Chronic Obstructive Pulmonary Disease

Guillermo Domínguez-Cherit and Juan Gabriel Posadas-Calleja

In 1997, the U.S. National Heart Lung and Blood Institute and the World Health Organization held an international workshop that led to the first Global Initiative on Obstructive Lung Disease (GOLD) report. The most recent iteration of the GOLD guidelines defines chronic obstructive pulmonary disease (COPD) as a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. Its pulmonary component is characterized by chronic airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with abnormal inflammatory response of the lungs to noxious particles and gases.¹

Definitions

Although controversies remain over the definition of exacerbation, how they should be monitored, and their underlying mechanisms, acute exacerbations of COPD (AECOPD) are major and increasingly recognized events in the disease course. They typically occur one to three times per year. Exacerbations are associated with an increase in economic burden ² and a decline in health-related quality of life.³ Those patients with more than two exacerbations per year have significantly worse health-related complications and decline in lung function than those with two or fewer exacerbations.⁴ As mentioned before, there is no general agreement on the definition of AECOPD, but it has been defined according to the presence of specific signs and symptoms, worsening in symptoms, and the need for medical intervention, and each of these approaches has positive and negative connotations. It is well recognized, however, that the presence of increased shortness of breath, increased sputum volume, and increased purulence are the three specific symptoms that represent an exacerbation.⁵

Background

COPD affects more than 200 million people worldwide and is the fourth leading cause of death. COPD is a disease that is both preventable and treatable. COPD is a major cause of morbidity and death in the world, with an increasing burden due to epidemiologic changes that expose more of the population to COPD risk factors. Although the major environmental risk for COPD is tobacco smoking, only 20% of smokers develop COPD. Indoor air pollution from burning biomass fuel is associated with increased risk of COPD in developing countries. In the United States, COPD is the fourth leading cause of death ⁶ and is exceeded only by heart attacks, cancer, and stroke.

COPD has had a similar effect on health and mortality rate throughout the developed and underdeveloped sectors of the world, and many of the important issues surrounding COPD in the United States apply elsewhere.⁷

The real prevalence is masked by the burden of undiagnosed COPD; when the British Lung Foundation “missing millions” campaign performed spirometry screening in 3802 adults, they found that the prevalence of COPD was 10.2% (4.4% having GOLD II or worse) with only a quarter having a prior diagnosis.⁸

Pathophysiology

The main pathophysiologic feature in COPD is the limitation to expiratory flow.⁹ Chronic expiratory flow limitation and hyperinflation are the mechanical hallmarks of COPD.¹⁰ Expiratory airflow limitation results from many factors; among them, narrowing of the peripheral airways,¹¹ mucus hypersecretion,¹² and impaired ciliary clearance¹³ are the most important factors.

Several mechanistic concepts have been implicated in the pathogenesis of COPD. First, the hallmark of COPD is development of exaggerated chronic inflammation in the lung in response to inhalation of cigarette smoke compared with smokers without lung disease.¹⁴ Host factors including genetic susceptibility, epigenetic changes, and oxidative stress contribute by amplifying inflammation induced by cigarette smoke. Second, patients with deficiency of α₁-antitrypsin, the main inhibitor of neutrophil elastase, develop emphysema early in life owing to an increase in proteolytic activity.¹⁵ Third, an imbalance between oxidants and antioxidants in the lungs of patients with COPD, resulting in excessive oxidative stress, not only amplifies airway inflammation in smokers but also induces cell death of structural cells in the lung. Disruption of the balance between cell death and replenishment of structural cells in the lung contributes to the destruction of alveolar septa, leading to emphysema.¹⁶ Autoimmunity has been proposed as a late pathogenic event in the progressive course of the disease.

COPD is characterized by a specific pattern of inflammation involving increased numbers of CD8⁺ T_C lymphocytes present only in smokers who develop the disease. These cells as well as neutrophils and macrophages release inflammatory mediators and interact with epithelial cells in the airways, lung parenchyma, and pulmonary endothelium; all these relationships and interactions produce structural changes in the lungs by activation of growth factors.¹⁷ Changes in the airway architecture, endothelium, and lung parenchyma lead to the characteristic physiologic abnormalities and symptoms of COPD.

In acute exacerbations there is an increase in sputum neutrophil numbers as well as an increase in neutrophils in bronchial biopsies, which rarely are seen in the stable state.¹⁸ Interestingly virally induced exacerbations are associated with increased expression of eosinophils in sputum. Viral infections induce the expression of chemokine (C-C motif) ligand 5 (CCL5) in airway epithelial cells,¹⁹ CCL5 may act synergistically with CD8⁺ cells to enhance the apoptosis of virally infected cells, thus leading to increased tissue destruction.²⁰ Also, an increase in the concentration of the elastolytic enzyme matrix metalloproteinase-1 during exacerbations is consistent with evidence of elastolysis, which may provide a causal link between exacerbations and accelerated decline in lung function.²¹

Data from patients with AECOPD that required mechanical ventilation indicates the presence of increased central drive, dyspnea, tachypnea, reduced tidal volume, and development of hypercapnic respiratory failure, but ventilation/perfusion match remains relatively preserved.²² AECOPD appears to be characterized by increased central drive, decreased inspiratory capacity, and decreased inspiratory muscle force, perhaps secondary to dynamic hyperinflation. There is an association between increased serum levels of interleukin 6 (IL-6) and leukotriene B4 (LTB4) and the magnitude of dyspnea, respiratory rate, and inspiratory capacity, suggesting that it may be possible to detect serum changes that reflect the inflammatory burden of the exacerbation.²³

Although hypercapnia depends on the severity of airflow limitation, there is considerable variability in the relationship of PaCO₂ to forced expiratory volume in 1 second (FEV₁) and total lung resistance, best explained by contribution of dead space and minute ventilation. In stable COPD patients with severe airflow obstruction, shallow breathing is the main factor associated with CO₂ retention,²⁴ the diaphragm is less effective than in normal subjects, and with increasing airflow obstruction and hyperinflation, the contribution of the rib cage muscle to the generation of ventilatory pressure increases.²⁵ Abdominal muscles are recruited during expiration in patients with severe COPD, and the expiratory rise in gastric pressure is directly related to intrinsic positive end-expiratory pressure (PEEPi). During acute exacerbation, patients with severe airflow obstruction increase the inspiratory recruitment of the rib cage muscles relative to the diaphragm. This recruitment is associated with abdominal muscle contraction and a reduction in abdominal volume at end expiration, which contributes to PEEPi. Dynamic hyperinflation can be overestimated during chronic and acute airway obstruction if abdominal muscle function is not evaluated.²⁶

The worsening gas exchange and the deterioration of the arterial blood gas values during acute exacerbations in patients with severe COPD can be explained by several factors. These factors are, in no particular order, respiratory muscle fatigue,²⁷ increases in dead space ventilation, and alveolar hypoventilation.²⁸ Minute ventilation may be normal early in an exacerbation, but the respiratory rate is generally increased. There is an associated increase in physiologic dead space that impairs CO₂ elimination and may result in acidemia.²⁹ The hypoxemia seen during exacerbations results from the combination of two factors: alveolar hypoventilation and, later, worsening of ventilation/perfusion matching. Increases in ventilation/perfusion heterogeneity are attributed to (1) a reduction in the effectiveness of hypoxic vasoconstriction as a protective mechanism as pulmonary artery pressure rises and vasodilatory inflammatory mediators are released, and (2) the failure to redirect perfusion away from inadequately ventilated regions because of the reduction in cross-sectional area of the pulmonary vascular bed.

Clinical Manifestations

Most COPD patients with acute exacerbations initially demonstrate some combination of increasing cough, worsening of dyspnea, increased sputum production, purulent sputum, or increase in viscosity of the sputum, rather than a deterioration noted by laboratory or respiratory function parameters (Box 39.1). Symptoms may come on slowly over several days or acutely, depending somewhat on the severity of the underlying disease. Often, patients have a history of upper respiratory tract infection. Patients generally appear in acute distress. Vital signs typically demonstrate tachycardia and tachypnea, and blood pressure can be reduced in response to the effect of PEEPi. Use of accessory inspiratory muscles may be seen with increasing severity of exacerbations. With inspiration, the diaphragm normally moves down as it contracts, forcing the abdominal contents out. With diaphragmatic fatigue, the diaphragm no longer functions as a primary muscle of inspiration but instead assists the intercostal muscles’ inspiratory effort by fixing the rib cage. This action is associated with a rise in the diaphragm, and the abdomen moves in instead of out, as it does with normal inspiration. This sign is called paradoxical breathing²⁸ and it implies respiratory muscle fatigue and often imminent ventilatory failure and respiratory arrest.²⁹ Wheezing and other auscultatory findings of obstruction are also present. Cyanosis is an insensitive manifestation, but when seen, it denotes severe hypoxemia. Patients with severe acute CO₂ retention may present in coma.

Box 39.1 Clinical Signs of Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Increasing cough

Worsening dyspnea

Increased sputum production

Purulent sputum

Precipitating Factors

The most common precipitant factor is respiratory infection, either bacterial or viral.30,31 Air pollution can also precipitate exacerbations of COPD^32,33; however, the cause of one third of AECOPD events cannot be identified. Some other conditions that can ether mimic or induce an exacerbation include pneumonia, arrhythmia, pneumothorax, pulmonary embolism,³⁴ and pleural effusion. Medication failure and lack of compliance have been shown also to lead to exacerbations.

Infections

Bacteria and viruses account for the vast majority of episodes of exacerbation. Respiratory viruses are associated with 30% of exacerbations with or without a superimposed bacterial infection.³⁵ Another study reported that up to 78% of the patients admitted into the hospital with severe AECOPD had evidence of viral or bacterial infection.¹⁹

Several studies have been conducted to investigate airway bacterial infections as etiologic factors involved in COPD exacerbations.36–38 Bronchoscopic sampling of the distal airway has demonstrated the presence of pathogenic bacteria in 50% of exacerbations. Acquisition of new strains of bacterial pathogens has been associated with more than twofold increase in the risk of AECOPD.³⁹ At present, there appears to be an agreement that the major pathogens isolated from sputum during acute exacerbation are Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis⁴⁰; however, all of these bacteria can be isolated in patients during the stable phases of COPD.^41,42 Atypical bacteria, mostly Chlamydia pneumoniae, have been implicated in approximately 10% of acute exacerbations.^43,44 Other potential microorganisms that should be considered include other Streptococcus species, enteric gram-negative bacilli, and Legionella.⁴⁵ Bacterial colonization may be a factor increasing airway inflammation.⁴⁶ There is an association between bacterial colonization and increased markers of inflammation in sputum and in the frequency of exacerbations.⁴⁷

Approximately 50% of AECOPD events are associated with upper respiratory tract virus infections. Infections with rhinovirus, respiratory syncytial virus, and influenza virus have been associated with AECOPD.⁴⁸ COPD patients with a history of frequent exacerbations may be more susceptible to respiratory viral infections. There is increasing recognition that many patients with exacerbations have concomitant viral and bacterial infection. Approximately a quarter of patients admitted to hospital with AECOPD have coinfection with viruses and bacteria, and those patients have more severe exacerbations.⁴⁸

Environmental Factors

Environmental factors are among noninfectious causes of COPD exacerbation that should be investigated as precipitating causes.32,49,50 Epidemiologic studies have shown that hospital admissions with AECOPD increase slightly with a rise in atmospheric levels of sulfur dioxide, ozone, nitrogen dioxide, and particulates. There is convincing evidence that exposure to particulates with a 50% cutoff aerodynamic diameter of 10 µm is associated with increased hospital admissions for AECOPD.⁵¹ Air pollution is implicated as a trigger of exacerbations⁵²; however, a direct cause-and-effect relationship has been difficult to establish over the last 50 years.⁵³ From an epidemiologic viewpoint, definitive evidence exists regarding a role of air pollutants in the increased death rates seen in cities during periods of heavy pollution.⁵⁴ The recent dramatic increase in motor vehicle traffic has produced a relative increase in the levels of newer pollutants, such as ozone and fine-particulate air pollution. Elucidation of the mechanisms of the harmful effects of these pollutants should allow improved risk assessment for the patients with airway diseases who are susceptible to the effects of these air pollutants.

Pulmonary Thromboembolism

Pulmonary thromboembolism (PTE) can precipitate acute COPD exacerbations through either impairment of gas exchange or increases in pulmonary vascular pressures.55,56 Some evidence suggests that deep venous thrombosis occurs in more than 5 million people each year. More than 500,000 people eventually develop PTE, which is the primary cause of death in more than 100,000 patients annually in the United States.⁵⁷ The precise incidence of PTE in COPD is unknown. Studies in COPD patients have found pulmonary embolus in up to 50% of autopsies and in patients admitted to hospital with severe AECOPD of unknown cause; 25% had pulmonary embolism confirmed by spiral computed tomography (CT).⁵⁸ PTE risk factors inherent to COPD are sedentary lifestyle, right ventricular failure, right ventricular mural thrombi, and secondary polycythemia.⁵⁹ Patients with COPD have also been shown to have increased platelet aggregation and increased plasma β-thromboglobulin.⁶⁰

Up to 30% of untreated thromboembolic patients die. The necessity of diagnosing PTE as the precipitating factor in acute COPD exacerbation is crucial. However, the diagnosis of PTE is extremely difficult in COPD exacerbation. Nonetheless, the approach to diagnosis is similar to that used with other patients.⁶¹ Unfortunately, most patients with COPD have an indeterminate ventilation/perfusion scan, usually making this scan unhelpful in evaluation for PTE.⁶² For patients with such indeterminate results (low or intermediate probability), noninvasive testing of the lower extremity should be conducted.^63–65 If positive results for deep venous thrombosis are obtained, anticoagulation therapy must be initiated. It has been proposed that use of newer D-dimer assays may also have a role as a diagnostic tool; however, even with a sensitivity of 98%, specificity is problematic, with a value of 39%.⁶⁶ When the diagnosis is still in doubt (intermediate-probability scan and negative leg study or low-probability scan and negative leg study with intermediate clinical probability of PTE), helical CT or conventional pulmonary angiography may be required. Even though the safety of pulmonary angiography in patients with cor pulmonale has been questioned, data from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study support both safety and accuracy in patients with COPD.⁶¹ Helical CT has become an increasingly accepted technique and is the method of choice for direct visualization of pulmonary emboli (PE). The quantitative assessment of tissue perfusion may yield more important information for patient management than the direct visualization of emboli by CT alone. Enhanced multislice helical CT with thin collimation can be used to analyze precisely the subsegmental pulmonary arteries and may identify even more distal pulmonary arteries. Recent data suggest that spiral CT may be an alternative to angiography, particularly when results are not discordant with pretest clinical probability of PE and when combined with other tests that support CT findings (D-dimer, leg ultrasound, lung scanning), and may have adequate sensitivity and specificity in the COPD population.⁶²

Medication Failure or Noncompliance

Many acute COPD exacerbations can be explained in terms of inadequate pharmacologic therapy or noncompliance with pharmacologic therapy. These factors are likely underestimated causes of exacerbation in COPD patients. It is also possible that patients have toxic drug effects of cardiac, gastrointestinal, or metabolic nature. Certain pharmacologic drug interactions can precipitate toxicity or loss of effect of one drug, and the physician must ascertain whether newer medications for other conditions have recently been added to the patient’s therapeutic regimen.67,68

Other Causes

Clinical decompensation in patients with stable COPD may also occur as a result of acute congestive heart failure (CHF) or cardiac arrhythmia. One study found that 27% of COPD patients die as a result of coronary disease,⁶⁹ likely related to risk factors such as smoking, diabetes mellitus, and vasculopathy. Heart failure may also lead to a symptomatic exacerbation of COPD; however, it may be difficult to differentiate the symptoms of CHF and those of AECOPD.⁷⁰

Other causes of exacerbation include sleep-disordered breathing,71–73 vocal cord paralysis, tumor or scarring from prior intubations, and the development of spontaneous pneumothorax.^74,75 Finally, pleural effusion can also produce respiratory deterioration, especially in patients with poor respiratory reserve.⁷⁶

Initial Management

Because chronic airflow obstruction cannot be reversed, acute management of COPD is directed at reversible pathogenic mechanisms, including pulmonary infection, airway tissue inflammation, bronchoconstriction, and support of failing muscular function. Box 39.2 summarizes initial general management.

Box 39.2 General Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Adjust O₂ to SpO₂ goal 88% to 92%

Initiate and maintain β-agonist and anticholinergic agents combined

Start prednisone 50 mg/day for 7 days

Start antibiotics if signs of infection

Oxygen

Long-term oxygen treatment has been demonstrated to significantly reduce mortality rate in patients with COPD and severe resting arterial hypoxemia.⁷⁷ Oxygen therapy is indicated for patients with an arterial oxygen tension (PaO₂) of less than 55 mm Hg. The therapeutic goal is to maintain oxygen saturation greater than 90% during rest, sleep, and exertion, as it is now well established that such measures increase survival and that 24 hours is more effective than 12 hours. There is a clear rationale for the use of oxygen in severe COPD. Enhancing blood oxygenation by increasing the concentration of inspired oxygen compensates for a major physiologic consequence of COPD with hypoxemia. Oxygen remains the mainstay of initial therapy in most COPD exacerbations. Relief of hypoxemia, and consequently of hypoxemic pulmonary vasoconstriction, decreases pulmonary vascular resistance, with variable effects on the ventilation/perfusion ratio.^78,79 Oxygen delivery may increase as a result of increases in oxygen arterial content and anticipated improved right-sided heart function. However, one study demonstrated that relief of hypoxemia did not increase cardiac output.⁸⁰

Hypercapnia is well tolerated when it is chronic.81–83 However, oxygen should be administered cautiously in patients who are chronically hypercapnic because it is known to lead to clinically significant rises in PaCO₂ in select COPD patients as a result of changes in the physiologic dead space and perhaps suppression of the respiratory drive.^84,85 Acute increases in PaCO₂ are more likely to occur in patients with elevated baseline PaCO₂. A randomized study has shown that, although oxygen administration worsened hypercapnia and respiratory acidosis, these changes were well tolerated in most patients.⁸⁶ Oxygen therapy should not be withheld in acutely ill hypoxemic patients because tissue hypoxia can lead to acute organ dysfunction. However, oxygen should be initiated at a low FIO₂ and slowly titrated up as necessary with vigilant monitoring to document improvement and stabilization in PaO₂, with special attention paid to maintaining the oxyhemoglobin between 88% and 92% or greater without producing dangerous falls in pH as a result of rises in CO₂. These dangerous rises in PaCO₂ are typically associated with worsening mental status. Nasal cannulas or Venturi masks can be used to initiate a low FIO₂. Either nasal cannula at a flow rate of 1 L/minute or a Venturi mask initially at the lowest setting (25%) is appropriate for initiating oxygen in patients known or suspected to be chronic CO₂ retainers. However, in the presence of acute severe hypoxemia in patients with impending respiratory failure, high-flow oxygen therapy may be in the patient’s best interest, regardless of the risk for CO₂ retention.⁸⁷

Drug Treatment

Bronchodilators

Bronchodilator therapy has important roles in both the prevention and treatment of AECOPD. Bronchodilators are the primary treatment to alleviate patient symptoms, improve physiologic state, and prevent or reverse respiratory failure; however, its use has not been shown to improve survival. Systematic reviews have demonstrated that inhaled delivery of short-acting β₂-selective agonists and anticholinergic agents have greater effect on spirometry and is the therapy of choice for AECOPD over parenteral bronchodilators.⁸⁸ Bronchodilator treatment in acutely ill COPD patients has been shown to decrease inspiratory muscle loading, with an increase in FEV₁ and a decrease in functional residual capacity (FRC) and dynamic hyperinflation.⁸⁹ In mechanically ventilated patients, a reduction in expiratory resistance and dynamic hyperinflation (measured as a decrease in PEEPi) has been described.⁹⁰

There is no evidence supporting the use of one inhaled β₂-selective agonist over another. There is no difference in outcome between β₂-agonist compared with ipratropium bromide and no evidence that the combination of these two drugs is any more effective in AECOPD; these results are in contrast with the greater efficacy of these combinations in stable COPD.⁸⁸ The widespread use of inhaled β-agonists has been accompanied by clinical concern of cardiac complications in elderly patients and those with coronary artery disease. However, in a study performed on clinically stable COPD or asthma patients with a history of myocardial ischemia, no ischemic events, or dysrhythmias, were observed when commonly used doses of salbutamol were administered.⁹¹ To date, no clinical studies have evaluated the use of inhaled long-acting bronchodilators (either β₂-agonist or anticholinergic agents) with or without inhaled corticosteroids during AECOPD.

Several studies have suggested that the combination of β₂-agonists and anticholinergic agents prevent exacerbations, particularly long-acting agents.92–96 It is possible that these agents reduce exacerbation frequency as a result of the effect on reduction of dynamic hyperinflation at rest and exercise,⁹⁷ as well as nonbronchodilator mechanisms, such as anti-inflammatory effect.⁹⁸

Intravenous methylxanthines (theophylline or aminophylline) are considered second-line therapy, only to be used in selected cases when there is insufficient response to short-acting bronchodilators. Side effects of methylxanthines are significant and the clinical response is inconsistent.

Corticosteroids

COPD is recognized as an inflammatory disorder, and the severity of airway inflammation correlates with the severity of the underlying COPD.⁹⁹ During exacerbations, there is a large increase in concentration of proinflammatory cells, including neutrophils. Systemic corticosteroids improve lung function significantly, shorten hospital stay, and reduce the risk for relapses as compared with placebo in patients with AECOPD.¹⁰⁰ In the ISOLDE trial, the median exacerbation rate was reduced by 25%, and there was also a reduction in the health status deterioration.¹⁰¹ Systemic corticosteroids have been demonstrated to improve respiratory mechanics in mechanically ventilated patients, with a decrease in airway resistance and dynamic air-trapping.¹⁰² A meta-analysis demonstrated that the use of systemic corticosteroids was associated with significant reduction in treatment failure, defined as either clinical deterioration, withdrawal from the study due to unsatisfactory clinical improvement, or relapse of exacerbation symptoms during the follow-up period. It also showed beneficial effects in reducing the length of hospitalization by a weighted mean of 1.42 days.¹⁰³

Oral corticosteroids have beneficial effects in the management of AECOPD. Prednisolone, administered at 30 mg/day for 14 days, shortened the length of hospitalization by 2 days, improved FEV₁ by 60 mL/day, and accelerated recovery from symptoms.¹⁰⁴ The majority of patients with COPD probably requires only 2 weeks with oral corticosteroids and therapy for 8 weeks produced no incremental benefits above those achieved at 2 weeks.¹⁰⁵ One of the most important concerns regarding the use of corticosteroids in AECOPD is the possibility of confusing it with community-acquired pneumonia. Nevertheless, there is no evidence that corticosteroid use worsened the prognosis of community-acquired pneumonia if appropriate antibiotics are used; moreover, systemic corticosteroids may reduce morbidity and mortality rates in community-acquired pneumonia.¹⁰⁶

The use of inhaled corticosteroids is associated with decrease in exacerbation events by 12% to 25%.¹⁰⁷ Studies involving inhaled corticosteroids and long-acting β₂-agonist showed reduction in exacerbation frequency to a greater extent than using either corticosteroid or long-acting β₂-agonist alone.^108,109 There is also a trend toward mortality rate reduction over 3 years of 17.5%, although without statistical significance.¹¹⁰ There is no evidence that the addition of inhaled corticosteroids to systemic corticosteroids in AECOPD has any impact either in recovery or in mortality rate.

Antibiotics

Use of antibiotics in AECOPD remains a controversial topic, with some authors recommending antibiotic therapy and others not, maybe in part because of the heterogeneity of the population studied.111,112 Compared with placebo, antibiotic use during AECOPD reduced treatment failures by 46%, defined as requiring additional antibiotics within the first 7 days or unchanged or deteriorated symptoms within 21 days. Antibiotics reduced treatment failures particularly in those patients who were hospitalized but not when they were used in ambulatory patients.¹¹³ Three clinical trials involving 181 patients demonstrated that in-hospital mortality rate can be reduced by 78% with the use of antibiotics during AECOPD.^114,115 Patients who present with dyspnea and increased sputum volume or purulence or patients who require mechanical ventilation benefit from a 3- to 7-day course of oral or parenteral antibiotics.¹¹⁶

Although routine sputum cultures are recommended in all patients with AECOPD, invasive techniques (transtracheal aspirates,117,118 bronchoscopic aspirates, or protected specimen brushing^5,119–123) are not indicated. Exceptions include culture-negative community-acquired pneumonia not responding to therapy and ventilator-associated pneumonia (VAP).^124,125 Because many COPD patients have airway colonization by bacteria, without clinical signs of infection and exacerbation, there is no clear significance of a positive culture in a COPD patient; however, in the presence of exacerbation associated with an alteration in sputum character or quantity, potentially pathogenic organisms grown from sputum should be covered with an appropriate antibiotic.¹²⁶ Thus, the selection of empiric antibiotics to treat AECOPD should depend on the severity of underlying disease and severity of COPD exacerbation. Therapy for more severe exacerbations should include coverage for antibiotic-resistant bacteria, such as Pseudomonas or methicillin-resistant Staphylococcus aureus.