Chronic obstructive pulmonary disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editors-In-Chief: Cafer Zorkun, M.D., Ph.D. [3], Priyamvada Singh, MBBS [4], Seyedmahdi Pahlavani, M.D. [5]

Chronic obstructive pulmonary disease is characterized by the pathological limitation of airflow in the airway that is not fully reversible ^[1]. COPD is the umbrella term for chronic bronchitis, emphysema which could be differentiated according to pathologic findings. Airflow limitation may lead to shortness of breath (dyspnea), cough, wheezing, and finally respiratory failure. In clinical practice, COPD is defined by its characteristically low airflow on lung function tests.^[2] In contrast to asthma, this limitation is poorly reversible and usually gets progressively worse over time. Hallmark pathologic features of chronic bronchitis include: hyperplasia (increased number) and hypertrophy (increased size) of the goblet cells (mucous gland) of the airway, resulting in an increase in secretion of mucus, which contributes to the airway obstruction. Emphysema is determined by destruction of pulmonary acinus. Acinus is the structures distal to the terminal bronchiole, consisting of the respiratory bronchiole, alveolar ducts, alveolar sacs, and alveoli. COPD is mostly due to tobacco smoking; but can be due to other airborne irritants such as coal dust, asbestos or solvents, congenital conditions such as alpha-1-antitrypsin deficiency and as well as preserved meats containing nitrites. Diagnosis of COPD is based on spirometry findings in appropriate clinical setting. Smoking cessation is the main stay in the treatment. Bronchodilators and anticholinergic inhalers are the main pharmacologic therapy in COPD patients. Pulmonary rehabilitation and sometimes lung volume reduction surgery are required in specific circumstances.

For the first time, in 1679, Bonet described a condition of “voluminous lungs”. Matthew Baillie illustrated an emphysematous lung in 1789 and described the destructive character of the condition. In 1808, bronchitis was first described by Charles Badham in England. The terms chronic bronchitis and emphysema were formally defined at the CIBA guest symposium of physicians in 1959. COPD has probably always existed but has been called by different names in the past. The term COPD was first used by William Briscoe in 1965 and has gradually overtaken other terms to become established today as the preferred name for this disease.

COPD may be classified based on pathology, into two types: chronic bronchitis, emphysema. Emphysema may be classified further in to four sub-types such as panacinary, centroacinary, congenital lobar emphysema and paraseptal. 

Pathologic changes in chronic obstructive pulmonary disease (COPD) occur in the large (central) airways, the bronchioles, and the lung parenchyma. Increased numbers of activated polymorphonuclear leukocytes and macrophages release elastases, proteinase-3 and macrophage-derived matrix metalloproteinases (MMPs), cysteine proteinases, and a plasminogen activator resulting in lung destruction. The antiprotease in the body cannot counteract effectively these elastases. Additionally, increased oxidative stress caused by free radicals in cigarette smoke, phagocytes, and polymorphonuclear leukocytes all may lead to apoptosis. In addition to macrophages, T lymphocytes, particularly CD8+, play an important role in the pathogenesis of smoking-induced airflow limitation.

Chronic obstructive pulmonary disease (COPD), is most often due to tobacco smoking; but can be due to other airborne irritants such as coal dust, asbestos or solvents, congenital conditions such as alpha-1-antitrypsin deficiency and as well as preserved meats containing nitrites. In the United States, tobacco use is a key factor in the development and progression of COPD, exposure to air pollutants in the home and workplace, genetic factors, and respiratory infections also play a role. In developing countries, indoor air quality is thought to play a larger role in the development and progression of COPD than it does in the United States.

COPD should be differentiated from other diseases presenting with chronic cough, shortness of breath and tachypnea, such as congestive heart failure, chronic asthma, bronchiectasis, and bronchiolitis obliterans.

The Global Burden of Disease Study reports a prevalence of 251 million cases of COPD globally in 2016. According to WHO estimates, 65 million people have moderate to severe chronic obstructive pulmonary disease (COPD) worldwide. COPD occurs in 34 out of 1000 greater than 65 years old. In England, an estimated 842,100 of 50 million people have a diagnosis of COPD; translating into approximately one person in 59 receiving a diagnosis of COPD at some point in their lives. In the most socioeconomically deprived parts of the country, one in 32 people were diagnosed with COPD, compared with one in 98 in the most affluent areas. In the United States, the age adjusted prevalence of COPD is approximately 6.4%, totalling approximately 15.7 million people in USA, or possibly approximately 25 million people if undiagnosed cases are included. COPD is the third cause of death among adult population in the United States.

Common risk factors in the development of COPD, are cigarette smoking, occupational pollutants, air pollution and genetics. Other risk factors are increasing age, male gender, allergy and repeated airway infection.

COPD is a slowly progressive disease that may lead to death. The rate at which it gets worse varies between individuals. The factors that predict a poorer prognosis are severe airflow obstruction (low FEV₁), poor exercise capacity, shortness of breath, significantly underweight or overweight, complications like respiratory failure or corpulmonale, continued smoking, frequent acute exacerbations. Prognosis in COPD can be estimated using the Bode Index. This scoring system uses FEV1, body-mass index, 6-minute walk distance, and the modified MRC dyspnea scale to estimate outcomes in COPD. There is no cure for COPD. However, COPD can be managed and disease progression can be mitigated. Prognosis depends largely on the timing of diagnosis. Its complications include, recurrent pneumonia, cor pulmonale, anemia, depression, and even respiratory failure.

The diagnosis of COPD requires lung function tests.

Chronic obstructive pulmonary disease is a group of diseases that can present with symptoms such as shortness of breath, wheezing, persistent cough and sputum production. Some clinical differences can help distinguish between the types of COPD. While chronic bronchitis patient present with productive cough with gradual progression to intermittent shortness of breath; recurrent pulmonary infections; and in later stage progressive cardiac/respiratory failure presenting with edema and weight gain. Classic findings for patients with emphysema include a long history of progressive shortness of breath with late onset of nonproductive cough; usually mucopurulent; and eventual decrease in appetite and respiratory failure.

Chronic obstructive pulmonary disease can be diagnostically evaluated by physical examination through auscultation. Physical examination are quite specific and sensitive for severe disease. The signs are usually difficult to detect in cases of mild to moderate diseases. Findings on general physical examination can be cyanosis, tachypnea, use of accessory respiratory muscles, paradoxical indrawing of lower intercostal spaces is evident (known as the Hoover sign), elevated jugular venous pulse and peripheral edema. Pulmonary examination in can be barrel chest (emphysema), wheezing, hyperresonance, crackles and rhonchi

Chronic obstructive pulmonary disease has irreversible airflow limitation specially during forced expiration. This is due to the destruction of lung tissue and increase in resistance to flow in the conducting airways. Thus, it doesn’t show an improvement in FEV1 post bronchodilator administration (unlike asthma). This characteristic feature is used as an diagnostic criteria for COPD, i.e. a COPD is diagnosed by spirometry if FEV1/FVC < 70% for a matched control. Arterial blood gas may show hypoxemia with or without hypercapnia depending on the disease severity. pH may be normal due to renal compensation. A pH less than 7.3 usually indicate severe respiratory compromise. A blood sample taken from an artery, i.e. Arterial Blood Gas (ABG), can be tested for blood gas levels which may show low oxygen (hypoxaemia) and/or high carbon dioxide (respiratory acidosis if pH is also decreased). A blood sample taken from a vein may show a high blood count (reactive polycythemia), a reaction to long-term hypoxemia.

Electrocardiogram can be used in establishing that hypoxia is due to underlying respiratory cause and not cardiac.

On chest x-ray, the classic signs of COPD are overexpanded lung (hyperinflation), a flattened diaphragm, increased retrosternal airspace, and bullae.^[3] It can be useful to help exclude other lung diseases, such as pneumonia, pulmonary edema or a pneumothorax.^[3]

A high-resolution computed tomography scan of the chest may show the distribution of emphysema throughout the lungs and can also be useful to exclude other lung diseases.

Echocardiography helps in a diagnosis of pulmoanry hypertension in the patients with COPD.

The diagnosis of COPD is confirmed by spirometry,^[4] a test that measures the forced expiratory volume in one second (FEV₁), which is the greatest volume of air that can be breathed out in the first second of a large breath. Spirometry also measures the forced vital capacity (FVC), which is the greatest volume of air that can be breathed out in a whole large breath. Normally, at least 70% of the FVC comes out in the first second (i.e. the FEV₁/FVC ratio is >70%). A ratio less than normal defines the patient as having COPD. Six minute walk tests act as an predictor of mortality in patients with moderate COPD (patients who desaturate have worse mortality compared with those who don’t desaturate.)

Important management strategies are smoking cessation, vaccinations, rehabilitation, and drug therapy (often using inhalers). Some patients go on to require long-term oxygen therapy or lung transplantation.^[4]

Treatment of COPD requires a careful and thorough evaluation by a physician. The most important aspect of treatment is avoiding tobacco smoke and removing other air pollutants from the patient’s home or workplace. Symptoms such as coughing or wheezing can be treated with bronchodilator medications like Beta 2 receptor agonist, anticholinergic drugs. The drugs used cause benefit via relaxation of smooth muscle or decreasing inflammatory factors. . Respiratory infections should be treated with antibiotics, if appropriate. Patients who have low blood oxygen levels in their blood are often given supplemental oxygen. Currently, no treatment has been found to be totally curative against COPD except lung transplant. The treatments aim to improve lung function and quality of life. The initial treatment can be done either with Beta 2 agonist or anticholinergic. Both anticholinergics or Beta adrenergic receptor agonists have proved to be equally beneficial but the combination of the two has shown synergistic effects. Long acting bronchodilators are more beneficial than short-acting ones ^[5], ^[6].

Patients with emphysema may have big bullae ranging from 1-4 cm and may occupy third of lung space. These bullae can cause compromise to ventilation and perfusion. Bullectomy is the surgical removal of these bullae. It is commonly done in patients with FEV1 < 50% of predicted and who are symptomatic. Bullectomy helps in re-expansion of the lung tissue. Lung reduction surgery may be an option for patients with severe symptoms that are not responding to maximal medical therapy.

Smoking cessation, control of air pollutants and decrease job exposure to dusts or fumes are the main preventive measures for chronic obstructive pulmonary disease.

To decrease the number and rate of COPD deaths, public health programs should continue efforts to reduce all personal exposure to 1) tobacco smoke, including passive smoke exposure; 2) occupational dusts and chemicals; and 3) other indoor and outdoor air pollutants linked to COPD. Once COPD is diagnosed, chronic disease management programs should work to prevent further deterioration in lung function and reduce COPD mortality.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Mehrian Jafarizade, M.D [2], Seyedmahdi Pahlavani, M.D. [3], Cafer Zorkun, M.D., Ph.D. [4]

For the first time, in 1679, Bonet described a condition of “voluminous lungs”. Matthew Baillie illustrated an emphysematous lung in 1789 and described the destructive character of the condition. In 1808, bronchitis was first described by Charles Badham in England. The terms chronic bronchitis and emphysema were formally defined at the CIBA guest symposium of physicians in 1959. COPD has probably always existed but has been called by different names in the past. The term COPD was first used by William Briscoe in 1965 and has gradually overtaken other terms to become established today as the preferred name for this disease.

• In 1679, Bonet for the first time described voluminous lungs.
• In 1721, Ruysh described enlarged lung airspaces in emphysema.
• In 1769, Giovanni Morgagni described nineteen cases in which the lungs were “turgid” particularly from air.
• In 1789, Matthew Baillie illustrated an emphysematous lung and described the destructive character of the condition.
• In 1808, bronchitis was first described by Charles Badham in England. He classified acute bronchitis to three forms by his definition (Br. acuta, asthenica and chronica)^[1]
• In 1837, René Laennec, the physician who invented the stethoscope, used the term “emphysema” in his book A Treatise on the Diseases of the Chest and of Mediate Auscultation to describe lungs that did not collapse when he opened the chest during an autopsy. He noted that they did not collapse as usual because they were full of air and the airways were filled with mucus.^[2]
• In 1842, John Hutchinson invented the spirometer, which allowed the measurement of the vital capacity of the lungs. However, his spirometer could only measure volume, not airflow.^[3]
• In 1944, Ronald Christie defined the diagnosis for emphysema based on dyspnea on exertion, after exclusion of bronchospasm, or left ventricular failure.
• In 1947, Tiffeneau and Pinelli, and in 1950 and 1951, Gaensler described the principles of measuring airflow.
• in 1952, Gough explained the pathology of emphysema.
• In 1956, Barach and Bickerman described treatment for emphysema in their comprehensive textbook.
• In 1959, the terms chronic bronchitis and emphysema were formally defined at the CIBA guest symposium of physicians.
• In 1962, American Thoracic Society Committee on Diagnostic Standards defined the components of COPD and this definition is the foundation of COPD description today.
• In 1964, Gross produced destruction of alveoli and hyperinflation, by injection of pancreatic extracts (papain) into the airways of guinea pigs.
• In 1965, the term COPD was first used by William Briscoe and has gradually overtaken other terms to become established today as the preferred name for this disease.
• In 1967, Reid described the pathology of emphysema and other components of COPD.
• In 1976, Thurlbeck illustrated the various types of emphysema in his book.
• In 2003, Choe used methylprednisolone to produce emphysema in rats. They conclude that systemic methylprednisolone increases the activity of matrix metalloproteinases in the lung and causes emphysema. ^[4]
• In 2004, GOLD offered a new classification of the severity of COPD. ^[5]
• In 2005, Voelkel and Taraseviciene-Stewart offered emphysema as an autoimmune vascular disease. ^[6]

• In 1956, Barach and Bickerman described treatment for emphysema in their comprehensive textbook.
• In 1980, for treatment of COPD patients, a clinical trial was performed and the use of nocturnal oxygen therapy for emphysema proved. ^[7]
• In 1998, Paggiaro performed a multicentre clinical trial of corticosteroids for emphysema treatment.^[8]

Below table is a summery of COPD historical prospective:

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COPD may be classified based on pathology, into two types: chronic bronchitis type, and emphysema type. Emphysema may be classified further in to four sub-types such as panacinary, centroacinary, congenital lobar emphysema and paraseptal.

COPD may be classified based on pathology, into two types: chronic bronchitis and emphysema.

There is no classification system established for chronic bronchitis.

Emphysema can be classified by location into four categories:^[1]

• The entire respiratory acinus, from respiratory bronchiole to alveoli, is expanded. Occurs more commonly in the lower lobes (especially basal segments) and in the anterior margins of the lungs.^[2]

• The respiratory bronchiole (proximal and central part of the acinus) is expanded. The distal acinus or alveoli are unchanged. Occurs more commonly in the upper lobes.^[2][3]

3- Congenital lobar emphysema (CLE):

• CLE results in over-expansion of a pulmonary lobe, and resultant compression of the remaining lobes of the ipsi-lateral lung (and possibly also the contralateral lung). There is bronchial narrowing because of weakened or absent bronchial cartilage.^[4] There may be congenital extrinsic compression, commonly by an abnormally large pulmonary artery. This causes malformation of bronchial cartilage, making them soft and collapsible.^[4] CLE is a potentially reversible (yet possibly life-threatening) cause of respiratory distress in the neonate.^[4]

4- Paraseptal emphysema:

• Para-septal emphysema is a type of emphysema which involves the alveolar ducts and sacs at the lung periphery. The emphysematous areas are sub-pleural in location and often surrounded by inter-lobular septa (hence the name). It may be an incidental finding in young adults, and may be associated with spontaneous pneumothorax. It may also be seen in older patients with centri-lobular emphysema. Both centri-lobular and para-septal emphysema may progress to bullous emphysema. A bulla is defined as being at least 1 cm in diameter, and with a wall less than 1 mm thick. Bullae are thought to arise by air trapping in emphysematous spaces, causing local expansion.^[5]

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Pathologic changes in chronic obstructive pulmonary disease (COPD) occur in the large (central) airways, the bronchioles, and the lung parenchyma. Increased numbers of activated polymorphonuclear leukocytes and macrophages release elastases, proteinase-3 and macrophage-derived matrix metalloproteinases (MMPs), cysteine proteinases, and a plasminogen activator resulting in lung destruction. The antiprotease in the body cannot counteract effectively these elastases. Additionally, increased oxidative stress caused by free radicals in cigarette smoke, phagocytes, and polymorphonuclear leukocytes all may lead to apoptosis. In addition to macrophages, T lymphocytes, particularly CD8+, play an important role in the pathogenesis of smoking-induced airflow limitation.

• 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.^[1]
• 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, resulting in an increase in the volume of air in the lungs, a process called dynamic hyperinflation.^[1]
• Dynamic hyperinflation is closely linked to dyspnea in COPD.^[2]
• 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 gases 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 and heart failure.
• 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.

• Several molecular signatures associated to lung function decline and corollaries of disease severity have been proposed, a majority of which are characterized in easily accessible surrogate tissue, including blood derivatives such as serum and plasma. A recent 2010 clinical study proposes alpha 1B-glycoprotein precursor/A1BG, alpha 2-antiplasmin, apolipoprotein A-IV precursor/APOA4, and complement component 3 precursor, among other coagulation and complement system proteins as corollaries of lung function decline, although ambiguity between cause and effect is unresolved.^[3]

• Hallmark features include: hyperplasia (increased number) and hypertrophy (increased size) of the goblet cells (mucous gland) of the airway, resulting in an increase in secretion of mucus, which contributes to the airway obstruction.^[5]
• 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.

• On microscopic histopathological analysis, there is infiltration of the airway walls with inflammatory cells, particularly CD8+ T-lymphocytes and neutrophils.^[6] Inflammation is followed by scarring and remodeling that thickens the walls resulting in narrowing of the small airways.

• Emphysema is the destruction of pulmonary acinus. Acinus is the structures distal to the terminal bronchiole, consisting of the respiratory bronchiole, alveolar ducts, alveolar sacs, and alveoli. 

An acute exacerbation of COPD is a sudden worsening of COPD symptoms (shortness of breath, quantity and color of phlegm) that typically lasts for several days. Airway inflammation is increased during the exacerbation, resulting in increased hyperinflation, reduced expiratory air flow and worsening of gas transfer. This can also lead to hypoventilation and eventually hypoxia, insufficient tissue perfusion, and then cell necrosis.

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Chronic obstructive pulmonary disease (COPD), is most often due to tobacco smoking; but can be due to other airborne irritants such as coal dust, asbestos or solvents, congenital conditions such as alpha-1-antitrypsin deficiency and as well as preserved meats containing nitrites. In the United States, tobacco use is a key factor in the development and progression of COPD, but asthma, exposure to air pollutants in the home and workplace, genetic factors, and respiratory infections also play a role. In the developing world, indoor air quality is thought to play a larger role in the development and progression of COPD than it does in the United States.

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.^[1][2] Exposure to cigarette smoke is measured in pack-years,^[3] the average number of packages of cigarettes smoked daily multiplied by the number of years of smoking. The likelihood of developing COPD increases with age and cumulative smoke exposure, and almost all life-long smokers will develop COPD, provided that smoking-related, extra-pulmonary diseases (cardiovascular, diabetes, cancer) do not claim their lives beforehand.^[4]

Intense and prolonged exposure to workplace dusts found in coal mining, gold mining, and the cotton textile industry and chemicals such as cadmium, iso-cyanates, and fumes from welding have been implicated in the development of airflow obstruction, even in non-smokers.^[5] 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.^[6] The effect of occupational pollutants on the lungs appears to be substantially less important than the effect of cigarette smoking.^[7]

Studies in many countries have found people who live in large cities have a higher rate of COPD compared to people who live in rural areas.^[8] 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. Studies of the industrial waste gas and COPD/asthma-aggravating compound, sulfur dioxide, and the inverse relation to the presence of the blue lichen Xanthoria (usually found abundantly in the countryside, but never in towns or cities) have been seen to suggest combustive industrial processes do not aid COPD sufferers. 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.^[9]

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.^[10] 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 caused by protease enzymes, such as elastase and trypsin, that can be released as a result of an inflammatory response to tobacco smoke.^[11]

There is mounting evidence that there may be an autoimmune component to COPD, triggered by lifelong smoking.^[12] Many individuals with COPD who have stopped smoking have active inflammation in the lungs.^[13] The disease may continue to get worse for many years after stopping smoking due to this ongoing inflammation.^[13] This sustained inflammation is thought to be mediated by autoantibodies and autoreactive T cells.^[13][14][15]

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.^[7] 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 (possibly due to the preservative sodium nitrite) may be related to the development of COPD.

• Abnormal activity of tissue inhibitors of metalloproteinase (TIMP-1)
• Age
• Alpha-1-antitrypsin deficiency
• Asthma (controversial)
• Atopy
• Bronchopulmonary dysplasia
• Cadmium
• Cigarette smoking
• Decreased function of microsomal epoxide hydrolase
• Decreased function of microsomal epoxide hydrolase
• Decreased glutathione levels
• Decreased glutathione S-transferase P1 activity
• Deficiency of antioxidant vitamins
• Environmental air pollution such as coal, grain
• Excess elastase
• First-degree relatives severe premature COPD
• Fumes from welding
• Gender (controversial)
• Genetic influences
• Heredity
• History of childhood respiratory infections
• Increased airway responsiveness
• Increased Matrix metalloproteinases (MMP)-2 (gelatinase A)
• Increased Matrix metalloproteinases (MMP)-8 (Collagenase 2)]]
• Increased Matrix metalloproteinases ( MMP)-9 (gelatinase B)]]
• Isocyanates
• Low socioeconomic status
• Metalloproteinase dysregulation
• Occupation pollution exposure to dusts and chemicals
• Pulmonary tuberculosis
• Second hand smoking
• Several gene polymorphisms of Transforming growth factor beta 1
• Several SNPs (Several gene polymorphisms) of the leptin receptor (LEPR) gene
• Silicosis
• Sulfur dioxide
• Tumor necrosis factor-alpha (TNF-a) gene polymorphisms
• Use of biomass fuels for cooking
• Vitamin C deficiency
• Vitamin E deficiency
• Zanamivir

http://www.cdc.gov/copd/index.htm

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COPD should be differentiated from other diseases presenting with chronic cough, shortness of breath and tachypnea, such as pneumonia, congestive heart failure, pulmonary embolism, and bronchiectasis.

COPD should be differentiated from other diseases presenting with chronic cough, shortness of breath and tachypnea. The differentials include the following:^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]}

Chronic obstructive pulmonary disease (COPD) may be confused with congestive heart failure due to similar presentations like wheezing and shortness of breath. Features specific to congestive heart failure are:

• Orthopnea
• Paroxysmal nocturnal dyspnea
• Fine crackles on ausculatation
• Chest X ray findings of cardiac enlargement, pulmonary congestion (Kerley B lines, and pleural effusion)
• The peak expiratory flow is low in COPD whereas there is higher flow in heart failure
• Comet-tail sign on ultrasonography is a good indicator of heart failure–related dyspnea ^[21]

• Copious purulent sputum
• Coarse crackles
• Clubbing
• CT findings suggestive of Bronchiectasis.

• History of collagen vascular disease.
• Young patient usually without a history of smoking
• CT scan shows finding of mosaic attenuation and no evidence of emphysema.

• Chronic asthma responds well to bronchodilators.
• Normal diffusion capacity of lung on pulmonary function test.

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The Global Burden of Disease Study reports a prevalence of 251 million cases of COPD globally in 2016. According to WHO estimates, 65 million people have moderate to severe chronic obstructive pulmonary disease (COPD) worldwide. COPD occurs in 34 out of 1000 greater than 65 years old. In England, an estimated 842,100 of 50 million people have a diagnosis of COPD; translating into approximately one person in 59 receiving a diagnosis of COPD at some point in their lives. In the most socioeconomically deprived parts of the country, one in 32 people were diagnosed with COPD, compared with one in 98 in the most affluent areas. In the United States, the age adjusted prevalence of COPD is approximately 6.4%, totalling approximately 15.7 million people in USA, or possibly approximately 25 million people if undiagnosed cases are included. COPD is the third cause of death among adult population in the United States.

• The Global Burden of Disease Study reports a prevalence of 251 million cases of COPD globally in 2016. According to WHO estimates, 65 million people have moderate to severe chronic obstructive pulmonary disease (COPD) worldwide.
• Almost 15.7 million Americans (6.4%) reported that they have been diagnosed with COPD.
• Age adjusted prevalence of COPD is approximately 4900 per 100,000 individuals in the United States.

• Globally, it is estimated that 3.17 million deaths were caused by the disease in 2015 (that is, 5% of all deaths globally in that year).
• COPD, was the third leading cause of death in the United States in 2014.

• During 2000–2005, COPD was the underlying cause of death for 718,077 persons overall aged >25 years in the United States. The number of deaths from COPD increased from 116,494 in 2000 to 121,267 in 2003, decreased to 117,134 in 2004, and increased to 126,005 in 2005.
• To update national estimates of deaths from COPD for the period 2000-2005 (the most recent years for which data are available), CDC analyzed data from the National Vital Statistics System (NVSS). Results of that analysis indicated that an estimated 126,005 deaths of persons aged >25 years occurred in 2005 with COPD as the underlying cause, an increase of 8% from 116,494 deaths in 2000.
• In 2005, approximately one in 20 deaths in the United States had COPD as the underlying cause.
• Smoking is estimated to be responsible for at least 75% of COPD deaths.

• Prevalence of COPD increased, from 3.2% among those aged 18–44 years to >11.6% among those aged ≥65 years.

• Age-standardized COPD mortality rates remained fairly stable during the period (2000-2005) overall. Age-standardized death rates per 100,000 population decreased during 2000–2004; the rate in 2005 was similar to that for 2003.

• COPD usually affects individuals of the Caucasian race.Hispanics are less likely to develop COPD.

• For each year during 2000–2005, COPD mortality rates were higher among whites than among blacks or persons of all other races. During this period, the rate for blacks remained stable, except for 2004, when the rate was lower. In 2005, the death rate among white men was 80.2 (95% confidence interval [CI] = 79.5–80.9) compared with 63.8 (CI = 61.8–65.8) among black men, 60.3 (CI = 59.8–60.8) among white women, and 29.9 (CI = 28.9–30.9) among black women.

• Women are more commonly affected by COPD than men (6.7% vs 5.8%)

• From 2000 to 2005, the annual number of deaths from COPD increased 5% among men, and the number of deaths was higher in 2005 than in 2004. The death rate for men declined during 2000–2005 and was lower in 2004 than in 2005. Among women, the annual number of deaths increased 11% from 2000 to 2005 and was lower in 2005 than in 2004. The death rate for women increased from 2000 to 2003, decreased in 2004, and increased in 2005. The death rate was higher for men compared with the rate for women in each year, but the number of deaths was greater for women. For women, the number of deaths related to COPD in 2005 was 65,193, while for men it was 60,812.
• Women were more likely to report COPD than men (6.7% compared to 5.2%)^[1][2].
• Age adjusted death rates of men have decreased between 1999 and 2014 but this rate was stable among women.
• COPD death rates for women have risen steadily. Today, more women than men die from COPD each year.

• The total economic costs of COPD in the United States were estimated to be $49.9 billion in 2010, and the total direct cost of medical care is approximately $29.5 billion per year.^[3] Excess health-care expenditures are estimated at nearly $6,000 annually for every COPD patient in the United States.

• By state, in 2005, age-standardized death rates from COPD for adults aged >25 years ranged from 27.1 per 100,000 in Hawaii to 93.6 per 100,000 population in Oklahoma. States with COPD death rates in the highest quartile were as follows: Idaho, Indiana, Kansas, Kentucky, Maine, Montana, Nevada, Ohio, Oklahoma, Vermont, West Virginia, and Wyoming. Among adults aged 25–64 years, rates ranged from 6.2 (Massachusetts and New Jersey) to 19.2 (Oklahoma) per 100,000 population for men and from 3.8 (New Jersey) to 16.5 (West Virginia) in women. Among adults aged >65 years, rates ranged from 169.0 (Hawaii) to 540.4 (Vermont) per 100,000 population in men and from 94.7 (Hawaii) to 394.9 (Nevada) in women.

Age-standardized death rates for chronic obstructive pulmonary disease (COPD), by state, aggregated over 1999–2006. State rates are grouped into quartiles. Data were obtained from the National Vital Statistics System at http://wonder.cdc.gov. COPD as the underlying cause of death was defined by ICD-10 codes J40-J44. Death rates are reported per 100,000 population and were age-standardized to the 2000 U.S. standard population.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Philip Marcus, M.D., M.P.H. [3]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [4]

Common risk factors in the development of COPD are cigarette smoking, occupational pollutants, air pollution and genetics. Other risk factors are increasing age, male gender, allergy and repeated airway infection.

A primary factor of COPD is chronic tobacco smoking. In the United States, around 90% of cases of COPD are due to smoking.^[1] Not all smokers will develop COPD, but continuous smokers have at least a 25% risk.^[2]

Some occupational pollutants, such as cadmium and silica, have shown to be a contributing risk factor for COPD. The people at highest risk for these pollutants include:

• Coal workers
• Construction workers
• Metal workers
• Cotton workers

However, in most cases these pollutants are combined with cigarette smoking further increasing the chance of developing COPD.These occupations are commonly associated with other respiratory diseases, particularly pneumoconiosis (black lung disease).

• Urban air pollution may be a contributing factor for COPD as it is thought to impair the development of the lung function. In developing countries indoor air pollution, usually due to biomass fuel, has been linked to COPD, especially in women.

• Very rarely, there may be a deficiency in an enzyme known as alpha 1-antitrypsin which causes a form of COPD.^[3]

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”. ^[4]

• Increasing age
• Male gender
• Allergy
• Repeated airway infection
• General impaired lung function

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Philip Marcus, M.D., M.P.H. [2]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [3]; Tarek Nafee, M.D. [4], Mehrian Jafarizade, M.D [5]

COPD is a slowly progressive disease that may lead to death. The rate at which it gets worse varies between individuals. The factors that predict a poorer prognosis are severe airflow obstruction (low FEV₁), poor exercise capacity, shortness of breath, significantly underweight or overweight, complications like respiratory failure or corpulmonale, continued smoking, frequent acute exacerbations. Prognosis in COPD can be estimated using the Bode Index. This scoring system uses FEV1, body-mass index, 6-minute walk distance, and the modified MRC dyspnea scale to estimate outcomes in COPD. There is no cure for COPD. However, COPD can be managed and disease progression can be mitigated. Prognosis depends largely on the timing of diagnosis. Its complications include, recurrent pneumonia, cor pulmonale, anemia, depression, and even respiratory failure.

COPD is slowly progressive disease that may lead to death. The rate at which it gets worse varies between individuals. Depending on the severity of the disease and the degree of acute desaturation, if left untreated, patients may experience severe dyspnea, hypercapnia, hypoxemia, and death. In the absence of an acute exacerbation, COPD patients may have a prolonged, insidious course that may result in neurological manifestations of chronic mild to moderate hypoxemia such as cognitive deficit, depression, anxiety, brain atrophy.

Common complications of COPD include:

• Recurrent pneumonia: chronic inflammation and airways damage predispose chronic bronchitis patients to recurrent pneumonia either viral or bacterial infections. Additionally, chronic use of inhaled corticosteroids may cause recurrent infections^[1]
• Depression: may require psychiatry consultation^[2]
• Cor pulmonale: chronic hypoxia and subsequent vasoconstriction in pulmonary vasculature results in pulmonary hypertension and right sided heart failure, termed cor pulmonale^[3]
• Anemia: anemia of chronic disease may develop in this patients and indicates a poor prognosis.
• Polycythemia: secondary to chronic hypoxemia, Hematocrit level may rise up to 60 (normal range: adult men: 46±4, adult women:40±4).
• Inability to perform functional activities of daily living (ADL)
• Moderate to severe dyspnea
• Respiratory failure
• Cognitive deficit
• Severe hypoxemia leading to coma or death.

A good prognosis of COPD relies on an early diagnosis and prompt treatment. Majority of patients will have improvement in lung function once treatment is started, owever 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.

• The most important prognostic factor is the FEV1 level.
• Other determining factors include:^[4]
  • Cigarette smoking
  • BMI ≤ 21
  • Decreased exercise capacity
  • Increased C-reactive protein level
  • Co-morbid diseases.

Chronic bronchitis however is dependent on early recognition and smoking cessation which improves the outcome significantly.

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.

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