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INTRODUCTION — Chronic obstructive pulmonary disease (COPD) is a common respiratory condition involving the airways and characterized by airflow limitation [1,2]. It affects more than 5 percent of the population and is associated with high morbidity and mortality . 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) .
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 .
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 acute 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.
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 :
“Chronic obstructive pulmonary disease (COPD), a common preventable and treatable disease, is characterized by airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients."
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. This definition has been used in many studies, despite the arbitrarily selected symptom duration.
Emphysema — Emphysema is defined by 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 [9,10]. 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 [11,12].
The various subtypes of emphysema (eg, proximal acinar, panacinar, distal acinar) are described below. (See 'Pathology' below.)
Asthma — The Global Initiative for Asthma 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 of COPD subtypes — Early definitions of COPD distinguished different types (ie, chronic bronchitis, emphysema, asthma), a distinction that is not included in the current definition [14-16]. 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:
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 . Similarly, the nature of the bronchial inflammation varies widely even among individuals with a single type of COPD. A number of initiatives are in progress to provide rigorous phenotyping of COPD patients in order to define more homogeneous groups.
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 .
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 . 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 [22-26]. 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) [21,27,28]. Among patients with chronic bronchitis who have mucus hypersecretion, an increased number of goblet cells and enlarged submucosal glands are typically seen.
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.
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.
Smoking and inhalational exposure history — The most important risk factor for COPD is cigarette smoking and 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 (80 percent) of patients with COPD have a history of cigarette smoking [29,30]. It is useful to ask 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]) [31,32].
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 [30,33,34]. (See "Chronic obstructive pulmonary disease: Risk factors and risk reduction".)
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 :
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, coronary heart disease, osteoporosis, metabolic syndrome, skeletal muscle weakness, depression, and cognitive dysfunction. Patients may also report a family history of COPD or other chronic respiratory illness [6,37-42].
Physical examination — The findings on physical examination of the chest vary with the severity of the COPD (table 1A-B).
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) [6,31]. All patients are evaluated with spirometry and selected patients have laboratory testing and imaging studies. (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.
Pulmonary function tests — Pulmonary function tests, 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 microg) 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 suggestive of COPD rather than asthma. (See "Office spirometry", section on 'Post-bronchodilator spirometry'.)
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 — Traditionally, a postbronchodilator FEV1/FVC ratio less than 0.70 has been considered diagnostic of 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 <0.70, has been advocated as a dividing point for the diagnosis of COPD [7,11,47-50]. 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 in whom an increased mortality was noted among those with an FEV1/FVC <0.70, but a normal LLN FEV1/FVC when compared with those whose FEV1/FVC was 0.70 or higher . (See "Office spirometry", section on 'Ratio of FEV1/FVC'.)
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 [52-55]. 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 lower limit of normal (LLN) for FEV1/FEV6 from NHANES III should be used to diagnose airflow limitation. (See "Office spirometry", section on 'Forced expiratory volume in 6 seconds' and "Office spirometry", section on 'Ratio of FEV1/FVC'.)
Peak expiratory flow — Peak expiratory flow 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 peak flow 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, PaO2 <92 mmHg) 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.
Arterial blood gases — Pulse oximetry, which is obtained in the majority of patients, has reduced the number of patients who require arterial blood gases (ABGs). However, pulse oximetry does not provide information about alveolar ventilation or hypercapnia (PaCO2 >45 mmHg), 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 "Use of oxygen in patients with hypercapnia", section on 'Effects of hypercapnia'.)
The indications for measuring ABGs (eg, arterial oxygen tension [PaO2], carbon dioxide tension [PaCO2], and acidity [pH]), which must be considered in the clinical context, include the following:
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 forced expiratory volume in one second (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 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). However, imaging is not required to diagnose COPD. (See 'Diagnosis' below.)
Chest radiography — The main reason to obtain a chest radiograph when evaluating a patient for COPD is to exclude alternative diagnoses, evaluate for comorbidities (eg, lung cancer with airway obstruction, bronchiectasis, pleural disease, interstitial lung disease, heart failure), or when a change in symptoms suggests a complication of COPD (eg, pneumonia, pneumothorax). 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:
Computed tomography — Computed tomography (CT) has greater sensitivity and specificity than standard chest radiography for the detection of emphysema, but not chronic bronchitis or asthma. This is particularly true with high resolution CT (ie, collimation of 1 to 2 mm) [58-60]. (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. (See "Evaluation and medical management of giant bullae in COPD", section on 'Evaluation and diagnosis' and "Lung volume reduction surgery in COPD", section on 'Patient selection' and "Diagnosis of acute pulmonary embolism".)
Certain CT scan features can determine whether the emphysema is centriacinar (centrilobular) or panacinar, although this is usually not necessary for clinical management.
Newer CT scanners with higher resolution and new analytical methods can resolve airway dimensions, although the clinical significance of these measures is undefined [61,62]. 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.
DIAGNOSIS — The diagnosis of COPD is based upon the following findings :
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 . (See 'Laboratory' above and "Chronic obstructive pulmonary disease: Risk factors and risk reduction".)
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.
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 [67,68]. 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 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 FEV1 (expressed as a percentage of predicted) to stage disease severity. However, the FEV1 only captures one component of COPD severity, and 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 [6,70].
Several tools for evaluating symptom severity have been proposed. The GOLD guidelines suggest using instruments such as the modified Medical Research Council (mMRC) dyspnea scale (table 5), the Clinical COPD Questionnaire (table 6), or the COPD Assessment Tool (CAT) [6,71-74]. In our practice, we typically use the mMRC scale. The most widely used 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 [75-77].
The Gold guidelines suggest using a combination of an individual’s symptoms, history of exacerbations, and FEV1 to assess the exacerbation risk and guide therapy . Symptom severity is assessed using the modified Medical Research Council (mMRC) or COPD assessment test (CAT) . The number of 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 suggests a low future risk of exacerbations, while two or more exacerbations suggest a high future risk . The severity of lung function impairment is stratified based on the postbronchodilator FEV1, using the GOLD classification (table 3). These three components are combined as follows:
Other systems for assessing disease severity in the COPD patient have been proposed. The BODE index, which 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 [78-81]. (See "Chronic obstructive pulmonary disease: Prognostic factors and comorbid conditions", section on 'BODE index'.)
Other staging systems for COPD (eg, DOSE, ADO) have also been developed, but are not used routinely in clinical practice. The DOSE staging system comprises dyspnea, airflow obstruction, smoking status, and exacerbation frequency , while the ADO staging system combines age, dyspnea (by MRC scale), and airflow obstruction .
The FEV1/FVC ratio is not used for staging 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. Different clinical practice guidelines use different cut-off values, but most are similar to the GOLD staging system (table 3) . (See "Chronic obstructive pulmonary disease: Prognostic factors and comorbid conditions", section on 'Forced expiratory volume in one second'.)
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