Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — Chronic obstructive pulmonary disease (COPD) is a common respiratory condition characterized by airflow limitation [1,2]. It affects more than 5 percent of the population and is associated with high morbidity and mortality [3,4]. It is the third-ranked cause of death in the United States, killing more than 120,000 individuals each year . As a consequence of its high prevalence and chronicity, COPD causes high resource utilization with frequent clinician office visits, frequent hospitalizations due to acute exacerbations, and the need for chronic therapy (eg, supplemental oxygen therapy, medication) .
Establishing a correct diagnosis of COPD is important because appropriate management can decrease symptoms (especially dyspnea), reduce the frequency and severity of exacerbations, improve health status, improve exercise capacity, and prolong survival . As current and former smokers are also at risk for a number of other medical problems for which treatment is very different, respiratory symptoms should not be attributed to COPD without appropriate evaluation and diagnosis.
The definition, clinical manifestations, diagnostic evaluation, and staging of COPD are discussed in this topic review. The risk factors, natural history, prognosis, and treatment of COPD are discussed separately. (See "Chronic obstructive pulmonary disease: Risk factors and risk reduction" and "Chronic obstructive pulmonary disease: Prognostic factors and comorbid conditions" and "Management of stable chronic obstructive pulmonary disease" and "Management of exacerbations of chronic obstructive pulmonary disease".)
DEFINITIONS — The definition of COPD and its subtypes (emphysema, chronic bronchitis, and chronic obstructive asthma) and the interrelationships between the closely related disorders that cause airflow limitation provide a foundation for understanding the spectrum of patient presentations.
Several features of COPD patients identify individuals with different prognoses and/or responses to treatment. Whether these features identify separate "phenotypes" of COPD or reflect disease severity remains unclear . However, evaluation of these features can help guide clinical management, and their use in classification of patients is now recommended [8,9]. (See 'Staging' below.)
COPD — The Global Initiative for Chronic Obstructive Lung Disease (GOLD), a project initiated by the National Heart, Lung, and Blood Institute (NHLBI) and the World Health Organization (WHO), defines COPD as follows :
"COPD is a common, preventable, and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases. The chronic airflow limitation that characterizes COPD is caused by a mixture of small airways disease (eg, obstructive bronchiolitis) and parenchymal destruction (emphysema), the relative contributions of which vary from person to person. Chronic inflammation causes structural changes, small airways narrowing, and destruction of lung parenchyma. A loss of small airways may contribute to airflow imitation and mucociliary dysfunction, a characteristic feature of the disease."
Chronic bronchitis — Chronic bronchitis is defined as a chronic productive cough for three months in each of two successive years in a patient in whom other causes of chronic cough (eg, bronchiectasis) have been excluded . It may precede or follow development of airflow limitation [8,10]. This definition has been used in many studies, despite the arbitrarily selected symptom duration. Symptoms of chronic bronchitis may develop in cigarette smokers as early as 36 years of age and have been associated with a higher frequency of exacerbation events, even in the absence of airflow obstruction . Current and former smokers have increased airway mucin concentration (MUC5AC and MUC5B), compared with never smokers; those with symptoms of chronic bronchitis also have higher concentrations than those of similar GOLD stage without symptoms .
Emphysema — Emphysema is a pathological term that describes some of the structural changes sometimes associated with COPD. These changes include abnormal and permanent enlargement of the airspaces distal to the terminal bronchioles that is accompanied by destruction of the airspace walls, without obvious fibrosis (ie, there is no fibrosis visible to the naked eye) . Exclusion of obvious fibrosis was intended to distinguish the alveolar destruction due to emphysema from that due to the interstitial pneumonias. However, many studies have found increased collagen in the lungs of patients with mild COPD, indicating that fibrosis can be a component of emphysema [14,15]. While emphysema can exist in individuals who do not have airflow obstruction, it is more common among patients who have moderate or severe airflow obstruction [8,16].
The various subtypes of emphysema (eg, proximal acinar, panacinar, distal acinar) are described below. (See 'Pathology' below.)
Asthma — The Global Initiative for Asthma (GINA) gives the following definition of asthma: "Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment ."
Interrelationships among asthma, chronic bronchitis, and emphysema — Early definitions of COPD distinguished different types (ie, chronic bronchitis, emphysema, asthma), a distinction that is not included in the current definition [18-20]. However, individual patients present with a spectrum of manifestations of COPD and related processes, so understanding the types of COPD, as illustrated in the figure (figure 1), can be helpful diagnostically. Important points about their interrelationship include:
●Patients with asthma whose airflow obstruction is completely reversible are not considered to have COPD (subset nine in the figure).
●Patients with asthma whose airflow obstruction does not remit completely are considered to have COPD (subsets six, seven, and eight in the figure). The etiology and pathogenesis of the COPD in such patients may be different from that of patients with chronic bronchitis or emphysema.
●Chronic bronchitis and emphysema with airflow obstruction commonly occur together (subset five in the figure) . Some of these patients may also have asthma (subset eight in the figure).
●Individuals with asthma may develop a chronic productive cough, either spontaneously or due to exposure (eg, cigarette smoke, allergen). Such patients are often referred to as having asthmatic bronchitis, although this terminology has not been officially endorsed in clinical practice guidelines (subset six in the figure).
●Persons with chronic bronchitis, emphysema, or both are not considered to have COPD unless they have airflow obstruction (subsets one, two, and eleven in the figure) [22,23].
●Patients with airflow obstruction due to diseases that have a known etiology or a specific pathology (eg, cystic fibrosis, bronchiectasis, obliterative bronchiolitis) are not considered to have COPD (subset 10 in the figure). However, these exclusions are loosely defined .
Asthma-COPD overlap — Consistent with the idea that significant overlap exists among the different types of COPD, many individuals have bronchial inflammation with features of both asthma and chronic bronchitis/emphysema [8,25-27]. Similarly, the nature of the bronchial inflammation varies widely even among individuals with a single type of COPD. In recognition of this overlap, GOLD and GINA issued a consensus statement on Asthma, COPD, and Asthma-COPD Overlap Syndrome (ACOS, also referred to as asthma-COPD overlap [ACO]) , which describes the overlap as "characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD. ACOS is therefore identified in clinical practice by the features that it shares with both asthma and COPD."
Further study of this overlap will be needed to determine with certainty how treatment algorithms should be tailored to these patients . As an example, a subgroup of patients with sputum eosinophilia may experience lung function improvement with anti-interleukin-5 receptor monoclonal antibody that depletes blood and sputum eosinophils  and further investigation into this medication class is ongoing. Similarly, an evolving literature suggests differential responses to inhaled glucocorticoids in patients with or without increased circulating eosinophils [30,31].
PATHOLOGY — The predominant pathologic changes of COPD are found in the airways, but changes are also seen in the lung parenchyma and pulmonary vasculature. In an individual, the pattern of pathologic changes depends on the underlying disease (eg, chronic bronchitis, emphysema, alpha-1 antitrypsin deficiency), possibly individual susceptibility, and disease severity . While radiographic methods do not have the resolution of histology, high resolution computed tomography can assess lung parenchyma , airways , and pulmonary vasculature .
●Airways – Airways abnormalities in COPD include chronic inflammation, increased numbers of goblet cells, mucus gland hyperplasia, fibrosis, narrowing and reduction in the number of small airways, and airway collapse due to the loss of tethering caused by alveolar wall destruction in emphysema . Among patients with chronic bronchitis who have mucus hypersecretion, an increased number of goblet cells and enlarged submucosal glands are typically seen. Chronic inflammation in chronic bronchitis and emphysema is characterized by the presence of CD8+ T-lymphocytes, neutrophils, and CD68+ monocytes/macrophages (picture 1) in the airways [35-39]. In comparison, the bronchial inflammation of asthma is characterized by the presence of CD4+ T-lymphocytes, eosinophils, and increased interleukin (IL)-4 and IL-5 (algorithm 1) [25,40,41]. While these paradigms are helpful conceptually, they are not diagnostic and overlaps exist. For example, there may be a set of asthmatic patients who progress to develop COPD.
●Lung parenchyma – Emphysema affects the structures distal to the terminal bronchiole, consisting of the respiratory bronchiole, alveolar ducts, alveolar sacs, and alveoli, known collectively as the acinus. These structures in combination with their associated capillaries and interstitium form the lung parenchyma. The part of the acinus that is affected by permanent dilation or destruction determines the subtype of emphysema.
•Proximal acinar (also known as centrilobular) emphysema refers to abnormal dilation or destruction of the respiratory bronchiole, the central portion of the acinus. It is commonly associated with cigarette smoking, but can also be seen in coal workers’ pneumoconiosis.
•Panacinar emphysema refers to enlargement or destruction of all parts of the acinus. Diffuse panacinar emphysema is most commonly associated with alpha-1 antitrypsin deficiency, although it can be seen in combination with proximal emphysema in smokers. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency".)
•In distal acinar (also known as paraseptal) emphysema, the alveolar ducts are predominantly affected. Distal acinar emphysema may occur alone or in combination with proximal acinar and panacinar emphysema. When it occurs alone, the usual association is spontaneous pneumothorax in a young adult. (See "Primary spontaneous pneumothorax in adults".)
●Pulmonary vasculature – Changes in the pulmonary vasculature include intimal hyperplasia and smooth muscle hypertrophy/hyperplasia thought to be due to chronic hypoxic vasoconstriction of the small pulmonary arteries . Destruction of alveoli due to emphysema can lead to loss of the associated areas of the pulmonary capillary bed and pruning of the distal vasculature, which can be detected radiographically .
Smoking and inhalational exposure history — The most important risk factor for chronic obstructive pulmonary disease (COPD) is cigarette smoking. Other exposures including passive smoke and biomass fuel use also play roles [8,43,44].
The amount and duration of smoking contribute to disease severity. Thus, a key step in the evaluation of patients with suspected COPD is to ascertain the number of pack years smoked (packs of cigarettes per day multiplied by the number of years), as the majority (about 80 percent) of patients with COPD in the United States have a history of cigarette smoking [45,46]. A smoking history should include the age of starting and the age of quitting, as patients may underestimate the number of years they smoked. With enough smoking, almost all smokers will develop measurably reduced lung function . While studies have shown an overall "dose-response curve" for smoking and lung function, some individuals develop severe disease with fewer pack years and others have minimal to no symptoms despite many pack years .
The exact threshold for the duration/intensity of cigarette smoking that will result in COPD varies from one individual to another. In the absence of a genetic/environmental/occupational predisposition, smoking less than 10 to 15 pack years of cigarettes is unlikely to result in COPD. On the other hand, the single best variable for predicting which adults will have airflow obstruction on spirometry is a history of more than 40 pack years of smoking (positive likelihood ratio [LR], 12 [95% CI, 2.7-50]) [47,48].
The chronologically taken environmental/occupational history may disclose other important risk factors for COPD, such as exposure to fumes or organic or inorganic dusts. These exposures help to explain the 20 percent of patients with COPD (defined by lung function alone) and the 20 percent of patients who die from COPD who never smoked [46,49,50]. A history of asthma should also be sought, as COPD is often misdiagnosed as asthma. In addition, asthma may progress to fixed airflow limitation and COPD . (See "Chronic obstructive pulmonary disease: Risk factors and risk reduction" and 'Asthma-COPD overlap' above.)
Symptoms and pattern of onset — The three cardinal symptoms of COPD are dyspnea, chronic cough, and sputum production and the most common early symptom is exertional dyspnea. Less common symptoms include wheezing and chest tightness (table 1A). However, any of these symptoms may develop independently and with variable intensity.
There are three typical ways in which patients with COPD present :
●Patients who have an extremely sedentary lifestyle but few complaints require careful questioning to elicit a history that is suggestive of COPD. Some patients unknowingly avoid exertional dyspnea by shifting their expectations and limiting their activity. They may be unaware of the extent of their limitations or that their limitations are due to respiratory symptoms, although they may complain of fatigue.
●Patients who present with respiratory symptoms generally complain of dyspnea and chronic cough. The dyspnea may initially be noticed only during exertion. However, it eventually becomes noticeable with progressively less exertion or even at rest. The chronic cough is characterized by the insidious onset of sputum production, which occurs in the morning initially, but may progress to occur throughout the day. The daily volume rarely exceeds 60 mL. The sputum is usually mucoid, but becomes purulent during exacerbations.
●Patients who present with episodes of increased cough, purulent sputum, wheezing, fatigue, and dyspnea that occur intermittently, with or without fever. Diagnosis can be problematic in such patients. The combination of wheezing plus dyspnea may lead to an incorrect diagnosis of asthma. Conversely, other illnesses with similar manifestations are often incorrectly diagnosed as a COPD exacerbation (eg, heart failure, bronchiectasis, bronchiolitis) (table 2). The interval between exacerbations decreases as the severity of the COPD increases. (See "Management of exacerbations of chronic obstructive pulmonary disease".)
Approximately 62 percent of patients with moderate to severe COPD report variability in symptoms (eg, dyspnea, cough, sputum, wheezing, or chest tightness) over the course of the day or week-to-week; morning is typically the worst time of day .
Patients with COPD may experience weight gain (due to activity limitations), weight loss (possibly due to dyspnea while eating), limitation of activity (including sexual), cough syncope, or feelings of depression or anxiety. Weight loss generally reflects more advanced disease and is associated with a worse prognosis. However, the majority of COPD patients are overweight or obese.
Comorbid diseases that may accompany COPD include lung cancer, bronchiectasis, cardiovascular disease, osteoporosis, metabolic syndrome, skeletal muscle weakness, anxiety, depression, and cognitive dysfunction. Patients may also report a family history of COPD or other chronic respiratory illness [8,53-58].
It is also important to note that current and former smokers without spirometric evidence of airflow obstruction can have a substantial respiratory symptom and radiographic burden of disease. While such individuals are being actively investigated, the natural history of such individuals has not been fully studied and there is currently no evidence base to guide treatment in such individuals [59,60].
Physical examination — The findings on physical examination of the chest vary with the severity of the COPD (table 1A-B).
●Early in the disease, the physical examination may be normal, or may show only prolonged expiration or wheezes on forced exhalation.
●As the severity of the airway obstruction increases, physical examination may reveal hyperinflation (eg, increased resonance to percussion), decreased breath sounds, wheezes, crackles at the lung bases, and/or distant heart sounds . Features of severe disease include an increased anteroposterior diameter of the chest ("barrel-shaped" chest) and a depressed diaphragm with limited movement based on chest percussion.
●Patients with end-stage COPD may adopt positions that relieve dyspnea, such as leaning forward with arms outstretched and weight supported on the palms or elbows. This posture may be evident during the examination or may be suggested by the presence of callouses or swollen bursae on the extensor surfaces of forearms. Other physical examination findings include use of the accessory respiratory muscles of the neck and shoulder girdle, expiration through pursed lips, paradoxical retraction of the lower interspaces during inspiration (ie, Hoover's sign) [62,63], cyanosis, asterixis due to severe hypercapnia, and an enlarged, tender liver due to right heart failure. Neck vein distention may also be observed because of increased intrathoracic pressure, especially during expiration.
●Yellow stains on the fingers due to nicotine and tar from burning tobacco are a clue to ongoing and heavy cigarette smoking .
Clubbing of the digits is not typical in COPD (even with associated hypoxemia) and suggests comorbidities such as lung cancer, interstitial lung disease, or bronchiectasis.
EVALUATION — Evaluation for COPD is appropriate in adults who report dyspnea, chronic cough, chronic sputum production or have had a gradual decline in level of peak activity, particularly if they have a history of exposure to risk factors for the disease (eg, cigarette smoking, indoor biomass smoke) [8,47]. All patients are evaluated with spirometry and selected patients have laboratory testing and imaging studies. There is no evidence to support the benefit of population based screening of asymptomatic adults for COPD , but the Global Initiative for Chronic Obstructive Lung Disease (GOLD) does advocate active case finding among at risk individuals. (See "Chronic obstructive pulmonary disease: Risk factors and risk reduction".)
Laboratory — No laboratory test is diagnostic for COPD, but certain tests are sometimes obtained to exclude other causes of dyspnea and comorbid diseases.
●Assessment for anemia is an important step in the evaluation of dyspnea. Measurement of plasma brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) concentrations is useful as a component of the evaluation of suspected heart failure (HF). Blood glucose, urea nitrogen, creatinine, electrolytes, calcium, phosphorus, and thyroid stimulating hormone may be appropriate depending on the degree of clinical suspicion for an alternate diagnosis. (See "Approach to the patient with dyspnea", section on 'Initial testing in chronic dyspnea'.)
●Among stable COPD patients with normal kidney function, an elevated serum bicarbonate may indirectly identify chronic hypercapnia. In the presence of chronic hypercapnia, the serum bicarbonate is typically increased due to a compensatory metabolic alkalosis (figure 2). Abnormal results must be confirmed with arterial blood gas measurement. (See "Simple and mixed acid-base disorders", section on 'Respiratory acid-base disorders'.)
●Testing for alpha-1 antitrypsin (AAT) deficiency should be obtained in all symptomatic adults with persistent airflow obstruction on spirometry. Especially suggestive subsets include the presence of emphysema in a young individual (eg, age ≤45 years), emphysema in a nonsmoker or minimal smoker, emphysema characterized by predominantly basilar changes on the chest radiograph, or a family history of emphysema . However, AAT deficiency may be present in a patient with otherwise "typical" COPD. A serum level of AAT below 11 micromol/L (~57 mg/dL by nephelometry) in combination with a severe deficient genotype is diagnostic. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency", section on 'Evaluation and diagnosis'.)
Pulmonary function tests — Pulmonary function tests (PFTs), particularly spirometry, are the cornerstone of the diagnostic evaluation of patients with suspected COPD . In addition, PFTs are used to determine the severity of the airflow limitation, assess the response to medications, and follow disease progression. (See 'Diagnosis' below and "Office spirometry".)
Spirometry — When evaluating a patient for possible COPD, spirometry is performed pre and post bronchodilator administration (eg, inhalation of albuterol 400 mcg) to determine whether airflow limitation is present and whether it is partially or fully reversible. Airflow limitation that is irreversible or only partially reversible with bronchodilator is the characteristic physiologic feature of COPD. Screening spirometry is not currently recommended. In contrast, spirometry should be performed in patients with suggestive symptoms . (See "Office spirometry", section on 'Post-bronchodilator spirometry' and 'Screening' below.)
The most important values measured during spirometry are the forced expiratory volume in one second (FEV1) and the forced vital capacity (FVC). The postbronchodilator ratio of FEV1/FVC determines whether airflow limitation is present ; the postbronchodilator percent predicted value for FEV1 determines the severity of airflow limitation as shown in the table (table 3).
Lower limit of normal FEV1/FVC — GOLD guidelines support using the traditional postbronchodilator FEV1/FVC ratio less than 0.7 as the threshold that indicates airflow limitation . However, the FEV1/FVC ratio decreases with age, so use of the fifth percentile lower limit of normal (LLN) of the FEV1/FVC ratio, rather than the absolute value of <0.7, has been advocated by some as a dividing point for the diagnosis of COPD [68-72]. However, the distinction between the LLN and the fixed ratio as dividing points is unlikely to lead to major clinical problems because current recommendations combine physiologic assessment with assessment of symptoms and exacerbations in staging severity. Moreover, in a study of 13,847 subjects, an increased mortality was noted among those with an FEV1/FVC <0.7, but >LLN FEV1/FVC, when compared with those whose FEV1/FVC was 0.7 or higher . (See "Office spirometry", section on 'Ratio of FEV1/FVC'.)
Global Lung Initiative equations — As an alternative to using the LLN of FEV1/FVC to define normal airflow on spirometry, a new approach may utilize equations developed by the Global Lung Initiative (GLI) [8,74,75]. Using GLI equations, z scores (number of standard deviations above or below mean) were calculated for FEV1, FVC, and FEV1/FVC and compared with fixed ratio data. The findings suggest that among adults with GLI-defined normal spirometry, the use of a fixed ratio may misclassify individuals as having respiratory impairment. These findings await additional study in other cohorts.
Forced expiratory volume in six seconds — The forced expiratory volume in six seconds (FEV6), obtained by stopping the expiratory effort after 6 seconds rather than at cessation of airflow, is an acceptable surrogate for the FVC [76-80]. The advantages of the FEV1/FEV6 include less frustration by the patient and technician trying to achieve an end-of-test plateau, less chance of syncope, shorter testing time, and better repeatability, without loss of sensitivity or specificity. The appropriate LLN for FEV1/FEV6 from NHANES III should be used to diagnose airflow limitation. (See "Office spirometry", section on 'Forced expiratory volume in six seconds' and "Office spirometry", section on 'Ratio of FEV1/FVC'.)
Peak expiratory flow — Peak expiratory flow (PEF) is often used as a measure of airflow limitation in asthma, but may underestimate the degree of airflow limitation in COPD . In addition, a low PEF is not specific for airflow limitation and requires corroboration with spirometry. (See "Peak expiratory flow rate monitoring in asthma".)
Lung volumes — Lung volume measurement is not needed for all patients with suspected COPD. However, when a reduced FVC is noted on postbronchodilator spirometry, lung volume measurement by body plethysmography is used to determine whether the reduction in FVC is due to airtrapping, hyperinflation, or a concomitant restrictive ventilatory defect. Decreased inspiratory capacity (IC) and vital capacity, accompanied by an increased total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV) are indicative of hyperinflation. An increased FRC with a normal TLC is indicative of air trapping without hyperinflation. (See "Overview of pulmonary function testing in adults", section on 'Lung volumes' and "Dynamic hyperinflation in patients with COPD".)
Diffusing capacity — The diffusing capacity for carbon monoxide (DLCO) is an excellent index of the degree of anatomic emphysema in smokers with airflow limitation, but is not needed for routine assessment of COPD. The indications for performing a DLCO measurement include hypoxemia by pulse oximetry (eg, arterial oxygen tension [PaO2] <92 mmHg), breathlessness out of proportion to the degree of airflow limitation, and evaluation for lung resection or lung volume reduction surgery. The DLCO decreases in proportion to the severity of emphysema; however, it cannot be used to detect mild emphysema because it is neither a sensitive nor a specific test.
Pulse oximetry and arterial blood gases — Pulse oximetry is a noninvasive, easily performed test that assesses blood oxygen saturation. It has reduced the number of patients who require arterial blood gases (ABGs), as supplemental oxygen is not needed when the pulse oxygen saturation (SpO2) is >88 percent. However, pulse oximetry does not provide information about alveolar ventilation or hypercapnia (PaCO2 >45mmHg), and assessment of oxygenation by pulse oximetry may be inaccurate in the setting of an acute exacerbation of COPD . (See "Pulse oximetry" and "Arterial blood gases" and "The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure".)
The indications for measuring ABGs (eg, PaO2, PaCO2, and acidity [pH]), which must be considered in the clinical context, include the following:
●Low FEV1 (eg, <50 percent predicted)
●Low oxygen saturation by pulse oximetry (eg, <92 percent)
●Depressed level of consciousness
●Acute exacerbation of COPD
●Assessment for hypercapnia in at risk patients 30 to 60 minutes after initiation of supplemental oxygen (see "The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure")
In patients with mild to moderate COPD, arterial blood gases usually reveal mild or moderate hypoxemia without hypercapnia. As the disease progresses, the hypoxemia becomes more severe and hypercapnia may develop. Hypercapnia becomes progressively more likely when the FEV1 approaches or falls below one liter. Blood gas abnormalities worsen during acute exacerbations and may also worsen during exercise and sleep. The compensatory responses to acute and chronic respiratory acidosis are shown in the figure and discussed separately (figure 3). (See "Simple and mixed acid-base disorders", section on 'Respiratory acidosis'.)
Imaging — Chest radiography and computed tomography (CT) are typically performed in patients with COPD when the cause of dyspnea or sputum production is unclear and during acute exacerbations to exclude complicating processes (eg, pneumonia, pneumothorax, heart failure). Imaging is not required to diagnose COPD. However, in patients with severe COPD, CT scanning identifies individuals with predominantly upper lobe disease who may be candidates for lung volume reduction surgery. (See 'Diagnosis' below.)
Chest radiography — The main reasons to obtain a chest radiograph when evaluating a patient for COPD are to exclude alternative diagnoses, evaluate for comorbidities (eg, lung cancer with airway obstruction, bronchiectasis, pleural disease, interstitial lung disease, heart failure), or to look for complications of COPD (eg, pneumonia, pneumothorax) that might be suggested by a change in symptoms.
Plain chest radiographs have a poor sensitivity for detecting COPD. As an example, only about half of patients with COPD of moderate severity are identified as having COPD by a plain chest radiograph (ie, sensitivity of 50 percent).
Radiographic features suggestive of COPD (usually seen in advanced disease) include:
●Rapidly tapering vascular shadows, increased radiolucency of the lung, a flat diaphragm, and a long, narrow heart shadow on a frontal radiograph (image 1).
●A flat diaphragmatic contour and an increased retrosternal airspace on a lateral radiograph (image 2). These findings are due to hyperinflation.
●Bullae, defined as radiolucent areas larger than one centimeter in diameter and surrounded by arcuate hairline shadows. They are due to locally severe disease, and may or may not be accompanied by widespread emphysema (image 3).
●When advanced COPD leads to pulmonary hypertension and cor pulmonale, prominent hilar vascular shadows and encroachment of the heart shadow on the retrosternal space may be seen [82,83]. The cardiac enlargement may become evident only by comparison with previous chest radiographs. (See "Classification and prognosis of pulmonary hypertension in adults".)
Computed tomography — CT has greater sensitivity and specificity than standard chest radiography for the detection of emphysema. This is particularly true with high resolution CT (ie, collimation of 1 to 2 mm) [84-87]. The use of expiratory scans, particularly when used in conjunction with the inspiratory scans, can also be used to assess non-emphysematous air trapping as a surrogate measure for small airway abnormality  (see "High resolution computed tomography of the lungs"). However, CT scanning is not needed for the routine diagnosis of COPD. Usually, it is performed when a change in symptoms suggests a complication of COPD (eg, pneumonia, pneumothorax, giant bullae), an alternate diagnosis (eg, thromboembolic disease), or when a patient is being considered for lung volume reduction surgery or lung transplantation . (See "Evaluation and medical management of giant bullae", section on 'Evaluation' and "Lung volume reduction surgery in COPD", section on 'Patient selection' and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)
Certain CT scan features can determine whether the emphysema is centriacinar (centrilobular), panacinar, or paraseptal, although this is usually not necessary for clinical management [87,89].
●Centriacinar emphysema occurs preferentially in the upper lobes and produces holes in the center of secondary pulmonary lobules. The walls of emphysematous spaces are usually imperceptible, but central vessels may be visible (image 4). In contrast, the walls of cysts in pulmonary Langerhans histiocytosis, another cystic lung disease of cigarette smokers, are thicker (image 5). (See 'Pathology' above.)
●Panacinar emphysema more commonly involves the lung bases and involves the entire secondary pulmonary lobule (image 6). Panacinar emphysema can cause a generalized paucity of vascular structures. Among patients with alpha-1 antitrypsin deficiency, panacinar emphysema is the more common pattern. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency", section on 'Clinical manifestations'.)
●Paraseptal (distal acinar) emphysema produces small, subpleural collections of gas located in the periphery of the secondary pulmonary lobule (image 7). It is considered to be the precursor of bullae (image 8). (See 'Pathology' above.)
Newer CT scanners with higher resolution and new analytical methods can resolve airway dimensions, although the clinical significance of these measures is undefined [87,90,91]. Quantitative parameters based on lung density, as measured by CT scan, have been established to gauge emphysema, but are currently used primarily as research tools.
The use of low dose CT scans to screen for lung cancer is discussed separately. (See "Screening for lung cancer", section on 'Low-dose chest CT'.)
DIAGNOSIS — The presence of symptoms compatible with COPD (eg, dyspnea at rest or on exertion, cough with or without sputum production, progressive limitation of activity) are suggestive of the diagnosis, especially if there is a history of exposure to triggers of COPD (eg, tobacco smoke, occupational dust, indoor biomass smoke), a family history of chronic lung disease, or presence of associated comorbidities (table 4). The diagnosis of COPD is confirmed by the following :
●Spirometry demonstrating airflow limitation (ie, a forced expiratory volume in one second/forced vital capacity [FEV1/FVC] ratio less than 0.7 or less than the lower limit of normal [LLN] PLUS an FEV1 less than 80 percent of predicted) that is incompletely reversible after the administration of an inhaled bronchodilator (table 1A-B). (See 'Pulmonary function tests' above.)
●Absence of an alternative explanation for the symptoms and airflow limitation (table 2) . The differential diagnosis of COPD is discussed below. (See 'Differential diagnosis' below and "Approach to the patient with dyspnea".)
After confirming the presence of COPD, the next step is to consider the cause. For the majority of patients, the etiology is long-term cigarette smoking. However, it is important to review with the patient whether underlying asthma, workplace exposures, indoor use of biomass fuel, a prior history of tuberculosis, or familial predisposition is contributory, because mitigation of ongoing exposures may reduce disease progression.
In areas of high prevalence of alpha-1 antitrypsin (AAT) deficiency, it is appropriate to screen all patients with COPD by obtaining an AAT serum level and AAT genotyping [8,93]. (See 'Laboratory' above and "Chronic obstructive pulmonary disease: Risk factors and risk reduction" and "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency", section on 'Laboratory testing'.)
DIFFERENTIAL DIAGNOSIS — Among patients who present in mid or later life with dyspnea, cough, and sputum production, the differential diagnosis is broad (eg, heart failure, COPD, interstitial lung disease, thromboembolic disease) (table 2). Typically, the finding of persistent airflow limitation on pulmonary function testing and the absence of radiographic features of heart failure or interstitial lung disease direct the clinician to a narrower differential of COPD, chronic obstructive asthma, bronchiectasis, tuberculosis, constrictive bronchiolitis, and diffuse panbronchiolitis . Importantly, these conditions can commonly occur together, for example, patients with asthma may develop COPD and patients with COPD may have concurrent bronchiectasis.
●Chronic obstructive asthma – In some patients with chronic asthma, a clear distinction from COPD is not possible. As an example, a patient, who has had atopic asthma since childhood and smoked cigarettes for 15 years in their twenties and thirties could present in their fifties with a combination of asthma and COPD. The importance of recognizing the coexistence of these diseases is in devising a treatment plan that is adapted to reflect both underlying disease processes. (See 'Interrelationships among asthma, chronic bronchitis, and emphysema' above and "Diagnosis of asthma in adolescents and adults".)
●Chronic bronchitis with normal spirometry – A small portion of cigarette smokers have a chronic productive cough for three months in two successive years, but do not have airflow limitation on pulmonary function tests. They are not considered to have COPD, although they may develop COPD if they continue to smoke. Some treatments for COPD may improve their cough. (See 'Interrelationships among asthma, chronic bronchitis, and emphysema' above.)
●Central airway obstruction – Central airway obstruction can be caused by numerous benign and malignant processes and can mimic COPD with a slowly progressive dyspnea on exertion followed by dyspnea with minimal activity (table 5). Monophonic wheezing or stridor may be present. Symptoms are minimally improved by inhaled bronchodilator, if at all. A high index of suspicion is needed as conventional chest radiographs are rarely diagnostic. Though insensitive, flow volume loops can show the characteristic changes of central airway obstruction, frequently before abnormalities in the spirometric volumes are noted (figure 4 and figure 5) . A high resolution CT scan with three-dimensional reconstruction can be helpful. The gold standard for diagnosis is direct visualization. (See "Clinical presentation, diagnostic evaluation, and management of central airway obstruction in adults", section on 'Diagnostic evaluation and initial management'.)
●Bronchiectasis – Bronchiectasis, a condition of abnormal widening of the bronchi that is associated with chronic or recurrent infection, shares many clinical features with COPD, including inflamed and easily collapsible airways, obstruction to airflow, and exacerbations characterized by increased dyspnea and sputum production. Bronchiectasis is suspected on the basis of prominent symptoms of cough and daily mucopurulent sputum production. The diagnosis is usually established clinically based on the characteristic cough and sputum production and the presence of bronchial wall thickening and luminal dilatation on chest computed tomographic (CT) scans. (See "Clinical manifestations and diagnosis of bronchiectasis in adults".)
●Heart failure – Heart failure is a common cause of dyspnea among middle-aged and older patients and some patients experience chest tightness and wheezing with fluid overload due to heart failure. Occasionally, airflow limitation is noted, although a restrictive pattern is more common. Heart failure is usually differentiated by the presence of fine basilar crackles, radiographic evidence of an increased heart size and pulmonary edema. The brain natriuretic peptide is typically increased in heart failure, but can also be increased during right heart strain from cor pulmonale. (See "Evaluation of the patient with suspected heart failure".)
●Tuberculosis – In an area endemic for tuberculosis, the overall prevalence of airflow obstruction was 31 percent among those with a past history of tuberculosis compared with 14 percent among those without. This association was unchanged after adjustment for respiratory disease in childhood, smoking, and exposure to dust and smoke [95,96]. Thus, tuberculosis is both a risk factor for COPD and a potential comorbidity . (See "Clinical manifestations and complications of pulmonary tuberculosis".)
●Constrictive bronchiolitis – Constrictive bronchiolitis, also known as bronchiolitis obliterans, is characterized by submucosal and peribronchiolar fibrosis that causes concentric narrowing of the bronchiolar lumen. Constrictive bronchiolitis is most commonly seen following inhalation injury, transplantation (eg, bone marrow, lung), or in the context of rheumatoid lung or inflammatory bowel disease (table 6). Symptoms include progressive onset of cough and dyspnea associated with hypoxemia at rest or with exercise. Crackles may be present. Pulmonary function tests show a progressive and irreversible airflow limitation. Findings on inspiratory CT scan include centrilobular bronchial wall thickening, bronchiolar dilation, tree-in-bud pattern, and a mosaic ground-glass attenuation pattern. (See "Bronchiolitis in adults", section on 'Bronchiolitis obliterans'.)
●Diffuse panbronchiolitis – Diffuse panbronchiolitis is predominantly seen in male nonsmokers of Asian descent. Almost all have chronic sinusitis. On pulmonary function testing, an obstructive defect is common, although a mixed obstructive-restrictive pattern may also be seen. Chest radiographs and high resolution CT scans show diffuse centrilobular nodular and linear opacities corresponding to thickened and dilated bronchiolar walls with intraluminal mucous plugs. (See "Diffuse panbronchiolitis", section on 'Diagnosis'.)
●Lymphangioleiomyomatosis – Lymphangioleiomyomatosis (LAM) is seen primarily in young women of childbearing age. Pulmonary function testing frequently reveals mild airflow obstruction, although a mixed obstructive-restrictive pattern may be seen. CT scans typically demonstrate small, thin-walled cysts that can at times be confused with emphysema. However, the airspaces in emphysema are not actually cysts but are caused by the destruction of alveolar walls and permanent enlargement of distal airspaces, so the "walls" are typically inapparent. (See 'Diagnosis' above and "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis".)
SCREENING — Routine screening spirometry is generally not indicated for adults who have none of the features suggestive of COPD (eg, no dyspnea, cough, sputum production or progressive decline in activity), as asymptomatic mild airflow obstruction does not require treatment [47,97]. Asymptomatic and nonsmoking subjects with mild airflow obstruction, but no history of asthma, do not have the same progressive decline in lung function that is observed among individuals who have a similar degree of airflow obstruction and are symptomatic or continue to smoke .
On the other hand, waiting for patients to report symptoms may miss a large number of patients who have COPD, as 20 percent of individuals with severe airway obstruction due to smoking or asthma will not report symptoms. Decrements in forced expiratory volume in one second (FEV1), even within the normal range, are associated with increased risk of acute cardiac events independent of age, gender, and smoking history . Thus, performance of spirometry seems reasonable whenever COPD is a diagnostic consideration. The diagnosis of COPD may alter management of concurrent conditions and may affect the approach to exercise. Exclusion of COPD can often contribute to clinical management as much as its diagnosis by leading to alternative diagnoses.
STAGING — The initial Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines used the forced expiratory volume in one second (FEV1; expressed as a percentage of predicted) to stage disease severity. However, the FEV1 only captures one component of COPD severity: two patients with the same percent predicted FEV1 can have a substantially different exercise tolerance and prognosis. Other aspects of disease, such as the severity of symptoms, risk of exacerbations, and the presence of comorbidities, are important to the patient's experience of the disease and prognosis and are included in newer staging systems, such as the revised GOLD classification [8,99].
Several tools for evaluating symptom severity have been proposed. The GOLD guidelines suggest using the COPD Assessment Tool (CAT) [8,100-104] or the modified Medical Research Council (mMRC) dyspnea scale (table 7), although the latter does not assess COPD-related symptoms other than breathlessness. The most widely used research tool, the St. George's Respiratory Questionnaire (SGRQ), is a 76 item questionnaire that includes three component scores (ie, symptoms, activity, and impact on daily life) and a total score. While valuable for research purposes in patients with COPD, asthma, and bronchiectasis, it is too long and complicated for use in routine clinical practice [105-107].
GOLD system — The therapeutic strategy of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, updated in 2017, suggests using an assessment of airflow limitation in parallel with a combined assessment of an individual's symptoms and exacerbation history to guide therapy . The severity of lung function impairment is stratified based on the postbronchodilator FEV1, using the GOLD classification (table 3). GOLD continues to prefer using the ratio of 0.70 for FEV1/forced vital capacity (FVC) as the threshold for determining the presence of airflow limitation. (See 'Spirometry' above.)
Symptom severity is assessed using the CAT or mMRC (table 7) . Lung function in addition to the number of exacerbations and hospitalizations for exacerbations in the previous 12 months can be used to predict future risk. A history of zero or one exacerbation in the past 12 months and GOLD 1 or 2 spirometric level suggests a low future risk of exacerbations, while two or more exacerbations or a hospitalized exacerbation or GOLD 3 or 4 spirometric level suggest a high future risk . These components are combined into four groups as follows:
●Group A: Low risk, less symptoms: 0 to 1 exacerbation per year and no prior hospitalization for exacerbation; and CAT score <10 or mMRC grade 0 to 1.
●Group B: Low risk, more symptoms: 0 to 1 exacerbation per year and no prior hospitalization for exacerbation; and CAT score ≥10 or mMRC grade ≥2.
●Group C: High risk, less symptoms: ≥2 exacerbations per year or ≥1 hospitalization for exacerbation; and CAT score <10 or mMRC grade 0 to 1.
●Group D: High risk, more symptoms: ≥2 exacerbations per year or ≥1 hospitalization for exacerbation; and CAT score ≥10 or mMRC grade ≥2.
BODE index — The BODE index, which is another system for assessment of COPD severity and prognosis, is calculated based on weight (BMI), airway obstruction (FEV1), dyspnea (mMRC dyspnea score), and exercise capacity (six-minute walk distance) (calculator 1), has been used to assess an individual’s risk of death. This index provides better prognostic information than the FEV1 alone and can be used to assess therapeutic response to medications, pulmonary rehabilitation therapy, and other interventions [108-111]. (See "Chronic obstructive pulmonary disease: Prognostic factors and comorbid conditions", section on 'BODE index'.)
COPD Foundation system — The COPD Foundation has introduced a staging system that includes seven severity domains, each of which has therapeutic implications (figure 6) [9,47]. These domains are based upon assessment of spirometry, regular symptoms, number of exacerbations in the past year, oxygenation, emphysema on computed tomography scan, presence of chronic bronchitis, and comorbidities. Within these domains, the COPD Foundation uses five spirometric grades:
●SG 0: Normal spirometry
●SG 1: Mild, postbronchodilator FEV1/FVC ratio <0.7, FEV1 ≥60 percent predicted
●SG 2: Moderate, postbronchodilator FEV1/FVC ratio <0.7, 30 percent ≤FEV1 <60 percent predicted
●SG 3: Severe, postbronchodilator FEV1/FVC ratio <0.7, FEV1 <30 percent predicted
●SG U: Undefined, postbronchodilator FEV1/FVC ratio >0.7, FEV1 <80 percent predicted
An advantage of this staging system is that it simplifies the interpretation of spirometry; any spirometric finding results in a classification, which is not the case in GOLD.
While FEV1 is used to gauge severity, the FEV1/FVC ratio is not used for this purpose because measurement of FVC becomes less reliable as the disease progresses (the long exhalations are difficult for the patients), thus making the ratio less accurate. (See "Chronic obstructive pulmonary disease: Prognostic factors and comorbid conditions", section on 'Forced expiratory volume in one second'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic obstructive pulmonary disease".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient education: Chronic obstructive pulmonary disease (COPD), including emphysema (The Basics)" and "Patient education: Chronic bronchitis (The Basics)" and "Patient education: Medicines for chronic obstructive pulmonary disease (COPD) (The Basics)")
●Beyond the Basics topics (see "Patient education: Chronic obstructive pulmonary disease (COPD), including emphysema (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines COPD as follows: "Chronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases. The chronic airflow limitation that characterizes COPD is caused by a mixture of small airways disease (eg, obstructive bronchiolitis) and parenchymal destruction (emphysema), the relative contributions of which vary from person to person. Chronic inflammation causes structural changes, small airways narrowing and destruction of lung parenchyma. A loss of small airways may contribute to airflow limitation and mucociliary dysfunction, a characteristic feature of the disease. (See 'Definitions' above.)
●Substantial overlap exists between COPD and the other disorders that cause airflow limitation (eg, emphysema, chronic bronchitis, asthma, bronchiectasis, bronchiolitis) as illustrated in the figure (figure 1). (See 'Interrelationships among asthma, chronic bronchitis, and emphysema' above.)
●Common presentations of COPD include patients with few complaints, but an extremely sedentary lifestyle; patients with chronic, daily respiratory symptoms (eg, dyspnea on exertion, cough); and patients with recurrent acute exacerbations (eg, wheezing, cough, dyspnea, fatigue). The physical examination of the chest varies with the severity of the COPD, but is often normal in mild disease (table 1A-B). (See 'Clinical features' above.)
●The diagnosis of COPD should be considered and spirometry performed in all patients who report any combination of dyspnea, chronic cough, or chronic sputum production, especially if there is a history of exposure to triggers of COPD (eg, tobacco smoke, occupational dust, indoor biomass smoke), a family history of chronic lung disease, or presence of associated comorbidities (table 4). (See 'Pulmonary function tests' above and 'Diagnosis' above.)
●COPD is confirmed when a patient with compatible symptoms is found to have irreversible airflow limitation (ie, a post bronchodilator forced expiratory volume in one second [FEV1]/forced vital capacity [FVC] ratio less than 0.7 [or less than the lower limit of normal] and an FEV1 <80 percent predicted) and no alternative explanation for the symptoms and airflow obstruction. (See 'Pulmonary function tests' above and 'Diagnosis' above.)
●In areas of high prevalence of alpha-1 antitrypsin (AAT) deficiency, all symptomatic adults with fixed airflow obstruction on spirometry should be tested for AAT deficiency with an AAT serum level. (See 'Laboratory' above and "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency", section on 'Evaluation and diagnosis'.)
●In the evaluation of patients with COPD, chest radiography is typically performed to exclude alternative diagnoses, evaluate for comorbidities, or assess a change in symptoms that suggests a complication of COPD. Chest computed tomography is performed to evaluate abnormalities seen on the conventional chest radiograph, to exclude certain complications of COPD (eg, thromboembolic disease, lung cancer), or when a patient is being considered for lung volume reduction surgery or lung transplantation. (See 'Imaging' above.)
●The original FEV1-based GOLD staging system is shown in the table (table 3). Although well-recognized and commonly used, it has been criticized for underestimating the importance of the extrapulmonary manifestations of COPD in predicting outcome. The revised GOLD strategy uses a combination of an individual's symptoms and history of exacerbations and hospitalizations due to exacerbations to assess exacerbation risk and guide therapy. Other multidimensional staging systems include the BODE index (calculator 1) and the COPD Foundation system. (See 'Staging' above.)
●The management of COPD and strategies for smoking cessation are discussed separately. (See "Management of stable chronic obstructive pulmonary disease" and "Overview of smoking cessation management in adults".)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Stephen Rennard, MD, who contributed to an earlier version of this topic review.
- Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study. Lancet 2007; 370:741.
- Gershon AS, Warner L, Cascagnette P, et al. Lifetime risk of developing chronic obstructive pulmonary disease: a longitudinal population study. Lancet 2011; 378:991.
- Centers for Disease Control and Prevention (CDC). Chronic obstructive pulmonary disease among adults--United States, 2011. MMWR Morb Mortal Wkly Rep 2012; 61:938.
- GBD 2015 Chronic Respiratory Disease Collaborators. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med 2017; 5:691.
- Miniño AM, Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2008. Natl Vital Stat Rep 2011; 59:1.
- Rennard SI, Vestbo J. COPD: the dangerous underestimate of 15%. Lancet 2006; 367:1216.
- Han MK, Agusti A, Calverley PM, et al. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med 2010; 182:598.
- Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 Report www.goldcopd.org (Accessed on February 10, 2017).
- Rennard S, Thomashow B, Crapo J, et al. Introducing the COPD Foundation Guide for Diagnosis and Management of COPD, recommendations of the COPD Foundation. COPD 2013; 10:378.
- Elbehairy AF, Raghavan N, Cheng S, et al. Physiologic characterization of the chronic bronchitis phenotype in GOLD grade IB COPD. Chest 2015; 147:1235.
- Allinson JP, Hardy R, Donaldson GC, et al. The Presence of Chronic Mucus Hypersecretion across Adult Life in Relation to Chronic Obstructive Pulmonary Disease Development. Am J Respir Crit Care Med 2016; 193:662.
- Kesimer M, Ford AA, Ceppe A, et al. Airway Mucin Concentration as a Marker of Chronic Bronchitis. N Engl J Med 2017; 377:911.
- Rennard SI. COPD: overview of definitions, epidemiology, and factors influencing its development. Chest 1998; 113:235S.
- PIERCE JA, HOCOTT JB, EBERT RV. The collagen and elastin content of the lung in emphysema. Ann Intern Med 1961; 55:210.
- Vlahovic G, Russell ML, Mercer RR, Crapo JD. Cellular and connective tissue changes in alveolar septal walls in emphysema. Am J Respir Crit Care Med 1999; 160:2086.
- McDonough JE, Yuan R, Suzuki M, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med 2011; 365:1567.
- Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA). www.ginasthma.org (Accessed on January 30, 2015).
- Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society. Am J Respir Crit Care Med 1995; 152:S77.
- Siafakas NM, Vermeire P, Pride NB, et al. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). The European Respiratory Society Task Force. Eur Respir J 1995; 8:1398.
- National Institute for Health and Care Excellence. Chronic obstructive pulmonary disease: Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update). http://www.nice.org.uk/guidance/CG101 (Accessed on May 07, 2015).
- Obstructive lung disease. Med Clin North Am 1990; 74:547.
- Rosenbloom J, Campbell EJ, Mumford R, et al. Biochemical/immunologic markers of emphysema. Ann N Y Acad Sci 1991; 624 Suppl:7.
- Petty TL, Silvers GW, Stanford RE. Mild emphysema is associated with reduced elastic recoil and increased lung size but not with air-flow limitation. Am Rev Respir Dis 1987; 136:867.
- O'Brien C, Guest PJ, Hill SL, Stockley RA. Physiological and radiological characterisation of patients diagnosed with chronic obstructive pulmonary disease in primary care. Thorax 2000; 55:635.
- Jeffery PK. Comparison of the structural and inflammatory features of COPD and asthma. Giles F. Filley Lecture. Chest 2000; 117:251S.
- Postma DS, Rabe KF. The Asthma-COPD Overlap Syndrome. N Engl J Med 2015; 373:1241.
- Leung JM, Sin DD. Asthma-COPD overlap syndrome: pathogenesis, clinical features, and therapeutic targets. BMJ 2017; 358:j3772.
- http://www.goldcopd.org/asthma-copd-overlap.html (Accessed on August 26, 2015).
- Brightling CE, Bleecker ER, Panettieri RA Jr, et al. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med 2014; 2:891.
- Siddiqui SH, Guasconi A, Vestbo J, et al. Blood Eosinophils: A Biomarker of Response to Extrafine Beclomethasone/Formoterol in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2015; 192:523.
- Pascoe S, Locantore N, Dransfield MT, et al. Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med 2015; 3:435.
- Castaldi PJ, San José Estépar R, Mendoza CS, et al. Distinct quantitative computed tomography emphysema patterns are associated with physiology and function in smokers. Am J Respir Crit Care Med 2013; 188:1083.
- Hersh CP, Washko GR, Estépar RS, et al. Paired inspiratory-expiratory chest CT scans to assess for small airways disease in COPD. Respir Res 2013; 14:42.
- Estépar RS, Kinney GL, Black-Shinn JL, et al. Computed tomographic measures of pulmonary vascular morphology in smokers and their clinical implications. Am J Respir Crit Care Med 2013; 188:231.
- Aoshiba K, Nagai A. Differences in airway remodeling between asthma and chronic obstructive pulmonary disease. Clin Rev Allergy Immunol 2004; 27:35.
- Baraldo S, Turato G, Badin C, et al. Neutrophilic infiltration within the airway smooth muscle in patients with COPD. Thorax 2004; 59:308.
- Sutherland ER, Martin RJ. Airway inflammation in chronic obstructive pulmonary disease: comparisons with asthma. J Allergy Clin Immunol 2003; 112:819.
- Turato G, Zuin R, Miniati M, et al. Airway inflammation in severe chronic obstructive pulmonary disease: relationship with lung function and radiologic emphysema. Am J Respir Crit Care Med 2002; 166:105.
- Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med 2009; 360:2445.
- Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 2004; 364:709.
- Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004; 350:2645.
- Harkness LM, Kanabar V, Sharma HS, et al. Pulmonary vascular changes in asthma and COPD. Pulm Pharmacol Ther 2014; 29:144.
- Oh YM, Bhome AB, Boonsawat W, et al. Characteristics of stable chronic obstructive pulmonary disease patients in the pulmonology clinics of seven Asian cities. Int J Chron Obstruct Pulmon Dis 2013; 8:31.
- Tan WC, Sin DD, Bourbeau J, et al. Characteristics of COPD in never-smokers and ever-smokers in the general population: results from the CanCOLD study. Thorax 2015; 70:822.
- Kuempel ED, Wheeler MW, Smith RJ, et al. Contributions of dust exposure and cigarette smoking to emphysema severity in coal miners in the United States. Am J Respir Crit Care Med 2009; 180:257.
- Lamprecht B, McBurnie MA, Vollmer WM, et al. COPD in never smokers: results from the population-based burden of obstructive lung disease study. Chest 2011; 139:752.
- Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med 2011; 155:179.
- Simel D, Rennie D. The rational clinical examination: Evidence-based clinical diagnosis, McGraw Hill (Ed), New York 2008.
- Mannino DM, Gagnon RC, Petty TL, Lydick E. Obstructive lung disease and low lung function in adults in the United States: data from the National Health and Nutrition Examination Survey, 1988-1994. Arch Intern Med 2000; 160:1683.
- Mannino DM, Buist AS, Petty TL, et al. Lung function and mortality in the United States: data from the First National Health and Nutrition Examination Survey follow up study. Thorax 2003; 58:388.
- Rennard S, Decramer M, Calverley PM, et al. Impact of COPD in North America and Europe in 2000: subjects' perspective of Confronting COPD International Survey. Eur Respir J 2002; 20:799.
- Kessler R, Partridge MR, Miravitlles M, et al. Symptom variability in patients with severe COPD: a pan-European cross-sectional study. Eur Respir J 2011; 37:264.
- Sin DD, Wu L, Man SF. The relationship between reduced lung function and cardiovascular mortality: a population-based study and a systematic review of the literature. Chest 2005; 127:1952.
- Eisner MD, Blanc PD, Yelin EH, et al. COPD as a systemic disease: impact on physical functional limitations. Am J Med 2008; 121:789.
- Kjensli A, Falch JA, Ryg M, et al. High prevalence of vertebral deformities in COPD patients: relationship to disease severity. Eur Respir J 2009; 33:1018.
- Puente-Maestu L, Pérez-Parra J, Godoy R, et al. Abnormal mitochondrial function in locomotor and respiratory muscles of COPD patients. Eur Respir J 2009; 33:1045.
- Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J 2009; 33:1165.
- Swallow EB, Barreiro E, Gosker H, et al. Quadriceps muscle strength in scoliosis. Eur Respir J 2009; 34:1429.
- Woodruff PG, Barr RG, Bleecker E, et al. Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function. N Engl J Med 2016; 374:1811.
- Regan EA, Lynch DA, Curran-Everett D, et al. Clinical and Radiologic Disease in Smokers With Normal Spirometry. JAMA Intern Med 2015; 175:1539.
- Badgett RG, Tanaka DJ, Hunt DK, et al. Can moderate chronic obstructive pulmonary disease be diagnosed by historical and physical findings alone? Am J Med 1993; 94:188.
- Lemyze M, Bart F. Hoover sign. CMAJ 2011; 183:E133.
- Garcia-Pachon E, Padilla-Navas I. Frequency of Hoover's sign in stable patients with chronic obstructive pulmonary disease. Int J Clin Pract 2006; 60:514.
- NCBI PubChem. Nicotine. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=89594#x27 (Accessed on January 02, 2014).
- Guirguis-Blake JM, Senger CA, Webber EM, et al. Screening for Chronic Obstructive Pulmonary Disease: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2016; 315:1378.
- American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2003; 168:818.
- Brusasco V, Martinez F. Chronic obstructive pulmonary disease. Compr Physiol 2014; 4:1.
- Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004; 23:932.
- Shirtcliffe P, Weatherall M, Marsh S, et al. COPD prevalence in a random population survey: a matter of definition. Eur Respir J 2007; 30:232.
- Vaz Fragoso CA, Gill TM, McAvay G, et al. Use of lambda-mu-sigma-derived Z score for evaluating respiratory impairment in middle-aged persons. Respir Care 2011; 56:1771.
- Vaz Fragoso CA, Concato J, McAvay G, et al. Respiratory impairment and COPD hospitalisation in older persons: a competing risk analysis. Eur Respir J 2012; 40:37.
- Vaz Fragoso CA, Gill TM, McAvay G, et al. Respiratory impairment in older persons: when less means more. Am J Med 2013; 126:49.
- Mannino DM, Diaz-Guzman E. Interpreting lung function data using 80% predicted and fixed thresholds identifies patients at increased risk of mortality. Chest 2012; 141:73.
- Vaz Fragoso CA, McAvay G, Van Ness PH, et al. Phenotype of Spirometric Impairment in an Aging Population. Am J Respir Crit Care Med 2016; 193:727.
- Vaz Fragoso CA, McAvay G, Van Ness PH, et al. Phenotype of normal spirometry in an aging population. Am J Respir Crit Care Med 2015; 192:817.
- Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 2005; 26:319.
- Swanney MP, Jensen RL, Crichton DA, et al. FEV(6) is an acceptable surrogate for FVC in the spirometric diagnosis of airway obstruction and restriction. Am J Respir Crit Care Med 2000; 162:917.
- Demir T, Ikitimur HD, Koc N, Yildirim N. The role of FEV6 in the detection of airway obstruction. Respir Med 2005; 99:103.
- Vandevoorde J, Verbanck S, Schuermans D, et al. FEV1/FEV6 and FEV6 as an alternative for FEV1/FVC and FVC in the spirometric detection of airway obstruction and restriction. Chest 2005; 127:1560.
- Bhatt SP, Kim YI, Wells JM, et al. FEV(1)/FEV(6) to diagnose airflow obstruction. Comparisons with computed tomography and morbidity indices. Ann Am Thorac Soc 2014; 11:335.
- Kelly AM, McAlpine R, Kyle E. How accurate are pulse oximeters in patients with acute exacerbations of chronic obstructive airways disease? Respir Med 2001; 95:336.
- Matthay RA, Niederman MS, Wiedemann HP. Cardiovascular-pulmonary interaction in chronic obstructive pulmonary disease with special reference to the pathogenesis and management of cor pulmonale. Med Clin North Am 1990; 74:571.
- Iyer AS, Wells JM, Vishin S, et al. CT scan-measured pulmonary artery to aorta ratio and echocardiography for detecting pulmonary hypertension in severe COPD. Chest 2014; 145:824.
- Klein JS, Gamsu G, Webb WR, et al. High-resolution CT diagnosis of emphysema in symptomatic patients with normal chest radiographs and isolated low diffusing capacity. Radiology 1992; 182:817.
- Park KJ, Bergin CJ, Clausen JL. Quantitation of emphysema with three-dimensional CT densitometry: comparison with two-dimensional analysis, visual emphysema scores, and pulmonary function test results. Radiology 1999; 211:541.
- Mair G, Miller JJ, McAllister D, et al. Computed tomographic emphysema distribution: relationship to clinical features in a cohort of smokers. Eur Respir J 2009; 33:536.
- Lynch DA, Austin JH, Hogg JC, et al. CT-Definable Subtypes of Chronic Obstructive Pulmonary Disease: A Statement of the Fleischner Society. Radiology 2015; 277:192.
- Galbán CJ, Han MK, Boes JL, et al. Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression. Nat Med 2012; 18:1711.
- Smith BM, Austin JH, Newell JD Jr, et al. Pulmonary emphysema subtypes on computed tomography: the MESA COPD study. Am J Med 2014; 127:94.e7.
- Hasegawa M, Nasuhara Y, Onodera Y, et al. Airflow limitation and airway dimensions in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006; 173:1309.
- Grydeland TB, Dirksen A, Coxson HO, et al. Quantitative computed tomography: emphysema and airway wall thickness by sex, age and smoking. Eur Respir J 2009; 34:858.
- Qaseem A, Snow V, Shekelle P, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2007; 147:633.
- Brantly ML, Sandhaus RA, Turino G, et al. The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. Chronic Obstr Pulm Dis (Miami) 2016; 3:668.
- Modrykamien AM, Gudavalli R, McCarthy K, et al. Detection of upper airway obstruction with spirometry results and the flow-volume loop: a comparison of quantitative and visual inspection criteria. Respir Care 2009; 54:474.
- Menezes AM, Hallal PC, Perez-Padilla R, et al. Tuberculosis and airflow obstruction: evidence from the PLATINO study in Latin America. Eur Respir J 2007; 30:1180.
- Jordan TS, Spencer EM, Davies P. Tuberculosis, bronchiectasis and chronic airflow obstruction. Respirology 2010; 15:623.
- US Preventive Services Task Force (USPSTF), Siu AL, Bibbins-Domingo K, et al. Screening for Chronic Obstructive Pulmonary Disease: US Preventive Services Task Force Recommendation Statement. JAMA 2016; 315:1372.
- de Marco R, Accordini S, Antò JM, et al. Long-term outcomes in mild/moderate chronic obstructive pulmonary disease in the European community respiratory health survey. Am J Respir Crit Care Med 2009; 180:956.
- Lange P, Marott JL, Vestbo J, et al. Prediction of the clinical course of chronic obstructive pulmonary disease, using the new GOLD classification: a study of the general population. Am J Respir Crit Care Med 2012; 186:975.
- Jones PW, Tabberer M, Chen WH. Creating scenarios of the impact of COPD and their relationship to COPD Assessment Test (CAT™) scores. BMC Pulm Med 2011; 11:42.
- Kelly JL, Bamsey O, Smith C, et al. Health status assessment in routine clinical practice: the chronic obstructive pulmonary disease assessment test score in outpatients. Respiration 2012; 84:193.
- van der Molen T, Willemse BW, Schokker S, et al. Development, validity and responsiveness of the Clinical COPD Questionnaire. Health Qual Life Outcomes 2003; 1:13.
- COPD Assessment Test (CAT). http://www.catestonline.org (Accessed on February 10, 2017).
- Gupta N, Pinto LM, Morogan A, Bourbeau J. The COPD assessment test: a systematic review. Eur Respir J 2014; 44:873.
- Weatherall M, Marsh S, Shirtcliffe P, et al. Quality of life measured by the St George's Respiratory Questionnaire and spirometry. Eur Respir J 2009; 33:1025.
- Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev Respir Dis 1992; 145:1321.
- Wilson CB, Jones PW, O'Leary CJ, et al. Validation of the St. George's Respiratory Questionnaire in bronchiectasis. Am J Respir Crit Care Med 1997; 156:536.
- Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004; 350:1005.
- Celli BR. Change in the BODE index reflects disease modification in COPD: lessons from lung volume reduction surgery. Chest 2006; 129:835.
- Puhan MA, Mador MJ, Held U, et al. Interpretation of treatment changes in 6-minute walk distance in patients with COPD. Eur Respir J 2008; 32:637.
- Cote CG, Pinto-Plata VM, Marin JM, et al. The modified BODE index: validation with mortality in COPD. Eur Respir J 2008; 32:1269.