COPD reference

Chronic obstructive pulmonary disease (COPD) is a disease of the lungs where the airways become narrowed. This leads to a limitation of the flow of air to and from the lungs causing shortness of breath. In contrast to asthma, the limitation of airflow is not fully reversible and usually gradually gets worse over time. COPD is associated with an abnormal inflammatory response of the lung to noxious particles or gases[1], most commonly tobacco smoke. The inflammatory response in the larger airways is known as chronic bronchitis which often results in people with COPD regularly coughing up sputum or mucus. In the smaller airways, the inflammatory response causes small airways inflammation[2]. In the alveoli, the inflammatory response causes destruction of the tissue of the lung, a process known as emphysema. Individuals with COPD vary in the way the disease affects their lungs. Some have mostly chronic bronchitis, others have mostly emphysema and many have a mixture of inflammatory responses.

COPD is the 4th leading cause of death in the US[3]. Worldwide, COPD ranked sixth as the cause of death in 1990. It is projected to be the third leading cause of death worldwide by 2020 due to an increase in smoking rates and demographic changes in many countries[1]. The economic burden of COPD in the US in 2007 was $42.6 billion in health care costs and lost productivity[4].

COPD is also known as chronic obstructive airway disease (COAD), chronic airflow limitation (CAL), chronic obstructive lung disease and chronic obstructive respiratory disease. Some respiratory diseases such as tuberculosis and bronchiectasis can have features of COPD such as chronic airflow obstruction that is not fully reversible. The causes, treatment and prognosis of these conditions are different from COPD and these diseases are usually not thought of as examples of COPD

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Signs and symptoms

One of the most common symptoms of COPD is shortness of breath (dyspnea). People with COPD commonly describe this as: “My breathing requires effort”, “I feel out of breath” or “I can not get enough air in”[5]. People with COPD typically first notice dyspnea during vigorous exercise when the demands on the lungs are greatest. Over the years, dyspnea tends to get gradually worse so that it can occur during milder, everyday activities such as housework. In the advanced stages of COPD, dyspnea can become so bad that it occurs during rest and is constantly present. Other sypmtoms of COPD are a persistent cough, sputum or mucus production, wheezing, chest tightness and tiredness.U.S. National Heart Lung and Blood Institute - Signs and Symptoms[6]. People with advanced (very severe) COPD sometimes develop respiratory failure. When this happens, cyanosis, a bluish discoloration of the lips caused by a lack of oxygen in the blood, can occur. An excess of carbon dioxide in the blood can cause headaches, drowsiness or twitching (asterixis). A complication of advanced COPD is cor pulmonale, a strain on the heart due to the extra work required by the heart to pump blood through the affected lungs.[7] Symptoms of cor pulmonale are peripheral edema, seen as swelling of the ankles, and dyspnea.

There are a few medical signs of COPD that a healthcare worker may detect although they can be seen in other diseases. Some people have COPD and have none of these medical signs. Common signs are:

* tachypnea, a rapid breathing rate
* wheezing sounds or crackles in the lungs heard through a stethoscope
* breathing out taking a longer time than breathing in
* enlargement of the chest, particularly the front-to-back distance (hyperinflation)
* active use of muscles in the neck to help with breathing
* breathing through pursed lips

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Etiology

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Smoking

The primary risk factor for COPD is chronic tobacco smoking. In the United States, 80 to 90% of cases of COPD are due to smoking.[8] Exposure to cigarette smoke is measured in pack-years, the average number of packages of cigarettes smoked daily multiplied by the number of years of smoking. Not all smokers will develop COPD, but continuous smokers have at least a 25% risk after 25 years.[9] The likelihood of developing COPD increases with increasing age as the cumulative smoke exposure increases. Inhaling the smoke from other peoples' cigarettes (passive smoking) can lead to impaired lung growth and could be a cause of COPD.

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Occupational exposures

Intense and prolonged exposure to workplace dusts found in coal mining, gold mining, and the cotton textile industry and chemicals such as cadmium, isocyanates, and fumes from welding have been implicated in the development of airflow obstruction, even in nonsmokers[10]. Workers who smoke and are exposed to these particles and gases are even more likely to develop COPD. Intense Silica dust exposure causes silicosis, a restrictive lung disease distinct from COPD however less intense silica dust exposures have been linked to a COPD-like condition[11]. The effect of occupational pollutants on the lungs appears to be substantially less important than the effect of cigarette smoking[12].

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Air pollution

Studies in many countries have found that people who live in large cities have a higher rate of COPD compared to people who live in rural areas[13]. Urban air pollution may be a contributing factor for COPD as it is thought to slow the normal growth of the lungs although the long-term research needed to confirm the link has not been done. In many developing countries indoor air pollution from cooking fire smoke (often using biomass fuels such as wood and animal dung) is a common cause of COPD, especially in women[14].

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Genetics

Only about half of all long-term smokers will ever develop COPD. Some factor in addition to heavy smoke exposure is required for a person to develop COPD. This factor is probably a genetic susceptibility. COPD is more common among relatives of COPD patients who smoke than unrelated smokers[15]. The genetic differences that make some peoples' lungs susceptible to the effects of tobacco smoke are mostly unknown. Alpha 1-antitrypsin deficiency is a genetic condition that is responsible for about 2% of cases of COPD. In this condition, the body does not make enough of a protein, alpha 1-antitrypsin. Alpha 1-antitrypsin protects the lungs from damage from protease enzymes such as trypsin that can be released by tobacco smoke.[16]

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Other risk factors

A tendency to sudden airway constriction in response to inhaled irritants, bronchial hyperresponsiveness, is a characteristic of asthma. Many people with COPD also have this tendency. In COPD, the presence of bronchial hyperresponsiveness predicts a worse course of the disease[12]. It is not known if bronchial hyperresponsiveness is a cause or a consequence of COPD. Other risk factors such as repeated lung infection and possibly a diet high in cured meats may be related to the development of COPD.

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COPD as an autoimmune disease



There is mounting evidence that there may be an autoimmune component to COPD. Many individuals with COPD who have stopped smoking have active inflammation in the lungs. The disease may continue to get worse for many years after stopping smoking due to this ongoing inflammation. This sustained inflammation is thought to be mediated by autoantibodies and autoreactive T cells.[17][18][19]

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Disease process
Enlarged view of lung tissue showing the difference between healthy lung and COPD
Enlarged view of lung tissue showing the difference between healthy lung and COPD

It is not fully understood how tobacco smoke and other inhaled particles damage the lungs to cause COPD. The most important processes causing lung damage are:

* Oxidative stress produced by the high concentrations of free radicals in tobacco smoke.
* Cytokine release due to inflammation as the body responds to irritant particles such as tobacco smoke in the airway.
* Tobacco smoke and free radicals impair the activity of antiprotease enzymes such as alpha 1-antitrypsin, allowing protease enzymes to damage the lung.

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Pathology

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Chronic bronchitis


Lung damage and inflammation in the large airways results in chronic bronchitis. Chronic bronchitis is defined in clinical terms as a cough with sputum production on most days for 3 months of a year, for 2 consecutive years[20]. In the airways of the lung, the hallmark of chronic bronchitris is an increased number (hyperplasia) and increased size (hypertrophy) of the goblet cells and mucous glands of the airway. As a result, there is more mucus than usual in the airways, contributing to narrowing of the airways and causing a cough with sputum. Microscopically there is infiltration of the airway walls with inflammatory cells. Inflammation is followed by scarring and remodeling that thickens the walls and also results in narrowing of the airways. As chronic bronchitis progresses, there is squamous metaplasia (an abnormal change in the tissue lining the inside of the airway) and fibrosis (further thickening and scarring of the airway wall). The consequence of these changes is a limitation of airflow.

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Emphysema



Lung damage and inflammation of the air sacs (alveoli) results in emphysema. Emphysema is defined as enlargement of the air spaces distal to the terminal bronchioles, with destruction of their walls[20]. The destruction of air space walls reduces the surface area available for the exchange of oxygen and carbon dioxide during breathing. It also reduces the elasticity of the lung itself, which results in a loss of support for the airways that are embedded in the lung. These airways are more likely to collapse causing further limitation to airflow.

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Pathophysiology

Narrowing of the airways reduces the rate at which air can flow to and from the air sacs (alveoli) and limits the effectiveness of the lungs. In COPD, the greatest reduction in air flow occurs when breathing out (during expiration) because the pressure in the chest tends to compress rather than expand the airways. In theory, air flow could be increased by breathing more forcefully, increasing the pressure in the chest during expiration. In COPD, there is often a limit to how much this can actually increase air flow, a situation known as expiratory flow limitation[22].

If the rate of airflow is too low, a person with COPD may not be able to completely finish breathing out (expiration) before he or she needs to take another breath. This is particularly common during exercise when breathing has to be faster. A little of the air of the previous breath remains within the lungs when the next breath is started. When this happens, there is an increase in the volume of air in the lungs, a process called dynamic hyperinflation[22].

Dynamic hyperinflation is closely linked to shortness of breath (dyspnea) in COPD[23]. It is less comfortable to breathe with hyperinflation because it takes more effort to move the lungs and chest wall when they are already stretched by hyperinflation.

Another factor contributing to shortness of breath in COPD is the loss of the surface area available for the exchange of oxygen and carbon dioxide with emphysema. This reduces the rate of transfer of these gasses between the body and the atmosphere and can lead to low oxygen and high carbon dioxide levels in the body. A person with emphysema may have to breathe faster or more deeply to compensate, which can be difficult to do if there is also flow limitation or hyperinflation.

Some people with advanced COPD do manage to breathe fast to compensate, but usually have dyspnea as a result. Others, who may be less short of breath, tolerate low oxygen and high carbon dioxide levels in their bodies but this can eventually lead to headaches, drowsiness, heart failure and death.

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Diagnosis

The diagnosis of COPD is suggested by symptoms; it is a clinical diagnosis and no single test is definitive. A history is taken of smoking and occupation, and a physical examination is done. Measurement of lung function with a spirometer can reveal the loss of lung function.

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Exams and Tests

An examination often reveals increased work involved in breathing: nasal flaring may be evident during air intake, and the lips may be pursed (the shape lips make when you whistle) while exhaling.

During a flare of disease, chest inspection reveals contraction of the muscles between the ribs during inhalation (intercostal retraction) and the use of accessory breathing muscles. The respiratory rate (amount of breaths per minute) may be elevated, and wheezing may be heard through a stethoscope.

A chest X-ray can show an over-expanded lung (hyperinflation) and a flattened diaphragm while a chest CT scan may show emphysema.

A sample of blood taken from an artery (arterial blood gas) can show low levels of oxygen (hypoxemia) and high levels of carbon dioxide (respiratory acidosis) also a veinous blood sample may show a reactive polythycaemia (increase no. of RBC'S)caused by the chronicity of hypoxia . Pulmonary function tests show decreased airflow rates while exhaling and over-expanded lungs. [24]

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Physical examination

A systematic review has concluded that no single medical sign or symptom can adequately exclude the diagnosis of COPD.[25] One study found that the presence of either "a history of smoking more than 30 pack-years, diminished breath sounds, or peak flow less than 350 L/min" has a sensitivity of 98 percent.[26]

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Management

Although COPD is not curable, it can be controlled in a variety of ways. Clinical practice guidelines by Global Initiative for Chronic Obstructive Lung Disease (GOLD), a collaboration including the American National Heart, Lung, and Blood Institute and the World Health Organization, are available.[1]

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Smoking cessation



Smoking cessation is one of the most important factors in slowing down the progression of COPD. Even at a late stage of the disease it can reduce the rate of deterioration and prolong the time taken for disability and death.[21]

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Occupational change

Workers may be able to transfer to a significantly less contaminated area of the company depending on circumstances. Often however, workers may need complete occupational change.

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Pharmacotherapy

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Bronchodilators

There are several types of bronchodilators used clinically with varying efficacy: β2 agonists, M3 antimuscarinics, leukotriene antagonists, cromones and xanthines.[27] These drugs relax the smooth muscles of the airway allowing for improved airflow. The change in FEV1 may not be substantial, but changes in the vital capacity are significant. Many patients feel less breathless after taking bronchodilators.

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β2 agonists

There are several highly specific β2 agonists available. Salbutamol (Ventolin) is the most widely used short acting β2 agonist to provide rapid relief and should be prescribed as a front line therapy for all classes of patients. Other β2 agonists are Bambuterol, Clenbuterol, Fenoterol, and Formoterol. Long acting β2 agonists (LABAs) such as Salmeterol act too slowly to be used as relief for dypsnea so these drugs should be used as maintenance therapy in the appropriate patient population. The TORCH study showed that LABA therapy reduced COPD exacerbation frequency over a 3 year period, compared to placebo.[28] An increased risk is associated with long acting β2 agonists due to decreased sensitivity to inflammation so generally the use of a concomitant corticosteroid is indicated[29][30][31].

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M3 muscarinic antagonists (anticholinergics)

Specific antimuscarinics were found to provide effective relief to COPD. Inhaled antimuscarinics have the advantage of avoiding endocrine and exocrine M3 receptors. The quaternary M3 muscarinic antagonist Ipratropium is widely prescribed with the β2 agonist salbutamol. [2]. Ipratropium formerly was offered combined with salbutamol (Combivent) and with fenoterol (Duovent) but due to the CFC propellant, these products have been withdrawn.

Tiotropium provides improved specificity for M3 muscarinic receptors. It is a long acting muscarinic antagonist that has shown good efficacy in the reduction of exacerbations of COPD, especially when combined with a LABA and inhaled steroid.[32]

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Cromones

Cromones are mast cell stabilizers that are thought to act on a chloride channel found on mast cells that help reduce the production of histamine and other inflammatory factors. Chromones are also thought to act on IgE-regulated calcium channels on mast cells. Cromoglicate and Nedocromil, which has a longer half-life, are two chromones available.[33]

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Leukotriene antagonists

More recently leukotriene antagonists block the signalling molecules used by the immune system. Montelukast, Pranlukast, Zafirlukast are some of the leukotrienes antagonists.[34]These agents have not been tested in good, controlled trials, [35] and as such, there is no data to support the use of these agents in COPD.[36]

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Xanthines

Theophylline is the prototype of the xanthine class of drug. Teas are natural sources of methylxanthines, xanthines and caffeine while cocoa is a natural source of theobromine. Caffeine is approximately 16% metabolized into theophylline. Nebulized theophylline is used in the EMR for treatment of dyspnea (Difficulty in breathing). Patients need continual monitoring as theophylline has a narrow therapeutic range. More aggressive EMR interventions include IV H1 antihistamines and IM dexamethasone.

Theophylline antagonizes phosphodiesterase, and small reductions in COPD exacerbation rates have been demonstrated.[37] The investigative phosphodiesterase-4 antagonists, roflumilast and cilomilast have completed Phase-2 clinical trials.

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Corticosteroids

Enteral and parenteral corticosteroid therapy has long been the mainstay of treatment of COPD, and is known to reduce length of stay in hospital. Similarly, inhaled corticosteroids (specifically glucocorticoids) act in the inflammatory cascade and improve airway function considerably,[21] and have been shown in the ISOLDE trial to reduce the number of COPD exacerbations by 25%.[38] Corticosteroids are often combined with bronchodilators in a single inhaler. Some of the more common inhaled steroids in use are beclomethasone, mometasone, and fluticasone.

Salmeterol and fluticasone are combined (Advair), however the reduction in death from all causes among patients with COPD in the combination therapy group did not reach the predetermined level of statistical significance.[39][40]

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TNF antagonists

Tumor necrosis factor antagonists (TNF) are the most recent class of medications designed to deal with refractory cases. Tumor necrosis factor-alpha is a cachexin or cachectin and is considered a so-called biological drug. They are considered immunosopressive with attendant risks. These rather expensive drugs include infliximab, adalimumab and etanercept.[41]Infliximab has been trialled in COPD with no evidence of benefit, with the possibility of harm. This was a relatively small study (77-79 patients in each arm).[42]

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Supplemental Oxygen

In general, long-term administration of oxygen is usually reserved for individuals with COPD who have arterial hypoxemia (PaO2 less than 55 mm Hg), or a PaO2 between 55 and 60 mm Hg with evidence of pulmonary hypertension, cor pulmonale, or secondary erythrocytosis (hematocrit >55%). In these patients, continuous home oxygen therapy (for >15 h/d) sufficient to correct hypoxemia has been shown to improve survival. [43] The use of low flow oxygen may be necessary in some patients because in the COPD patient, control of respiration is driven mainly by the blood oxygen level rather than the carbon dioxide level, increased oxygen delivery can diminish this response and cause respiratory failure. The American Thoracic Society Guidelines on COPD cover the use of oxygen therapy and its risks.[44]

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Vaccination

Patients with COPD should be routinely vaccinated against influenza, pneumococcus and other diseases to prevent illness and the possibility of death.[27]

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Pulmonary rehabilitation

Pulmonary rehabilitation is a program of disease management, counseling and exercise coordinated to benefit the individual.[45] Pulmonary rehabilitation has been shown to relieve difficulties breathing and fatigue. It has also been shown to improve the sense of control a patient has over their disease as well as their emotions.[46]

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Diet

A recent French study conducted over 12 years with almost 43,000 men concluded that eating a Mediterranean diet "halves the risk of serious lung disease like emphysema and bronchitis".

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Treatment

Treatment for COPD includes inhalers that dilate the airways (bronchodilators) and sometimes theophylline. The COPD patient must stop smoking. In some cases inhaled steroids are used to suppress lung inflammation and, in severe cases or flare-ups, intravenous or oral steroids are given.

Antibiotics are used during flare-ups of symptoms as infections can worsen COPD. Chronic, low-flow oxygen, non-invasive ventilation, or intubation may be needed in some cases. Surgery to remove parts of the disease lung has been shown to be helpful for some patients with COPD.[citation needed]

Lung rehabilitation programs may help some patients.

Lung transplant is sometimes performed for severe cases.

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Support Groups

The stress of illness can often be helped by joining a support group where members share common experiences and problems. [49]

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Prognosis

A good prognosis of COPD relies on an early diagnosis and prompt treatment. Most patients will have improvement in lung function once treatment is started, however eventually signs and symptoms will worsen as COPD progresses. The median survival is about 10 years if two-thirds of expected lung function was lost by diagnosis.

"End Stages" of COPD are diagnosed as the normal ratio of carbon dioxide being inordinately higher than the volume of oxygen in the bloodstream. Although end stage COPD may mean death is imminent in cases dealing with degenerative diseases, forced oxygen therapy and other treatments may successfully be used to prolong life but have not been proven to be successful for the long run. These types of therapy may be successfully used in COPD cases caused by curable diseases such as bronchitis.

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Bronchitis

Acute bronchitis usually resolves in 2-10 years.

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Emphysema

The outcome is better for patients with less damage to the lung who stop smoking immediately. Still, patients with extensive lung damage may live for many years so predicting prognosis is difficult. Death may occur from respiratory failure, pneumonia, or other complications.

[edit] Pneumoconiosis

The outcome is good for patients with minimal damage to the lung. However, patients with extensive lung damage may live for many years so predicting prognosis is difficult. Death may occur from respiratory failure, pneumonia, cor pulmonale or other complications.

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Pulmonary neoplasms

The stage of the tumor(s) has a major impact on neoplasm prognosis. Staging is the process of determining tumor size, growth rate, potential metastasis, lymph node involvement, treatment options and prognosis. Two-year prognosis for limited small cell pulmonary neoplasms is twenty percent and for extensive disease five percent. The average life expectancy for someone with recurrent small cell pulmonary neoplasms is two to three months.[50]

The 5-year overall survival rate for pulmonary neoplasms is 14%.[51]

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Epidemiology

According to the World Health Organization (WHO), 80 million people suffer from moderate to severe COPD and 3 million died due to it in 2005. The WHO predicts that by 2030, it will be the 3rd largest cause of mortality worldwide.[52]

Since COPD is not diagnosed until it becomes clinically apparent, prevalence and mortality data greatly underestimate the socioeconomic burden of COPD.[27] In the UK, COPD accounts for about 7% of all days of sickness related absence from work.[21]

Smoking rates in the industrialized world have continued to fall, causing rates of emphysema and pulmonary neoplasms to slowly decline.