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Chronic Obstructive Pulmonary Disease

What is COPD?

Chronic obstructive pulmonary disease (COPD) is comprised primarily of two related diseases - chronic bronchitis and emphysema. In both diseases, there is chronic obstruction of the flow of air through the airways and out of the lungs, and the obstruction generally is permanent and progressive over time.

Asthma also is a pulmonary disease in which there is obstruction to the flow of air out of the lungs, but unlike chronic bronchitis and emphysema, the obstruction in asthma usually is reversible. Between "attacks" of asthma the flow of air through the airways usually is good.

There are exceptions, however. In some patients with COPD the obstruction can be partially reversed by medications that enlarge or dilate the airways (bronchodilators) as with asthma. Conversely, some patients with asthma can develop permanent airway obstruction if chronic inflammation of the airways leads to scarring and narrowing of the airways. This process is referred to as lung remodeling. These asthma patients with a fixed component of airway obstruction are also considered to have COPD.

There also is frequent overlap among COPD patients. Thus, patients with emphysema may have some of the characteristics of chronic bronchitis. Similarly, patients with chronic bronchitis also may have some of the characteristics of emphysema.

How does the normal lung work?

The lung is the organ for gas exchange; it transfers oxygen from the air into the blood and carbon dioxide (a waste product of the body) from the blood into the air. To accomplish gas exchange the lung has two components; airways and alveoli. The airways are branching, tubular passages that allow air to move in and out of the lungs.

The wider segments of the airways are the trachea and the two bronchi (going to either the right or left lung). The smaller segments are called bronchioles. At the ends of the bronchioles are the alveoli, thin-walled sacs. (The airways and alveoli can be conceptualized as bunches of grapes with the airways analogous to the stems and the alveoli analogous to the grapes.) Small blood vessels (capillaries) run in the walls of the alveoli, and it is across the thin walls of the alveoli where gas exchange between air and blood takes place.

Breathing involves inspiration followed by exhalation. During inspiration, muscles of the diaphragm and the rib cage contract and expand the size of the chest (as well as the airways and alveoli) causing negative pressure within the airways and alveoli. As a result, air is sucked through the airways and into the alveoli. During exhalation, the same muscles relax to their resting positions, shrinking the chest and creating positive pressure within the airways and alveoli. As a result, air is expelled from the lungs.

The walls of the bronchioles are weak and have a tendency to collapse, especially while exhaling. Normally, the bronchioles are kept open by the elasticity of the lung. Elasticity of the lung is supplied by elastic fibers which surround the airways and line the walls of the alveoli. When lung tissue is destroyed, as it is in patients with COPD who have emphysema, there is loss of elasticity and the bronchioles can collapse and obstruct the flow of air.

What is chronic bronchitis?

Chronic bronchitis involves inflammation and swelling of the lining of the airways that leads to narrowing and obstruction of the airways. The inflammation also stimulates production of mucous (sputum), which can cause further obstruction of the airways. Obstruction of the airways, especially with mucus, increases the likelihood of bacterial lung infections. Chronic bronchitis usually is defined clinically as a daily cough with production of sputum for 3 months, two years in a row. For more, please read the Bronchitis article.

What is emphysema?

There is permanent enlargement of the alveoli due to the destruction of the walls between alveoli in emphysema. The destruction of the alveolar walls reduces the elasticity of the lung overall. Loss of elasticity leads to the collapse of the bronchioles, obstructing airflow out of the alveoli. Air becomes "trapped" in the alveoli and reduces the ability of the lung to shrink during exhalation. The reduced expansion of the lung during the next breath reduces the amount of air that is inhaled. As a result, less air for the exchange of gasses gets into the lungs. This trapped air also can compress adjacent less damaged lung tissue, preventing it from functioning to its fullest capacity.

The exchange of carbon dioxide and oxygen between air and the blood in the capillaries takes place across the thin walls of the alveoli. Destruction of the alveolar walls decreases the number of capillaries available for gas exchange. This adds to the decrease in the ability to exchange gases.

Usually, energy is only required for inhalation to inflate the lungs. The stretch of the lungs and distension of the chest cavity springs back to rest during exhalation, a passive process that does not require energy. However, in emphysema, inefficient breathing occurs because extra effort and energy has to be expended to empty the lungs of air due to the collapse of the airways. This essentially doubles the work of breathing, since now energy is required for both inhalation and exhalation. In addition, because of the reduced capacity to exchange gases with each breath (due to the collapse of the bronchioles and loss of capillaries), it is necessary to breathe more frequently.

What is chronic asthma?

Asthma, like chronic bronchitis, is a disease of the airways. Obstruction to the flow of air is due to inflammation of the airways as well as spasm of muscles surrounding the airways in asthma. The narrowing that results from spasm of the muscles is called bronchospasm. Generally, bronchospasm in asthma is reversible and subsides spontaneously or with the use of bronchodilators (medications that relax the muscles surrounding the airways).

We now know that a major component of asthma is inflammation of the airways, and this inflammation causes thickening of the walls of the airways. In many asthmatics, anti-inflammatory medications such as inhaled steroids are required to reduce this inflammation. In long standing asthma, this chronic inflammation can lead to scarring and fixed airway obstruction. For more, please read the Asthma article.

What is bronchiectasis?

Bronchiectasis is another abnormality that can be found in patients with COPD. In bronchiectasis, serious and repeated infections of the lung as well as abnormal development of the lung results in permanent damage to the airways. The damaged airways become enlarged tubes or, in more severe cases, large sacs. These segments of lung can impair clearance of secretions. The damaged, mucus-filled airways often become infected, resulting in further inflammation and damage to the airways. Patients with bronchiectasis often have a vigorous cough producing large amounts of infected mucus.

What causes COPD?

Smoking is responsible for 90% of COPD in the United States. Although not all cigarette smokers will develop COPD, it is estimated that 15% will. Smokers with COPD have higher death rates than nonsmokers with COPD. They also have more frequent respiratory symptoms (coughing, shortness of breath, etc.) and more deterioration in lung function than non-smokers.

Effects of passive smoking or "second-hand smoke" on the lungs are not well-known; however, evidence suggests that respiratory infections, asthma, and symptoms are more common in children who live in households where adults smoke.

Cigarette smoking damages the lungs in many ways. For example, the irritating effect of cigarette smoke attracts cells to the lungs that promote inflammation. Cigarette smoke also stimulates these inflammatory cells to release elastase, an enzyme that breaks down the elastic fibers in lung tissue.

Air pollution can cause problems for persons with lung disease, but it is unclear whether outdoor air pollution contributes to the development of COPD. However, in the non-industrialized world, the most common cause of COPD is indoor air pollution. This is usually due to indoor stoves used for cooking.

Some occupational pollutants such as cadmium and silica do increase the risk of COPD. Persons at risk for this type of occupational pollution include coal miners, construction workers, metal workers, cotton workers, etc. (Most of this risk is associated with cigarette smoking and these occupations, an issue not well controlled for. These occupations are more often associated with interstitial lung diseases, especially the pneumoconioses) Nevertheless, the adverse effects of smoking cigarettes on lung function are far greater than occupational exposure.

Another well-established cause of COPD is a deficiency of alpha-1 antitrypsin (AAT). AAT deficiency is a rare genetic (inherited) disorder that accounts for less than 1% of the COPD in the United States.

As discussed previously, normal function of the lung is dependent on elastic fibers surrounding the airways and in the alveolar walls. Elastic fibers are composed of a protein called elastin. An enzyme called elastase that is found even in normal lungs (and is increased in cigarette smokers) can break down the elastin and damage the airways and alveoli. Another protein called alpha-1 antitrypsin (AAT) (produced by the liver and released into the blood) is present in normal lungs and can block the damaging effects of elastase on elastin.

The manufacture of AAT by the liver is controlled by genes which are contained in DNA-containing chromosomes that are inherited. Each person has two AAT genes, one inherited from each parent. Individuals who inherit two defective AAT genes (one from each parent) have either low amounts of AAT in the blood or AAT that does not function properly. The reduced action of AAT in these individuals allows the destruction of tissue in the lungs by elastase to continue unopposed. This causes emphysema by age 30 or 40. Cigarette smoking accelerates the destruction and results in an even earlier onset of COPD.

Individuals with one normal and one defective AAT gene have AAT levels that are lower than normal but higher than individuals with two defective genes. These individuals MAY have an increased risk of developing COPD if they do not smoke cigarettes; however, their risk of COPD probably is higher than normal if they smoke. Though their Alpha-1 antitrypsin blood levels may be in the normal range, the function of this enzyme is impaired to relative to normals.

What are the symptoms of COPD?

Typically, after smoking 20 or more cigarettes a day for more than twenty years, patients with COPD develop a chronic cough, shortness of breath (dyspnea) and frequent respiratory infections.

In patients affected predominantly by emphysema, shortness of breath may be the major symptom. Dyspnea usually is most noticeable during increased physical activity, but as emphysema progresses, dyspnea occurs at rest.

In patients with chronic bronchitis as well as bronchiectasis, chronic cough and sputum production are the major symptoms. The sputum is usually clear and thick. Periodic chest infections can cause fever, dyspnea, coughing, production of purulent (cloudy and discolored) sputum and wheezing. (Wheezing is a high pitched noise produced in the lungs during exhalation when mucous, bronchospasm, or loss of lung elasticity obstructs airways.) Infections occur more frequently as bronchitis and bronchiectasis progress.

In advanced COPD, patients may develop cyanosis (bluish discoloration of the lips and nail beds) due to a lack of oxygen in blood. They also may develop morning headaches due to an inability to remove carbon dioxide from the blood. Weight loss occurs in some patients, primarily (other possibility is reduced intake of food) because of the additional energy that is required just to breathe. In advanced COPD, small blood vessels in the lungs are destroyed, and this blocks the flow of blood through the lungs. As a result, the heart must pump with increased force and pressure to get blood to flow through the lungs.

(The elevated pressure in the blood vessels of the lungs is called pulmonary hypertension.) If the heart cannot manage the additional work, right heart failure also known as Cor pulmonale results and leads to swelling of the feet and ankles. Patients with COPD may cough up blood (hemoptysis). Usually hemoptysis is due to damage to the inner lining of the airways and the airways' blood vessels; however, occasionally, hemoptysis may signal the development of lung cancer.

How is COPD diagnosed?

COPD usually is first diagnosed on the basis of a medical history which discloses many of the symptoms of COPD and a physical examination which discloses signs of COPD. Other tests to diagnose COPD include chest x-ray, computerized tomography (CT or CAT scan) of the chest, tests of lung function (pulmonary function tests) and the measurement of oxygen and carbon dioxide levels in the blood.

COPD is suspected in chronic smokers who develop shortness of breath with or without exertion, have chronic persistent cough with sputum production, and frequent infections of the lungs such as bronchitis or pneumonia.

Sometimes COPD is first diagnosed after a patient develops a respiratory illness necessitating hospitalization. Some physical findings of COPD include enlarged chest cavity and wheezing. Faint and distant breath sounds are heard when listening to the chest with a stethoscope. Air is trapped in the lungs from the patient's inability to empty their lungs with exhalation. This extra air dampens the sounds heard and results in the overinflated chest cavity.

In patients affected predominantly with emphysema, the chest x-ray may show an enlarged chest cavity and decreased lung markings reflecting destruction of lung tissue and enlargement of air-spaces. In patients with predominantly chronic bronchitis, the chest x-ray may show increased lung markings which represent the thickened, inflamed and scarred airways.

Computerized tomography (CT or CAT scan) of the chest is a specialized x-ray that can accurately demonstrate the abnormal lung tissue and airways in COPD. Chest x-rays and CT scans of the chest also are useful in excluding lung infections (pneumonia) and cancers. CT scan of the chest usually is not necessary for the routine diagnosis and management of COPD.

The most commonly used pulmonary function test is spirometry, a test which quantitates the amount of airway obstruction. During spirometry, the patient takes a full breath and then exhales fast and forcefully into a tube connected to a machine that measures the volume of expired air.

The FEV1 (the volume of air expired in 1 second) is a reliable and useful measure of airflow obstruction. This is compared to the total amount of air blown out of the lungs, the forced vital capacity (FVC). The ratio of the FEV1 to the FVC is usually 70%.

When obstruction is present, this ratio is reduced; the lower the RATIO, the greater the airway obstruction. The FEV1 can be determined again after treatment with bronchodilators. Improvement in FEV1 after bronchodilator treatment means that airway obstruction is reversible. Demonstrating improvement in FEV1 also helps doctors select the proper bronchodilators for patients. Measurements of FEV1 AND FVC can be repeated over time to determine how rapidly airway obstruction is progressing.

Oxygen and carbon dioxide levels can be measured in samples of blood obtained from an artery, but this requires inserting a needle into an artery. A less invasive method to measure oxygen levels in the blood is called pulse oximetry. Pulse oximetry works on the principle that the degree of redness of hemoglobin (the protein in blood that carries oxygen) is proportional to the amount of oxygen, that is, the more oxygen there is in blood, the redder the blood.

A probe (oximeter) is placed around a fingertip. On one side of the finger the probe shines a light. Some of the light is transmitted through the fingertip, and the transmitted light is measured on the opposite side of the finger by the probe. Depending on the redness of the blood within the fingertip (that is, the amount of oxygen in the blood) more or less light is transmitted through the fingertip. Thus, by measuring the amount of light transmitted, it is possible to determine the amount of oxygen in the blood.

What treatment is available for COPD?

The goals of COPD treatment are 1) to prevent further deterioration in lung function, 2) to alleviate symptoms, 3) to improve performance of daily activities and quality of life.

The treatment strategies include 1) quitting cigarette smoking, 2) taking medications to dilate airways (bronchodilators) and decrease airway inflammation, 3) vaccinating against flu influenza and pneumonia and 4) regular oxygen supplementation and 5) pulmonary rehabilitation.

Quitting cigarette smoking

The most important treatment for COPD is quitting cigarette smoking. Patients who continue to smoke have a more rapid deterioration in lung function when compared to others who quit. Aging itself can cause a very slow decline in lung function.

In susceptible individuals, cigarette smoking can result in a much more dramatic loss of lung function. It is important to note that when one stops smoking the decline in lung function eventually reverts to that of a non-smoker.

Unfortunately, only about one third of the patients can abstain from smoking long term. Reasons for difficulty in quitting include nicotine addiction, stress in the workplace and at home, depression, peer pressure, and advertising from cigarette companies.

Nicotine in cigarettes is addictive, and, therefore, cessation of smoking can cause symptoms of nicotine withdrawal including anxiety, irritability, anger, depression, fatigue, difficulty concentrating or sleeping, and intense craving for cigarettes.

Patients likely to develop withdrawal symptoms typically smoke more than 20 cigarettes a day, need to smoke shortly after waking up in the morning, and have difficulty refraining from smoking in non-smoking areas. However, some 25% of smokers can stop smoking without developing these symptoms. Even in those smokers who develop symptoms of withdrawal, the symptoms will decrease after several weeks of abstinence.

To help those patients with symptoms of withdrawal during the early weeks of smoking cessation, nicotine chewing gum (Nicorette Gum) and nicotine skin patches (Transderm Nicotine) are available in the United States. Both the gum and skin patches can deliver enough nicotine into the blood to reduce but not totally eliminate withdrawal symptoms.

Nicotine replacement methods in conjunction with intense patient education and behavioral modification programs have improved the rates at which individuals quit smoking. Nicotine skin patches are easy to use. They generally are used for four to six weeks, sometimes with a tapering period of several additional weeks. The addiction potential of nicotine skin patches is low.

Bupropion (Zyban, Wellbutrin) is an antidepressant that has been found to decrease cravings for cigarettes. It has been shown to be of benefit to patients who want to quit smoking. Recently, varencline (Chantix), a new medication is available to aid in smoking cessation, has been approved for use in the US. Varenicline works in two ways; by cutting the pleasure of smoking and reducing the withdrawal symptoms that lead smokers to light up again and again. This medicine is taken over a 12 week course and can work in ways that bupropion does not.

In addition to nicotine withdrawal symptoms, quitting cigarette smoking also may lead to weight gain of about 8-10 pounds on average though more in some patients. Quitting smoking also can lead to depression and worsening of symptoms of chronic ulcerative colitis. Therefore quitting smoking should be undertaken with a doctor's supervision. Nevertheless, the benefits of quitting smoking (decreasing the rate of lung deterioration, decreasing risks of heart attack, lung cancer and other cancers, decreasing the chance of developing stomach ulcers, etc.) far outweigh these potential negative effects.

For more information on quitting cigarette smoking, please read the Smoking and Quitting Smoking article.

Bronchodilators

Treating airway obstruction in COPD with bronchodilators is similar but not identical to treating bronchospasm in asthma. Bronchodilators are medications that relax the muscles surrounding the small airways thereby opening the airways. Bronchodilators can be inhaled, taken orally or administered intravenously. Inhaled bronchodilators are popular because they go directly to the airways where they work. As compared with bronchodilators given orally, less medication reaches the rest of the body, and, therefore, there are fewer side effects.

Metered dose inhalers (MDIs) are used to deliver bronchodilators. An MDI is a pressurized canister containing a medication that is released when the canister is compressed. A standard amount of medication is released with each compression of the MDI. To maximize the delivery of the medications to the airways, the patient has to learn to coordinate inhalation with each compression. Incorrect use of the MDI can lead to deposition of much of the medication on the tongue and the back of the throat instead of on the airways.

To decrease the deposition of medications on the throat and increase the amount reaching the airways, spacers can be helpful. Spacers are tube-like chambers attached to the outlet of the MDI canister. Spacer devices can hold the released medications long enough for patients to inhale them slowly and deeply into the lungs. Proper use of spacer devices can greatly increase the proportion of medication reaching the airways.

Beta-agonists

Historically, one of the first medications used for asthma was adrenaline (epinephrine). Adrenaline has a rapid onset of action in opening the airways. It is still used in certain emergency situations for attacks of asthma. Unfortunately, adrenaline has many side effects including rapid heart rate, headache, nausea, vomiting, restlessness, and a sense of panic. Therefore, it is not used in the treatment of COPD.

Beta-2 agonists have the bronchodilating effects of adrenaline without many of its unwanted side effects. Beta-2 agonists can be administered by MDI inhalers or orally. They are called "agonists" because they activate the beta-2 receptor on the muscles surrounding the airways. Activation of beta-2 receptors relaxes the muscles surrounding the airways and opens the airways.

Dilating airways helps to relieve the symptoms of dyspnea (shortness of breath). Beta-2 agonists have been shown to relieve dyspnea in many COPD patients, even among those without demonstrable reversibility in airway obstruction. The action of beta-2 agonists starts within minutes after inhalation and lasts for about 4 hours. Because of their quick onset of action, beta-2 agonists are especially helpful for patients who are acutely short of breath. Because of their short duration of action, these medications should be used for symptoms as they develop rather than as maintenance.

Evidence suggests that when these drugs are used routinely, their effectiveness is diminished. These are referred to as rescue inhalers. Examples of beta-2 agonists include albuterol (Ventolin, Proventil), metaproterenol (Alupent), pirbuterol (Maxair), terbutaline (Brethaire), and isoetharine (Bronkosol). Levalbuterol (Xopenex) is a recently approved Beta-2 agonist.

In contrast, Beta-2 agonists with a slower onset of action but a longer period of activity, such as salmeterol xinafoate (Serevent) and formoterol fumarate (Foradil) may be used routinely as maintenance medications. These drugs last twelve hours and should be taken twice daily and no more. Along with some of these inhalers to be mentioned, these are often referred to as maintenance inhalers.

Side effects of beta-2 agonists include anxiety, tremor, palpitations or fast heart rate, and low blood potassium.

Anti-cholinergic Agents

Acetylcholine is a chemical released by nerves that attaches to receptors on the muscles surrounding the airway causing the muscles to contract and the airways to narrow. Anti-cholinergic drugs such as ipratropium bromide (Atrovent) dilate airways by blocking the receptors for acetylcholine on the muscles of the airways and preventing them from narrowing. Ipratropium bromide (Atrovent) usually is administered via a MDI.

In patients with COPD, ipratropium has been shown to alleviate dyspnea, improve exercise tolerance and improve FEV1. Ipratropium has a slower onset of action but longer duration of action than the shorter-acting beta-2 agonists. Ipratropium usually is well tolerated with minimal side effects even when used in higher doses. Tiotropium (SPIRIVA) is a long acting and more powerful version of Ipratropium and has been shown to be more effective.

In comparing ipratropium with beta-2 agonists in the treatment of patients with COPD, studies suggest that ipratropium may be more effective in dilating airways and improving symptoms with fewer side effects. Ipratropium is especially suitable for use by elderly patients who may have difficulty with fast heart rate and tremor from the beta-2 agonists. In patients who respond poorly to either beta-2 agonists or ipratropium alone, a combination of the two drugs sometimes results in a better response than to either drug alone without additional side effects.

Methylxanthines

Theophylline (Theo-Dur, Theolair, Slo-Bid, Uniphyl, Theo-24) and aminophylline are examples of methylxanthines. Methylxanthines are administered orally or intravenously. Long acting theophylline preparations can be given orally once or twice a day. Theophylline, like a beta agonist, relaxes the muscles surrounding the airways but also prevents mast cells around the airways from releasing bronchoconstricting chemicals such as histamine.

Theophylline also can act as a mild diuretic and increase urination. Theophylline also may increase the force of contraction of the heart and lower pressure in the pulmonary arteries.

Thus, theophylline can help patients with COPD who have heart failure and pulmonary hypertension. Patients who have difficulty using inhaled bronchodilators but no difficulty taking oral medications find theophylline particularly useful.

The disadvantage of methylxanthines is their side effects. Dosage and blood levels of theophylline or aminophylline have to be closely monitored. Excessively high levels in the blood can lead to nausea, vomiting, heart rhythm problems, and even seizures. In patients with heart failure or cirrhosis, dosages of methylxanthines are lowered to avoid high blood levels. Interactions with other medications, such as cimetidine (Tagamet), calcium channel blockers (Procardia), quinolones (Cipro), and allopurinol (Zyloprim) also can alter blood levels of methylxanthines.

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