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Chronic Obstructive Pulmonary Disease (COPD) is a generalized term for diseases in the lung that obstruct the airways. These diseases are chronic bronchitis, bronchiolitis and emphysema. The most significant contribution to COPD is smoking, although only 10-20% of chronic smokers will ever develop COPD1. A genetic disorder called α-1-antitrypsin deficiency is the most common inherited genetic defect in Caucasians2 and results in enzymatic attack of healthy lung tissue, resulting in emphysema. Other risk factors include air pollution, coal dust, welding fumes and mineral dusts. COPD causes 5% of all deaths each year in the UK3.
Pathology of COPD:
Chronic bronchitis is defined by the American Thoracic Society and the UK Medical Research Council as 'the production of sputum on most days for at least three months in at least two consecutive years'4. Hypersecretion of mucus from the goblet cells and mucus glands causes an increased resistance to airflow and inflammation of the bronchial. Smokers' goblet cells are present in higher numbers and extend further into the airways increasing their chance of developing chronic bronchitis4. Mucus gland enlargement is measured by the Reid index and shows the distance between the mucus gland and the basement membrane in the bronchial wall. The gland/wall ratio is normally less than 0.4 but may exceed 0.7 in severe chronic bronchitis5.
Small-airways disease/ bronchiolitis
Bronchiolitis causes inflammation in the smaller bronchi and the bronchioles. This increases the peripheral airway resistance and causes structural narrowing of airway lumen, loss of alveolar support and, as the condition continues, scar tissue formation resulting in further narrowing of the airways. The resistance produced by bronchiolitis in the peripheral airways contributes to most of the airway resistance in COPD2.
Emphysema is defined as the permanent enlargement of airspaces distal to the terminal bronchioles accompanied by destruction of their wall4. It results from the excessive release of trypsin from alveolar macrophages in response to inhaled cigarette smoke. The unusually high amount of trypsin destroys the lung tissue as well as the foreign material, resulting in emphysema. The lung is usually protected by α-1-antitrypsin and so patients with the genetic deficiency can develop emphysema without the presence of cigarette smoke or excessive trypsin release. Classes of emphysema are identified following their pattern of airspaces. Centriacinar consists of enlarged airspaces around the upper regions of the lung and affects the centre of the lobule. Panacinar involves enlargement that has hardly any preference, and affects most of the acinar unit. Pericacinar shows enlarged airspaces along the edge of the acinar unit. Areas in excess of 1cm are referred to as bullae.
Figure 2: Centriacinar emphysema
Figure 1: Healthy Lung
Images adapted from W. MacNee and S. Rennard, 2004, Fast facts: Chronic Obstructive pulmonary disease
Figure 3: Panacinar emphysema
Figure 4: Periacinar emphysema
Signs and symptoms
A common symptom of COPD is breathlessness which can be monitored and identified using The Medical Research Council Dyspnea Scale:
Table 1: The Dyspnea Scale for Breathlessness
Degree of breathless related to activities
Not troubled by breathlessness except on strenuous exercise.
Short of breath when hurrying or walking up a slight hill.
Walks slower than contemporaries on the level because of breathlessness, or has to stop for breath when walking at own pace.
Stops for breath after walking about 100m or after a few minutes on the level.
Too breathless to leave the house or breathless when dressing or undressing.
Breathless at rest.
Other symptoms include:
Coughing (usually worse in the mornings)
Production of sputum which is usually white or grey
Yellow or green sputum during exacerbations4
Wheezing and chest pains (not specific to COPD)
Severe COPD symptoms:
Muscle weakness (due to reduced oxygen delivery)
Copious amounts of frothy sputum (indication of left ventricular failure and pulmonary oedema4)
Overinflation of chest (can look 'barrel-shaped' and the ribs appear to be horizontal)
Hypercapnia, causing peripheral vasodilation (warm peripheries and a high volume pulse)
Difficultly in hearing apex beat of the heart (exaggerated second heart sound could indicate pulmonary oedema4)
Tender and pulsating liver (as diaphragm is pushed lower)
COPD patients are usually classified into two different clinical representations; a pink puffer or a blue bloater.
Quiet breathe sounds
Normal jugular vein pressure and blood gas levels
Hypercapnia and hypoxemia
Increased jugular vein pressure
Cardiac enlargement due to congested lungs
Breath tests are carried out using a spirometer machine. The spirometer can determine the severity of lung function impairment. The spirometer measures the following values:
FEV1: forced expiratory volume in 1 second. In healthy patients the FEV1 varies depending upon age, sex and height. COPD patient values are compared to 'predicted value' to provide a percentage predicted value.
FVC: forced vital capacity. The total volume of air that can be exhaled from maximum inhalation to maximum exhalation. This value is also measured as a percentage of the predicted value.
FEV1/FVC% (FEV1:FVC): ratio of FEV1to FVC expressed as a percentage. In a healthy patient 70-80% of total volume of air in lungs should be exhaled in the first second. COPD patients are unable to exhale as much air in the first second due to obstruction in the airways.
The values recorded by the spirometer help diagnose the severity of COPD using the GOLD classification of severity of COPD6.
Table 2: GOLD classification of severity of COPD
I: Mild COPD
FEV1:FVC < 70%
FEV1 ≥ 80% predicted
II: Moderate COPD
FEV1:FVC < 70%
50% ≤ FEV1 < 80% predicted
III: Severe COPD
FEV1:FVC < 70%
30% ≤ FEV1 < 50% predicted
IV: Very Severe COPD
FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure.
Gas transfer test is used to measure a patient's TLCO; if a patient with COPD shows a decrease TLCO value it could indicate alveolar destruction by emphysema, however, a normal TLCO does not exclude COPD4.
Blood tests do not diagnose COPD, but if COPD has been diagnosed in a young patient, or a patient who has never smoked, then a blood test is important to test for α-antitrypsin deficiency.
Exercise tests can also help determine how advanced the disease is and how it will affect them from day to day.
Chest x-rays do not show any significant difference in a patient with or without COPD but will eliminate the possibilities of other diseases3. Overinflation, indicating emphysema, can be seen using chest radiography; a low flattened diaphragm and enlarged lung fields can be seen.
Managing COPD with drugs
NICE guidelines7 indicate when the following drugs should be used to manage COPD:
Inhaled bronchodilator therapy (anticholinergics and β2-agonists):
Short acting bronchodilators are the initial treatment for the relief of breathlessness and exercise limitations. If symptoms persist treatment should include long-acting bronchodilators or combined therapy of short acting β2-agonist and short acting anticholinergic. Long acting bronchodilators should be used when patient experiences more than 2 exacerbations per year.
Theophylline, in slow release form, should only be used after trialling short acting and long acting bronchodilators, or if patient is unable to use inhaled therapy, as it requires constant monitoring. If macrolides or fluroquinolones are being used for exacerbations theophylline dose should be reduced as drugs interact.
Inhaled corticosteroids are not licensed for use alone to manage COPD. They are used in combination to treat patients with FEV1 ≤ 50% predicted who are having 2 or more exacerbation per year. Patients taking corticosteroids are at risk of developing osteoporosis and should be monitored. Oral corticosteroids are not usually recommended to patients for maintenance use unless diagnosed with advanced COPD. They work to reduce inflammation of the airways, although the mechanism is unclear3.
Patients who remain symptomatic on mono therapy are recommended to try combination therapy. Good combinations include:
β2-agonist and anticholinergic
β2-agonist and theophylline
anticholinergic and theophylline
long acting β2-agonist and inhaled corticosteroids
Mucoclytics are thought to reduce viscosity of sputum, recommended to patients who experience coughs producing thick, sticky mucus. Diuretics are given to patients who have developed oedema in severe COPD. Cough suppressants could also be prescribed.
The main inhaled short-acting bronchodilators are Ipratropium and Salbutamol. Salbutamol is a β2-agonist; it increases the cyclic AMP which causes a relaxation of smooth muscle, resulting in bronchial dilation regardless of the spasmogen. Salbutamol also inhibits mediator release from mast cells and TNF-α release from monocytes, to decrease inflammation, and increases mucus clearance by action of the cilia8. Ipratropium is a non-selective muscuranic receptor antagonist (anticholinergic). Three muscarinic receptors play a role in the airways. M1 receptor facilitates the neurotransmission of acetylcholine, from the preganglionic nerve, acting on the nicotinc receptor on the parasympathetic ganglion. The postganglionic nerve then releases acetylcholine to act on M3 receptor on the airway smooth muscle to cause a contraction. M2 receptors inhibit the release of Ach from the postganglionic nerve and therefore reduces the effect on M3 receptor. An anticholinergic will cause a relaxation by blocking M1 and M3 receptors; however, due to the blockage of M2 receptor, there will be a decrease of antagonistic effect on M3 receptor.
The most common long-acting β2-agonists are Salmeterol and Formoterol and both work in the same way as Salbutamol. The only long-acting anticholinergic is Tiotropium which works on all three muscarinic receptors but selectivity for M1 and M3 over M2 has been shown and has a half-life of 540minutes compared to 81minutes for Ipratropium2.
Theophylline is also a bronchodilator. It inhibits phosphodiesterase which results in an increase of cyclic AMP and relaxation of smooth muscle. It also blocks adenosine receptors which inhibits bronchoconstriction. Theophylline is metabolised by P450 in the liver so should be avoided in patients with liver failure. It is not often used due to troublesome side effects such as irregular, fast heart beat, nausea and vomiting, abdominal pain and diarrhoea.
Smooth muscle cell
Image 5: Drugs working on smooth muscle cell
Image adapted from W. MacNee and S. Rennard, 2004, Fast facts: Chronic Obstructive pulmonary disease
Managing COPD without Drugs
The NICE guidelines7 state the pulmonary rehabilitation should be offered to all patients who consider themselves functionally disabled by COPD, however is unsuitable for patients who can't walk, have unstable angina or recently had a myocardial infarction. The aim of pulmonary rehabilitation is to break the cycle of breathlessness, inactivity and reduced fitness levels. The programme consists of exercise training, education and nutritional advice. Exercise training can improve the distance a patient can walk, increase muscle strength and reduce symptoms. Some programmes include strengthening of specific muscles, such as upper limbic girdle muscle, to help with daily tasks4. The programme educates patients on the disease itself to improve understanding as well as teaching breathing control exercises, relaxation techniques and positions to adopt when feeling breathless. Advice is also given on drug treatment and how to manage exacerbations. Many COPD patients become underweight or overweight and should be advised appropriately and given advice to improve their general health. It has been proven that after a year of rehabilitation the distance walked in 6 minutes and muscle strength show a significant improvement9.
Many exacerbations are caused by viruses and bacteria. The two main vaccines offered for COPD patients are the pneumoccal vaccine and the influenza vaccine. Influenza vaccine should not be given to patients with an egg allergy as vaccine is prepared from parts of chick embryos3. Zanamivir and Oseltamivir are recommended for treatment of at-risk adults with flu-like illness who can start therapy within 48 hours of onset of sypmtoms7. Zanamivir is used with caution in COPD as there is a risk of bronchospasm7.
Lung reduction surgery involves the removal of inefficient parts of the lung. The NICE guidance7 recommends referral for consideration if patient meets all of the following criteria:
FEV1> 20% predicted
Upper lobe predominant emphysema
TLCO more than 20% predicted
Some patients have a bulla occupying a large volume of the lung. Patients who are breathless, and have a single large bulla on CT scan and FEV1<50% can be referred for consideration of bullectomy7.
Patients with severe COPD who remain breathless despite maximal therapy can be considered for lung transplant if they are under 60 years (both lungs) or under 65 years (single lung). Other considerations include FEV1, PaCO2, homogenously distributed emphysema and pulmonary artery pressure7. Patient will need to be on powerful anti-rejection drugs for the rest of their life after the transplant.
Oxygen in COPD
Long-term oxygen therapy (LTOT) is assessed for patients with PaO2< 7.3KPa, FEV1<30% predicted, cyanosis, polycythaemia, peripheral oedema and increased jugular venous pressure7. The patient should breathe oxygen for 15 hours per day and measurements of arterial blood gasses should by carried out. Ambulatory oxygen is given to patients on LTOT that wish to continue with oxygen therapy away from their home. Short burst oxygen is recommended for patients with severe episodes of breathlessness which are not relieved by other treatments.
Exacerbations are abrupt episodes of worsened symptoms. Treatment at home involves a course of steroid tablets taken for 7-14 days and antibiotics for up to 7 days3. A 'reliever' inhaler should be used as often as possible. At the hospital a full examination is carried out; including temperature, pulse, breathing rate, blood pressure and oxygen levels. Oxygen is given via face mask or nasal cavity and steroids and antibiotics can be given through the vein. For more severe exacerbations ventilation may be required.
As the major risk factor in COPD is smoking the most useful long-term intervention is smoking cessation. If a patient has been tested positive for α1-antitrypsin deficiency then they can inhale genetically engineered α1-antitrypsin to increase the concentration in the epithelial lining fluid and prevent the development of COPD2.
A new developed posphodiesterase 4 inhibitor called Roflumilast has shown statistically significant reductions in exacerbations and improves lung function by reducing inflammation10. If this drug was approved for general use it could be used as a substitute for inhaled corticosteroids. A new theory has recently been developed that stem cells could help treat COPD. Mesenchymal stem cells protect lung tissue by suppressing proinflammatory cytokines and triggering production of reparative growth factors11.