Introduction and History
Chronic obstructive pulmonary disease (COPD), as it is currently defined, is a spectrum of lung abnormalities characterized physiologically by persistent airflow obstruction. The histologic abnormalities seen most commonly are lung tissue destruction, or emphysema, and airway disease, recognized clinically as chronic bronchitis. From a historical perspective, emphysema was recognized first. Dating back to the 17th and 18th centuries, clinicians recognized what were termed abnormally “voluminous” lungs. In 1789, Baillie published a series of illustrations demonstrating the classic pathologic features of emphysema. A bit later, chronic bronchitis was described, best documented by the clinician, pathologist, and inventor of the stethoscope, Laennec. In his 1821 “A Treatise on the Diseases of the Chest,” Laennec describes lungs that are hyperinflated and do not empty well. But, upon pathologic inspection, he also noted the “bronchus of the trachea are often…filled with mucous fluid.” At that time, smoking was not common and Laennec attributed the principal causes of this disease to environmental and genetic factors. However, it is important to note that Laennec identified both of the characteristic features of COPD: emphysema and chronic bronchitis.
By the 1940s, master clinicians were becoming familiar with an entity characterized by dyspnea on exertion in patients with physical signs of emphysema along with chronic bronchitis and asthma. However, the ability to diagnose this entity reliably was not possible until the invention of spirometry. In 1846, John Hutchinson invented the spirometer, which was capable of measuring vital capacity, but 100 years later, it was Tiffeneau who introduced the concept of a timed vital capacity as a measure of airflow that allowed the spirometer to become a diagnostic instrument for airflow obstruction. By the 1950s, clinicians recognized that specific spirometric and flow volume patterns indicated the presence of emphysema. In fact, the first edition of Hinshaw and Garland in 1956 depicted spirograms indicating airflow obstruction in emphysema.
Groundwork for the modern definition of COPD was established at two major scientific conferences, the CIBA Guest Symposium in 1959 and the American Thoracic Society (ATS) Committee on Diagnostic Standards in 1962. The ATS committee defined chronic bronchitis clinically as chronic cough lasting at least 3 months for at least 2 years; emphysema was defined histologically as enlarged alveolar spaces; asthma was defined as airway hyperresponsiveness. It was then that Dr. William Briscoe at the ninth Aspen Emphysema Conference in 1965 first introduced the term “COPD.” Several years later, Drs. Charles Fletcher and Richard Peto provided support for the link between smoking and the development of COPD in their 1976 landmark book documenting that continued smoking accelerates the disease, whereas smoking cessation attenuates lung function loss.
The modern definition of COPD, as put forth by the ATS and European Respiratory Society (ERS), describes it as “a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences.” While this definition describes a physiologic abnormality associated with exposure to noxious stimuli, the challenge that remains for both clinician and researcher is understanding the significant heterogeneity in disease presentation and progression that still exists within this umbrella definition.
Clinical Features
Symptoms
Individuals with early COPD are often asymptomatic. However, as the disease progresses, dyspnea, wheezing, cough and sputum production typically become more prominent. Any of these features should trigger an evaluation including spirometry both for diagnosis, if not already established, and for disease staging. Early in the disease course, dyspnea may be experienced only with exertion and patients may attribute these symptoms to other factors and not seek treatment. Patients may also modify their activities to avoid dyspnea so that the progression of pulmonary limitation may be rather insidious. In fact, patients’ activity may be severely limited even when they believe their disease process is still mild. Eventually, however, as the disease progresses, dyspnea may ultimately be present with activities of daily living. Whereas the mechanism for dyspnea in COPD is likely multifactorial, exercise-induced air trapping otherwise known as “dynamic hyperinflation” likely plays a significant role ( Fig. 44-1 ).
As with dyspnea, patients may attribute cough to other factors such as smoking and therefore may not complain about this symptom unless prompted. In general, current smokers have more sputum production, which paradoxically may increase transiently after smoking cessation. While the presence of cough and sputum production in COPD is often more variable than the presence of dyspnea, it can significantly impact quality of life. Sputum, when present, tends to be mucoid, clear to white in appearance, and more purulent with exacerbations. Chronic bronchitis is also clinically significant because it is associated with more frequent exacerbations and has specific therapeutic implications (see Treatment ). . Excessive sputum production (more than 2 to 3 tablespoons daily) may indicate the presence of bronchiectasis, which has been reported to range in prevalence between 29% and 52% in moderate-to-severe COPD and has been associated with increased mortality. Hemoptysis may be seen with both chronic bronchitis and bronchiectasis, particularly during COPD exacerbations. However, the presence of hemoptysis in a patient with COPD should raise concern for other possible causes, including lung cancer, given the increased risk for lung cancer in this patient population.
Several instruments have been developed to assess health status in COPD, most notably the St. George’s Respiratory Questionnaire (SGRQ) and the COPD Assessment Test (CAT) ( Fig. 44-2 ). Both are multidimensional instruments encompassing symptoms such as cough and sputum production as well as breathlessness and activity limitation. Both the SGRQ and CAT demonstrate rough but imperfect correlations with forced expiratory volume in 1 second (FEV 1 ) but, more importantly, demonstrate changes after interventions and with exacerbations. While the SGRQ is longer and used primarily in the research setting, the CAT consists of only eight questions and is practical for use within the clinical setting. The Modified Medical Research Council scale is a 5-point dyspnea scale that, while not developed specifically for COPD, is relevant because it relates to mortality in COPD alone or when used to calculate the BODE (BMI, obstruction, dyspnea, exercise capacity) index, a mortality predictor in COPD ( Table 44-1 ).
| Variable | Points on the BODE index | |||
|---|---|---|---|---|
| 0 | 1 | 2 | 3 | |
| B—Body mass index (kg/m 2 ) * | >21 | ≤21 | — | — |
| O—FEV 1 (% of predicted) † | ≥65 | 50–64 | 36–49 | ≤35 |
| D—Distance walked in 6 min (m) | ≥350 | 250–349 | 150–249 | ≤149 |
| E—MMRC dyspnea scale (score) | 0–1 | 2 | 3 | 4 |
* Values for body mass index are 0 or 1 owing to the inflection point in the inverse relationship between survival and body mass index at a value of 21 kg/m2.
† FEV 1 categories are based upon stages identified by the American Thoracic Society.
Physical Examination
Early in the course of the disease, no specific abnormalities may be noted on physical examination. Wheezing may or may not be present and does not necessarily relate to the severity of airflow obstruction. Prolonged expiratory time is a more consistent finding in COPD, particularly as the disease progresses. A forced expiratory time of more than 6 seconds corresponds to an FEV 1 / forced vital capacity (FVC) ratio of less than 50% to 60%. In very severe disease, patients develop physical signs indicative of hyperinflation, including a barrel-shaped chest, decreased breath sounds, distant heart sounds, and increased resonance to percussion. Patients may breathe in a “tripod” position in which the individual learns forward and supports his or her upper body with extended arms. This maneuver takes advantage of the accessory muscles of the neck and upper chest to increase air movement. Patients with severe disease may also use pursed-lip breathing, which involves exhaling through tightly pressed, pursed lips. This technique creates back-pressure and is thought to reduce dynamic hyperinflation although it may also work by reducing bronchoconstriction via neutrally mediated mechanisms.
In patients with severe disease, other systemic manifestations may include signs of cor pulmonale, or right-sided heart failure, leading to lower extremity edema. An accentuated P2 or pulmonic component of the second heart sound may also be appreciated. Tar stains on the fingers from cigarette smoking may be present. Clubbing is not a typical feature of COPD, even when hypoxemia is present, and should suggest evaluation for other comorbidities including lung cancer.
Two commonly recognized COPD subtypes are the “pink puffers” and “blue bloaters.” Pink puffers, typically associated with significant emphysema, compensate by hyperventilation and often manifest muscle wasting and weight loss. Compared with blue bloaters, pink puffers are less hypoxemic and therefore appear “pink.” Blue bloaters typically have chronic bronchitis and tend to have decreased ventilation and greater ventilation-perfusion (V/Q) mismatch than pink puffers, leading to hypoxemia and hence cyanosis and to cor pulmonale with edema or “bloating.”
Pulmonary Function Testing and Diagnosis
Spirometry
Pulmonary function testing (see Chapter 25 ) and, in particular, spirometry is essential to establish a diagnosis of COPD. While symptoms suggest a diagnosis, unfortunately their predictive value for a diagnosis of COPD is poor. Several screening tools have been developed, including questionnaires and questionnaires used in conjunction with peak expiratory flow. Several studies suggest that among the various risk factors, older age and smoking history are the two most important risk factors for development of COPD. Spirometry can be performed in the physician’s office and should be done in any patient with symptoms (e.g., cough, sputum, dyspnea) and risk factors. When performing spirometry, a subject exhales forcefully and the FEV 1 is compared against the total air exhaled, which is the FVC. COPD is defined by a reduction in the FEV 1 /FVC ratio. The degree of FEV 1 reduction defines the severity of airflow obstruction. The flow volume loop in COPD typically has a concave appearance and the volume-time curve demonstrates a prolonged expiratory time ( Fig. 44-3 ).
The ATS and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that post-bronchodilator values be used to help distinguish COPD from asthma. GOLD recommends an FEV 1 /FVC less than 0.70 as the threshold for presence of airflow obstruction. Rather than using the fixed ratio, the ATS/ERS recommends using the fifth percentile for the lower limit of normal. In general, the fixed ratio approach leads to overdiagnosis in older subjects because the FEV 1 /FVC ratio declines with age, even in healthy individuals. However, the fixed ratio approach carries the advantage of simplicity.
While COPD severity has typically been graded based on FEV 1 % predicted, which is part of the GOLD ( Table 44-2 ) and ATS/ERS recommendations, recent updates to the GOLD recommendations now incorporate symptoms and exacerbation risk as part of disease staging.
| In Patients with FEV 1 /FVC < 0.70 | |
| GOLD 1: mild | FEV 1 ≥ 80% predicted |
| GOLD 2: moderate | 50% ≤ FEV 1 < 80% predicted |
| GOLD 3: severe | 30% ≤ FEV 1 < 50% predicted |
| GOLD 4: very severe | FEV 1 < 30% predicted |
Lung Volumes
Other lung volumes including total lung capacity (TLC) and residual volume (RV) must be measured via plethysmography, which is typically performed in a pulmonary function laboratory. TLC is increased in COPD, particularly in the presence of emphysema where there is significant loss of elastic recoil, resulting in lung hyperinflation. Increases in RV and functional residual capacity may also be seen. RV tends to increase to a greater extent than TLC, leading to an increase in the RV/TLC ratio. Vital capacity in COPD is also typically decreased because of hyperinflation.
Diffusing Capacity
Diffusing capacity for carbon monoxide (D l CO ) reflects the alveolar capillary blood volume and consequently is decreased in the presence of emphysema, but may also be reduced in the presence of other abnormalities that affect the alveolar capillary bed including pulmonary fibrosis. Near-normal spirometry and lung volumes in the setting of severely reduced diffusing capacity and radiographic evidence of emphysema should suggest a possible diagnosis of combined pulmonary fibrosis emphysema syndrome.
Exercise Testing
The 6-minute walk test (6MWT) is probably the most frequently employed exercise test in COPD. The distance that a patient can walk in 6 minutes is termed the 6-minute walk distance (6MWD). Measuring distance walked during a defined time period was first described in the early 1960s. An advantage of the 6MWT is that it requires little training to administer and no specialized equipment. While a 6MWT is not required to make a diagnosis of COPD, it allows the clinician to assess oxygenation during ambulation and the potential need for supplemental oxygen. 6MWD is also frequently employed during lung transplant evaluation to gauge functional status and prognosis. 6MWD has been demonstrated to relate to mortality in COPD and is a component of the BODE mortality index. The 6MWT however does not provide diagnostic information regarding specific causes for dyspnea or exercise limitation, which can only be obtained through more formal cardiopulmonary exercise testing (CPET). CPET can be performed with either a treadmill or cycle ergometer. A large number of parameters can be measured or derived during a CPET, including maximal oxygen uptake ( 
), carbon dioxide output ( 
), maximal work rate, and anaerobic threshold. While there is good correlation between 6MWD and peak oxygen uptake in end-stage lung disease, the 6MWT should be considered complementary to the CPET. Most patients do not achieve maximal exercise capacity during the 6MWT and consequently the 6MWD may better reflect functional exercise capacity. The 6MWD also correlates better with quality of life measures; therapeutic interventions resulting in changes in 6MWD also correlate with improvements in dyspnea. Some form of exercise testing is typically employed before and after pulmonary rehabilitation to assess improvement. CPET is also a necessary part of evaluation for lung volume reduction surgery (LVRS), because LVRS may provide a survival benefit for those with a low work rate after pulmonary rehabilitation.
Imaging
Chest radiography and computed tomography (CT) are the two imaging modalities most commonly used in COPD. While not required to diagnose COPD, imaging can be helpful to rule out concomitant processes. Chest radiographs are frequently obtained to investigate dyspnea or hemoptysis or to look for pneumonia, heart failure, lung cancer, or pneumothorax. Chest radiography is not particularly sensitive or specific for the diagnosis of COPD. There are certain features, however, that are often seen in COPD. Radiolucency, diaphragmatic flattening, and increased retrosternal airspace on the lateral radiograph may be seen when hyperinflation is present ( Fig. 44-4 , 
) Occasionally large bullae may manifest as radiolucent areas.
Chest CT allows better detection and quantification of emphysema than does traditional chest radiography. Areas of low attenuation are a marker of emphysema; thickened airways indicative of bronchial thickening may also be seen ( Fig. 44-5 ). If expiratory views are obtained, areas of air trapping indicative of small airway obstruction and emphysema may also be seen. CT is not indicated in the routine diagnosis or evaluation of COPD, but can be helpful when evaluating individuals with very severe COPD. CT imaging is required to quantify emphysema extent and distribution for the purposes of LVRS. Individuals with very severe COPD undergoing transplant evaluation typically require a chest CT to rule out the presence of lung cancer and aid with surgical planning. CT imaging is also helpful when the clinician is concerned about a concomitant process such as interstitial lung disease which may be suggested on pulmonary function testing (see section on PFT’s) or when hemoptysis or other unexplained changes in symptoms develop. Bronchiectasis, which may be reflected by copious sputum production and cough and has been associated with increased mortality, is also best assessed on CT.
Although CT is not required for routine practice, the potential clinical importance of CT imaging is becoming better appreciated. Several studies demonstrate a strong relationship between emphysema and both lung function decline and mortality. Bronchial thickening as assessed by CT also appears to have a strong relationship with symptoms as measured by the SGRQ.
The COPD patient population is at increased risk for lung cancer and the mortality benefit of screening CTs in smokers has now been established. Therefore a low-dose screening CT for lung cancer in individuals aged 55 to 74 years with at least a 30 pack-year smoking history, including those who quit in the preceding 15 years, may be appropriate (see Chapters 18 and 53 ).
Laboratory Testing
Arterial Blood Gases
Arterial blood gases (ABGs) are not indicated as part of the routine evaluation for patients with mild to moderate COPD. For many patients, pulse oximetry will suffice to provide an estimate of oxygen saturation. However, ABGs can be helpful to assess hypoxemia and to provide information regarding hypercapnia, particularly in individuals with more severe disease or during an acute exacerbation. ABG abnormalities also tend to worsen during exercise and sleep. Early in the disease course, mild to moderate hypoxemia without hypercapnia is typically seen. Later in the disease course, hypercapnia may develop, particularly in individuals with FEV 1 less than 1 L.
Erythrocytosis.
Elevated hemoglobin may be seen in COPD, particularly in the presence of chronic hypoxemia. A hemoglobin value is also helpful in the evaluation of dyspnea because anemia is a common cause of dyspnea that should be ruled out. In addition, D l CO is most accurate when adjusted for hemoglobin.
Serum Bicarbonate.
An elevated serum bicarbonate can suggest chronic hypercapnia; in the setting of hypercapnia, serum bicarbonate is increased due to compensatory metabolic alkalosis.
Alpha 1 -Antitrypsin Deficiency
The ATS guidelines recommend testing for A1AT deficiency for all individuals with persistent airflow obstruction. A1AT is a protease that inactivates neutrophil elastase. Clinical features suggestive of A1AT deficiency include emphysema at a young age, emphysema in an individual with minimal or no smoking history, lower lobe predominant emphysema, and a family history of emphysema. However, A1AT deficiency can also be present in patients with more typical COPD presentations. In individuals with established COPD, diagnostic testing is recommended. Concern for the diagnosis is raised based on A1AT serum levels below 11 micromol/L (approximately 50 mg/dL using nephelometry (i.e., immunoturbidimetry) and 80 mg/dL by radial immunodiffusion) but should be confirmed with genotyping (high-risk genotypes include S, Z, and null alleles as the most deficient). Occasionally the serum level and genotyping are discordant; in this situation, protein phenotype analysis via electrophoresis can identify alleles with abnormal protein migration patterns. The chest radiograph and CT show the predominantly lower lobe distribution of emphysema, consistent with a panacinar pattern ( Fig. 44-6 , 
) and different from the more common centriacinar pattern (see Fig. 44-4 and ).
Sputum.
Sputum evaluation is not indicated in the routine diagnosis and care of the COPD patient. In patients with stable disease, sputum examination typically reveals a predominance of macrophages and few bacteria. During exacerbations, the number of organisms on Gram stain typically increases. The most common pathogens identified on sputum culture include Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae. Less frequently identified organisms include Staphylococcus aureus, Pseudomonas aeruginosa, and other gram-negative rods. However, the relationship between identification of organisms in sputum and pathogenic contribution to acute exacerbations has been questioned because longitudinal studies have suggested that the incidence of bacterial isolation from sputum during an acute exacerbation of COPD was no different from that of the stable state, although bacteria identified in sputum during stable COPD have been associated with a greater exacerbation frequency and lung function decline. In general, exacerbations typically respond to empirical treatment.
Complications
Pneumothorax
Pneumothoraces may develop spontaneously in patients with COPD. Depending on the degree of respiratory impairment, a pneumothorax may result in significant dyspnea and even acute respiratory failure. Pneumothoraces are treated similarly in COPD as in other conditions, although patients with severe emphysema are at increased risk for persistent air leaks, which may be difficult to treat.
Giant Bullae
Emphysema may present with large bullae that can occupy a good portion of the hemithorax. Surgical treatment can be considered if compression of adjacent lung tissue is significant and surgical intervention is expected to improve pulmonary mechanics. Bullae may also become infected. An increased frequency of lung cancer has been reported in association with large bullae, seen either as a mass within the bulla or a thickening of the wall.
Pneumonia
Pneumonia is not uncommon in patients with COPD and should be in the differential diagnosis for any patient with COPD presenting with increased dyspnea, cough, sputum production, and/or fever, which can make it difficult to distinguish from an acute exacerbation of COPD without a chest radiograph. While COPD is believed to increase the risk for pneumonia, epidemiologic data are limited. Inhaled corticosteroids (ICS), which are frequently employed in the treatment of COPD because they reduce the frequency of COPD exacerbations, have been associated with an increased risk for pneumonia, particularly in older patients with COPD . All patients with COPD should be immunized against pneumococcus.
Cor Pulmonale
Cor pulmonale refers to altered structure or function of the right ventricle resulting from pulmonary hypertension (PH) associated with chronic lung disease (see Chapter 59 ). The prevalence of cor pulmonale in COPD is not known with certainty but reported prevalence ranges from 1% to more than 70% depending on the patient population examined and the methodology employed for defining PH. When PH develops in the setting of COPD, the severity tends to be modest; severe resting PH due to COPD is relatively uncommon (see Fig. 59-3 ). Signs and symptoms of cor pulmonale include an increase in dyspnea, chest pain, and syncope. Severe cor pulmonale often presents with an increase in lower extremity edema, which should prompt further investigation. Other physical examination findings include right ventricular heave, prominent pulmonic component to the second heart sound, tricuspid regurgitation murmur, and a right-sided S4. Electrocardiographic findings may include right axis deviation, evidence of right ventricular hypertrophy, and right bundle-branch block (see Fig. 59-6 ), but overall these findings are rather insensitive for diagnosis of PH. Echocardiography can be diagnostically helpful (see Fig. 59-7 and 
and ), although not infrequently images are limited in patients with parenchymal lung disease and hyperinflation. In addition, the correlation between echocardiogram and right heart catheterization is imperfect; sensitivity tends to be better than specificity, suggesting that normal results on echocardiogram can help exclude significant cor pulmonale. Right heart catheterization remains the “gold standard” for diagnosis (see Fig. 59-9 ). PH in COPD is associated with worse outcomes, including increased risk for hospitalization and worse survival. There are few data to support the use of vasodilators for treatment of PH in COPD. Oxygen is the only therapy for PH in COPD and also improves mortality in appropriately selected patients.
Sleep Disorders
As many as 40% of COPD patients report sleep difficulties such as poor sleep quality or difficulties initiating or maintaining sleep. The combination of COPD and obstructive sleep apnea (OSA) is commonly referred to as “overlap syndrome.” The frequency of OSA in the COPD patient population has been estimated to be approximately 16%, which is roughly similar to that of the general population, although the consequences of OSA in patients with COPD are more significant. Compared to patients with OSA alone or with COPD alone, patients with COPD with OSA tend to have more severe nocturnal hypercapnia and hypoxemia as well as increased risk for PH. OSA in COPD is also associated with poorer quality of life, frequent exacerbations, and increased mortality. Diagnosis of OSA in COPD is important because continuous positive airway pressure therapy for patients with overlap syndrome has been associated with both decreased risk of death and decreased incidence of severe exacerbations.
Systemic Manifestations and Comorbidities
Cardiovascular Disease
Ischemic cardiovascular disease is a leading cause of death in COPD. Tobacco use is a shared risk factor that contributes to this association, but epidemiologic data suggest impaired lung function is an independent risk factor for increased cardiovascular mortality even when adjusted for smoking status. Among those with COPD, FEV 1 also predicts the presence of atherosclerosis and cardiovascular mortality. Patients with COPD are also at increased risk for hospitalization due to cardiovascular events. Atherosclerosis is a disease of systemic inflammation, which may help explain the link to COPD. Elevated C-reactive protein levels correlate not only with the presence of COPD but also with the presence of exacerbations, severity of lung function, and risk for hospitalization and death. Although clinicians need to be aware of the increased risk for the presence of both disorders, no therapeutic strategies have yet been demonstrated to benefit this subgroup of patients specifically. Cardioselective β-blocker medications that are frequently used in patients with cardiovascular disease have traditionally raised safety concerns in patients with COPD. However, while clinicians should be aware that β-blockers can theoretically worsen bronchospasm, accumulating data from several studies now suggest that β-blocker medication in COPD actually reduces all-cause mortality, suggesting an overall benefit to the use of β-blockers in COPD.
Osteoporosis
A clear association between osteoporosis and COPD has been established, with studies suggesting a twofold to fivefold increase in prevalence of osteoporosis in patients with COPD compared with age-matched controls. Multiple shared risk factors between COPD and osteoporosis likely influence this association, including oral and inhaled steroid use, smoking, and low body mass index. However these factors do not completely explain the association because lower bone mineral density in patients with COPD has been documented even in the absence of systemic steroids. Clinicians must be mindful of this association in both their male and female patients with COPD. Pulmonary rehabilitation improves the functional status of patients with COPD and may diminish fracture risk by decreasing the risk of falls.
Diabetes
As with osteoporosis, diabetes is another comorbidity with increased prevalence in COPD. Decreased lung function has been associated with the coexistence of metabolic syndrome as well as the development of insulin resistance and diabetes. The cause for this association is not known with certainty. ICS may be a contributing factor. Some data suggest a dose-dependent association between ICS use and diabetes control or new-onset diabetes, while a retrospective analysis of 8 COPD trials and 26 asthma trials found no association between ICS use and new onset diabetes or hyperglycemia.
Gastroesophageal Reflux Disease
The prevalence of gastroesophageal reflux disease in COPD also appears to be increased. More importantly, gastroesophageal reflux disease in the setting of COPD has specific clinical implications. Reflux in COPD is associated with poorer quality of life, as well as more frequent exacerbations. Reflux may also be more common in COPD patients with chronic bronchitis . A clear cause for the association between gastroesophageal reflux disease and COPD has not been identified. Unfortunately, only limited data suggest that treatment for gastroesophageal reflux disease may reduce the risk of exacerbations.
Depression and Anxiety
Coexistent depression and anxiety are prevalent in COPD, with conservative estimates suggesting anxiety and depression may be present in at least 10% of the general COPD population. Significantly higher estimates have been reported for patients with severe COPD. Risk factors for depression in COPD also include limited mobility, need for supplemental oxygen therapy, comorbid conditions, and female gender. Patients with COPD and comorbid depression and anxiety experience poorer clinical outcomes. Patients with anxiety are at increased risk for COPD exacerbations and higher mortality. Depressive symptoms are also associated with increased risk of death. Specific therapies for anxiety and depression have not been demonstrated to improve COPD outcomes, although pulmonary rehabilitation has been shown to improve not only anxiety and depression but also other outcomes in patients with COPD, including quality of life and functional capacity.
Differential Diagnosis
Several disorders may mimic aspects of COPD, and certainly many conditions may be associated with dyspnea. However, there are a handful of disorders that are particularly challenging because they may be associated with cough, sputum production, airflow obstruction, or emphysema-like radiographic changes. Careful clinical assessment can help differentiate these disorders from COPD although, in some instances, these disorders may be present in addition to COPD.
Chronic Obstructive Asthma
Chronic asthma may be associated with the development of persistent airflow obstruction that is not completely reversible (i.e., due to “remodeling”). Hence, a clear distinction from COPD may not be possible; chronic asthma may also coexist with COPD. However, several clinical features tend to be more likely associated with each of the two disorders. In general, the age of onset for asthma tends to be earlier. Asthmatic patients may have a history of atopy and a family history of asthma. Airflow obstruction abnormalities are usually less severe with asthma, with greater prevalence of reversibility. Sputum production is less common in asthma. These patients also tend to have less of a smoking history and greater steroid responsiveness than patients with COPD. Chronic asthma is also not associated with emphysema; the D l CO is normal or increased in chronic asthma, whereas it is decreased in emphysema.
Chronic Bronchitis Without Airflow Obstruction
Chronic cough and sputum production may be present in the absence of airflow obstruction. The accepted definition for chronic bronchitis is a productive cough for 3 months for 2 successive years. Diagnostically, this is often mistaken for COPD because chronic bronchitis even in the absence of airflow obstruction is often associated with smoking. Chronic exposure to poor air quality or industrial dusts/fumes also increase risk for this disorder. While no specific therapies have been developed for chronic bronchitis without airflow obstruction, the morbidity and mortality associated with this disorder should not be ignored. Such patients still experience poorer quality of life and increased risk of death as opposed to healthy controls.
Bronchiectasis
Bronchiectasis is characterized by dyspnea and in particular copious mucopurulent sputum that tends to be greater than in typical COPD. Diagnosis can be established with the aid of high-resolution CT wherein bronchial wall thickening and luminal dilation is seen. It is not uncommon to see concurrent mild bronchiectasis in both COPD and asthma. Bronchiectasis in COPD is associated with increased mortality. Moderate to severe bronchiectasis should raise a clinician’s concern for immunodeficiency, cystic fibrosis, rheumatic disorders, ciliary motility disorders, alpha 1 -antitrypsin deficiency, allergic bronchopulmonary aspergillosis, and mycobacterial infection.
Bronchiolitis Obliterans
Bronchiolitis obliterans (BO) is also known as constrictive bronchiolitis. This disorder is characterized by submucosal fibrosis resulting in narrowing of the bronchiolar lumen. BO is a known complication of lung, heart, and bone marrow transplants but also may be seen in association with connective tissue diseases and inflammatory bowel disease. Inhalation of dusts or toxins, infection, and drug reactions are less frequent causes of BO. In some cases, no clear etiology is identified. As opposed to those with COPD, patients with BO may have no significant smoking history and typically do not have significant emphysema on CT, which may show only hyperinflation and air trapping. Mosaic attenuation indicative of localized air trapping is common. Bronchial wall thickening may also be present. Pulmonary function testing demonstrates severe, progressive, and irreversible airflow obstruction but is not typically associated with severe D l CO impairment. Unfortunately, BO responds poorly to therapy (see Chapter 50 ).
Diffuse Panbronchiolitis
Diffuse panbronchiolitis is a rare form of bronchiolitis involving the upper and lower respiratory tracts that is seen primarily in Japan and only rarely outside the Far East. Genetic factors, specific human leukocyte antigen (HLA) haplotypes, are thought to contribute to the pathogenesis and geographic distribution of this disease. Such patients typically present with chronic sinusitis, cough productive of copious sputum, dyspnea, wheezing, and weight loss. Airflow obstruction is a common feature, and HRCT may show diffusely thickened and dilated bronchi or tree-in-bud opacities corresponding to bronchiolitis. Confirming this diagnosis is important, because diffuse panbronchiolitis often improves with macrolide antibiotics.
Lymphangioleiomyomatosis
Lymphangioleiomyomatosis is a rare disorder affecting women almost exclusively. It is caused by a mutation in the tuberous sclerosis-1 or -2 gene, either sporadically or in the setting of tuberous sclerosis, resulting in the proliferation of interstitial smooth muscle cells and pulmonary cyst formation. Other clinical characteristics include renal angiomyolipomas and chylous effusions. Lymphangioleiomyomatosis is also characterized by airflow obstruction and spontaneous pneumothoraces. Therefore it is not infrequently mistaken for emphysema. However, an expert radiologist should be able to distinguish pulmonary cystic changes from emphysematous holes. The presence of other characteristic clinical features can be helpful in the diagnosis.
Epidemiology
COPD is currently the third leading cause of death in the United States and is projected to be the third leading cause of death worldwide by 2020. To give some sense of its impact, in 2006, COPD killed more American women than breast cancer and diabetes combined. COPD is also associated with significant morbidity. In the United States in 2006, COPD was responsible for an estimated 672,000 hospitalizations. The cost for caring for patients with COPD continues to increase, with an estimated $49.9 billion spent in 2010. A significant proportion of these costs are attributable to acute exacerbations. COPD patients also have significant comorbidities that likely contribute to their increased cost of care. (For a more detailed discussion of COPD epidemiology, see Chapter 43 .)
Environmental Influences
The primary risk factor for the development of COPD is tobacco smoke exposure. Data suggest the prevalence of COPD in smokers is approximately 20% compared with 4% in nonsmokers. While not all smokers develop COPD, smokers still lose lung function in a dose-dependent manner. Furthermore, smoking is associated with reduced life expectancy. The life expectancy for nonsmokers with COPD is modestly reduced; for current and former smokers with COPD, life expectancy is significantly reduced. Data from smoking cessation studies provide additional support for the association between smoking and COPD. The rate of FEV 1 decline is greatest in patients who smoke the most and is lowest in those who quit smoking. “Second hand smoke” or “environmental tobacco smoke” exposure has also been associated with increased risk for COPD.
Data from the Third National Health and Nutrition Epidemiological Survey put the prevalence of COPD in nonsmokers in the United States at approximately 6.6%, although worldwide estimates for non–tobacco-related COPD range from 20% to 50% of all COPD cases depending on locale. Factors such as traffic, outdoor pollution, and biomass smoke contribute to these findings. Smoke generated from biomass fuels is an important etiology of COPD, particularly in women in developing countries where biomass fuels are used for cooking. In total it has been estimated that the attributable fraction of COPD due to cigarette smoking is approximately 80% to 90%, while occupational exposures including gas, dust, and fumes contribute to the population burden of COPD by approximately 15%.
Host Factors
Genetics
COPD results from an interaction between environmental exposures, most notably tobacco smoke, and increased genetic susceptibility. Family history of COPD also appears to be a risk factor for COPD development, independent of family smoking history, personal smoking history, or childhood environmental tobacco exposure. The strongest genetic risk factor that has been identified is mutation in the A1AT protease, resulting in a deficiency in the resultant protein (discussed previously). Unfortunately, the combination of A1AT deficiency and smoking leads to a marked acceleration in loss of lung function compared with the presence of either alone. The discovery of A1AT deficiency more than 40 years ago raised hopes that other COPD susceptibility genes would be identified rapidly. However, it is only recently that data from genome-wide association studies have led to consistent associations between new genetic loci and COPD susceptibility. Data from genome-wide association studies provide good evidence that the cholinergic nicotinic acetylcholine receptor CHRNA3/5 , HHIP , and FAM13A loci all appear to be associated with disease susceptibility. In particular, the CHRNA3/5 locus appears to be associated with increased smoking intensity and emphysema in individuals with COPD. The HHIP locus has been associated with the systemic components of COPD, frequency of COPD exacerbations, and FEV 1 /FVC ratio. The FAM13A locus has also been associated with FEV 1 /FVC. Efforts to identify other genetic loci are ongoing in multiple cohorts. (For more discussion of the genetics of COPD, see Chapter 45 .)
Other Modifying Factors
Gender is an important clinical feature that also may influence multiple aspects of COPD, including susceptibility. Conflicting data have been published regarding whether women are more susceptible to developing COPD adjusted for smoking exposure. However, the most recent epidemiologic data suggest the prevalence of COPD worldwide by gender is becoming increasingly similar and likely reflective of cigarette and other environmental exposures. Gender may modify other aspects of the disease, however. In general, women report more dyspnea, similar severity of cough, but less sputum than men. Recent data also suggest that COPD exacerbations are more frequent in women, but whether this represents a difference in disease biology or reporting patterns is unknown. Maternal smoking and female gender have also been associated with severe, early-onset COPD.
Several other factors have been identified that modify COPD prevalence and presentation. Lower socioeconomic status significantly increases morbidity and mortality of COPD. The reasons for this are not understood with certainty but may be connected to differences in access to care. Less data are available on the influences of race although, within the United States, there appears to be increasing prevalence of COPD among African Americans as well as a significant increase in mortality. African Americans may also be more susceptible to the harm from tobacco smoke than whites. Exacerbations during hospitalization may also be more frequent in African Americans. Cultural, socioeconomic, and biologic influences could all contribute to these findings.
Treatment
Until recently, treatment of COPD was focused entirely on relief of symptoms, because treatment options were few and were believed to be largely ineffective. In fact, the literature reported that the only interventions that changed the natural history of COPD were smoking cessation, and oxygen in patients with hypoxemia. More recently, however, clinical trials have demonstrated that pharmacologic treatments can prevent or attenuate acute exacerbations of COPD, and the data suggest that some can slow the inexorable loss of lung function over time that is the hallmark of COPD. These observations have appropriately shifted the focus to a more proactive approach, aiming to identify patients earlier in the course of their disease and to implement treatment regimens that would not only relieve symptoms but also prevent exacerbations, prevent disease progression, improve exercise tolerance, and improve quality of life.
General Principles of Treatment
Goals of treatment of COPD are to reduce symptoms, which includes relief of dyspnea, improved exercise tolerance, and improved health status, to reduce risk by preventing and treating exacerbations, preventing disease progression, and reducing mortality, and, at the same time, to minimize the adverse effects of medications.
Reduction of Risk Factors
In the case of COPD, risk reduction refers to interventions that may decrease the likelihood of developing the disease, slow disease progression, decrease exacerbations, and reduce mortality. Although our knowledge of the factors that contribute to each of these is limited, there are substantial data on some factors that contribute to each of these.
Smoking Cessation.
Throughout the developed world, cigarette smoking is the most important risk factor for the development of COPD. Public health and educational programs aimed at discouraging people from smoking (“primary prevention”) and efforts to help active smokers stop are probably the most important intervention for COPD. In their landmark publication in 1977, Fletcher and Peto showed that, in patients with COPD who stopped smoking, the accelerated loss of lung function slowed until it more closely paralleled the annual decrement seen in nonsmokers ( Fig 44-7 ) (see Chapter 43 ). Nearly 2 decades later, the National Institutes of Health–sponsored Lung Health Study demonstrated that in smokers with COPD, smoking cessation reduced the rate of decline in lung function, whereas inhaled bronchodilator did not. In a 14.5-year follow-up to the Lung Health Study, Anthonisen and colleagues reported that the lung-function benefit continued for persistent quitters; there was also a mortality (all cause) benefit for those who maintained abstinence. Perhaps more important, even those whose smoking cessation was intermittent experienced a benefit compared with continued smokers. Smoking cessation education and support should be offered to every patient with COPD, at every visit. (For more detail on smoking cessation, see Chapter 46 .)
Biomass Fuel.
In the developing world, cigarette smoke is less of an issue than is exposure to biomass fuel, used for cooking and heating. The exposure is particularly great for women and their young children, who may spend the greater part of each day indoors with an unvented fire, fueled by wood, dung, or kerosene. Such exposure has been associated with chronic bronchitis and COPD. Guarnieri and colleagues showed that something as simple as a vented stove can decrease gene expression for markers of inflammation in sputum. (For more information, see Chapter 74 .)
Environmental Controls.
In addition to active and secondary smoke exposure, allergens and air pollutants may have an impact on COPD. Catastrophic air pollution events in the Meuse Valley, Donora, and London speak to the potential for air quality to impact people with lung disease. In addition, a growing body of evidence suggests that long-term exposure to even low levels of air pollution increase the risk for COPD. Also, people with COPD who also have allergic disease have higher levels of respiratory symptoms and are at higher risk for COPD exacerbations. As a consequence, people with COPD should avoid noxious exposures, heed air quality warnings, and be cautious of ongoing occupational exposures.
Prevention of Respiratory Infections.
A significant proportion of COPD exacerbations are triggered by respiratory infections. Although there are some data to suggest that patients with COPD are more susceptible to respiratory infections because of impaired mucociliary clearance, a more important issue is that those with COPD are more susceptible to the consequences of respiratory tract infections. As a general rule, every patient with COPD should be immunized annually against influenza, which is effective at reducing the incidence of influenza regardless of the severity of COPD, and has been demonstrated to reduce mortality in older adults. In addition all should be vaccinated against S. pneumoniae . Despite a belief that older patients with COPD might not respond well to immunization, pneumococcal vaccines have been shown to work in this population. Chronic antibiotics for prophylaxis are not a part of standard care for COPD because early trials showed they were not useful. However, more recent trials with erythromycin and moxifloxacin have demonstrated a reduction in exacerbations. There has been a particular interest in macrolide antibiotics, because of their demonstrated value in diffuse panbronchiolitis and in cystic fibrosis, and because they may have anti-inflammatory as well as antimicrobial properties. In a prospective, randomized, double-blind trial of 1142 patients with exacerbation-prone COPD, the National Heart, Lung, and Blood Institute’s COPD Clinical Research Network found that daily azithromycin for 1 year decreased the frequency of exacerbations by 27% and improved quality of life. Enthusiasm for this approach has been tempered by the small risk of ototoxicity and by the potential for QTc prolongation by macrolides. Data suggest that screening subjects for history of cardiac disease and obtaining ECGs prior to starting macrolides reduces the risk of cardiac rhythm disturbance. Thus, in selected patients who neither have cardiac disease nor take concomitant medications that affect the QTc interval and who experience frequent exacerbations with the attendant morbidity and mortality, the small risk of azithromycin is probably warranted.
Prevention of Exacerbations.
Exacerbations of COPD are sentinel events and are closely associated with disease progression. Increasing severity of COPD is associated with increased exacerbations and need for hospitalization, but for every stage of severity, severe exacerbations are associated with increases in short-term and long-term all-cause mortality. Exacerbations have an independent negative effect on prognosis, and mortality increases with the frequency of hospitalizations. In one study of 305 men with COPD, only 20% to 30% of patients who were readmitted for exacerbations survived 5 years. Although supporting data are lacking, the hope is that, by preventing exacerbations, lung function may be preserved and deterioration prevented. ICS, long-acting β-agonists, long-acting muscarinic antagonists, and macrolide antibiotics have all been shown to reduce exacerbations. Unfortunately, even patients taking these medications may still experience as many as 1.4 exacerbations per year.
Pharmacotherapy
The goal of treatment was once primarily symptom relief. Now that goal includes an attempt to improve lung function or slow the loss of lung function, and to prevent exacerbations. Most medications for COPD are administered by inhalation. Standard therapy consists of inhaled bronchodilators, either β-agonists or antimuscarinics (anticholinergics), and ICS. Oral agents, used less commonly, include methylxanthines (e.g., theophylline), phosphodiesterase-4 inhibitors (e.g., roflumilast), and corticosteroids (prednisone or prednisolone).
The choice of medications should be based on an assessment of the severity of airflow obstruction, symptoms, frequency and severity of exacerbations, and patient’s functional limitation, as well as on the availability and local cost of medications. Formerly, medication decisions were based primarily on severity of airflow obstruction; guidelines now, as exemplified by GOLD, emphasize a metric that includes obstruction (GOLD grade), based on FEV 1 percent predicted (see Table 44-2 ), symptoms (based on either the Medical Research Council dyspnea scale or the COPD Assessment Test ), and risk of exacerbations. Using this tool, patients can be categorized into class A, B, C, or D ( Fig. 44-8 ), and GOLD provides specific treatment recommendations for each category ( Table 44-3 ).
| Patient Group | Recommended First choice | Alternative Choice | Other Possible Treatments † |
|---|---|---|---|
| A | SAMA prn or SABA prn | LAMA or LABA or SABA and SAMA | Theophylline |
| B | LAMA or LABA | LAMA and LABA | SABA and/or SAMA Theophylline |
| C | ICS + LABA or LAMA | LAMA and LABA or LAMA and PDE4-inh . or LABA and PDE4-inh. | SABA and/or SAMA Theophylline |
| D | ICS + LABA and/or LAMA | ICS and LABA and LAMA or ICS and LABA and PDE4-inh. or LAMA and LABA or LAMA and PDE4-inh . | C arbocysteine SABA and / or SAMA Theophylline |
* Medications in each box are mentioned in alphabetical order, and therefore not necessarily in order of preference.
† Medications in this column can be used alone or in combination with other options in the Recommended First Choice and Alternative Choice columns.
Bronchodilators
Bronchodilators are recommended for all patients with COPD. Pharmaceutical classes of bronchodilators include β-agonists, antimuscarinics (anticholinergics), and methylxanthines. Unlike asthma, where bronchodilator reversibility is part of the definition, airflow obstruction in COPD is often thought of as “irreversible.” This is not, however, completely true. Although the diagnosis of COPD requires airflow obstruction that persists after bronchodilators, most patients with COPD demonstrate some improvement in spirometry. This response can vary from day to day. In one study of 1552 patients with COPD who were tested with albuterol, ipratropium, or the combination on four occasions over 3 months, only 37% to 56% had 15% or better improvement in FEV 1 on all four test dates, but 90% or more had greater than or equal to 15% reversal on at least one occasion. Therefore, even patients who do not respond to bronchodilator testing in the pulmonary function laboratory should be given a clinical trial of bronchodilators. Although the increase in FEV 1 may be modest, it may be sufficient to improve lung emptying and, by this mechanism, reduce dynamic hyperinflation. In multiple studies, bronchodilators have been shown to reduce dyspnea and increase exercise tolerance in patients with chronic stable COPD.
β-Adrenergic Agonists
These medications bind directly to β-receptors located on airway smooth muscle and dilate the airway. Less prominent effects include increased ciliary beat frequency that promotes mucus transport along the mucociliary escalator and improved respiratory muscle endurance. β-agonists are available in both short-acting and long-acting preparations, and can be administered by inhalation, orally, subcutaneously, or intravenously. For treatment of COPD, β-agonists should only be given as inhaled aerosols, because the other routes are associated with an unacceptably high risk of systemic adverse effects.
Short-acting beta agonists (SABAs) include albuterol (salbutamol), levalbuterol, terbutaline, and fenoterol. Albuterol is a racemic mixture of both (R)- and (S)-enantiomers of albuterol; levalbuterol is the (R)-enantiomer alone. The (R)-enantiomer is thought to be responsible for bronchodilation while the (S)-enantiomer is believed to cause tremor, tachycardia, and perhaps airway inflammation. Thus, levalbuterol would be expected to be better tolerated than albuterol. In fact, for most patients with stable COPD who use their short-acting β-agonist for symptom management, the added advantage of levalbuterol over albuterol is probably not significant. Albuterol is also available in combination with ipratropium (a muscarinic antagonist). Terbutaline inhalers are no longer sold in the United States; fenoterol is available in many parts of the world, but not in the United States.
Short-acting β-agonists for inhalation are available in solution for administration by nebulizer, as well as by metered-dose inhaler and dry powder inhaler (DPI). The combination of albuterol and ipratropium is available in a soft mist inhaler. Many studies have shown that metered-dose inhalers, DPIs, and soft mist inhalers are as effective as nebulizers in patients who are able to use the devices properly. Unfortunately, the proper technique for using different devices is not the same, and patients need detailed instruction and periodic assessment of their technique. In addition, DPIs require a much higher inspiratory flow than do metered-dose inhalers and some patients with moderate-to-severe COPD may not be able to generate adequate flows. For these individuals and for those whose medical or mental status makes coordinated breathing efforts difficult, nebulized β-agonists may be preferable.
The major advantage of short-acting β-agonists is their rapid onset of action, within 5 to 15 minutes after inhalation. Their effects last for 2 to 6 hours. As noted earlier, most patients with COPD demonstrate a modest improvement in FEV 1, and many studies and meta-analyses support their use for COPD. The combination of albuterol and ipratropium results in greater and more sustained improvement in lung function than either drug alone. When used at the recommended doses, inhaled short-acting β-agonists are thought to be safe. The major adverse effects include tremor, anxiety, tachycardia, and hypokalemia. A recent retrospective case-control cohort study of more than 70,000 patients with COPD from Quebec suggested that the new use of short- or long-acting beta agonists was associated with increased risk for arrhythmias, but the study did not account for multiple potential confounders. Adverse effects are dose-dependent and are less common with inhaled compared with systemic dosing, and when inhaler technique is optimized. Fortunately, tachyphylaxis to the systemic side effects of β-agonists is greater than tachyphylaxis to the bronchodilator effect.
Long-acting β-agonists (LABAs) typically produce bronchodilation that lasts for 12 hours or more. Salmeterol was the first LABA to be studied extensively. Its onset of action is much slower than that of albuterol, on the order of 20 to 30 minutes. Formoterol has a similar duration of action, but an onset of action that is nearly identical to albuterol. Both salmeterol and formoterol must be taken twice daily. Arformoterol is the (R)-enantiomer of formoterol. Indicaterol has a rapid onset and a duration of action of nearly 24 hours, and thus requires only once daily dosing. The bronchodilator effect of indicaterol is greater than that of salmeterol or formoterol. Vilanterol is another LABA with a rapid onset of action and a duration of action of approximately 24 hours. It is not used as monotherapy, but has recently been approved in the United States and in Europe for use in combination with the ICS fluticasone.
Many studies have demonstrated a benefit of LABAs in patients with stable COPD. Salmeterol and formoterol significantly improve lung function, dyspnea, quality of life, and the rate of exacerbations. Salmeterol has been shown to reduce hospitalizations. Indicaterol improves dyspnea and health status, and reduces exacerbations. The adverse effects reported with LABAs are similar to those described for short-acting β-agonists. Of note, the association of LABA use with deaths that raised concern in the asthma community (see Chapter 42 ) has not been seen for COPD, and monotherapy with an LABA appears to be both safe and efficacious.
LABAs are frequently combined with an ICS in the same inhaler, and currently available preparations include salmeterol/fluticasone, formoterol/budesonide, formoterol/mometasone, and vilanterol/fluticasone. Many studies have shown that combination therapy is often more effective than either agent alone, and various guidelines provide recommendations for how and when to escalate treatment beyond short-acting bronchodilators.
Antimuscarinics
Antimuscarinics, also known as anticholinergics or muscarinic antagonists, block the effects of acetylcholine on M3 muscarinic receptors on airway smooth muscle. Anticholinergics were used historically, long before β-agonists, in the form of stramonium and belladonna alkaloids, then atropine. The newer quaternary amines such as ipratropium and glycopyrrolate, as well as tiotropium and aclidinium, are better tolerated because they do not cross the blood-brain barrier. In addition, both tiotropium and aclidinium have pharmacokinetic selectivity for the M3 receptor and dissociate more rapidly from M2 receptors, which are found on cholinergic nerve terminals and inhibit acetylcholine release. Thus, the relative lack of M2 binding by these muscarinic antagonists may allow acetylcholine to bind to M2 receptors, thereby inhibiting further acetylcholine release and reducing bronchoconstriction.
Short-acting muscarinic antagonists (SAMAs) include ipratropium and oxitropium. They increase FEV 1 with an onset of action of 10 to 15 minutes and a duration of action of 4 to 6 hours. Ipratropium improves lung function, increases exercise capacity, decreases dyspnea, and decreases cough. The magnitude of bronchodilation with ipratropium is comparable to that seen with albuterol but, when used in combination, their effects are additive and the duration is longer.
Long-acting muscarinic antagonists (LAMAs) include tiotropium and aclidinium, which are slower in onset than ipratropium, but last longer, with bronchodilation lasting at least 12 hours after aclidinium and more than 24 hours after tiotropium. In the United States, tiotropium is available as the HandiHaler DPI; in Europe, it is available as a soft-mist inhaler (RespiMat). Aclidinium is provided in a DPI that registers when a dose is inhaled. Tiotropium decreases symptoms, improves health status, and reduces exacerbations by 20% to 25% and hospitalizations. It appears to improve the effectiveness of pulmonary rehabilitation, perhaps by decreasing dynamic hyperinflation. When compared head-to-head with salmeterol, tiotropium increased time to first exacerbation and reduced the annual rate of exacerbations more than did salmeterol. Although less data are available for aclidinium, its effects on lung function and on dyspnea appears to be similar to those of tiotropium.
In general, both short- and long-acting muscarinic antagonists have good safety profiles. The most common side effects are dry mouth and urinary retention. Medication that contacts the eye, either by hand contact or by aerosolization, can cause blurred vision and can precipitate glaucoma. A retrospective database review and a meta-analysis of ipratropium and tiotropium in COPD suggested that anticholinergic therapy was associated with an increased risk of cardiovascular death, myocardial infarction, and stroke. However, a prospective study of almost 6000 patients with COPD who were treated with tiotropium or placebo found no increased risk of cardiovascular events or mortality, and a long-term study of more than 17,000 patients with COPD, designed specifically to examine safety, concluded that tiotropium administered by the new soft-mist Respimat device had a safety profile similar to tiotropium delivered by the current DPI HandiHaler device in patients with COPD and was not associated with an increased risk of death.
Methylxanthines
Methylxanthines are nonselective inhibitors of phosphodiesterase, and by this mechanism have a modest bronchodilator effect. Theophylline is the most commonly used methylxanthine and, in stable COPD, its effect is greater than that of placebo but less than that of LABAs or LAMAs. In addition to its bronchodilator effect, theophylline is reported to improve inspiratory muscle function and to have anti-inflammatory effects. Its effect on reducing symptoms is greater than its effect on airway function, suggesting that these alternative mechanisms may be important. Because theophylline is a nonselective phosphodiesterase inhibitor, its actions are not all beneficial. The major adverse effects are insomnia, nausea, vomiting, cardiac arrhythmias, and seizures. These toxicities are dose-dependent, but the onset of severe adverse events (e.g., ventricular arrhythmias, seizures) may not be preceded by nausea or insomnia. In addition, blood levels are affected by age, by liver disease, by congestive heart failure, and by many drug interactions. To minimize toxicity, current guidelines recommend target blood levels of 5 to 10 µg/mL rather than 15 to 20 µg/mL as was done previously. Because of its narrow therapeutic index and modest benefits, theophylline is not recommended as a first line drug, but can serve as an alternative for patients intolerant of LABAs and LAMAs or in settings where these drugs are too expensive.
Phosphodiesterase-4 Inhibitors
Phosphodiesterase-4 (PDE-4) inhibitors act by blocking the breakdown of cyclic adenosine monophosphate. By this mechanism, they decrease airway inflammation; they have no direct bronchodilator activity. Roflumilast is an oral PDE-4 inhibitor that has been approved for patients with chronic bronchitis and a history of exacerbations. In a meta-analysis of 23 randomized trials of two different PDE-4 inhibitors (roflumilast and cilomilast), the PDE-4 inhibitors reduced exacerbations (OR 0.78, 95% CI 0.72 to 0.85) and produced a modest increase in FEV 1 (50 mL, 95% CI 39 to 52). When roflumilast was added to salmeterol or tiotropium, the prebronchodilator FEV 1 increased. Because its effect on exacerbations is much greater than its effect on airway function, guidelines recommend that roflumilast be used in combination with a long-acting bronchodilator. Use of PDE-4 inhibitors has been limited by side effects. The most common are nausea, anorexia, abdominal pain, diarrhea, weight loss, sleep disturbances, and headache. Monitoring weight during treatment is warranted.
Corticosteroids
Inhaled Corticosteroids.
Airway as well as systemic inflammation are critical components of the pathogenesis of COPD. Therefore, corticosteroids, with their anti-inflammatory effects, are an appealing intervention. ICS offer the additional advantage of minimizing systemic exposure. Early studies of ICS sought unsuccessfully to alter the natural history of COPD. However, ICS have been shown to improve symptoms, lung function, and quality of life, and to reduce the frequency of COPD exacerbations, especially in patients with an FEV 1 less than or equal to 60% of predicted. The improvement in FEV 1 achieved with ICS (50 to 100 mL) is typically less than that observed with bronchodilators. The reduction of exacerbations by ICS is more significant and is comparable to that observed with LABAs or LAMAs (approximately 20% to 25%). Guidelines recommend that ICS be used in combination with a long-acting bronchodilator in subjects who are prone to exacerbations, but that they not be used as monotherapy. Four large trials in which patients with COPD were treated with ICS for 3 to 5 years failed to reduce the loss of lung function over time. However, in a post hoc analysis of the TORCH trial in which 6112 subjects with moderate-to-severe COPD were randomly treated for 3 years with placebo, fluticasone, salmeterol, or the fluticasone/salmeterol combination, Celli and colleagues reported that each active treatment arm reduced the rate of decline in FEV 1 . Whether this benefit reflects the reduction in exacerbations or a more direct effect on the airway, perhaps by decreasing inflammation, is not known.
ICS are relatively safe, especially in comparison to systemic corticosteroids. The most common adverse effects are oral candidiasis (thrush) and dysphonia, both of which can be minimized by careful inhalation technique followed by rinsing the mouth and gargling. Increased skin bruising is probably a manifestation of capillary fragility. Reduced bone density has been reported after long-term treatment with triamcinolone, but studies with budesonide and fluticasone have not found similar results, perhaps because these patients with COPD had a high prevalence of osteoporosis at baseline. Finally, although ICS clearly reduce the frequency of exacerbations in COPD, they have been associated with an increased incidence of pneumonia.
Systemic Corticosteroids.
With rare exceptions, the use of systemic corticosteroids should be reserved for the treatment of exacerbations. In patients with stable disease, even when severe, the risk of adverse effects is probably greater than the likelihood of benefit. Chronic use of systemic corticosteroids is associated with increased mortality, which may reflect corticosteroid effects or the underlying severity of the COPD. Occasionally, in exacerbation-prone patients who require frequent courses of high dose systemic corticosteroids, a very low daily dose of corticosteroids may protect against exacerbations and thereby reduce the total annual steroid exposure. If this unusual approach is followed, the lowest possible dose of corticosteroids should be used. Spirometric stability may be useful in encouraging patients who are experiencing nonpulmonary benefit that dose reduction is safe.
Combination Therapy
Patients who remain symptomatic after a period of treatment with a single long-acting bronchodilator (either LABA or LAMA) may benefit from addition of a second drug. Choices include either an ICS or a second long-acting bronchodilator from the other pharmacologic class; literature to inform this decision is not clear. ICS should probably be considered as the first addition in patients with evidence of airway inflammation and those with frequent exacerbations. In two large trials, combination therapy improved outcomes significantly compared to each of the other treatment arms alone (placebo LABA, ICS, LAMA). In the TORCH trial of 6112 patients with moderate-to-severe COPD, the combination of salmeterol/fluticasone improved lung function, health status, and exacerbations more than either agent alone and was cost effective. In the INSPIRE trial, 1323 patients with severe COPD were randomly treated with salmeterol/fluticasone or tiotropium for 2 years. There was no difference in exacerbations, but mortality was less in the salmeterol/fluticasone group and health status was better. Pneumonia was more frequent in the salmeterol/fluticasone group. Combinations of formoterol/budesonide, formoterol/mometasone, and vilanterol/fluticasone have also been shown to improve some clinical outcomes.
While many studies have compared the ICS/LABA combination to its individual components, fewer studies have compared ICS/LABA to LABA/LAMA. Rabe and colleagues randomized 592 patients with moderate-to-severe COPD to tiotropium/formoterol or fluticasone/salmeterol. After 6 weeks, FEV 1 was larger in the tiotropium/formoterol group and the use of rescue medications did not differ.
Finally, guidelines suggest “triple inhaler therapy” for subjects whose symptoms are not controlled by any of the combinations already described. This recommendation is in part empirical, because each of the drugs or combinations have been shown to be effective. However, several retrospective cohort studies have described decreased mortality, and fewer exacerbations and hospitalizations with triple therapy. The only prospective data comes from the UPLIFT trial, in which patients were randomized to receive “usual care” with or without tiotropium. In those patients who were already taking an ICS and a LABA (two thirds of the group), the addition of tiotropium significantly improved lung function, reduced exacerbations, and improved health-related quality of life. Further studies are needed to define the role of triple-therapy.
Stepwise Pharmacologic Management
We have made enormous progress from the time, not long ago, when we had few drugs for COPD in our therapeutic armamentarium. Now there are many pharmaceutical categories that have been shown to improve outcomes in COPD. Often there are many choices within each drug class, and a variety of ways to progress through a therapeutic algorithm. The GOLD guidelines provide a framework for making these decisions.
In the past, recommendations for pharmacologic treatment were based primarily on spirometry, and Table 44-2 shows the GOLD classification scheme based on lung function. Recognizing that FEV 1 alone is a poor descriptor of disease status, the GOLD committee revised the approach to include symptoms and future risk of exacerbations, in addition to lung function (see Fig. 44-8 ). Based on these three variables, patients are assigned to groups A, B, C, or D, and recommendations for initial management are provided for each group (see Table 44-3 ).
Antioxidants and Mucolytics
Increased mucus production by hypertrophied and hyperplastic airway submucosal glands and goblet cells, together with impaired mucociliary clearance and cough are frequent in patients with COPD. Although mucolytics have been evaluated in a number of long-term studies in COPD, the results are mixed and, in those studies demonstrating benefit, the effect is modest. N-acetylcysteine (NAC) is a mucolytic and antioxidant that has been tested for its ability to slow the decline in lung function and prevent exacerbations. In the BRONCUS study, 523 patients at 50 centers were randomly assigned to 600 mg NAC or placebo daily. Patients were followed for 3 years. Neither the yearly rate of decline in FEV 1 nor the number of exacerbations per year differed between the NAC and the placebo group. However, subgroup analysis of those subjects who were not treated with an ICS suggested that NAC reduced exacerbations and hyperinflation. A Cochrane review of 30 trials that included more than 7000 patients treated with NAC or other mucolytics concluded that there was a small effect on exacerbations, but no effect on quality of life. In its 2014 revision, the GOLD panel advised against the widespread use of these agents.
Leukotriene Modifiers
Although the 5-lipoxygenase inhibitor zileuton and the cysteinyl leukotriene antagonists montelukast and zafirlukast are sometimes used for COPD, there are no data to support their use and guidelines do not recommend their use.
Nonpharmacologic Treatment
Mucus Clearance
In patients with mucus hypersecretion and airflow obstruction, it may be very difficult to mobilize secretions. Maneuvers such as controlled cough and the huff cough can be helpful. In the former, patients take a deep breath, hold their breath for a few seconds, then cough two or three times with their mouth open and without taking another breath. The sequence is then repeated several times. Huff coughing involves one or two forced expirations starting at mid-lung volume and performed with the glottis open. Mucus clearance can also be facilitated by having patients breathe or cough through a device that generates high amplitude oscillations, or with an external percussive device. These maneuvers are considered safe, but data supporting their use is limited.
Oxygen
Two landmark studies conducted more than 30 years ago demonstrated the value of long-term oxygen therapy in patients with COPD and hypoxemia. The National Institute of Health’s Nocturnal Oxygen Therapy Trial (NOTT) randomized 203 patients with COPD and hypoxemia to receive oxygen either for 12 hours overnight or for 24 hours/day for at least 12 months. Overall mortality in the nocturnal oxygen group was 1.94 times that in the continuous oxygen group ( P = 0.01). Almost simultaneously, the British Medical Research Council compared the effect of oxygen administered for 15 hours/day with no oxygen (control) in 87 patients with COPD, hypoxemia, carbon dioxide retention, and heart failure. Forty-five percent of the oxygen-treated patients died during the 5-year follow-up period compared with 67% of the control group. In addition to this survival benefit, administration of oxygen for at least 15 hours per day improves quality of life and neuropsychiatric metrics, reduces erythrocytosis, and improves pulmonary hemodynamics in patients with COPD and hypoxemia.
Indications for Oxygen.
Based on these data, guidelines recommend long-term administration of oxygen (>15 hours/day) to patients with COPD with resting hypoxemia. Criteria include arterial P o 2 less than 55 mm Hg, or arterial S o 2 less than 88% while breathing room air at rest. For those whose resting arterial P o 2 is between 56 and 59 mm Hg, long-term oxygen treatment is indicated if they demonstrate erythrocytosis (hematocrit ≥ 55%) or cor pulmonale. Following an exacerbation or another acute respiratory event, patients often have hypoxemia that resolves slowly over 1 to 2 months. For this reason, patients given oxygen as they are recovering should be reevaluated after approximately 1 month to determine if they continue to meet criteria for long-term oxygen treatment.
Oxygen During Exercise.
Patients whose arterial P o 2 or Sp o 2 are borderline at rest may develop worsening hypoxemia with exercise. This is especially true for patients with emphysema and a low diffusing capacity. Supplementary oxygen improves exercise endurance, and even patients without hypoxemia may improve their exercise capacity with supplementary oxygen. However, long-term benefits of oxygen in this patient group are unknown. The National Heart, Lung, and Blood Institute is sponsoring the Long-term Oxygen Treatment Trial (LOTT) that will examine mortality, hospitalizations, quality of life, and a variety of other outcomes in 737 patients with COPD and Sp o 2 between 89% and 93% at rest, or greater than 94% at rest with a desaturation to less than 90% with exercise.
One of the goals of oxygen therapy is to permit patients to remain active. Ambulatory oxygen systems are intended to provide a lightweight, portable source of oxygen that can be carried as the patient pursues activities of daily living. Unfortunately, patients are often provided with “portable” systems that are not really conducive to ambulation. The standard E-cylinder, for example, weighs 22 pounds and must be pulled along on a bulky wheeled cart. Various lightweight oxygen reservoirs do exist, weighing as little as 4 pounds; portable oxygen concentrators are another lightweight option. Health care providers must specify to oxygen vendors which ambulatory system they want for their patients.
Oxygen During Sleep.
Just as they do with exercise, patients with COPD may experience a significant drop in arterial oxygen tension during sleep, due to a combination of increases in ventilation-perfusion mismatch and a change in ventilatory pattern. In patients who are not hypoxemic at rest, the long-term consequences of these episodes of nocturnal hypoxemia are unknown, as are the benefits of long-term oxygen for these patients. Although many clinicians prescribe nocturnal oxygen for these patients, there is no evidence to support this approach. The LOTT trial will provide information on this clinical subgroup.
Oxygen for Air Travel.
When flying at altitudes greater than 12,000 feet, aircraft are pressurized to protect passengers and crew from hypoxemia and other manifestations of altitude sickness (see Chapter 77 ). The Federal Aviation Administration (FAA) mandates that the cabin altitude must not exceed 8000 ft. Although this pressurization is sufficient to prevent most barotrauma and altitude sickness, it does not eliminate the possibility of hypoxemia. Arterial P o 2 will drop and in patients who are hypoxemic at rest at sea level or those who are borderline, the arterial P o 2 may fall to dangerous levels at altitude. Patients whose resting arterial P o 2 at sea level is greater than 70 mm Hg are likely to be safe to fly without supplementary oxygen. When there is uncertainty about a patient’s potential oxygen requirement at altitude, an altitude simulation test can be performed, using 16% oxygen to simulate the partial pressure of oxygen at 8000 feet.
For patients who require in-flight oxygen, arrangements must be made with the airline in advance. In general, patients may not bring their own oxygen supply, and airlines usually charge for the oxygen they provide. Lightweight portable oxygen concentrators have become available in recent years, and these are approved by the FAA for commercial air travel. Some airlines allow passengers to travel with their own concentrators.
Technical Issues for Oxygen Use
Most patients receive oxygen via a nasal cannula. Flow rates should be adjusted to achieve an Sp o 2 greater than 90% (arterial P o 2 > 60 mm Hg). In general, patients who use oxygen 24 hours/day should increase the oxygen flow by 1 L/min during sleep and exercise, to prevent falls in arterial P o 2 during these periods. Oxygen conserving devices that improve the efficiency of oxygen delivery increase the time that a given volume of portable oxygen will last, allowing patients greater mobility. These include nasal cannulae with reservoirs that store oxygen during exhalation for delivery during inhalation, as well as breath-activated regulators that deliver an oxygen pulse only during inspiration. For use in the home, electric-powered oxygen concentrators are the most convenient, for they do not require refilling or replacement as is the case with gas cylinders or liquid oxygen. It is important that patients who depend on a concentrator have back up cylinders on hand, in case of a power failure. Ambulatory systems include E-cylinders on wheeled carts, lightweight aluminum cylinders, liquid oxygen reservoirs, and portable concentrators. Many of these ambulatory systems weigh less than 10 pounds and provide oxygen for 4 to 6 hours at a flow of 2 L/min.
Pulmonary Rehabilitation
Pulmonary rehabilitation is a comprehensive program that combines exercise training, smoking cessation, nutrition counseling, and education, in an attempt to improve the functional capacity and quality of life of patients with COPD. Formal rehabilitation programs have been shown to improve exercise capacity and quality of life, and to decrease dyspnea and health care utilization. In addition, a recent Cochrane review suggests that pulmonary rehabilitation decreases mortality. Pulmonary rehabilitation should be offered to all patients with COPD who are symptomatic (see Chapter 105 ).
Surgical Treatment of Emphysema
More than 50 years ago, anecdotal reports of symptomatic improvement in patients with emphysema who underwent resection of concomitant lung cancers or bullae led physiologists to consider lung volume reduction surgery (LVRS) to improve the mechanical efficiency of respiratory muscles. Because of hyperinflation, respiratory muscles are forced to operate on the disadvantageous part of the length-to-tension curve; reducing hyperinflation was predicted to improve force generation by respiratory muscles, to improve lung elastic recoil, and to improve expiratory flow rates. Unfortunately, early procedures were associated with an unacceptably high mortality rate. In 1995, Cooper and colleagues reported on their experience with 20 patients who underwent bilateral LVRS. By using a linear stapling device and strips of bovine pericardium to minimize air leak through the staple holes, they were able to eliminate this major cause of early mortality, and reported very impressive improvements in FEV 1 , arterial P o 2 , 6MWD, dyspnea, and quality of life. This was followed by the National Emphysema Treatment Trial (NETT), a precedent-setting collaborative effort of the Centers for Medicare and Medicaid Services, the National Heart, Lung, and Blood Institute, and the Agency for Healthcare Research and Quality. NETT enrolled 1218 patients with severe emphysema and compared LVRS to maximal medical treatment. In patients with upper lobe predominant emphysema and a low post-rehabilitation exercise capacity, LVRS improved survival and quality of life. In those patients with FEV 1 less than or equal to 20% predicted and either homogeneous distribution of emphysema or D l CO less than or equal to 20% predicted, mortality was greater with LVRS compared to medical management. These criteria are currently used to select patients for LVRS.
In an attempt to minimize risk, several groups have developed techniques for bronchoscopic lung volume reduction. Using a flexible bronchoscope, one-way endobronchial valves are placed in airways that lead to emphysematous areas of the lung. In the presence of intact interlobular fissures (and thus little collateral ventilation), air leaves and cannot reenter these areas, causing them to collapse. As a result, hyperinflation is less, and more ventilation goes to more normal lung. The largest prospective trial to date described modest improvements in lung function, 6MWD, and symptoms, but this was associated with more frequent exacerbations of COPD, more pneumonia, and hemoptysis after implantation. The role of endobronchial valves for emphysema remains to be determined, and studies are ongoing to define the best valve design, the best technique, and the most appropriate patient population.
Acute Exacerbations
Definition
Perhaps surprisingly, it has not been easy to define an acute exacerbation of COPD. GOLD states, “An exacerbation of COPD is an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication.” This works sufficiently well that it allows for classification of events in various studies and for comparisons across trials.
Triggers
Exacerbations of COPD are precipitated most often by respiratory tract infections. These may be viral or bacterial. Recent data suggest that a key event, even in individuals whose airways are chronically colonized by bacteria, is the acquisition of bacterial strains that are new to that patient. Many patients are sensitive to air pollutants and suffer an exacerbation when ambient levels increase. In perhaps 30% of patients with COPD, no cause for exacerbations can be identified. Interestingly, some patients have an exacerbation whenever one of these events takes place; others rarely do. Those who experience two or more exacerbations per year are often defined as “frequent exacerbators” and pose a unique challenge for management.
Treatment
The goal of treatment is to minimize the impact of the current exacerbation, to minimize loss of lung function, and to prevent the development of subsequent exacerbations. The vast majority of exacerbations can be managed without hospitalization. Indications for hospitalization include severe dyspnea or respiratory insufficiency, severe underlying COPD, serious comorbidities, frequent exacerbator phenotype, older age, and insufficient support at home. Supplemental oxygen should be administered if necessary, to achieve an Sp o 2 greater than 88%. After 30 to 60 minutes, arterial blood gases should be assessed for evidence of carbon dioxide retention.
Bronchodilators.
During an acute exacerbation, short-acting β-agonists should be used aggressively, alone or in combination with muscarinic antagonists. Although metered dose inhalers, when used correctly, can be as effective as nebulizers, it can be difficult for severely dyspneic patients to coordinate their efforts to use a metered-dose inhaler, or to generate sufficient inspiratory flow required for some devices.
Corticosteroids.
Substantial data support the use of systemic corticosteroids for treatment of exacerbations of COPD. Their use is associated with a more rapid recovery, improvement in lung function and hypoxemia, and a reduced risk of relapse. Guidelines recommend 40 to 60 mg prednisone per day for 2 weeks, but a recent prospective trial of more than 300 patients found that 5 days of prednisone was not inferior to 14 days of prednisone for preventing reexacerbation within 6 months and was associated with a significantly lower total corticosteroid exposure.
Antibiotics.
The use of antibiotics for exacerbations of COPD is somewhat controversial, largely because of the paucity of data documenting bacterial colonization or infection. Studies have suggested that nearly 50% of acute exacerbations are associated with H. influenzae, S. pneumoniae, and M. catarrhalis. Even when patients are chronically colonized, changes in strain may be associated with exacerbations. Sputum cultures are of limited utility because they do not distinguish between colonization and infection, and because of the time required for results. Most guidelines recommend empirical treatment when infection seems likely, based on what are sometimes called the “Anthonisen criteria”: increased dyspnea, sputum volume, and sputum purulence, with greater weight given to meeting all three criteria. The recommended length of antibiotic treatment is 5 to 10 days.
Development of New Treatments
Despite advances in recent years, treatment options for COPD are woefully inadequate. Other than smoking cessation and supplementary oxygen in patients who are hypoxemic, there are no treatments that reduce mortality. Several factors have contributed to the lack of progress. COPD is highly heterogeneous: in some patients, emphysema predominates; in others, bronchitis predominates. Still others may have both. COPD is a systemic disease and, as a consequence, comorbid extrapulmonary conditions are common. Because treatment effects are small, very large studies are required to test potential new interventions. For all of these reasons, investigators are beginning to explore individual patient subtypes, looking for subpopulations that might benefit from unique therapeutic regimens, and for intermediate outcomes measures that might increase the efficiency of clinical trials. To this end, the National Heart, Lung, and Blood Institute has funded the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS), a prospective observational study of COPD subjects and controls. Complementary studies such as Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) and COPDGene will hopefully add to the explosion of knowledge in the next few years, aimed at improving treatment for patients with COPD.
