The mechanisms of airway obstruction in COPD include all of the following except

General Rx

•

Pharmacologic treatment (Table 3) should be administered in a stepwise approach (Fig. 5)according to the severity of disease and patient’s tolerance for specific drugs. When using the GOLD assessment criteria, pulmonary rehabilitation is recommended for patients in groups B, C, and D. Those in group A should receive a short-acting or long-acting anticholinergic or β2-agonist for mild intermittent symptoms. For patients in group B, long-acting anticholinergics or long-acting β2-agonists should be added, and both if symptoms persist on one drug. Patients in group C or D are at high risk of exacerbations and should receive a long-acting anticholinergic or a combination of either an inhaled corticosteroid and a long-acting β2-agonist or a long-acting anticholinergic and long-acting bronchodilator if symptoms persist. Patients in group D are more complicated and require individual management, multiple drugs, and consideration of roflumilast and azithromycin.

Bronchodilators improve symptoms, quality of life, and exercise tolerance and decrease incidence of exacerbations. Inhaled bronchodilatorsshould be offered for stable COPD patients with respiratory symptoms and FEV1 between 60% and 80% of predicted. Long-acting bronchodilators arerecommended for stable COPD patients with respiratory symptoms and FEV1 <60% of predicted. Recent guidelines from ACP, ACCP, ATS, and ERS recommend that clinicians prescribe monotherapy using either long-acting inhaled anticholinergics or long-acting inhaled β-agonists for symptomatic patients with COPD and FEV1 <60% of predicted. Clinicians should base the choice of specific monotherapy on patient preference, cost, and adverse effect profile. Long-acting inhaled bronchodilators are superior to short-acting bronchodilators when taken as needed.

Short-acting β2-agonists (e.g., albuterol metered-dose inhaler 1 to 2 puffs q4 to 6h prn) or short-acting anticholinergic agents (e.g., ipratropium inhaler 2 puffs qid) are acceptable in patients with mild, variable symptoms. Anticholinergics (antimuscarinic agents) are also effective and are available in combination with albuterol (e.g., Combivent). Long-acting inhaled agents (long-acting antimuscarinic agents [LAMAs]) are preferred in patients with mild to moderate or continuous symptoms. Currently available inhaled LAMAs are tiotropium (Spiriva), aclidinium (Tudorza), and glycopyrrolate (Seebri Neohaler, Yupelri). Tiotropium is an excellent long-acting bronchodilator. It is very effective for long-term, once-a-day use. It has been shown to be superior to salmeterol, an inhaled long-acting β-agonist (LABA) in patients with moderate to severe COPD and may possibly slow the rate of decline in FEV1. Some recent trials, however, have shown higher hospitalization rates and mortality with tiotropium compared to LABAs. Indacaterol, umeclidinium, olodaterol, and vilanterol are other available LABAs for long-term maintenance treatment of bronchospasm associated with COPD. LABAs should not be used with other sympathomimetic drugs, medications that can prolong the QT interval, or beta-blockers. LABAs and LAMAs in different combinations are now available on the market. Although LAMAs and LABAs perform equally well for symptom control, LAMAs are generally preferred for symptom control.

Addition of inhaled steroids (fluticasone, budesonide, triamcinolone) is used to reduce exacerbations in patients with moderate to severe COPD. Inhaled steroids are reserved for patients with either ≥2 exacerbations annually or FEV1 <50% of predicted. The role of inhaled corticosteroids (ICS) in COPD is controversial. Although some trials have demonstrated mild improvement in patients’ symptoms and decreased frequency of exacerbations, most pulmonologists believe that these drugs are ineffective in most patients with COPD but should be considered for patients with moderate to severe airflow limitation who have persistent symptoms despite optimal bronchodilator therapy. ICS therapy does not affect 1-yr all-cause mortality among patients with COPD and is associated with a higher risk of pneumonia.

Roflumilast is a selective oral PDE4 inhibitor useful to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. It is not a bronchodilator and is not indicated for the relief of acute bronchospasm.

Recent guidelines from ACP (American College of Physicians), ACCP (American College of Chest Physicians), ATS (American Thoracic Society), and ERS (European Respiratory Society) suggest that clinicians may administer combination inhaled therapies for symptomatic patients with stable COPD and FEV1 <60% predicted. They also recommend that clinicians should prescribe pulmonary rehabilitation for symptomatic patients with an FEV1 <50% predicted and continuous oxygen therapy in patients with COPD who have resting hypoxemia (Pao2 <55 mm Hg or Spo2 <88%).

Chronic antibiotic therapy: Chronic antibiotic therapy, specifically macrolides such as azithromycin, should be considered in patients with frequent acute exacerbations of COPD despite optimal therapy with bronchodilators and antiinflammatory agents.

Systemic glucocorticoid therapy: Chronic systemic glucocorticoid therapy is generally not recommended even in severe COPD due to associated increase in mortality and morbidity.

Triple therapy (LAMA plus LABA plus ICS [e.g., vilanterol, umeclidinium, and fluticasone {Trelegy Ellipta}]): Indicated in patients with COPD at high risk for exacerbations. A double-blind, parallel group, RCT (TRINITY) reported that treatment with extrafine fixed triple therapy reduced rates of moderate-to-severe exacerbation and improved baseline FEV1 at 52 wk as compared with tiotropium in patients with symptomatic COPD, FEV1 <50%, and a history of exacerbations. Another double-blind RCT (FULFIL) reported similar benefits of single-inhaler triple therapy compared with ICS/LABA therapy in patients with advanced COPD. The greatest benefit occurs in patients with eosinophilia or concomitant asthma. Unfortunately, many patients start triple therapy without clear indications and continue it after they no longer need it.

Acute exacerbation of COPD (increase in sputum volume and purulence, worsening dyspnea) can be treated with:

Aerosolized β2-agonists (e.g., metaproterenol nebulizer solution 5% 0.3 ml or albuterol nebulized 5% solution 2.5-5 mg).

Anticholinergic agents, which have equivalent efficacy to inhaled beta-adrenergic agonists. Inhalant solution of ipratropium bromide 0.5 mg can be administered every 4 to 8 hr.

Short courses of systemic corticosteroids have been shown to improve spirometric and clinical outcomes. Treatment failure occurs less often in patients who receive low-dose steroids than in those receiving high-dose parenteral steroids. Oral prednisone 40 mg/day for 5 to 14 days is generally effective. Courses of treatment that are extended for >14 days confer no added benefit and increase the risk of adverse events. Trials have shown that in patients with acute COPD exacerbations, systemic glucocorticoid treatment for 5 days is not inferior to treatment for 14 days.

Use of noninvasive positive pressure ventilation (NIPPV) decreases the risk of endotracheal intubation and decreases intensive care unit admission rates. Contraindications to its use are uncooperative patient, decreased level of consciousness, hemodynamic instability, inadequate mask fit, and severe respiratory acidosis. Increased airway pressure can be delivered by using inspiratory positive airway pressure, continuous positive airway pressure, or bilevel positive airway pressure, which combines the other modalities. When using NIPPV, the nasal mask is usually tolerated the best; however, patients must be instructed to keep their mouths closed while breathing with the nasal apparatus. Oxygen can be delivered at 10 to 15 L/min and started in spontaneous ventilation mode with an initial expiratory positive airway pressure setting of 3 to 5 cm H2O and an inspiratory positive airway pressure setting of up to 10 cm H2O. Adjustments in these settings should be made in 2-cm H2O increments. It is important to monitor patients with frequent vital signs measurements, arterial blood gases, or pulse oximetry. Intubation and mechanical ventilation may be necessary if previous measures fail to provide improvement.

IV aminophylline administration is controversial and generally not recommended. When used in patients with refractory symptoms, serum levels should be closely monitored (keep level 8-12 mcg/ml) to minimize risks of tachyarrhythmias.

Approximately 50% of COPD exacerbations are caused by bacterial infection. Antibiotics are indicated in suspected bacterial respiratory infection (e.g., increased purulence and volume of phlegm).

Haemophilus influenzae andStreptococcus pneumoniae are frequent causes of acute bronchitis.

Oral antibiotics of choice are azithromycin, levofloxacin, amoxicillin-clavulanate, trimethoprim-sulfamethoxazole, doxycycline, and cefuroxime.

The two best predictors of potential benefit from antibiotics are purulent sputum and C-reactive protein (CRP) level >40 mg/L.

Procalcitonin-based protocols to trigger antibiotic use are associated with significantly decreased antibiotic use without affecting clinical outcomes such hospital length of stay, treatment failure, and mortality.

Guaifenesin may improve cough symptoms and mucus clearance; however, mucolytic medications are generally ineffective. Their benefits may be greatest in patients with more advanced disease.

Fig. 6 illustrates the management of acute exacerbations of COPD. Guideline recommendations for hospital management ofCOPD exacerbations are described inTable 4. Indications for invasive mechanical ventilation are described inBox 1.

Lung volume reduction surgery has been proposed as a palliative treatment for severe emphysema. Overall it increases the chance of improved exercise capacity but does not confer a survival advantage over medical therapy. It is most beneficial in patients with both predominantly upper-lobe emphysema and low baseline exercise capacity.

Preliminary trials involving lung volume reduction using bronchoscopic treatment with nitinol coils have shown improved exercise capacity in patients with severe emphysema. Selection criteria for lung volume reduction surgery is described inTable 5.Box 2 summarizes indications and contraindications for lung volume reduction surgery and lung transplantation.

Endobronchial valve (EBV) placement (Zephyr valve) via bronchoscopy to reduce lung volume with one-way valves that are allowed to leave but not enter a lung segment is now FDA approved since June 2018.

Single-lung transplantation (Box 2) should be considered a surgical option in patients with end-stage emphysema who have an FEV1 <25% of predicted normal value after administration of bronchodilator and additional complications such as severe hypoxemia, hypercapnia, and pulmonary hypertension.

Introduction

Chronic obstructive pulmonary disease (COPD) is a disease of the airways and lungs that is characterized by a progressive airflow limitation, which is not fully reversible and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases (Global initiative for chronic obstructive pulmonary disease, 2011; Brusselle et al., 2011). Cigarette smoking is by far the most important risk factor for COPD. However, only 20% of smokers develop COPD, implicating genetic determinants of the disease. Indoor air pollution and exposure to dust and gases in the occupational environment are other known risk factors (Salvi and Barnes, 2009). COPD is currently the fourth leading cause of death in the world and causes a substantial economic and social burden (Pauwels and Rabe, 2004; Lopez et al., 2006). Pharmacotherapy for COPD decreases symptoms; however, none of the existing medications for COPD has been shown to modify the accelerated decline in lung function.

Despite significant heterogeneity of clinical presentation, exacerbation frequency and disease progression, airflow limitation – as measured by spirometry – is the main diagnostic indicator for COPD. The Global initiative for chronic Obstructive Lung Disease (GOLD) grades the severity of COPD according to the degree of lung function impairment from GOLD stage I (mild COPD) to IV (very severe COPD) (GOLD, 2014). In the recently updated GOLD guidelines, the classification of COPD has become more multi-factorial, based on the combination of spirometric classification, symptoms, exacerbation risk and presence of comorbidities. This combined COPD assessment now ranks COPD from category A (low risk, less symptoms) to D (high risk, more symptoms) (GOLD, 2014).

The pathology of COPD includes a variable mixture of small airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema) (Vestbo et al., 2012). Several pathophysiologic mechanisms have been implicated in the development and progression of COPD. First, the main hallmark of COPD is the amplified chronic pulmonary inflammation, which persists despite smoking cessation (Brusselle et al., 2011; Hogg and Timens, 2009). Cells of both the innate and the adaptive immune system participate in the inflammatory response in COPD (Figure 1). Second, release of proteinases in excess of their inhibitors plays an essential role in the development of pulmonary emphysema. This proteinase/antiproteinase imbalance hypothesis was first proposed over 40 years ago, based on the observations that smokers with a deficiency of α1-antitrypsin, the main inhibitor of neutrophil elastase, were at increased risk for pulmonary emphysema (Laurell and Eriksson, 1963). Third, oxidative stress, resulting from an imbalance between oxidants and antioxidants, not only amplifies the airway inflammation in lungs of smokers, but also may induce cell death (by apoptosis or necrosis) of alveolar epithelial and endothelial cells (Rahman and Adcock, 2006). This contributes to a fourth mechanistic concept, an imbalance between cell death and replenishment of lung structural cells, resulting in a loss of alveolar septa and development of emphysema. Moreover, cellular senescence due to aging of the lungs might further impair tissue repair upon repeated cigarette smoke (CS) exposure (Tsuji et al., 2004). More recently, autoimmunity has been proposed as a late pathogenic event in the progressive course of COPD (Cicko et al., 2010). Importantly, these diverse mechanisms do not operate separately, but interact with one another, leading to development and progression of COPD.

Abstract

Chronic obstructive pulmonary disease (COPD) is a worldwide health problem that is increasing in prevalence. This progressive lung condition is characterized by irreversible airflow obstruction, mostly attributable to smoking, although environmental and occupational exposures have a role. The degree of symptoms and functional limitation that COPD causes can vary from person to person, often resulting in late diagnosis. COPD-related morbidity leads to significant health-care utilization and cost. This article provides a comprehensive overview of COPD epidemiology, pathophysiology, diagnosis, and management and highlights the challenges facing patients and physicians in dealing with this global health issue.

Medications

Commonly used medications for the treatment of stable COPD are listed inFigure 3. The beta-agonists stimulate beta 2 receptors on airway smooth muscle, causing muscle relaxation and bronchodilation. The short-acting beta-agonists have onset of action in 1 to 3 minutes and duration of action 4 to 6 hours. Because of their quick onset and short duration of action, they are used as “rescue” or prn medications. Some long-acting beta-agonists also have rapid onset of action, but the duration of action is 12 to 24 hours. Potential side effects of beta-agonists include tremor, tachycardia, and, uncommonly, hypokalemia.

The antimuscarinic bronchodilators bind to muscarinic receptors, which are found on smooth muscle and submucosal glands. Two of these receptors, the M1 and M3 receptor, facilitate acetylcholine transmission which results in bronchoconstriction. Potential side effects of the antimuscarinics include dry mouth and urinary hesitancy. The beta-agonists and antimuscarinics have additive effects on bronchial smooth muscle. Inhaled corticosteroids decrease airway inflammation and have been shown to decrease the frequency of exacerbation of COPD. Unlike asthma, inhaled corticosteroids are not used as sole maintenance therapy in COPD. Potential side-effects of the inhaled corticosteroids include a small increase in risk of pneumonia and oral candidiasis. There are now many varieties of inhaler devices. Instruction in the use of the devices and observation of proper technique is necessary to ensure maximal benefit.

In the 2019 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (Figure 4) (https://www.guidelines.co.uk/respiratory/gold-copd-2019-strategy/454454.article), medication recommendations are dictated by a classification system based on symptom score and exacerbation history. Patients are categorized as having either zero or one exacerbation, not requiring hospitalization, or two or more exacerbations, or at least one exacerbation requiring hospitalization. Symptom severity is based on a symptom scoring scale, such as the COPD Assessment Test (Figure 5). On the COPD Assessment Test, the patient is asked a series of 8 questions, grading severity as 0 to 5. The sum of the scores is used to categorize the patient in the GOLD classification grid.

Patients in group A are given a trial of short- or long-acting bronchodilator. The medication is continued if the patient is determined to have benefitted from the intervention. Group B patients should be started on a long-acting bronchodilator, either LABA or LAMA. If the patient has continued dyspnea, LAMA and LABA may be used together. For patients with severe dyspnea, treatment may begin with both agents. Initial therapy for group C patients is a LAMA. For patients with persisting exacerbations adding a LABA is the primary choice. Adding an ICS would be a secondary choice. Recommended initial treatment for group D patients is a LABA/LAMA combination. Consideration could be given to initiating treatment with a LABA/ICS combination, in patients with prominent asthmatic symptoms or an eosinophil count ≥300 cells/microLiter. Patients with continuing exacerbations may be switched to a LABA/LAMA/ICS combination. In patients with persisting exacerbations on this treatment, the phosphodiesterase-4 inhibitor roflumilast (Daliresp) 500 mcg/day or prophylactic azithromycin (Zithromax)1 250 mg/day or 500 mg on Monday, Wednesday, and Friday have been shown to decrease the frequency of exacerbations.

Introduction

Chronic obstructive pulmonary disease (COPD) is a progressive condition characterized by irreversible airflow limitation. In general, this condition results from an abnormal inflammatory response after exposure of the lung to noxious particles and/or gases. Since the early nineteenth century, an association between smoke exposure and symptoms of chronic lung disease has been recognized. To date, cigarette smoke remains the most significant risk factor for developing COPD. A worldwide increase in smoking has led to a dramatic rise in the prevalence of this condition. Individuals with COPD typically complain of nonspecific symptoms that include chronic cough, mucus hypersecretion, and shortness of breath. The identification of patients with COPD is often complicated by the fact that symptoms develop late in the course of the disease. To increase awareness of this condition, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) was established in 1998. This program, a cooperation between the World Health Organization and the National Institutes of Health in the United States outlines strategies for the diagnosis, prevention, and treatment of COPD. In this article, we will discuss the pathogenesis of COPD and review current strategies for managing this condition.

Introduction

Chronic obstructive pulmonary disease (COPD) is a major and increasing global health problem, which at present is poorly treated as there are no drugs that significantly suppress the underlying disease process and therefore reduce the progression or mortality of the disease (Barnes, 2000).

The Global Initiative on Obstructive Lung Disease defines COPD as “a common preventable and treatable disease, characterized by persistent airflow limitation that is usually progressive and associated with an enhanced inflammatory response in the airways and lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients.” This definition stresses the progressive nature of COPD, encompasses the idea that it is a chronic inflammatory disease, and emphasizes that exacerbations are an important component and that COPD is often associated with comorbid diseases (Vestbo et al., 2013).

Mortality

Chronic obstructive pulmonary disease is the fourth leading cause of death in the United States and Europe and is projected to be the third leading cause of death (now fifth) worldwide by 2020, a result of the increase in smoking in the developing world and the changing demographics in those countries with increasing longevity of their populations. Large international variations in mortality for COPD cannot be entirely explained by differences in diagnostic patterns, diagnostic labels, or smoking habits. Death certification figures underestimate mortality because as previously stated, COPD is often cited as a contributory factor to the cause of death. COPD death rates are low under age 45 and increase steeply with age. Although mortality from COPD in men has been falling slightly, mortality in women has increased. U.S. data (2000-2005) indicate that COPD accounts for 5% of all deaths, with age-standardized mortality rate stable at approximately 64 deaths per 100,000 population; however, mortality in males fell from 83.8 in 2000 to 77.3 per 100,000 in 2005 and increased in females from 54.4 to 56.0 per 100,000.

In the UK in 2003, an estimated 26,000 persons (14,000 men, 12,000 women) died from COPD, 4.9% of all deaths, 5.4% of all male deaths, and 4.2% of all female deaths. Mortality from COPD in the UK has fallen in men but risen in women over the last 25 years, except in the over-75 age-group. In American women the decline in mortality which was recorded until 1975 has reversed and has increased substantially between 1980 and 2000, from 20.1 to 56.7 per 100,000, whereas the increase in men has been more modest, from 73.0 to 82.6 per 100,000. These trends presumably relate to the later peak prevalence of cigarette smoking in women compared with men. In the UK, age-adjusted death rates from chronic respiratory diseases vary by a factor of 5 to 10 in different geographic locations. Mortality rates tend to be higher in urban areas than in rural areas.

In the UK, COPD reduces life expectancy by an average of 1.8 years (76.5 vs. 78.3). The reduction in life expectancy increases with age, from 1.1 year in mild disease to 1.7 years in moderate disease and 4.1 years in patients with severe disease.

1 What is chronic obstructive pulmonary disease (COPD)?

COPD is characterized by airflow limitation that is not fully reversible. Chronic airflow limitation results from a combination of small-airway disease and parenchymal destruction due to inflammatory processes. These inflammatory processes are often caused by exposure to noxious particles or gases.

2 How many people are affected by COPD?

COPD is the fourth leading cause of mortality and morbidity in the United States. The number of people affected by COPD worldwide continues to increase because of exposure to tobacco smoke and aging of the population. Historically the prevalence of disease was higher in men, but, with changing patterns of exposure to tobacco, women are now affected as frequently as men. Worldwide, exposure to indoor pollution from heating and cooking fuels substantially contributes to COPD in women.

3 What processes are involved in the pathogenesis of COPD?

COPD is characterized by chronic inflammation throughout the lung, with increased neutrophils, macrophages, and CD8+ T lymphocytes. An imbalance between proteinase-antiproteinase activity and oxidative stress also contributes to the pathogenesis of this disease. Oxidative stress and proteinase-antiproteinase imbalance can be related to a combination of factors, including the inflammation itself, environmental exposures (e.g., oxidative substances in cigarette smoke), and genetics (e.g., α1-antitrypsin deficiency).

4 What are the major pathologic changes in COPD?

All structures of the lung are subjected to pathologic changes in COPD. In the central airways, inflammatory cells infiltrate the surface epithelium, edema is present, mucus-secreting glands are enlarged, and the number of goblet cells increases with mucus hypersecretion. In the peripheral airways (small bronchi and bronchioles with an internal diameter < 2 mm), chronic inflammation leads to repeated injury and repair of the airway wall. In emphysema, destruction of alveolar septa leads to confluence of adjacent alveoli and enlarged terminal air spaces. Vascular changes include thickening of the vessel wall with increased smooth muscle, proteoglycans, and collagen deposition.

5 How is severity graded in COPD?

The staging system should be regarded as an educational tool and a guide to management (Table 22-1).

6 What are the benefits of smoking cessation for a patient with COPD?

Smoking cessation is the most important intervention. It is the most effective intervention to decelerate the decline in lung function characteristic of this disease. In addition to the modest improvement in forced expiratory volume in 1 second (FEV1) seen with smoking cessation, the rate of decline in FEV1 may be reduced, in some cases even to the rate found in healthy nonsmokers (± 30 mL/yr).

7 Why are bronchodilators used in the treatment of COPD?

Bronchodilators treat airway obstruction in patients with COPD. By reducing bronchomotor tone, they decrease airway resistance, which can improve airflow. This will improve emptying of the lungs and tends to reduce dynamic hyperinflation during rest and exercise and thus improve exercise performance. Spirometric changes after bronchodilator therapy may be minimal, despite significant clinical benefit, as quantified by changes in quality-of-life measures and exercise tolerance (e.g., 6-minute walk).

8 Which bronchodilators should be used in the treatment of COPD?

▪

Anticholinergic agents: These agents block cholinergic transmission. Ipratropium has a duration of action of 6 to 8 hours. Tiotropium bromide is more potent and has a longer duration of action, allowing once-daily administration. It is more convenient but more expensive.

β2-Adrenergic agents: β2-Adrenergic agents act on airway smooth muscle. Inhaled, short-acting β2-adrenergic agents are readily absorbed systemically and can lead to numerous systemic adverse effects, such as tachycardia, tremor, and arrhythmias. Long-acting inhaled β2-adrenergic agents are more effective and convenient but more expensive.

Methylxanthines: These are weak bronchodilators but have multiple other effects that might be important: an inotropic effect on diaphragmatic muscle, reduced muscle fatigue, increased mucociliary clearance and central respiratory drive, and some antiinflammatory effects. Because of the potential for toxicity with theophylline, other bronchodilators are preferred when available.

9 Are inhaled corticosteroids beneficial in COPD?

Although regular use of inhaled corticosteroids does not prevent loss of lung function in patients with COPD, inhaled corticosteroids in combination with long-acting bronchodilators are recommended for patients with severe disease (FEV1 < 50% predicted) and recurrent exacerbations. Data indicate that inhaled corticosteroids in combination with long-acting bronchodilators decrease the risk of exacerbations in patients with COPD. However, treatment with inhaled corticosteroids alone may increase the risk of pneumonia and does not reduce mortality.

10 What other pharmacologic treatments may benefit patients with COPD?

▪

α1-Antitrypsin replacement: This is recommended for patients with emphysema related to deficiency of α1-antitrypsin.

Vaccines: Patients with COPD are at risk for increased morbidity and mortality from respiratory tract infections. Pneumococcal and influenza vaccination, both alone and in combination, have been shown to reduce hospitalizations and mortality rates.

Phosphodiesterase-4 inhibitors: Roflumilast has recently been approved for treatment of COPD in the United States. It reduces inflammation through inhibiting the breakdown of intracellular cyclic adenosine monophosphate and appears to reduce the risk of exacerbations. It cannot be used with methylxanthines.

11 Who should get pulmonary rehabilitation?

Patients with all levels of COPD can benefit from exercise training programs. Pulmonary rehabilitation has been shown to improve functional status, decrease dyspnea, and reduce health care use. Pulmonary rehabilitation is currently recommended as part of the treatment plan for patients with moderate, severe, and very severe COPD.

12 What are the indications for long-term oxygen therapy in patients with COPD?

For a patient at rest breathing room air in a stable condition:

Arterial oxygen(PaO2)<55mm Hg or arterial oxygen saturation(SaO2)≤88%

or

PaO2=56−59mmHg/SaO2 =89%

and one of the following:

Right-sided heart failure or polycythemia

Desaturation during sleep

Desaturation during exercise

13 What level of oxygen should be prescribed for patients with the indications listed in question 12?

Oxygen should be prescribed in a dose sufficient to raise the PaO2 to 65 to 80 mm Hg at rest during wakefulness. This PaO2 usually is achieved with a 1- to 4-L/min oxygen flow through nasal prongs. The dose of O2 should be increased by 1 L/min during sleep or exercise to prevent hypoxemic episodes. Oxygen should be given continuously at least 19 hours per day.

14 Is lung volume reduction surgery effective in the treatment of COPD?

In lung volume reduction surgery, part of the lungs is resected to reduce hyperinflation. This has beneficial effects on the mechanical action of the respiratory muscles and improves elastic recoil, which facilitates emptying of the lungs. Lung volume reduction surgery does not improve long-term survival in COPD but does improve exercise capacity in a select group of patients. Patients who benefit from lung volume reduction surgery are those with predominantly upper lobe emphysema and a low exercise capacity.

15 What factors predict death in patients with COPD?

Long-term prognosis is hard to predict in patients with COPD. Factors that have been shown to predict mortality include low body mass index, degree of airflow obstruction, dyspnea, and exercise capacity as measured by the 6-minute walk test.

16 Are antibiotics useful in treating COPD exacerbations?

Giving antibiotics for COPD exacerbations is indicated when patients are seen with increased sputum purulence associated with increased sputum volume and/or dyspnea. For patients receiving mechanical ventilation for a COPD exacerbation, withholding antibiotics has been associated with increased mortality and hospital-acquired pneumonia.

17 What organisms cause COPD exacerbations?

Bacteria and viruses cause COPD exacerbations. In mild exacerbations Streptococcus pneumoniae is common. As severity of COPD increases, Haemophilus influenzae and Moraxella catarrhalis become more common, and, in severe COPD, Pseudomonas aeruginosa may occur.

18 What is the role of steroids in the treatment of COPD exacerbations?

Systemic glucocorticoids shorten the duration of the exacerbation and lead to faster improvements in lung function. A recent study suggested that nebulized budesonide may be an alternative to oral glucocorticoids in nonacidotic exacerbations but is likely to be more expensive.

19 What are the causes of acute respiratory failure in patients with COPD?

Causes include bronchial infection, pulmonary emboli, cardiac failure, pneumonia, pneumothorax, respiratory depression (usually by the injudicious use of sedatives or narcotic analgesic drugs), surgery (especially of chest and upper abdomen), stopping of medications, or occasionally malnutrition. In general, the criteria for the diagnosis of acute respiratory failure in patients with COPD include the following:

Hypoxemia (PaO2 < 60 mm Hg)

Hypercapnia (PaCO2 > 50-70 mm Hg)

Respiratory acidosis (pH < 7.35) associated with worsening of the patient's respiratory symptoms compared with baseline

20 What is the initial treatment of a severe COPD exacerbation?

Assess the patient's symptoms and signs, and obtain a chest radiograph and arterial blood gas analysis. Administer adequate oxygen: Death or irreversible brain damage results within minutes when severe hypoxemia is present, whereas hypercapnia may be well tolerated. The appropriate amount of oxygen is that which satisfies tissue oxygen needs: usually a PaO2 > 60 mm Hg, without worsening the respiratory acidosis and/or further depressing sensorium. Administer β2-agonist and anticholinergic bronchodilators. Add glucocorticoids and antibiotics. Consider noninvasive ventilation.

21 What is the role of noninvasive ventilation in the treatment of COPD exacerbations?

Noninvasive ventilation has been used for patients with moderate to severe dyspnea and moderate to severe acidosis from a COPD exacerbation. A number of trials report improvements in acid-base balance, reduced PaCO2, and decreased length of stay. Intubation rates are also reduced by noninvasive ventilation. Box 22-1 summarizes the indications and contraindications for noninvasive ventilation in COPD exacerbations; Box 22-2 summarizes indications for intubation and invasive mechanical ventilation in COPD exacerbation.

22 What is the prognosis for a patient requiring mechanical ventilation?

Many studies report reasonable short-term mortality rates (25%-30%) for patients with an endotracheal tube in place for a COPD exacerbation rate, and mortality is lower than among patients with an endotracheal tube for non-COPD causes. High mortality rates in the long term occur in patients with poor lung function (FEV1 < 30%) before intubation and those with significant other comorbidities.

23 What is the role of positive end-expiratory pressure (PEEP) in mechanical ventilation during a COPD exacerbation?

The presence of positive alveolar pressure at the end of exhalation (intrinsic PEEP) may prevent the patient from triggering the ventilator. The level of external PEEP should be set just below the level of intrinsic PEEP to allow the patient to trigger the ventilator with minimal effort.

24 What is the preferred mode of mechanical ventilation in a COPD exacerbation?

No mode of mechanical ventilation has been shown to be superior to another during a COPD exacerbation. In general, the principles of ventilation are to minimize hyperinflation by allowing adequate expiratory time and avoiding high tidal volumes. Oxygen should be titrated to maintain an arterial partial pressure of approximately 60 mm Hg. Overventilation should be avoided: These patients frequently have hypercapnia and a compensatory metabolic alkalosis at baseline.

Key Points

Chronic Obstructive Pulmonary Disease

COPD is the fourth leading cause of morbidity and mortality in the United States.

Spirometry is required to grade the severity and make a diagnosis of COPD.

Systemic glucocorticoids are indicated only in acute exacerbations.

Noninvasive ventilation improves outcomes in patients with impending respiratory failure.

Summary

Chronic obstructive pulmonary disease (COPD) is characterized by progressive and largely irreversible airflow limitation due to narrowing and fibrosis of small airways and loss of airway alveolar attachments as a result of emphysema. Cigarette smoking is the most important risk factor, but other noxious gases are important in developing countries. Genes likely determine which smokers are susceptible to the development of airflow obstruction, but these genes have not yet been consistently identified. Several single nucleotide polymorphisms of candidate genes have now been associated with COPD susceptibility, but most have not been replicated. More recent genome-wide association studies (GWAS) have shown few consistent findings apart from polymorphisms of the nicotine receptor (which may reflect nicotine addiction) and abnormalities in the hedgehog signaling pathways involved in lung development. There is a specific pattern of inflammation characterized by increased numbers of macrophages, neutrophils, and T-lymphocytes (particularly CD8+ cells), which is an amplification of the inflammation seen in normal cigarette smokers and increases with disease progression. This amplification may be due to reduced histone deacetylase (HDAC) activity, which could be genetically determined. Proteinases, particularly MMP-9, result in degradation of alveolar wall elastin, resulting in emphysema. There is an abnormal pattern of inflammatory protein expression in COPD, and most of these proteins are regulated at a transcriptional level. Gene microarray analysis of peripheral lung and specific cell types shows up-regulation of many genes in inflammatory and immune signaling pathways. Proteomic analysis also shows increased inflammatory proteins in the plasma of COPD patients. Management of COPD involves smoking cessation (which may be influenced by genetic factors). Bronchodilator therapy reduces hyperinflation, and long-acting inhaled β2-agonists and anticholinergics are the preferred therapy. Inhaled corticosteroids do not reduce inflammation because of reduced HDAC activity. Pharmacogenomics has not yet been applied to COPD, but polymorphisms of the β2-adrenoceptor have little influence on responses to β2-agonists. Future therapies may be identified by targeting new genes (or pathways) that regulate disease activity.