Obstructive Lung Disease: Chronic Obstructive Pulmonary Disease (COPD), Asthma, and Related Diseases

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Chapter 23

Obstructive Lung Disease

Chronic Obstructive Pulmonary Disease (COPD), Asthma, and Related Diseases

Enrique Diaz-Guzman, Raed A. Dweik and James K. Stoller

The spectrum of obstructive lung diseases is broad and includes chronic obstructive pulmonary disease (COPD) and asthma as the most common components and less common entities such as bronchiectasis and cystic fibrosis. This chapter reviews the major obstructive lung diseases, emphasizing their defining features, epidemiology, pathophysiology, clinical signs and symptoms, prognosis, and management.

Chronic Obstructive Pulmonary Disease

Overview and Definitions

The term chronic obstructive pulmonary disease (COPD), or sometimes chronic obstructive lung disease (COLD), refers to a disease state characterized by the presence of incompletely reversible airflow obstruction. New guidelines by the American Thoracic Society (ATS) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend the use of the term COPD to encompass both chronic bronchitis and emphysema. The ATS guidelines statement regarding COPD define this entity as follows ¹:

Chronic obstructive pulmonary disease (COPD) is 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.

The spectrum of COPD is shown in Figure 23-1, which presents a nonproportional Venn diagram representing the major components of COPD—chronic bronchitis and emphysema. Although asthma is no longer conventionally considered to be part of the spectrum of COPD, the diagram shows that considerable overlap between asthma and COPD exists. In actual practice, individuals with a history of asthma but with incompletely reversible airflow obstruction may be indistinguishable from patients with COPD.

FIGURE 23-1 Schema of COPD. This nonproportional Venn diagram shows subsets of patients with chronic bronchitis, emphysema, and asthma. The subsets constituting COPD are shaded. Subset areas are not proportional to actual relative subset sizes. Asthma is by definition associated with reversible airflow obstruction, although in variant asthma special maneuvers may be necessary to make the obstruction evident. Patients with asthma whose airflow obstruction is completely reversible *(subset 9)* are not considered to have COPD. Because in many cases it is virtually impossible to differentiate patients with asthma whose airflow obstruction does not remit completely from patients with chronic bronchitis and emphysema who have partially reversible airflow obstruction with airway hyperreactivity, patients with unremitting asthma are classified as having COPD (*subsets 6, 7,* and 8). Chronic bronchitis and emphysema with airflow obstruction usually occur together *(subset 5),* and some patients may have asthma associated with these two disorders *(subset 8).* Individuals with asthma who are exposed to chronic irritation, as from cigarette smoke, may develop a chronic, productive cough, a feature of chronic bronchitis *(subset 6).* Such patients are often referred to as having *asthmatic bronchitis* or the *asthmatic form of COPD*. Individuals with chronic bronchitis or emphysema without airflow obstruction (*subsets 1, 2,* and 11) are not classified as having COPD. Patients with airway obstruction caused by diseases with a known etiology or specific pathology, such as cystic fibrosis or obliterative bronchiolitis *(subset 10)*, are not included in this definition.

The two major entities constituting COPD—emphysema and chronic bronchitis—are defined in different ways. Emphysema is defined in anatomic terms as a condition characterized by abnormal, permanent enlargement of the airspaces beyond the terminal bronchiole, accompanied by destruction of the walls of the airspaces without fibrosis. Chronic bronchitis is defined in clinical terms as a condition in which chronic productive cough is present for at least 3 months per year for at least 2 consecutive years. The definition specifies further that other causes of chronic cough (e.g., gastroesophageal reflux, asthma, and postnasal drip) have been excluded. Figure 23-1 shows considerable overlap between chronic bronchitis and emphysema and some overlap with asthma—that is, when airflow obstruction is incompletely reversible. Figure 23-1 also shows that chronic bronchitis and emphysema can occur without airflow obstruction, although the clinical significance of these diseases usually stems from obstruction to airflow.

Epidemiology

COPD is one of the most frequent causes of morbidity and mortality worldwide.³ The World Health Organization predicts that COPD will become the fifth most prevalent disease in the world and the fourth leading cause of worldwide mortality by 2020. In the United States, COPD is currently the third leading cause of death; it was responsible for 145,075 deaths in 2008.⁴ Estimates suggest that 24 million Americans are affected.^4–6 Data from the National Health and Nutrition Examination Survey (NHANES) suggest that among adults 25 to 75 years old in the United States, mild COPD (defined as forced expiratory volume in 1 second [FEV₁]/forced vital capacity [FVC] <70%, and FEV₁ >80% predicted) occurs in 6.9% and moderate COPD (defined as FEV₁/FVC <79% and FEV₁ ≤80% predicted) occurs in 6.6%.³ COPD prevalence increases with aging, with a fivefold increased risk for adults older than 65 years compared with adults younger than 40 years, and some studies estimate a prevalence of 20% to 30% in adults older than 70 years.⁷

The growing health burden from COPD is caused in part by the aging of the population but mainly by the continued use of tobacco. The socioeconomic burden of COPD is also substantial. In 2000, COPD caused 726,000 hospitalizations (which accounted for 1.9% of all hospitalizations in the United States), 7,997,000 office visits to physicians, and 1,549,000 emergency department visits, and, in 2002, COPD resulted in a total health expenditure of $32.1 billion.³ In this regard, COPD is a problem that is a frequent challenge for the respiratory clinician.

Risk Factors and Pathophysiology

Although many risk factors exist for COPD (Box 23-1), the two most common are cigarette smoking (which has been estimated to account for 80% to 90% of all COPD-related deaths) and alpha₁-antitrypsin (AAT) deficiency.⁸ Evidence linking cigarette smoking to the development of COPD is strong and includes the following:

• Symptoms of COPD (e.g., chronic cough and phlegm production) are more common in smokers than in nonsmokers.

• Impaired lung function with evidence of an obstructive pattern of lung dysfunction is more common in smokers than in nonsmokers.

• Pathologic changes of airflow obstruction and chronic bronchitis are evident in the lungs of smokers.

• So-called susceptible smokers, who represent approximately 15% of all cigarette smokers, experience more rapid rates of decline of lung function than nonsmokers.

Information from the Lung Health Study (Figure 23-2) highlighted the accelerated rate of decrease of FEV₁ in smokers compared with former smokers who have achieved sustained quitting.^9,10 Overall, the strength of evidence implicating cigarette smoking as a cause of COPD has allowed the U.S. Surgeon General to conclude, “Cigarette smoking is the major cause of chronic obstructive lung disease in the United States for both men and women. The contribution of cigarette smoking to chronic obstructive lung disease morbidity and mortality far outweighs all other factors.”¹¹

FIGURE 23-2 Mean postbronchodilator FEV₁ for participants in the smoking intervention and placebo groups who were sustained quitters *(red circles)* and continuing smokers *(purple circles).* The two curves diverge sharply after baseline. (From Anthonisen SR, Connett JE, Kiley JP, et al: Effects of smoking intervention and the use of an anticholinergic bronchodilator on the rate of decline of FEV₁: the Lung Health Study. JAMA 272:1497–1504, 1994.)

As the second well-recognized cause of emphysema, AAT deficiency, sometimes called genetic emphysema, is a condition characterized by a deficient amount of the protein AAT, which may result in the early onset of emphysema and which is inherited as a so-called autosomal codominant condition. Accounting for 2% to 3% of all cases of COPD, AAT deficiency is severely underrecognized by health care providers but affects an estimated 100,000 Americans. In one 1995 survey, the mean interval between the first onset of pulmonary symptoms and initial diagnosis of AAT deficiency was 7.2 years, and 43% of individuals with severe deficiency of AAT reported seeing at least three physicians before the diagnosis of AAT deficiency was first made.¹² More recent studies suggested that underrecognition of AAT deficiency persisted as of 2003 and that the diagnostic delay interval had not decreased significantly.^12–14

The importance of early identification is emphasized by the need to test (by simply sending a serum level for AAT) first-degree relatives (e.g., siblings, parents, and children), by the favorable effect of primary prevention of smoking among individuals identified early, and by the availability of a specific therapy called intravenous augmentation therapy. The risk of developing emphysema for individuals with AAT deficiency increases as the serum AAT level decreases to less than 11 µmol/L, or less than approximately 57 mg/dl using nephelometry, and is enhanced by cigarette smoking.¹⁴

Study of AAT deficiency has helped formulate the protease-antiprotease hypothesis of emphysema.14,15 In this explanatory model (Figure 23-3), lung elastin, a major structural protein that supports the alveolar walls of the lung, is normally protected by AAT, a protein that opposes the degradative threat of neutrophil elastase. Neutrophil elastase is a protein contained within neutrophils that is released when neutrophils are attracted to the lung during inflammation or infection. Under normal circumstances of an adequate amount of AAT, neutrophil elastase is counteracted so as not to digest lung elastin. However, in the face of a severe deficiency of AAT (i.e., when serum levels decrease below a “protective threshold” value of 11 µmol/L, or 57 mg/dl), neutrophil elastase may go unchecked, causing breakdown of elastin and resulting in dissolution of alveolar walls. This protease-antiprotease model explains the pathogenesis of emphysema in AAT deficiency, but evidence suggesting its role in COPD in individuals with normal amounts of AAT is conflicting. Also, other proteases (e.g., matrix metalloproteinases and inflammation) are thought to contribute to the proteolysis that produces emphysema.¹⁶

FIGURE 23-3 Proposed biochemical links between cigarette smoking and the pathogenesis of emphysema. *(I)* Smoking recruits monocytes, macrophages, and (through macrophage chemotactic factors) polymorphonuclear neutrophils to the lung, elevating the connective tissue “burden” of elastolytic serine and metalloproteases. *(III)* At the same time, oxidants in smoke plus oxidants produced by smoke-stimulated lung phagocytes (and oxidizing products of chemical interactions between these two) inactivate bronchial mucus proteinase inhibitor and AAT, the latter representing the major antielastase “shield” of the respiratory units. *(II)* Other, unidentified water-soluble, gas-phase components of cigarette smoke (cyanide, copper chelators) inhibit lysyl oxidase–catalyzed oxidative deamination of epsilon-amino groups in tropoelastin and block formation of desmosine and presumably other cross-links during elastin synthesis, decreasing connective tissue repair. *(IV)* Antioxidants (ceruloplasmin, methionine-sulfoxide-reductase) may protect or reactivate elastase inhibitors, and other unidentified factors may modulate the chemical lesions induced in the lung by smoking to influence the risk of developing COPD. (Modified from Janoff A, Carp H, Laurent P, et al: The role of oxidative processes in emphysema. Am Rev Respir Dis 127[Suppl]:S31, 1983.)

COPD may occur in the absence of active cigarette smoking or AAT deficiency (see Box 23-1).^17,18 Factors such as passive smoking, air pollution, occupational exposure, and airway hyperresponsiveness may contribute to fixed airflow obstruction.

The mechanisms of airflow obstruction in COPD include inflammation and obstruction of small airways (<2 mm in diameter); loss of elasticity, which keeps small airways open when elastin is destroyed in emphysema; and active bronchospasm. Although traditionally considered to be characteristic of asthma, some reversibility of airflow obstruction has been observed in up to two-thirds of COPD patients when tested serially with inhaled bronchodilators.¹⁹

Clinical Signs and Symptoms

Common symptoms of COPD include cough, phlegm production, wheezing, and shortness of breath, typically on exertion. Dyspnea is often slow but progressive in onset and occurs later in the course of the disease, characteristically in the late sixth or seventh decade of life. One notable exception is AAT deficiency, in which dyspnea characteristically begins sooner (mean age approximately 45 years).⁸

Table 23-1 reviews the characteristic features of emphysema and chronic bronchitis and emphasizes traits that should suggest the possibility of AAT deficiency, including early onset of emphysema, emphysema in a nonsmoker, or a family history of emphysema. Suspicion of AAT deficiency should lead to a simple blood test by which the serum level can be established.^8,14

TABLE 23-1

Clinical Features of COPD: Distinctions Between Chronic Bronchitis and Emphysema, With Emphasis on Distinguishing Features of Alpha₁-Antitrypsin Deficiency

Features	Chronic Bronchitis	Emphysema	Severe Alpha₁-Antitrypsin Deficiency
Symptoms and Signs
Chronic cough, phlegm	Common	Less common	Less common, but may be present
Dyspnea on exertion	Less common	Common	Common
Cor pulmonale	Present (often with multiple exacerbations)	Present (but often in end-stage emphysema)	Present (but often in end-stage emphysema)
Age of patient at symptom onset	6th-7th decade	6th-7th decade	4th-5th decade (although late onset is possible)
Family history of COPD	Possible but not characteristic	Possible but not characteristic	Common in parents, children, and siblings
History of cigarette smoking	Present, often heavy	Present, often heavy	May be present, but COPD can occur in the absence of smoking
Physiologic Function
Airflow (FEV₁, FEV₁/FVC)	Decreased	Decreased	Decreased
Lung volumes, residual volume	Normal	Increased, suggesting air trapping	Increased
Gas exchange, diffusion PaO₂	Often decreased	Often preserved until advanced stage	Often preserved until advanced stage
PaCO₂	May be increased	Often preserved until advanced disease, then elevated	Often preserved until advanced disease, then elevated
Diffusion capacity	Often normal	Decreased	Decreased
Static lung compliance	Normal	Increased	Increased
Chest radiograph	“Dirty lungs” with peribronchial cuffing, suggesting thickened bronchial walls	Hyperinflation, with evidence of emphysema; greater at lung apex than at lung base	Hyperinflation, with evidence of emphysema; frequently greater at lung base than at lung apex (basilar hyperlucency)

Physical examination of the chest early on in a patient with COPD may show wheezing or diminished breath sounds. Later, signs of hyperinflation may be evident—that is, increased anteroposterior diameter (sometimes called a barrel chest), diaphragm flattening, and dimpling inward of the chest wall at the level of the diaphragm on inspiration (called Hoover sign). Other late signs of COPD include use of accessory muscles of respiration (e.g., sternocleidomastoid), edema from cor pulmonale, mental status changes caused by hypoxemia or hypercapnia (especially in acute exacerbations of chronic, severe disease), or asterixis (i.e., involuntary flapping of the hands when held in an extended position, as in “stopping traffic”).

Rule Of Thumb

In patients with COPD, PaCO₂ is usually preserved until airflow obstruction is severe (i.e., FEV₁ < 1 L), when PaCO₂ may increase.

Rule Of Thumb

Digital clubbing is not caused by COPD alone, even if hypoxemia is present. Clubbing in a patient with COPD warrants consideration of another cause (e.g., bronchogenic cancer, bronchiectasis).

Management

In managing patients with chronic, stable COPD, the following goals must guide the clinician 1,2:

• Establish the diagnosis of COPD.

• Optimize lung function.

• Maximize the patient’s functional status.

• Simplify the medical regimen as much as possible.

• Prolong survival whenever possible.

In managing an acute exacerbation of COPD, additional considerations are to reestablish the patient to baseline status as quickly and with as little incidence of morbidity and mortality as possible.20,21 Each of the treatments discussed in this section is considered in the context of these goals, recognizing differences in management between patients with chronic, stable COPD versus an acute exacerbation of COPD. In patients with COPD, PaCO₂ usually is generally preserved until airflow obstruction is severe (FEV₁ < 1 L), when the PaCO₂ level may increase.

Establishing the Diagnosis

Although a spectrum of diseases can give rise to obstructive lung disease, including some unusual entities such as chronic eosinophilic pneumonia, bronchiectasis, and allergic bronchopulmonary aspergillosis, the major challenge facing the clinician who encounters a patient with airflow obstruction is to distinguish COPD (i.e., emphysema or chronic bronchitis or both) from asthma. Distinguishing asthma from COPD may be very difficult in practice; features that tend to favor COPD include chronic daily phlegm production, which establishes the diagnosis of chronic bronchitis; diminished vascularity on chest radiograph; and a decreased diffusing capacity. The diagnosis of asthma is favored if the diminished FEV₁ obtained on spirometry can be normalized after use of an inhaled bronchodilator.

After the diagnosis of COPD is established, a secondary issue is for the clinician to consider whether the patient has an underlying predisposition to COPD, such as AAT deficiency or other cause listed in Box 23-1.^17,18 Underlying causes are present in fewer than 5% of patients with COPD, with AAT deficiency being the most common (2% to 3% of all patients with COPD).

Mini Clini

Determining the Severity of Chronic Obstructive Pulmonary Disease

Problem

You are called to see a patient with COPD (FEV₁ 40% predicted) and are asked to describe the severity of the patient’s illness to a colleague. How do you characterize the severity of COPD?

Discussion

The severity of COPD is described by the degree of airflow obstruction. Traditional descriptors such as hypoxemia and hypercapnia are useful for characterizing COPD. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has proposed a staging system for COPD.² According to this staging system, patients are categorized into one of the following four stages:

Stage	Description
I	Patients with FEV₁/FVC < 70% and FEV₁ > 80% predicted
II	Patients with FEV₁/FVC < 70% and FEV₁ 50%-79% predicted
III	Patients with FEV₁/FVC < 70% and FEV₁ 30%-49% predicted
IV	Patients with FEV₁/FVC < 70% and FEV₁ < 30% or FEV₁ < 50% predicted plus chronic respiratory failure

This patient would be described as having stage III COPD. The stages generally correspond to other physiologic features of COPD. Patients with stage I COPD do not usually have severe hypoxemia. Also, hypercapnia from airflow obstruction would not be expected in patients with stage I COPD, and an arterial blood gas analysis usually is not recommended. Patients with stage III or IV COPD may require supplemental O₂. A blood gas analysis may be helpful in assessment of these patients.

Optimizing Lung Function

Stable Chronic Obstructive Pulmonary Disease

Although airflow obstruction from emphysema itself is irreversible, most (up to two-thirds) patients with stable COPD exhibit a reversible component of airflow obstruction, defined as a 12% and 200-ml increase in postbronchodilator FEV₁ or FVC or both. For this reason, as indicated in an algorithm developed by GOLD (Figure 23-4),^2,22–24 bronchodilator therapy is recommended for patients with COPD.

FIGURE 23-4 COPD management algorithm. (From The Global Strategy for the Diagnosis, Management and Prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease [GOLD], 2006. http://www.goldcopd.com.)

Bronchodilators produce smooth muscle relaxation resulting in improved airflow obstruction, improved symptoms and exercise tolerance, and decrease in the frequency and severity of exacerbations, but they do not enhance survival. The results of the Lung Health Study,⁹ which compared the effects of inhaled ipratropium bromide (two puffs four times daily) with placebo in patients with mild, stable COPD, showed that regular, long-term use of ipratropium did not change the rate of decline of lung function but offered a one-time, small increase in FEV₁.

Both anticholinergic and adrenergic (beta agonist) bronchodilators can improve airflow in patients with COPD, although some clinicians favor an inhaled anticholinergic medication (e.g., ipratropium bromide or tiotropium 22–24) as first-line therapy (Figure 23-5). More recent concerns about the possible adverse cardiovascular effects of anticholinergic therapy in patients with COPD²⁵ have been dismissed by the results of a multicenter trial (UPLIFT [Understanding Potential Long-Term Impacts on Function with Tiotropium]), which found a significantly lower rate of cardiac adverse events and cardiovascular death in patients who received tiotropium.²⁶

FIGURE 23-5 Cumulative percent survival of patients in the Nocturnal Oxygen Therapy Trial (NOTT) and Medical Research Council (MRC) controlled trials of long-term domiciliary O₂ therapy for men older than 70 years. MRC control subjects *(red line)* received no O₂. NOTT subjects *(purple line)* received O₂ for 12 hours in the 24-hour day, including the sleeping hours. MRC O₂ subjects *(blue line)* received O₂ for 15 hours in the 24-hour day, including the sleeping hours, and continuous O₂ therapy (COT) subjects *(green line)* received O₂ for 24 hours in the 24-hour day (on average, 19 hours). (Modified from Flenley DC: Long-term oxygen therapy. Chest 87:99–193, 1985.)

The GOLD guidelines ² recommend the use of short-acting beta-adrenergic agents (≤6 hours) for symptomatic management of all patients with COPD. Also, the use of a long-acting beta agonist (e.g., salmeterol) or a long-acting anticholinergic drug (e.g., tiotropium) can lessen the frequency of acute exacerbations of COPD.²⁵

Other treatment options to optimize lung function include administering corticosteroids and methylxanthines. Systemic corticosteroids can produce significant improvements in airflow in a few (6% to 29%) patients with stable COPD.²⁷ To assess whether airflow obstruction is completely reversible (i.e., the patient has asthma) and whether a patient with COPD is responsive to steroids, a brief course of corticosteroids (20 to 40 mg/day of prednisone or equivalent for 10 to 14 days) is often recommended. Patients with a significant clinical response often are treated with long-term inhaled corticosteroids or rarely with the smallest necessary dose of systemic corticosteroids, recognizing that long-term systemic steroid therapy has risks.²⁸ Also, results of several major clinical trials (e.g., Lung Health Study II, Euroscop, ISOLDE, and Copenhagen City Study but not TORCH) agree that inhaled corticosteroids do not change the rate of decline of FEV₁ in patients with COPD, although their use is associated with a decreased frequency of acute exacerbations.^29,30

Studies of combined salmeterol and fluticasone versus placebo in patients with COPD suggest that adding an inhaled corticosteroid (fluticasone) to the long-acting beta agonist (salmeterol) can improve FEV₁ and can reduce the frequency of acute exacerbations of COPD but does not improve survival.29,30 The finding of a higher rate of pneumonia in inhaled corticosteroid users is concerning. Overall, the GOLD guidelines² recommend use of inhaled corticosteroids in patients with FEV₁ less than 50% and history of recurrent exacerbations (three episodes in the last 3 years), whereas the ATS/European Respiratory Society (ERS) guidelines recommend use of inhaled corticosteroids in patients with FEV₁ less than 50% who have required use of oral corticosteroids or oral antibiotics at least once within the last year.³¹

Treatment with methylxanthines offers little additional bronchodilation in patients using inhaled bronchodilators and generally is reserved for patients with debilitating symptoms from stable COPD despite optimal inhaled bronchodilator therapy. Controlled trials show lessened dyspnea in methylxanthine recipients despite a lack of measurable increases in airflow.³² Side effects of methylxanthines include anxiety, tremulousness, nausea, cardiac arrhythmias, and seizures. To minimize the chance of toxicity, current recommendations suggest maintaining serum theophylline levels at 8 to 10 mcg/ml.

Acute Exacerbations

Strategies for improving lung function during acute exacerbations of COPD generally include inhaled bronchodilators (especially beta-2 agonists), antibiotics, and systemic corticosteroids. Because of their rapid onset of action and efficacy, short-acting beta-2 agonists are first-line therapy for patients with COPD exacerbation. Inhaled beta-2 agonists are frequently administered through a nebulizer, although metered dose inhaler devices may have equal efficacy if administered appropriately.² A common practice is to administer 2.5 mg of albuterol by nebulizer every 1 to 4 hours as needed. Higher doses of albuterol (i.e., 5 mg) do not produce further improvement in pulmonary function and may cause cardiac side effects.³³ Similarly, continuous nebulization of short-acting beta-2 agonists in patients with COPD exacerbation is not recommended.

In addition to inhaled bronchodilator therapy, short-term systemic corticosteroids are recommended to reduce inflammation and improve lung function. An early randomized, controlled trial of intravenous methylprednisolone for patients with acute exacerbations showed accelerated improvement in FEV₁ within 72 hours.³⁴ Larger, more recent trials have confirmed the benefits of systemic corticosteroids in acute exacerbations and have shown that short-term oral courses (i.e., approximately 2 weeks) are as effective as longer courses (i.e., 8 weeks) with fewer adverse steroid effects.³⁵ For patients with acute exacerbations characterized by purulent phlegm, oral antibiotics (e.g., trimethoprim-sulfamethoxazole, amoxicillin, or doxycycline) administered for 7 to 10 days have produced accelerated improvement of peak flow rates compared with placebo recipients.^20,36,37

Finally, intravenous methylxanthines offer little benefit in the setting of acute exacerbations of COPD and have fallen into disfavor.38,39 Taken together, important elements of managing an acute exacerbation of COPD caused by purulent bronchitis include supplemental oxygen (O₂) to maintain arterial saturation at greater than 90%, inhaled bronchodilators, oral antibiotics, and a brief course of systemic corticosteroids.²⁰

For patients with hypercapnia and acute respiratory acidemia, the clinician also must decide whether to institute ventilatory assistance. Although intubation and mechanical ventilation historically have been the preferred approach, more recent studies suggest that noninvasive positive pressure ventilation can be an appealing alternative for patients with acute exacerbations of COPD, especially with severe exacerbations characterized by pH less than 7.30.⁴⁰ Specifically, based on available randomized, controlled clinical trials showing that noninvasive positive pressure ventilation can shorten intensive care unit (ICU) stay and avert the need for intubation, the American Association for Respiratory Care consensus conference and guidelines on noninvasive ventilation from other official societies have endorsed this approach.^41,42 Criteria defining candidacy for noninvasive ventilation include acute respiratory acidosis (without frank respiratory arrest); hemodynamic stability; ability to tolerate the interface needed for noninvasive ventilation; ability to protect the airway; and lack of craniofacial trauma or burns, copious secretions, or massive obesity.⁴¹

Maximizing Functional Status

In symptomatic patients with stable COPD, maximizing their ability to perform daily activities is a priority (see Figure 23-4). Pharmacologic treatments to maximize functional status include administration of bronchodilators to enhance lung function as much as possible and consideration of methylxanthine therapy, based on data that such drugs can lessen dyspnea and improve functional status ratings even in the absence of improved airflow.³²

Comprehensive pulmonary rehabilitation is a multidisciplinary intervention that consists of lower and upper extremity exercise conditioning, breathing retraining, education, and psychosocial support. Pulmonary rehabilitation is an additional important strategy for improving functional status.⁴³ Randomized, controlled trials show that although pulmonary rehabilitation does not improve lung function or survival, this strategy results in decreased dyspnea perception, improved health-related quality of life, fewer days of hospitalization, and decreased health care usage.^44,45

Finally, transcutaneous neuromuscular electrical stimulation is a new experimental therapy that has been successfully used to stimulate peripheral muscles in patients with COPD. Studies have shown significant improvements in quadriceps muscle function, exercise tolerance (including walk distance), and health status in patients with severe COPD.⁴⁶

Mini Clini

Recognizing and Managing an Acute Exacerbation of Chronic Obstructive Pulmonary Disease

Problem

A 70-year-old man with long-standing COPD is admitted to the hospital with an acute exacerbation. On physical examination, he is not dehydrated, and examination shows diminished breath sounds bilaterally without wheezing. Pertinent laboratory values show a hematocrit of 54% (normal is 40%-47%). An arterial blood gas analysis taken on room air revealed the following:

How do you describe his current status, what do his current laboratory values suggest about his long-term gas exchange status, and what treatment should be considered?

Solution

The patient has an acute exacerbation of COPD. The acidemia (pH 7.30) on his arterial blood gas analysis suggests an acute increase in PCO₂ superimposed on chronic hypercapnia, which is suggested by the elevated serum bicarbonate (HCO₃⁻), indicating renal compensation for chronic respiratory acidosis. Although his current hypoxemia may be due to worsened gas exchange accompanying the current flare-up of COPD, his elevated hematocrit, in the absence of dehydration, suggests chronic hypoxemia and secondary erythrocytosis. The goal of therapy is to restore his gas exchange to baseline and to avoid invasive or high-risk interventions, while optimizing survival.

To achieve these goals, treatment would consist of aggressive use of bronchodilators, intravenous corticosteroids, supplemental O₂, and antibiotics (if there is evidence of acute lung infection, either bronchitis or pneumonia). In view of the patient’s acute chronic respiratory acidemia, ventilatory support should be implemented. As indicated by several randomized, controlled trials, noninvasive positive pressure ventilation is an effective alternative to intubation.

Preventing Progression of Chronic Obstructive Pulmonary Disease and Enhancing Survival

Cigarette smoking is widely recognized as the major risk factor for accelerating airflow obstruction in smokers who are “susceptible.” For these individuals, smoking cessation can slow the rate of decline of FEV₁ and restore the rate of lung decline to that seen in healthy, age-matched nonsmokers.

Follow-up data from the Lung Health Study ⁹ confirm that a comprehensive smoking cessation program (including instruction, group counseling, and nicotine replacement therapy) can achieve sustained smoking cessation in 22% of participants and that the rate of annual FEV₁ decline in these sustained nonsmokers was significantly less than it was for continuing smokers, even over 11 years of follow-up.¹⁰ Participation in aggressive smoking cessation can enhance survival rates in patients with COPD.¹⁰

Critical elements in achieving successful abstinence from smoking include identifying “teachable moments” (i.e., during episodes of illness where smoking can be identified as a contributing factor ⁴⁷), identifying the role of smoking in adverse health outcomes, negotiating a “quit date,” and providing frequent follow-up reminders from health care providers.⁴⁸ A helpful strategy during counseling is to use the five A’s of smoking cessation²:

Ask if they are smoking

Advise to quit

Assess willingness to quit

Assist by providing a plan

Arrange a follow up

In this regard, the respiratory therapist (RT), who sees the patient frequently, has a special responsibility to provide frequent, constructive reminders about the advisability of smoking cessation.⁴⁹

Among available treatments for COPD, supplemental oxygen is important because, similar to smoking cessation and lung volume reduction surgery in selected individuals (see later), it can prolong survival.50–53 Box 23-2 reviews the indications for supplemental O₂, and Figure 23-5 shows the results of the American Nocturnal Oxygen Therapy Trial⁵⁰ and the British Medical Research Council trial of domiciliary O₂ (1980-1981).^51,52 Survival was improved when eligible patients used supplemental O₂ for as close to 24 hours as possible; survival improved less for patients using O₂ only 15 hours per day. No survival advantage was observed when O₂ use was confined to the sleeping hours. Patients should be assessed for supplemental O₂ use only after receiving optimal bronchodilator therapy because one-third of potential O₂ candidates can experience sufficient improvement with aggressive bronchodilation to avoid the need for long-term supplemental O₂. Also, patients prescribed to receive supplemental O₂ during acute exacerbations should be reassessed several months later to determine whether their candidacy and need for supplemental O₂ continue.⁵⁴ RTs can play a key role in ensuring compliance with this recommendation and optimizing O₂ therapy.^54,55

Box 23-2

Indications for Long-Term Oxygen Therapy

I Continuous O₂

A Resting PaO₂ ≤ 55 mm Hg

B Resting PaO₂ 56-59 mm Hg or SaO₂ 89% in the presence of any of the following:

1. Dependent edema, suggesting congestive heart failure

2. P. pulmonale on the electrocardiogram (P wave >3 mm in standard lead II, III, or aV_F)

3. Erythrocytosis (hematocrit >56%)

(a) Reimbursable only with additional documentation justifying O₂ prescription and a summary of more conservative therapy that has failed

II Noncontinuous O₂

A O₂ flow rate and number of hours per day must be specified

1. During exercise: PaO₂ ≤ 55 mm Hg or SaO₂ ≤ 88% with a low level of exertion

2. During sleep: PaO₂ ≤ 55 mm Hg or SaO₂ ≤ 88% with associated complications, such as pulmonary hypertension, daytime somnolence, or cardiac arrhythmias

From Tarpy SP, Celli BR: Long-term oxygen therapy. N Engl J Med 333:710–714, 1995.

Finally, preventive strategies such as annual influenza and pneumococcal vaccinations are recommended for all patients with chronic debilitating conditions such as COPD.⁵⁶ Specific indications for pneumococcal vaccination are presented in Box 23-3.

Box 23-3 Indications for Pneumococcal Vaccine Administration

Vaccination is recommended for the following adults:

• Adults age 65 years and older and adults of all ages with long-term illnesses that are associated with a high risk of contracting pneumococcal disease, including heart or lung diseases, diabetes, alcoholism, cirrhosis, or cerebrospinal fluid leaks

• Adults with diseases or conditions that lower the body’s resistance to infections, including abnormal function of the spleen or removed spleen, Hodgkin disease, lymphoma, multiple myeloma, kidney failure, nephrotic syndrome, or organ transplantation, and adults who are taking drugs that lower the body’s resistance to infections

• Adults with HIV/AIDS infection, with or without symptoms

Revaccination should be considered for the following groups:

• Individuals at the highest risk of fatal pneumococcal infection, such as individuals with abnormal function or removal of the spleen, who received the original pneumococcal vaccination (from 1979-1983) or who received the current vaccine (1983 to present) ≥6 years ago

• Individuals shown to lose protection rapidly (e.g., individuals with nephrotic syndrome, kidney failure, or transplants), who received the current vaccine ≥6 years ago

• Children ≤10 years old with nephrotic syndrome, abnormal function or removal of the spleen, or sickle cell anemia, who received the vaccine 3-5 years ago

Additional Therapies

Additional therapies for individuals with end-stage COPD include lung transplantation ⁵⁷ and lung volume reduction surgery (LVRS),^58–60 in which small portions of emphysematous lung are removed to reduce hyperinflation and improve lung mechanics of the remaining tissue. COPD is the most common current indication for lung transplantation. Lung transplantation is a consideration for patients with severe airflow obstruction (i.e., FEV₁ < 20% predicted) who are younger than 65 years old, who lack major dysfunction of other organs, and who are psychologically and motivationally suitable. Given the scarcity of available lungs to transplant, single-lung transplantation usually is performed for individuals with COPD. Although lung transplantation may be associated with significantly improved quality of life and functional status, major risks include rejection (manifested as bronchiolitis obliterans and progressive, debilitating airflow obstruction), infection with unusual opportunistic organisms, and death from these and other complications. The 5-year actuarial survival rate after single-lung transplantation is approximately 54% (Figure 23-6).

FIGURE 23-6 Actuarial survival curves according to pretransplant diagnosis. The overall survival rate of patients with emphysema (including AAT deficiency) is significantly higher than the survival rate of patients with idiopathic pulmonary fibrosis. (From Christie JD, Edwards LB, Kucheryavaya AY, et al: 27th offical adult lung and heart-lung transplant report, 2010 in the Registry of the International Society for Heart and Lung Transplantation. www.ishlt.org. Accessed January 6, 2010.)

LVRS has regained popularity after initial experiences were reported in 1957.⁵⁸ Results of randomized controlled trials of LVRS, including the large National Emphysema Treatment Trial, indicate that in selected subsets of patients with COPD (i.e., patients with heterogeneous emphysema that is upper lobe predominant and who have low exercise capacity after pulmonary rehabilitation), LVRS can prolong survival, improve quality of life, and increase exercise capacity.^59,60 LVRS should not be considered in individuals with very severe COPD (i.e., characterized by FEV₁ < 20% predicted with either a homogeneous pattern of emphysema or a diffusing capacity <20% predicted) because the mortality rate of LVRS is higher in such individuals than in medically treated patients.⁶¹

Given the positive results associated with LVRS in selected patients with COPD, nonsurgical bronchoscopic techniques have been developed in an attempt to reduce costs and expand treatment options for patients with high operative risk.⁶² With the use of the bronchoscope, deployment of unidirectional endobronchial valves into the airways results in collapse of the targeted lung parenchyma. Other techniques include application of biodegradable gel to induce lung collapse or application of bronchial stents to create fenestrations and allow gas escape from hyperinflated areas of the lung. None of the aforementioned devices is currently approved by the U.S. Food and Drug Administration (FDA) for treatment of emphysema in the United States.⁶³

Finally, for patients with AAT deficiency and established COPD, so-called intravenous augmentation with a purified preparation of AAT from human blood donors is recommended.¹⁴ Although no definitive randomized, controlled trials are available,^64,65 observational studies suggest that for individuals with severe AAT deficiency and moderate degrees of airflow obstruction (i.e., FEV₁ 35% to 60% predicted), weekly augmentation therapy may be associated with a slower rate of decline of lung function and improved survival. Difficulties with intravenous augmentation therapy include the substantial expense (approximately $100,000 per year); the inconvenience of frequent intravenous infusions for life; and the infusion itself, which confers a theoretical risk of transmitting a blood-borne infection. Despite these drawbacks, the facts that augmentation therapy can slow the rate of FEV₁ decline, can possibly slow the rate of computed tomography (CT) density loss, and is currently the only specific therapy for AAT deficiency have led to its endorsement in official guidelines from the ATS, the ERS, and the Canadian Thoracic Society.^14,48,66

Asthma

Definition

Asthma is a clinical syndrome characterized by airway obstruction, which is partially or completely reversible either spontaneously or with treatment; airway inflammation; and airway hyperresponsiveness (AHR) to various stimuli.67–69 Past definitions of asthma emphasized AHR and reversible obstruction; however, newer and more accurate definitions of asthma focus on asthma as a primary inflammatory disease of the airways, with clinical manifestations of increased airway hyperreactivity and airflow obstruction caused by the inflammation.

Table 23-2 outlines the stepwise approach currently recommended for long-term management of asthma. This approach provides a framework for an individually tailored dose of medication based on the severity of asthma in any patient at a particular time. This approach acknowledges that asthma is a chronic and dynamic disease, which needs optimum control. Control of asthma is defined as minimal to no chronic diurnal or nocturnal symptoms, infrequent exacerbations, minimal to no need for beta-2 agonists, no limitation to exercise activity, PEFR or FEV₁ greater than 80% predicted with less than 20% diurnal variation, and minimal to no adverse effects of medication.^67–69

TABLE 23-2

Stepwise Approach to Long-Term Management of Asthma Based on Severity

Severity*	Clinical Features Before Treatment^†	PEFR or FEV₁	Long-Term Preventive Medications	Quick-Relief Medications
Step 4
Severe persistent	Continuous symptoms	≤60% predicted	Inhaled corticosteroids ≥800-2000 mcg/day	Inhaled beta-2 agonist as needed for symptoms
Red zone	Frequent exacerbations	>30% variability	Long-acting bronchodilator^‡
	Nocturnal symptoms		Oral corticosteroids
	Symptoms limit activity
Step 3
Moderate persistent	Daily symptoms	>60%-<80% predicted	Inhaled corticosteroids ≥800-2000 mcg/day	Inhaled beta-2 agonist as needed for symptoms, not to exceed 3-4 times per day
Yellow zone	Exacerbations affect activity and sleep	>30% variability	Long-acting bronchodilator,^‡ especially for nocturnal symptoms
	Nocturnal symptoms more than once per week
	Daily use of short-acting beta-2 agonist
Step 2
Mild persistent	Symptoms at least once per week but <1 time per day	≥80% predicted	Inhaled corticosteroid, 200-500 mg/day, cromolyn, or nedocromil	Inhaled beta-2 agonist as needed for symptoms, not to exceed 3-4 times per day
Yellow zone	Exacerbations may affect activity or sleep	20%-30% variability	Long-acting bronchodilator^‡ for nocturnal symptoms
	Nocturnal symptoms more than twice per month
Step 1
Intermittent	Intermittent symptoms less than once per week	≥80% predicted	None needed	Inhaled beta-2 agonist needed for symptoms but less than once per week
Green zone	Nocturnal symptoms not more than twice per month	<20% variability		Inhaled beta-2 agonist or cromolyn before exercise or exposure to allergen
	Asymptomatic with normal lung function between exacerbations

^*Step-down: Review treatment every 3-6 months. If control is sustained for at least 3 months, consider a gradual stepwise reduction in treatment. Step-up: If control is not achieved, consider step-up, but first review patient medication technique, compliance, and environmental control.

^†The presence of one of the features of severity is sufficient to place a patient in that category.

^‡Long-acting beta-2 agonist or sustained-release theophylline.

Modified from Global Initiative for Asthma: Asthma management and prevention: a practical guide for public health officials and health care professionals, NIH publication no. 96-3659A, Bethesda, MD, 1995, National Institutes of Health, National Heart, Lung, and Blood Institute, and World Health Organization.

Mini Clini

Diagnosis of Wheezing

Problem

You are asked to see a patient with a history of wheezing. The patient notes that the wheezing has been continuous, has been present for several months, and has been unresponsive to bronchodilator medications, including systemic corticosteroids and various inhaled bronchodilators.

Solution

The patient has either refractory asthma or a condition mimicking asthma. The aphorism “all that wheezes is not asthma” applies here, and the clinician should suspect alternative diagnoses. Features that are atypical for asthma in this patient are the continuous nature of the wheezing and its complete refractoriness to medication. With this in mind, consideration of other “wheezy” disorders should include abnormalities of the upper airway. Specifically, tracheal stenosis or fixed upper airway obstruction (e.g., caused by tracheal tumors) could account for the patient’s symptoms. Another condition that mimics asthma is vocal cord dysfunction. Characteristically, vocal cord dysfunction causes stridor with convergence of the vocal cords on inspiration (a paradoxical response). However, vocal cord dysfunction also can cause expiratory wheezing, with closure of the vocal cords on expiration. Further assessment of this patient might include a flow-volume loop or a fiberoptic examination of the upper airway, observing both the vocal cords and the trachea to the level of the main stem bronchi.

Objective Measurement and Monitoring

Objective measurement of lung function is particularly important in asthma because subjective measures, such as patient reports of the degree of dyspnea and physical examination findings, often do not correlate with the variability and severity of airflow obstruction. It is recommended that spirometry be performed as part of the initial assessment of all patients being evaluated for asthma and periodically thereafter as needed.

Either spirometry or PEFR measurement can be used to assess response to therapy in the outpatient setting, emergency department, or hospital. NAEP guidelines also recommend that home PEFR measurement be used for patients with moderate to severe asthma.

When patients learn how to take PEFR measurements at home, the clinician is better able to recommend effective treatment. Daily monitoring of PEFR helps detect early stages of airway obstruction. All PEFR measurements are compared with the patient’s personal best value, which can be established during a 2- to 3-week asymptomatic period when the patient is being treated optimally.67–69

To help patients understand home PEFR monitoring, a zonal system corresponding to the traffic light system may be helpful (see Table 23-2). A PEFR measurement of 80% to 100% of the personal best is considered to be in the green zone. No asthma symptoms are present, and maintenance medications can be continued or tapered. A PEFR in the 60% to 80% range of the personal best is in the yellow zone and may indicate an acute exacerbation and requires a temporary step-up in treatment. A PEFR less than 60% of the personal best is in the red zone and signals a medical alert, requiring immediate medical attention if the patient does not return to the yellow zone or green zone with bronchodilator use.⁶⁹

Pharmacotherapy

Pharmacotherapy for asthma reflects the basic understanding that asthma is a chronic inflammatory airway disease that requires long-term antiinflammatory therapy for adequate control.67–76 Antiinflammatory agents, such as corticosteroids and cromolyn, suppress the primary disease process and its resultant airway hyperreactivity. Bronchodilators, such as beta-2-adrenergic agonists, anticholinergics, and theophylline, relieve asthma symptoms. Because asthma is a disease of the airways, inhalation therapy is preferred to oral or other systemic therapy. Inhaled therapy using metered dose inhalers or powders allows high concentration of the medication to be delivered directly to the airways, resulting in fewer systemic side effects. Spacer devices can be used to improve delivery of inhaled medication, but training and coordination are still required for patients using metered dose inhalers. Table 23-3 lists commonly used medications in the treatment of asthma.

TABLE 23-3

Medications Commonly Used in the Treatment of Asthma and COPD

Medication	Trade Names	Available Preparations	Usual Dosage
Inhaled Corticosteroids
Beclomethasone	Beclovent, Vanceril	MDI 42 mcg/puff, 200 puffs/canister	2 puffs tid-qid, maximum 20 puffs/day
Triamcinolone	Azmacort	MDI 100 mcg/puff, 240 puffs/canister	2-4 puffs qid, maximum 16 puffs/day
Flunisolide	AeroBid	MDI 250 mg/puff, 100 puffs/canister	2 puffs bid, maximum 8 puffs/day
Fluticasone	Flovent	MDI 44, 110, 220 mcg/puff	88-880 mcg/day
Mometasone	Asmanex	DPI 220 mcg/spray	1-2 sprays qd-bid, maximum 4 puffs/day
Budesonide	Pulmicort	DPI 90, 180 mcg/puff	360-720 mcg/day
Systemic Corticosteroids
Prednisone	Many	Tablets 1, 5, 20, 50 mg	5-50 mg/day
Methylprednisolone	Medrol	Tablets 2, 4, 8, 16, 24, 32 mg	4-48 mg/day
	Solu-Medrol	IV 40, 125, 500, 1000 mg	1-2 mg/kg q4-6h
Hydrocortisone	Solu-Cortef	IV 100, 250, 500, 1000 mg	4 mg/kg q4-6h
Beta-2 Agonists
Albuterol	Proventil	MDI 90 mcg/puff, 200 puffs/canister	2-4 puffs q4-6h, maximum 20 puffs/day
	Ventolin	Solution for nebulizer 0.083% and 0.5%	2.5-10 mg q6-8h
		Tablets 2, 4 mg	2-4 mg q6-8h
	Volmax	Sustained-release tablets 4, 8 mg	4-8 mg q12h
Metaproterenol	Alupent	MDI 650 mcg/puff, 200 puffs/canister	2-3 puffs q3-4h, maximum 12 puffs/day
	Metaprel	Solution 0.5%	2.5-10 mg q4-6h
		Tablets 10, 20 mg	10 mg q6-8h
Pirbuterol	Maxair	MDI 200 mcg/puff, 300 puffs/canister	1-2 puffs q4-6h, maximum 12 puffs/day
Terbutaline	Breathaire	MDI 200 mcg/puff, 300 puffs/canister 1-2 puffs q4-6h
	Bricanyl	Tablets 2.5, 5 mg	2.5-5 mg tid, maximum 15 mg/day
		Solution 1 mg/ml	0.25 mg SC q15-30min
Salmeterol	Serevent	MDI 50 mcg/puff	2 puffs q12h
Formoterol	Foradil	DPI 12 mcg/capsule	1 capsule inhaled q12h
Arformoterol	Brovana	Solution 15 mcg/ml	15 mcg inhaled bid
Anticholinergics
Ipratropium bromide	Atrovent	MDI 18 mcg/puff, 200 puffs/canister	2-4 puffs q6h
		Solution for nebulizer 0.02%
		0.5 mg/2.5 ml vial, 0.5 mg qid
Tiotropium	Spiriva	DPI 18 mcg/capsule	1 capsule inhaled/day
Methylxanthines
Aminophylline		IV	Load 5-6 mg/kg, maintenance
		Tablets or capsules	0.5-0.9 mg/kg/hr
Theophylline	Theo-Dur		300-1200 mg/day divided q6-8h
	Slo-bid		for immediate and q12-24h
	Theovent		for sustained
	Uniphyl
	(immediate or sustained release)
Leukotriene Inhibitors
Zafirlukast	Accolate	Tablets 20 mg	20 mg bid
Zileuton	Zyflo	Tablets 600 mg	600 mg qid
Montelukast	Singulair	Tablets 10 mg	10 mg qd
Other
Cromolyn	Intal	MDI 800 mcg/puff, 112 puffs/canister	2 puffs qid
		Spinhaler 20 mg/capsule	20 mg qid
Nedocromil	Tilade	MDI 1.75 mg/puff, 112 puffs/canister	2 puffs bid-qid

DPI, Dry powder inhaler; IV, intravenous; MDI, metered dose inhaler; SC, subcutaneous.

Corticosteroids

Corticosteroids are the most effective medication currently available for the treatment of asthma. Although their mode of action is still uncertain, corticosteroids probably act on various components of the inflammatory response in asthma.⁷⁶ Inhaled corticosteroids are effective locally, and regular use suppresses inflammation in the airways, decreases bronchial hyperreactivity and airflow obstruction, and reduces the symptoms of and mortality from asthma. Long-term, high-dose inhaled corticosteroids have far fewer side effects than oral corticosteroids. Side effects such as oropharyngeal candidiasis and dysphonia are controllable with spacer use and by rinsing the mouth after each treatment.

Oral corticosteroids are effective for treating asthma, but the potential for devastating side effects during long-term use restricts their use to patients not responding to other forms of asthma therapy. Short-term, high-dose (0.5 to 1.0 mg/kg/day) oral corticosteroid therapy during exacerbation reduces the severity and duration, decreases the need for emergency department visits and hospitalization, and reduces mortality.⁷⁶

Cromolyn

Cromolyn sodium is a noncorticosteroid antiinflammatory medication. Its mechanism of action is not completely understood, but it has a protective effect against provocative stimuli such as allergens, cold air, and exercise. The drug is most effective when administered prophylactically. Cromolyn does not dilate smooth muscle and is not useful for treating the symptoms of an acute asthma attack. Cromolyn is useful in cough-variant and exercise-induced asthma but otherwise has only limited usefulness in the treatment of adult asthmatics. However, many experts believe that cromolyn is the drug of choice for atopic children with asthma.⁷²

Nedocromil

In 1993, nedocromil was approved in the United States for use in metered dose inhalers. It is structurally different from cromolyn but has similar pharmacologic activity and is 4 to 10 times more potent in preventing acute allergic bronchospasm. Nedocromil can be used as an alternative to cromolyn, but neither nedocromil nor cromolyn has a clear advantage over inhaled corticosteroids.⁷²

Leukotriene Inhibitors

Leukotrienes are mediators of inflammation and bronchoconstriction and are thought to play a role in the pathogenesis of asthma. Three leukotriene antagonists are currently available for the treatment of asthma. Montelukast (Singulair; Merck, Whitehouse Station, NJ) and zafirlukast (Accolate; Astra Zeneca, London, United Kingdom) are leukotriene receptor antagonists, and zileuton (Zyflo; Abbott Laboratories, Chicago, IL) is a leukotriene synthesis inhibitor. These agents all are modestly effective for maintenance of mild to moderate asthma, but their exact role in asthma therapy remains to be determined. Inhaled steroids remain the antiinflammatory drugs of choice for the treatment of asthma.⁷⁷

Beta-2-Adrenergic Agonists

Inhaled beta-2-adrenergic agents are the most rapid and effective bronchodilators for the treatment of asthma. They are the drugs of choice for all types of acute bronchospasm, and they provide protection from all bronchoconstrictor challenges when given prophylactically. However, they do not prevent the late asthmatic response. Beta-2 agonists are the drugs of choice for exercise-induced asthma. They exert their action by attaching to beta receptors on the cell to produce smooth muscle relaxation and by blocking mediator release from mast cells.

The effectiveness of beta-2 agonists as bronchodilators is not disputed, and they are the drug of choice for acute emergency management of asthma. However, there is concern that they may worsen asthma control if used regularly and that excessive use may increase the risk of death from asthma, which makes the role of beta-2 agonists in long-term maintenance therapy questionable.

Although there is sufficient concern regarding fenoterol to justify avoiding its use, it remains unclear whether the association between excessive beta-2 agonist use and death from asthma is a genuine or spurious association.⁷⁷ It is clear, however, that excessive beta-2 agonist use by asthmatics indicates an increased risk of death from asthma and indicates the need for more effective antiinflammatory therapy. There is currently little definitive evidence to establish that treatment with conventional doses of the short-acting beta-2 agonists available in the United States is harmful to asthmatic patients.^75,76,78 The NAEP guidelines recommend that inhaled beta-2 agonists be used as needed. If a patient needs more than 3 or 4 puffs a day of a beta-2 agonist, additional antiinflammatory therapy should be considered.⁷⁷

Newer, longer acting (12 to 24 hours) beta-2 agonists, such as salmeterol and formoterol, are available in the United States. Their mechanism of action is different from the shorter acting beta-2 agonists discussed earlier. Long-acting beta-2 agonists have use in treating nocturnal asthma.67–69,78

Monotherapy with beta agonists has been shown to be inferior to use of inhaled corticosteroids, which are recommended as first-line treatment for asthma. When added to inhaled corticosteroids, long-acting beta agonists have been found to improve asthma control, symptoms, and exacerbations. However, a meta-analysis of randomized controlled clinical trials examining outcomes for asthma control found that long-acting beta agonists increase the risk for hospitalization from asthma, life-threatening asthma attacks, and asthma-related deaths compared with placebo.⁷⁹ Several mechanisms need to be considered to explain such reactions, including paradoxical bronchospasm, increased bronchial responsiveness, and tolerance. Racial and genetic factors may also influence these outcomes.

The FDA requested manufacturers of Serevent Diskus (salmeterol xinafoate inhalation powder), Advair Diskus (fluticasone propionate and salmeterol inhalation powder), and Foradil Aerolizer (formoterol fumarate inhalation powder) to update their existing product labels with new warnings and a medication guide for patients to alert health care professionals and patients that these medicines may increase the chance of severe asthma episodes and death when such episodes occur.⁸⁰ Inhaled corticosteroids remain the first choice of therapy in asthma, and careful monitoring is required when long-acting beta agonists are used for asthma control.

Methylxanthines

The role of theophylline and similar drugs in the treatment of acute asthma is controversial. The NAEP expert panel did not recommend using theophylline routinely in the emergency treatment of asthma but did recommend its use orally or intravenously for patients admitted to the hospital for an acute asthma attack. Sustained-release theophyllines added to long-term asthma management therapy may be helpful in controlling nocturnal asthma symptoms because they maintain therapeutic plasma concentrations overnight. They also are helpful in soothing the symptoms of labile asthmatics. However, the efficacy of theophylline is limited by its side effects of nausea, vomiting, headache, insomnia, seizures, and cardiac arrhythmias. Toxicity increases with blood levels greater than 15 mcg/ml, but levels of 8 to 10 mcg/ml are adequate for long-term therapy and are associated with fewer side effects.

Several factors affect the plasma levels of theophylline by increasing or decreasing hepatic metabolism of the drug. Conditions that tend to increase plasma concentrations include acute viral infections, cardiac failure, hepatic disease, and concomitant use of certain medications such as erythromycin or cimetidine. In these cases, the maintenance dose should be halved, and the theophylline blood levels should be monitored. Conditions that tend to decrease plasma levels of theophylline include cigarette smoking and use of medications that increase hepatic clearance, such as phenobarbital.67–69,72

Anticholinergics

Inhaled anticholinergic agents, such as ipratropium bromide, are effective dilators of airway smooth muscles. Although the regular use of these agents seems to be effective in patients with COPD, their benefit in the day-to-day management of asthma has not been established. Ipratropium produces bronchodilation by reduction of intrinsic vagal tone and by blocking vagal reflex bronchospasm. However, ipratropium does not stabilize mast cells or prevent mediator release and is a less potent bronchodilator than beta-2 agonists. Ipratropium has few side effects, is safe because it is poorly absorbed, adds a bronchodilator effect to beta-2 agonists, and is useful for treating cough-variant asthma. Ipratropium also can be used in treating acute asthma when first-line bronchodilators are ineffective. The long-acting anticholinergic agent, tiotropium, has been shown to enhance asthma control (e.g., improved peak expiratory flow, increased FEV₁, and improved symptoms) when added to an inhaled corticosteroid compared with doubling the inhaled steroid dose.⁸¹

Anti-IgE Therapy

IgE plays a key role in the pathogenesis of asthma, and many asthmatic patients have elevated levels of IgE.⁸² Corticosteroids do not inhibit synthesis of IgE by activated lymphocytes. Omalizumab, an antibody that binds IgE and blocks its biologic effects, has been approved by the FDA for patients with a history of allergy and with moderate to severe asthma that is poorly controlled with inhaled corticosteroids.⁸³ Studies have shown that treatment with omalizumab results in a reduction in the dose of inhaled glucocorticoids required to control symptoms and a reduction in the number of asthma exacerbation episodes.⁸⁴ For this reason, the NAEP asthma guidelines recommended that omalizumab should be considered as adjunctive therapy for patients with severe persistent asthma.⁶⁷

Emergency Department and Hospital Management

Emergency management of acute asthma should include early and frequent administration of aerosolized beta-2 agonists and therapy with systemic corticosteroids. Frequent assessment for response with PEFR should be performed. The NAEP guidelines recommend that only selective beta-2 agonists (i.e., albuterol, levalbuterol, pirbuterol) should be used in high doses to avoid cardiotoxicity.⁶⁷ It is unclear which subset of patients may benefit from continuous aerosolized beta-2 agonists.

Hospital and ICU care for patients with asthma should be aggressive. The goal is to decrease mortality and morbidity and to return the patient to preadmission stability and function as quickly as possible. Management includes O₂ supplementation, frequent administration of high doses of aerosolized beta-2 agonists (limited only by tachycardia or tremor), high-dose parenteral corticosteroids (>0.5 to 1.0 mg/kg/day), and antibiotics if there is evidence of infection. Sedatives and hypnotics should be avoided. Symptoms, PEFR, and arterial blood gases should be monitored.

Patients with severe asthma and respiratory failure (hypoxemia, hypercapnia, increased work of breathing) need ventilatory support and present special challenges. Mortality rates for these patients can reach 22%, and complications are common, especially barotrauma. These complications can be minimized by limiting peak inspiratory pressure to less than 50 cm H₂O and by the use of small tidal volumes, allowing “permissive hypercapnia” if necessary. When asthma control is achieved, hospital discharge criteria include being off O₂, with PaO₂ greater than 60 mm Hg; stable PEFR or FEV₁, with values close to the patient’s best or greater than 70% of predicted; asthma symptoms returning to preadmission levels; no nocturnal symptoms; and 12- to 24-hour stability on discharge medications.67–69

Rule Of Thumb

In a patient presenting with an acute asthma attack, PaCO₂ is usually low because of hyperventilation. A normal PaCO₂ in this situation indicates a severe attack and impending respiratory failure.

Mini Clini

Assessing the Severity of an Acute Asthma Attack

Problem

You have just obtained an arterial blood gas (ABG) analysis on a patient who sought treatment at the emergency department for an acute attack of asthma. How would the ABG analysis help you assess the severity of the attack?

Solution

In the early stages of an asthma attack, the ABG analysis shows a low PaCO₂ caused by hyperventilation. As the asthma attack progresses, and the FEV₁ decreases to less than 25% of predicted, the PaCO₂ returns to normal. When the FEV₁ decreases to less than 15% of predicted, carbon dioxide retention begins to occur. Changes in the pH reflect changes in the PaCO₂ level. The following table summarizes the ABG abnormalities based on the severity of an asthma attack:

Asthma Severity	Stage	PaO₂	PaCO₂	pH
Mild	I	Normal	Decreased	Increased
Moderate	II	Decreased	Decreased	Increased
Severe	III	Decreased	Normal	Normal
Very severe (respiratory failure)	IV	Decreased	Increased	Decreased

Bronchial Thermoplasty

Bronchial thermoplasty is a recently approved addition to treatment options for adults whose asthma remains uncontrolled despite use of inhaled steroids and long-acting beta agonists.⁸⁵ Bronchial thermoplasty is a procedure in which a probe is introduced into the central airways through a bronchoscope and heat is applied (through radiofrequency waves) to airways of 3 to 10 mm diameter with the goal to reduce the airway smooth muscle mass, reducing the ability of the airways to constrict. Studies have shown that bronchial thermoplasty improves asthma-specific quality of life and reduces the number of severe asthma exacerbation episodes and emergency department visits.^86,87 Although bronchial thermoplasty is a promising new treatment for patients with difficult to control asthma, the long-term side effects of this procedure have not been well studied, and more studies are needed before it can be recommended to all patients with poorly controlled asthma.

Immunotherapy

Immunotherapy is based on the theoretical rationale that part of the immunologic response to an administered allergen is the production of IgG-specific antibody to the allergen injected. This newly generated IgG does not affix to most cells but can react with the allergen diffusing into the tissues and “neutralize” it. Although immunotherapy is acceptable in the treatment of allergic rhinitis, its use in the treatment of asthma is not standardized and remains controversial. However, a meta-analysis of 88 randomized controlled trials of injection allergen immunotherapy for asthma reported that immunotherapy is effective, with evidence of significant reductions in asthma medications and symptoms and a reduction in the degree of bronchial hyperreactivity.⁸⁸

Environmental Control

The association between asthma and allergy has long been recognized. Of patients with asthma, 75% to 85% are reported to have positive immediate skin test reaction to common inhalant allergens. A thorough history is essential to diagnosing whether a patient’s asthma has an allergic component and to determining the relationship between exposure to an allergen and the occurrence of symptoms. Skin tests are more helpful for excluding an allergen as a cause of asthma symptoms because clinical sensitivity to an aeroallergen is rare in the absence of a positive skin test, whereas many positive skin tests do not have clinical relevance.

To prevent allergic reactions in asthma patients, environmental control measures to reduce exposure to indoor and outdoor allergens and irritants are essential. Patients should be advised to avoid outdoor antigens, primarily ragweed, grass, pollens, and molds. Exposure to outdoor allergens is best reduced by staying indoors, with the windows closed, in an air-conditioned environment, particularly during the midday and afternoon, when pollen and some mold counts are highest. Patients who are allergic to indoor allergens, primarily house-dust components and indoor molds, should implement strategies for eliminating these allergens from the home environment (e.g., single room air purifier). All warm-blooded pets, including small rodents and birds, should be removed from the house because they produce dander, urine, and saliva that can cause allergic reactions. House-dust mites depend on atmospheric moisture and human dander for survival. Essential house-dust mite control measures include encasing mattresses and pillows in airtight covers, washing the bedding in water of 130° F weekly, avoiding sleeping on upholstered furniture, and removing carpets that are laid on concrete.

Additional helpful control measures include reducing the indoor humidity to less than 50%, removing carpets from the bedroom, and using chemical agents to kill mites. Indoor air-cleaning devices, especially high-efficiency particulate air/aerosol filters, may be useful, but they cannot substitute for controlling the allergen source. Humidifiers are potentially harmful because they can harbor and aerosolize mold spores, and the increased humidity they generate may encourage production of both mold and house-dust mites.67–69

Patient Education

Much of the day-to-day responsibility for managing asthma falls on the patient and the patient’s family. Patient education is a powerful motivational tool, helping patients attain the skills and gain the confidence to control their asthma. Patient education involves helping patients understand asthma and learning and practicing the skills necessary to manage it. Patient education includes providing information; developing a partnership with the patient; involving the patient in decision making; and demonstrating and observing asthma management practices such as the proper use of inhalers, nebulizers, and peak flowmeters.⁷⁸

Special Considerations in Asthma Management

Exercise-Induced Asthma

Exercise-induced asthma is common in asthmatics, especially after participation in outdoor activities in cold weather. The causes are not fully understood, but heat loss from the airways seems to be one of the causes.⁷⁴ Treatment consists of prophylactic inhalation of a beta-2 agonist or cromolyn before exercise. Leukotriene inhibitors also may have a role in treatment of exercise-induced asthma.^67,68

Occupational Asthma

An estimated 2% to 5% of all asthma episodes may be caused by exposure to a specific sensitizing agent in the workplace. Occupational asthma is the most common form of occupational lung disease in many industrialized countries. In an attempt to distinguish occupational from preexisting asthma, occupational asthma is defined as a disease characterized by a variable airflow limitation or AHR secondary to causes and conditions attributable to a particular working environment and not to stimuli encountered outside the workplace. Toluene diisocyanate is the most common cause of occupational asthma and is the best studied. Other causes of occupational asthma are listed in Table 23-4.

TABLE 23-4

Occupational Causes of Asthma

Occupation or Industry	Agent
Laboratory animal workers, veterinarians	Animals (dander, urine protein)
Food processing	Shellfish, egg proteins, pancreatic enzymes
Dairy farming	Storage mites
Poultry farming	Poultry mites, droppings, feathers
Detergent manufacturing	Bacillus subtilis enzymes
Baking	Flour
Sawmill workers, carpentry	Wood dust (western red cedar, oak, mahogany, zebrawood, redwood)
Nursing	Psyllium
Refining	Platinum salts
Plating	Nickel salts
Stainless steel welding	Chromium salts
Cosmetology	Persulfate
Refinery workers	Vanadium
Rubber processing	Formaldehyde, ethylenediamine
Plastics industry	Toluene diisocyanate, trimellitic anhydride

Generally, the treatment of occupational asthma is identical to treatment of other types of asthma. However, early diagnosis is important, and emphasis is placed on environmental control, in particular, cessation of exposure. Complete cessation of exposure is usually necessary because once sensitization has occurred, bronchoconstriction can be triggered by minimal subsequent exposure.68,75

Cough-Variant Asthma

Coughing may be the sole complaint of patients with asthma. In such patients, the cough may be relieved by a bronchodilator or the avoidance of inhaled allergens. If bronchospasm is not present at the time of examination and spirometry is normal (which is often the case), the diagnosis can be confirmed by showing reversible airway obstruction by a methacholine challenge test. Ipratropium bromide may be particularly helpful in the treatment of cough-variant asthma. Otherwise, the treatment is the same as for other types of asthma.

Nocturnal Asthma

Nocturnal asthma is a characteristic problem in poorly controlled asthma and is reported by more than two-thirds of patients who receive suboptimal treatment. It probably is due to the known physiologic decrease in the airway tone during sleep, which has been attributed to variation in catecholamine and cortisol secretion. Aspiration of gastric acid also may play a role in some patients with increased symptoms at night.

After ensuring adequate antiinflammatory therapy, medications for nocturnal asthma should be focused toward the night and especially the early morning hours, when the airway tone is lowest. Sustained-release theophylline and newer long-acting beta-2 agonists such as salmeterol are particularly helpful for controlling nocturnal asthma symptoms.68,75 Addition of a proton pump inhibitor such as esomeprazole has not been shown to enhance asthma control.⁸⁹

Aspirin Sensitivity

At least 5% of adults with asthma experience severe and even fatal exacerbation of asthma after taking aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs). Many of these patients have nasal polyps, although the relationship is not causal. The presumed mechanism is the inhibition of the cyclooxygenase pathway by aspirin and NSAIDs, with subsequent shunting of all arachidonic acid into the 5-lipoxygenase pathway, causing overproduction of bronchoconstrictor leukotrienes. Individuals with asthma should avoid aspirin and NSAIDs and instead use alternatives such as acetaminophen (e.g., Tylenol). Patients should be informed that many over-the-counter medications contain aspirin and should be avoided as well.68,75

Gastroesophageal Reflux

The relationship between asthma and gastroesophageal reflux is controversial, although gastroesophageal reflux is nearly three times more prevalent in patients with asthma than in persons without asthma. Presumably, acid reflux into the esophagus causes vagal stimulation, resulting in a reflex increase in bronchial tone in patients with asthma. However, addition of a proton pump inhibitor to an asthma regimen has not been shown to enhance asthma control significantly.⁸⁹

Asthma During Pregnancy

During pregnancy, one-third of patients have worse control of their asthma, one-third have better control of asthma, and one-third have asthma that is unchanged. The potential threat of adverse effects from asthma medications is far outweighed by the danger of uncontrolled asthma to the fetus and mother. Poorly controlled asthma during pregnancy can cause increased perinatal mortality, increased prematurity, and low birth weight. Theophyllines, beta-2 agonists, inhaled or oral corticosteroids, or cromolyn can be used during pregnancy without significant risk of fetal abnormalities.⁹⁰

Sinusitis

Acute sinusitis and chronic sinusitis have been related to exacerbations and poor control of asthma by causing postnasal drip and interfering with nasal patency. A limited CT scan of the sinuses should be obtained for patients with uncontrolled asthma. If sinusitis is present, therapy with antibiotics for 2 to 3 weeks, nasal decongestants, and nasal corticosteroid inhalers may help improve asthma control.67,68

Surgery

Patients with asthma are predisposed to respiratory complications after surgery, including respiratory arrest during induction of anesthesia, hypoxemia and possible hypercapnia, impaired effectiveness of cough, atelectasis, and respiratory infection. The likelihood of these complications depends on the severity of the patient’s AHR, the degree of airflow obstruction, and the amount of excess airway secretions at the time of surgery. Optimizing the patient’s lung function before surgery, including the administration of perioperative corticosteroids, is an important strategy for minimizing perioperative complications.67,68

Bronchiectasis

Clinical Presentation

Bronchiectasis refers to the abnormal, irreversible dilation of the bronchi caused by destructive and inflammatory changes in the airway walls. Bronchiectasis has the following three major anatomic patterns ⁹¹:

1. Cylindrical bronchiectasis: Airway wall is regularly and uniformly dilated

2. Varicose bronchiectasis: Irregular pattern, with alternating areas of constriction and dilation

3. Cystic bronchiectasis: Progressive, distal enlargement of the airways, resulting in saclike dilations

Bronchiectasis is thought to result from damage to the bronchial wall by chronic inflammation. Predisposing conditions are listed in Box 23-4.

Evaluation

The hallmark of bronchiectasis is the chronic production of large quantities of purulent sputum. Dyspnea is variable and depends on the extent of involvement and the underlying disease. Hemoptysis occurs frequently and is usually mild, but severe hemoptysis can be seen. Radiographic studies confirm the diagnosis by showing airway dilation. A chest radiograph may show cystic spaces and tram tracks (thin parallel lines representing the airway walls). CT is the diagnostic standard; the diagnosis of bronchiectasis is established when the diameter of the bronchus exceeds the diameter of the adjacent pulmonary artery branch.⁹² Because reversible airway changes consistent with bronchiectasis can follow pneumonia, CT should be deferred for 6 to 8 weeks after pneumonia resolves, when a diagnosis of bronchiectasis can be made.

Management

Antibiotics and bronchopulmonary hygiene are the mainstays of bronchiectasis management. Antibiotics can be given as needed or following a regularly scheduled regimen. Sputum cultures may be helpful in guiding antibiotic choice. Inhaled aminoglycosides may be a useful option for patients with chronic colonization by Pseudomonas aeruginosa. Infection by P. aeruginosa in bronchiectasis patients is a marker of severity but is not linked to accelerated decline in pulmonary function.⁹³ Secretions can be cleared by chest physiotherapy with postural drainage, cough maneuvers, and humidification. Inhaled bronchodilators may be helpful in some patients because accompanying airflow obstruction is common.⁹¹ Inhaled hyperosmolar substances may be helpful in clearing secretion in patients with bronchiectasis. A Cochrane review concluded that dry powder mannitol improves tracheobronchial clearance in patients with bronchiectasis, patients with cystic fibrosis patients, asthmatics, and normal subjects.⁹⁴ Hypertonic saline has not been specifically tested in bronchiectasis, but it improves clearance in these other conditions and in chronic bronchitis. In cases that are complicated by massive hemoptysis, embolization of the bleeding bronchial artery may be helpful. Surgical resection should be reserved for patients with localized disease who develop massive hemoptysis or who are severely symptomatic despite appropriate medical therapy.^95–97