidly fallen since 1970, with steadier rates in cancer and diabetes mellitus. As a result, COPD has rapidly become a disease with one of the highest mortality rates. By 2020 COPD is predicted to be the third greatest cause of death35.
Aging is the proliferation of changes after the reproductive phase of life, characterised by homeostatic imbalance increasing the risk of death or disease24. There are different perceived forms of aging; programmed aging and non-programmed aging. Programmed aging is a natural, instinctive process by which aging occurs in humans. Senescence is when cells lose the ability to multiply37, resulting in cell death. The main mechanism behind this is telomere shortening
This results from a failure of organs to repair DNA damage by oxidative stress
(nonprogrammed aging) and from telomere shortening as a result of repeated cell division
(programmed aging). During aging, pulmonary function progressively deteriorates and pulmonary
inflammation increases, accompanied by structural changes, which are described as senile
emphysema. Environmental gases, such as cigarette smoke or other pollutants, may accelerate
the aging of lung or worsen aging-related events in lung by defective resolution of inflammation,
for example, by reducing antiaging molecules, such as histone deacetylases and sirtuins, and this
consequently induces accelerated progression of COPD. Recent studies of the signal transduction
mechanisms, such as protein acetylation pathways involved in aging, have identified novel
antiaging molecules that may provide a new therapeutic approach to COPD.
Telomere shortening (Chromatin remodelling)
Senescence (causation of accelerated aging)