Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

15. Asthma

H. William Kelly and Christine A. Sorkness


 Images Asthma is a disease of increasing prevalence that is a result of genetic predisposition and environmental interactions; it is one of the most common chronic diseases of childhood.

 Images Asthma is primarily a chronic inflammatory disease of the airways of the lung for which there is no known cure or primary prevention; the immunohistopathologic features include cell infiltration by neutrophils, eosinophils, T-helper type 2 lymphocytes, mast cells, and epithelial cells.

 Images Asthma is characterized by either the intermittent or persistent presence of highly variable degrees of airflow obstruction from airway wall inflammation and bronchial smooth muscle constriction; in some patients, persistent changes in airway structure occur.

 Images The inflammatory process in asthma is treated most effectively with corticosteroids, with the inhaled corticosteroids having the greatest efficacy and safety profile for long-term management.

 Images Bronchial smooth muscle constriction is prevented or treated most effectively with inhaled β2-adrenergic receptor agonists.

 Images Variability in response to medications requires individualization of therapy within existing evidence-based guidelines for management. This is most evident in patients with severe asthma phenotypes.

 Images Ongoing patient education, for a partnership in asthma care, is essential for optimal patient outcomes and includes trigger avoidance and self-management techniques.

Asthma has been known since antiquity, yet it is a disease that still defies precise definition. The word asthma is of Greek origin and means “panting.” More than 2,000 years ago, Hippocrates used the word asthma to describe episodic shortness of breath; however, the first detailed clinical description of the asthmatic patient was made by Aretaeus in the second century.1 The National Institutes of Health, National Asthma Education and Prevention Program (NAEPP) Expert Panel Report 3 (EPR3), has provided the following working definition of asthma2:

Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role: in particular, mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness (BHR) to a variety of stimuli. Reversibility of airflow limitation may be incomplete in some patients with asthma.

This definition encompasses the important heterogeneity of the clinical presentation of asthma by describing the scientific and clinically accepted characteristics of asthma.


Images An estimated 25.7 million persons in the United States have asthma (about 8.4% of the population).3 Asthma is the most common chronic disease among children in the United States, with approximately 7 million children affected. The prevalence rate is highest in children 0 to 17 years of age at 9.5%.3 In the United States, as in other industrialized countries, the prevalence of asthma is increasing from 7.3% in 2001. Asthma prevalence is higher in persons with incomes below 100% of poverty level at 11.2% and in blacks 11.2% and multiple races 14.1%. Asthma accounts for 1.6% of all ambulatory care visits (10.6 million physician office visits and 1.2 million hospital outpatient visits) and resulted in 440,000 hospitalizations and 1.7 million emergency department (ED) visits in 2006 (both declined from peaks in the 1990s).4 It is the third leading cause of preventable hospitalization in the United States; however, hospitalizations have decreased per 100 patients with asthma since 2001. Asthma accounts for more than 12.8 million missed school days per year.4 In young children (0 to 10 years of age), the risk of asthma is greater in boys than in girls, becomes about equal during puberty, and then is greater in women than in men.4

Ethnic minorities continue to share the burden of asthma disproportionately. African Americans are two times as likely to be hospitalized and approximately two times more likely to die from asthma than whites.3 Hispanics in general, with the exception of Puerto Ricans, at 16.1% prevalence have lower disease and hospitalization rates than African Americans or whites.

The estimated direct medical cost of asthma in the United States in 2007 was $14.7 billion.4 The societal burden of asthma (indirect medical expenditures: loss of productivity and death) in the United States was $5 billion. Prescription drugs were the largest single direct medical expenditure at $6.2 billion; however, the combined costs of emergency care of acute asthma exacerbations make up 36% of direct medical costs.4

The natural history of asthma is still not well defined. Although asthma can occur at any time, it is principally a pediatric disease, with most patients being diagnosed by 5 years of age and up to 50% of children having symptoms by 2 years of age.2 Between 30% and 70% of children with asthma will improve markedly or become symptom-free by early adulthood; chronic disease persists in about 30% to 40% of patients, and generally 20% or less develop severe chronic disease.2 Predictors of persistent adult asthma include atopy, onset during school age, and presence of bronchial hyperresponsiveness (BHR).2 Diminished lung growth may occur in some children (approximately 10%) with asthma.2

In adults, most longitudinal studies have suggested a more rapid rate of decline in lung function in asthmatics than in nonasthmatic normals, primarily reflected in forced expiratory volume in 1 second (FEV1).2 However, the annual decline in FEV1 is less than in smokers or in patients with a diagnosis of emphysema. In general, individuals with less frequent asthma attacks and normal lung function on initial assessment have higher remission rates, whereas smokers have the lowest remission and highest relapse rates.2 The level of BHR tends to predict the rate of decline in FEV1, with a greater decline with high levels of BHR.2 Thus, airway obstruction in asthma may become irreversible and also worsen over time owing to airway remodeling (see below).2 However, most patients do not die from long-term progression of their disease and their life span is not different from the general population.2

As with prevalence and morbidity, mortality from acute exacerbations of asthma has been decreasing over the past 10 years, with a death rate of 0.14 per 1,000 persons with asthma reported in 2009.3 Despite the relatively low number of asthma deaths, 80% to 90% are preventable.2 Most deaths from asthma occur outside the hospital, and death is rare after hospitalization. The most common cause of death from asthma is inadequate assessment of the severity of airway obstruction by the patient or physician and inadequate therapy. The most common cause of death in hospitalized patients is also inadequate or inappropriate therapy. Thus, the key to prevention of death from asthma, as advocated by the U.S. NAEPP, is education.2


Images Epidemiologic studies strongly support the concept of a genetic predisposition plus environmental interaction to the development of asthma, yet the picture remains complex and incomplete.5 Genetic factors account for 60% to 80% of the susceptibility. Asthma represents a complex genetic disorder in that the asthma phenotype is likely a result of polygenic inheritance or different combinations of genes. Initial searches focused on establishing links between atopy (genetically determined state of hypersensitivity to environmental allergens) and asthma, but more recent genome-wide searches have found linkages with genes for metalloproteinases (e.g., ADAM33) and handling bacteria (CHI3L1).5 Although genetic predisposition to atopy is a significant risk factor for developing asthma, not all atopic individuals develop asthma, nor do all patients with asthma exhibit atopy. Disparate phenotypes of asthma (progressive or remodeled vs. nonprogressive) are likely genetically determined.5

Images Environmental risk factors for the development of asthma include socioeconomic status, family size, exposure to secondhand tobacco smoke in infancy and in utero, allergen exposure, urbanization, respiratory syncytial virus (RSV) infection, and decreased exposure to common childhood infectious agents.6,7 The “hygiene hypothesis” proposes that genetically susceptible individuals develop allergies and asthma by allowing the allergic immunologic system (T-helper cell type 2 [Th2] lymphocytes) to develop instead of the system to fight infections (T-helper type 1 [Th1] lymphocytes) and may explain the increase of asthma in developed countries.6,7 The first 2 years of life appear to be most important for the exposures to produce an alteration in the immune response system.6 The hygiene hypothesis is supported by studies demonstrating a lower risk for asthma in children who are exposed to high levels of bacteria or endotoxin, in those with a large number of older siblings, in those with early enrollment into child care, in those with exposure to cats and dogs early in life, or in those with exposure to fewer antibiotics.57

Risk factors for early (<3 years of age) recurrent wheezing associated with viral infections include low birth weight, male gender, and parental smoking. However, this early pattern is due to smaller airways, and these risk factors are not necessarily risk factors for asthma in later life.6 Atopy is the predominant risk factor for children to have continued asthma.6,7 Asthma can begin in adults later in life. Occupational asthma in previously healthy individuals emphasizes the effect of environment on the development of asthma.8 The heterogeneity of the asthma phenotype appears most obvious when listing the diverse triggers of bronchospasm2,6 (Table 15-1). The various triggers have relative degrees of importance from patient to patient. Environmental exposures are the most important precipitants of severe asthma exacerbations9 (see Table 15-1). Epidemics of severe asthma in cities have followed exposures to high concentrations of aeroallergens.9 Viral respiratory tract infections remain the single most significant precipitant of severe asthma in children and are an important trigger in adults as well.10 Other possible factors include air pollution, sinusitis, food preservatives, and drugs.

TABLE 15-1 List of Agents and Events Triggering Asthma



 Images The major characteristics of asthma include a variable degree of airflow obstruction (related to bronchospasm, edema, and mucus hypersecretion), BHR, and airway inflammation (Fig. 15-1). To understand the pathogenetic mechanisms that underlie the many phenotypes of asthma, it is critical to identify factors that initiate, intensify, and modulate the inflammatory response of the airways and to determine how these processes produce the characteristic airway abnormalities.


FIGURE 15-1 Representative illustration of the pathology found in the asthmatic bronchus compared with a normal bronchus (upper right). Each section demonstrates how the lumen is narrowed. Hypertrophy of the basement membrane, mucus plugging, smooth muscle hypertrophy, and constriction contribute (lower section). Inflammatory cells infiltrate, producing submucosal edema, and epithelial desquamation fills the airway lumen with cellular debris and exposes the airway smooth muscle to other mediators (upper left).

Acute Inflammation

Inhaled allergen challenge models contribute most to our understanding of acute inflammation in asthma.7 Inhaled allergen challenge in allergic patients leads to an early phase reaction that, in some cases, may be followed by a late-phase reaction. The activation of cells bearing allergen-specific immunoglobulin E (IgE) initiates the early phase reaction. It is characterized by the rapid activation of airway mast cells and macrophages leading to the rapid release of proinflammatory mediators such as histamine, eicosanoids, and reactive oxygen (O2) species that induce contraction of airway smooth muscle, mucus secretion, and vasodilation.7 The bronchial microcirculation has an essential role in this inflammatory process. Inflammatory mediators induce microvascular leakage with exudation of plasma in the airways.7Acute plasma protein leakage induces a thickened, engorged, and edematous airway wall and a consequent narrowing of the airway lumen. Plasma exudation may compromise epithelial integrity, and the presence of plasma in the lumen may reduce mucus clearance.7 Plasma proteins also may promote the formation of exudative plugs mixed with mucus and inflammatory and epithelial cells. Together these effects contribute to airflow obstruction (Fig. 15-1).

The late-phase inflammatory reaction occurs 6 to 9 hours after allergen provocation and involves the recruitment and activation of eosinophils, CD4+ thymically derived lymphocytes (T cells), basophils, neutrophils, and macrophages.7 There is selective retention of airway T cells, the expression of adhesion molecules, and the release of selected proinflammatory mediators and cytokines involved in the recruitment and activation of inflammatory cells.7 The activation of T cells after allergen challenge leads to the release of Th2-like cytokines that may modulate the late-phase response.7 The release of preformed cytokines by mast cells is the likely initial trigger for the early recruitment of inflammatory cells that then recruit and induce the more persistent involvement by T cells.7 The enhancement of nonspecific BHR usually can be demonstrated after the late-phase reaction but not after the early phase reaction following allergen or occupational challenge.

Chronic Inflammation

Airway inflammation has been demonstrated in all forms of asthma, and an association between the extent of inflammation and the clinical severity of asthma has been demonstrated in selected studies.7 It is accepted that both central and peripheral airways are inflamed.

In asthma, all cells of the airways are involved and become activated (Fig. 15-2). Included are eosinophils, T cells, mast cells, macrophages, epithelial cells, fibroblasts, and bronchial smooth muscle cells. These cells also regulate airway inflammation and initiate the process of remodeling by the release of cytokines and growth factors.7,11


FIGURE 15-2 Diagrammatic presentation of the relationship between inflammatory cells, lipid and preformed mediators, inflammatory cytokines, and proposed pathogenesis and clinical presentation in asthma. See text for details. (GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; LT, leukotriene; MBP, major basic protein; PAF, platelet-activating factor; PG, prostaglandin.)

Epithelial Cells

Bronchial epithelial cells participate in mucociliary clearance and removal of noxious agents; however, they also enhance inflammation by releasing eicosanoids, peptidases, matrix proteins, cytokines, chemokines, and nitric oxide (NO).7,11 Epithelial cells can be activated by IgE-dependent mechanisms, viruses, pollutants, or histamine. In asthma, especially fatal asthma, extensive epithelial shedding occurs. The functional consequences of epithelial shedding may include heightened airway responsiveness, release of the chemokine eotaxin that attracts eosinophils, altered permeability of the airway mucosa, depletion of epithelial-derived relaxant factors, and loss of enzymes responsible for degrading proinflammatory neuropeptides. The integrity of airway epithelium may influence the sensitivity of the airways to various provocative stimuli. Epithelial cells also may be important in the regulation of airway remodeling and fibrosis.7,11


Eosinophils play an effector role in asthma by releasing proinflammatory mediators, cytotoxic mediators, and cytokines.7 Circulating eosinophils migrate to the airways by cell rolling, through interactions with selectins, and eventually adhere to the endothelium through the binding of integrins to adhesion proteins (vascular cell adhesion molecule 1 [VCAM-1] and intercellular adhesion molecule 1 [ICAM-1]). As eosinophils enter the matrix of the membrane, their survival is prolonged by interleukin 5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF). On activation, eosinophils release inflammatory mediators such as leukotrienes (LTs) and granule proteins to injure airway tissue.7


Mucosal biopsy specimens from patients with asthma contain lymphocytes, many of which express surface markers of inflammation. There are two types of T-helper CD4+ cells. Th1 cells produce IL-2 and interferon-γ (IFN-γ), both essential for cellular defense mechanisms. Th2 cells produce cytokines (IL-4, -5, and -13) that mediate allergic inflammation. It is known that Th1 cytokines inhibit the production of Th2 cytokines, and vice versa. It is hypothesized that allergic asthmatic inflammation results from a Th2-mediated mechanism (an imbalance between Th1 and Th2 cells).7 However, more recently it has been observed that there exists a low Th2 cytokine phenotype of asthma in adults that appears more resistant to usual therapies for asthma.12

Th1 and Th2 Cell Imbalance

The T-cell population in the cord blood of newborn infants is skewed toward a Th2 phenotype.6,7 The extent of the imbalance between Th1 and Th2 cells (as indicated by diminished IFN-γ production) during the neonatal phase may predict the subsequent development of allergic disease, asthma, or both. It has been suggested that infants at high risk of asthma and allergies should be exposed to stimuli that upregulate Th1-mediated responses in order to restore the balance during a critical time in the development of the immune system and the lungs.6

The basic premise of the hygiene hypothesis is that the newborn’s immune system needs timely and appropriate environmental stimuli to create a balanced immune response. Factors that enhance Th1-mediated responses include infection with Mycobacterium tuberculosis, measles virus, and hepatitis A virus; endotoxin exposure; increased exposure to infections through contact with older siblings; and daycare attendance during the first 6 months of life. Restoration of the balance between Th1 and Th2 cells may be impeded by frequent administration of oral antibiotics, with concomitant alterations in GI flora. Other factors favoring the Th2 phenotype include residence in an industrialized country, urban environment exposure, diet, and sensitization to house dust mites and cockroaches.6 Immune “imprinting” may begin in utero by transplacental transfer of allergens and cytokines.

Mast Cell

Mast cell degranulation is important in the initiation of immediate responses following exposure to allergens.2 Mast cells reside throughout the walls of the respiratory tract, and increased numbers of these cells (threefold to fivefold) have been described in the airways of allergic asthmatics.7 Once binding of allergen to cell-bound IgE occurs, mediators such as histamine; eosinophil and neutrophil chemotactic factors; LTs C4, D4, and E4; prostaglandins; platelet-activating factor (PAF); and others are released from mast cells (see Fig. 15-2). Histologic examination has revealed decreased numbers of granulated mast cells in the airways of patients who have died from acute asthma attacks, suggesting that mast cell degranulation is a contributing factor. Sensitized mast cells are also activated by osmotic stimuli to account for exercise-induced bronchospasm (EIB).13

Alveolar Macrophages

The primary function of alveolar macrophages in the normal airway is to serve as “scavengers,” engulfing and digesting bacteria and other foreign materials. Macrophages are found in large and small airways, ideally located for affecting the asthmatic response. A number of mediators produced and released by macrophages have been identified, including PAF, LTB4, LTC4, and LTD4.7 Additionally, alveolar macrophages are able to produce neutrophil chemotactic factor and eosinophil chemotactic factor, which in turn amplify the inflammatory process.


The role of neutrophils in the pathogenesis of asthma remains somewhat unclear because they normally may be present in the airways and usually do not infiltrate tissues showing chronic allergic inflammation despite the potential to participate in late-phase inflammatory reactions. However, high numbers of neutrophils have been observed in the airways of patients who died from sudden-onset fatal asthma and in those with severe disease.14 This suggests that neutrophils may play a pivotal role in the disease process, at least in some patients with long-standing or corticosteroid-resistant asthma.14 The neutrophil also can be a source for a variety of mediators, including PAF, prostaglandins, thromboxanes, and LTs, that contribute to BHR and airway inflammation.14

Fibroblasts and Myofibroblasts

Fibroblasts are found frequently in connective tissue. Human lung fibroblasts may behave as inflammatory cells on activation by IL-4 and IL-13. The myofibroblast may contribute to the regulation of inflammation via the release of cytokines and to tissue remodeling. In asthma, myofibroblasts are increased in numbers beneath the reticular basement membrane, and there is an association between their numbers and the thickness of the reticular basement membrane.7,11

Inflammatory Mediators

Associated with asthma for many years, histamine is capable of inducing smooth muscle constriction and bronchospasm and is thought to play a role in mucosal edema and mucus secretion.2 Lung mast cells are an important source of histamine. The release of histamine can be stimulated by exposure of the airways to a variety of factors, including physical stimuli (airway drying with exercise) and relevant allergens.7 Histamine is involved in acute bronchospasm following allergen exposure; however, other mediators such as LTs are also involved.

Besides histamine release, mast cell degranulation releases ILs, proteases, and other enzymes that activate the production of other mediators of inflammation. Several classes of important mediators, including arachidonic acid and its metabolites (i.e., prostaglandins, LTs, and PAF), are derived from cell membrane phospholipids.

Once arachidonic acid is released, it can be metabolized by the enzyme cyclooxygenase to form prostaglandins. Prostaglandin D2 is a potent bronchoconstricting agent; however, it is unlikely to produce sustained effects and its role in asthma remains to be determined. Similarly, prostaglandin F is a potent bronchoconstrictor in patients with asthma and can enhance the effects of histamine.2,7 However, its pathophysiologic role in asthma is unclear. Another cyclooxygenase product, prostacyclin (prostaglandin I2), is known to be produced in the lung and may contribute to inflammation and edema owing to its effects as a vasodilator.

Thromboxane A2 is produced by alveolar macrophages, fibroblasts, epithelial cells, neutrophils, and platelets within the lung.7 It may have several effects, including bronchoconstriction, involvement in the late asthmatic response, and involvement in the development of airway inflammation and BHR.

The 5-lipoxygenase pathway of arachidonic acid metabolism is responsible for the production of the cysteinyl LTs.7 LTC4, LTD4, and LTE4 are released during inflammatory processes in the lung. LTs D4 and E4 share a common receptor (LTD4 receptor) that, when stimulated, produces bronchospasm, mucus secretion, microvascular permeability, and airway edema, whereas LTB4 is involved with granulocyte chemotaxis.

Thought to be produced by macrophages, eosinophils, and neutrophils within the lung, PAF is involved in the mediation of bronchospasm, sustained induction of BHR, edema formation, and chemotaxis of eosinophils.7

Adhesion Molecules

Adhesion molecules are glycoproteins that facilitate infiltration and migration of inflammatory cells to the site of inflammation. They have additional functions involved in the inflammatory process aside from promoting cell adhesion, including activation of cells and cell–cell communication, and promoting cellular migration and infiltration.2 The many adhesion molecules are divided into families on the basis of their chemical structure. These families are the integrins, cadherins, immunoglobulin supergene family, selectins, vascular adressins, and carbohydrate ligands.7 Those thought to be important in inflammation include the integrins, immunoglobulin supergene family, selectins, and carbohydrate ligands, including ICAM-1 and VCAM-1.7 Adhesion molecules are found on a variety of cells, such as neutrophils, monocytes, lymphocytes, basophils, eosinophils, granulocytes, platelets, endothelial cells, and epithelial cells, and can be expressed or activated by the many inflammatory mediators present in asthma.7

Clinical Consequences of Chronic Inflammation

Chronic inflammation is associated with nonspecific BHR and increases the risk of asthma exacerbations. Exacerbations are characterized by increased symptoms and worsening airway obstruction over a period of days or even weeks, and rarely hours. Hyperresponsiveness of the airways to physical, chemical, and pharmacologic stimuli is a hallmark of asthma.2 BHR also occurs in some patients with chronic bronchitis and allergic rhinitis.2 Normal healthy subjects also may develop a transient BHR after viral respiratory infections or ozone exposure. However, the degree of BHR in patients with asthma is quantitatively greater than in other populations. Bronchial responsiveness of the general population fits a unimodal distribution that is skewed toward increased reactivity; individuals with clinical asthma represent the extreme end of this distribution. The degree of BHR within asthma correlates with its clinical course and medication requirement necessary to control symptoms.2 Patients with mild symptoms or in remission demonstrate lower levels of BHR.

The current understanding is that the BHR seen in asthma is at least in part due to and correlative with the extent of airway inflammation.2 Airway remodeling also correlates somewhat with BHR.11

Remodeling of the Airways

Acute inflammation is a beneficial, nonspecific response of tissues to injury and generally leads to repair and restoration of the normal structure and function. In contrast, asthma represents a chronic inflammatory process of the airways followed by healing that in some may result in altered structure referred to as remodeling.11 Repair involves replacement of injured tissue by parenchymal cells of the same type and replacement by connective tissue and its maturation into scar tissue. In asthma, remodeling presents as extracellular matrix fibrosis, an increase in smooth muscle and mucus gland mass, and angiogenesis.11

The precise mechanisms of remodeling of the airways are under intense study. Airway remodeling is of concern because it may represent an irreversible process that can have more serious sequelae such as the development of chronic obstructive pulmonary disease (COPD).2,11 Observations in children with asthma indicate that some loss of lung function may occur during the first 5 years of life.6 Importantly, no current therapies have been shown to alter either early decreased lung growth or later progressive loss of lung function.

Mucus Production

The mucociliary system is the lung’s primary defense mechanism against irritants and infectious agents. Mucus, composed of 95% water and 5% glycoproteins, is produced by bronchial epithelial glands and goblet cells.7 The lining of the airways consists of a continuous aqueous layer controlled by active ion transport across the epithelium in which water moves toward the lumen along the concentration gradient. Catecholamines and vagal stimulation enhance the ion transport and fluid movement. Mucus transport depends on its viscoelastic properties. Mucus that is either too watery or too viscous will not be transported optimally. The exudative inflammatory process and sloughing of epithelial cells into the airway lumen impair mucociliary transport. The bronchial glands are increased in size and the goblet cells are increased in size and number in asthma. Expectorated mucus from patients with asthma tends to have a high viscosity. The mucus plugs in the airways of patients who died in status asthmaticus are tenacious and tend to be connected by mucous strands to the goblet cells. Asthmatic airways also may become plugged with casts consisting of epithelial and inflammatory cells. Although it is tempting to speculate that death from asthma attacks is a result of the mucus plugging resulting in irreversible obstruction, there is no direct evidence for this. Autopsies of asthmatics who died from other causes have shown similar pathology. In addition, some patients who have died of sudden severe asthma did not show the characteristic mucus plugging on necropsy.7

Airway Smooth Muscle

The smooth muscle of the airways does not form a uniform coat around the airways but is wrapped around in a connecting network best described as a spiral arrangement.15 The muscle contraction displays a sphincteric action that is capable of completely occluding the airway lumen. The airway smooth muscle extends from the trachea through the respiratory bronchioles. When expressed as a percentage of wall thickness, the smooth muscle represents 5% of the large central airways and up to 20% of the wall thickness in the bronchioles. Total smooth muscle mass decreases rapidly past the terminal bronchioles to the alveoli, so the contribution of smooth muscle tone to airway diameter in this region is relatively small. In the large airways of asthmatics, smooth muscle may account for 11% of the wall thickness. It is possible that the increased smooth muscle mass of the asthmatic airways is important in magnifying and maintaining BHR in persistent disease. However, it appears that the hypertrophy and hyperplasia are secondary processes caused by chronic inflammation and are not the primary cause of BHR.15

Neural Control/Neurogenic Inflammation

The airway is innervated by parasympathetic, sympathetic, and nonadrenergic inhibitory nerves.2 Parasympathetic innervation of the smooth muscle consists of efferent motor fibers in the vagus nerves and sensory afferent fibers in the vagus and other nerves.15 The normal resting tone of human airway smooth muscle is maintained by vagal efferent activity. Maximum bronchoconstriction mediated by vagal stimulation occurs in the small bronchi and is absent in the small bronchioles. The nonmyelinated C fibers of the afferent system lie immediately beneath the tight junctions between epithelial cells lining the airway lumen.15 These endings probably represent the irritant receptors of the airways. Stimulation of these irritant receptors by mechanical stimulation, chemical and particulate irritants, and pharmacologic agents such as histamine produces reflex bronchoconstriction.7

The nonadrenergic, noncholinergic (NANC) nervous system has been described in the trachea and bronchi. Substance P, neurokinin A, neurokinin B, and vasoactive intestinal peptide (VIP) are the best characterized neurotransmitters in the NANC nervous system.7 VIP is an inhibitory neurotransmitter. Inflammatory cells in asthma can release peptidases that can degrade VIP, producing exaggerated reflex cholinergic bronchoconstriction. NANC excitatory neuropeptides such as substance P and neurokinin A are released by stimulation of C-fiber sensory nerve endings. The NANC system may play an important role in amplifying inflammation in asthma by releasing NO.

Nitric Oxide

NO is produced by cells within the respiratory tract. It has been thought to be a neurotransmitter of the NANC nervous system.16 Endogenous NO is generated from the amino acid L-arginine (L-Arg) by the enzyme NO synthase.16There are three isoforms of NO synthase. One isoform is induced in response to proinflammatory cytokines, inducible NO synthase (iNOS), in airway epithelial cells and inflammatory cells of asthmatic airways.16 NO produces smooth muscle relaxation in the vasculature and bronchials; however, it appears to amplify the inflammatory process and is unlikely to be of therapeutic benefit. Investigations measuring the fraction of exhaled NO (FeNO) concentrations have suggested that it may be a useful measure of ongoing lower airway inflammation in patients with asthma and for guiding asthma therapy.16


Chronic Asthma

Images Classic asthma is characterized by episodic dyspnea associated with wheezing; however, the clinical presentation of asthma is as diverse as the number of triggering events (see Clinical Presentation: Chronic Ambulatory Asthma below). Although wheezing is the characteristic symptom of asthma, the medical literature is replete with the warning that “not all that wheezes is asthma.” A wheeze is a high-pitched, whistling sound created by turbulent airflow through an obstructed airway, so any condition that produces significant obstruction can result in wheezing as a symptom. In addition, “all of asthma does not wheeze” is an equally justifiable warning. Patients may present with a chronic persistent cough as their only symptom.2

CLINICAL PRESENTATION Chronic Ambulatory Asthma


    • Asthma is a disease of exacerbation and remission, so the patient may not have any signs or symptoms at the time of examination.


    • The patient may complain of episodes of dyspnea, chest tightness, coughing (particularly at night), wheezing, or a whistling sound when breathing. These often occur in association with exercise, but also occur spontaneously or in association with known allergens.


    • Expiratory wheezing on auscultation, dry hacking cough, or signs of atopy (allergic rhinitis and/or eczema) may occur.


    • Spirometry demonstrates obstruction (reduced FEV1/forced vital capacity [FVC]) with reversibility following inhaled β2-agonist administration (at least a 12% improvement in FEV1).

Other Diagnostic Tests

    • A fall in FEV1 of at least 15% following 6 minutes of near maximal exercise. Elevated eosinophil count and IgE concentration in blood. Elevated FeNO (greater than 20 ppb in children less than 12 years of age and greater than 25 ppb in adults). Positive methacholine challenge (PC20 FEV1 less than 12.5 mg/mL) or mannitol challenge (FEV1 decrease of at least 15% from baseline after 635 mg or less).

There is no single diagnostic test for asthma. The diagnosis is based primarily on a good history2 (Table 15-2). The patient may have a family history of allergy or asthma or have symptoms of allergic rhinitis.2 Reversibility of airway obstruction following administration of a short-acting inhaled β2-agonist provides confirmation but is not by itself diagnostic. Patients with normal values of spirometry can be challenged by exercise or substances that produce bronchoconstriction, such as methacholine or mannitol, to determine if they have BHR, but, again, positive challenges are not diagnostic. Newer tests of inflammation in the airways such as induced sputum eosinophil and/or neutrophil counts and FeNO measurements are consistent with but not diagnostic of asthma.

TABLE 15-2 Sample Questionsa for the Diagnosis and Initial Assessment of Asthma


Asthma has a widely variable presentation from chronic daily symptoms to only intermittent symptoms. The intervals between symptoms can be days, weeks, months, or years. Asthma also can vary as to its severity, the intrinsic intensity of the disease process. Severity is most easily and directly measured in a patient who is not currently receiving asthma treatment. The NAEPP has provided a means of classifying asthma severity that is divided into two domains: impairment and risk.2 This classification system is individualized for three age groups (0 to 4, 5 to 11, and ≥12 years) and summarized in Table 15-3. The intermittent and/or chronic nature of symptoms does not necessarily determine the severity of symptoms during exacerbations. Asthma severity is determined by lung function, symptoms, nighttime awakenings, and interference with normal activity prior to therapy. Patients can present with a range from intermittent symptoms that require no medications or only occasional use of short-acting inhaled β2-agonists to severe persistent asthma symptoms despite treatment with multiple medications.

TABLE 15-3 Classifying Asthma Severity for Patients Who Are Not Currently Taking Long-Term Control Medications


Acute Severe Asthma

Uncontrolled asthma, with its inherent variability, can progress to an acute state where inflammation, airway edema, excessive mucus accumulation, and severe bronchospasm result in a profound airway narrowing that is poorly responsive to usual bronchodilator therapy2,9 (see Clinical Presentation: Acute Severe Asthma below). Although this progression is the most common scenario, some patients experience rapid-onset or hyperacute attacks.2,9Hyperacute attacks are associated with neutrophilic as opposed to eosinophilic infiltration and resolve rapidly with bronchodilator therapy, suggesting that smooth muscle spasm is the major pathogenic mechanism.9,14 In most cases, ED visits for acute severe asthma represent the failure of an adequate therapeutic regimen to control persistent asthma. Underutilization of antiinflammatory drugs and excessive reliance on short-acting inhaled β2-agonists are the major risk factors for severe exacerbations.2 However, frequent exacerbations may represent a specific phenotype of asthma.9 A blunted perception of airway obstruction may predispose certain individuals to fatal asthma attacks.2



    • An episode can progress over several days or hours (usual scenario) or progresses rapidly over 1 to 2 hours.


    • The patient is anxious in acute distress and complains of severe dyspnea, shortness of breath, chest tightness, or burning. The patient is only able to say a few words with each breath. Symptoms are unresponsive to usual measures (short-acting inhaled β2-agonist administration).


    • Signs include expiratory and inspiratory wheezing on auscultation (breath sounds may be diminished with very severe obstruction), dry hacking cough, tachypnea, tachycardia, pale or cyanotic skin, hyperinflated chest with intercostal and supraclavicular retractions, and hypoxic seizures if very severe.


    • Peak expiratory flow [PEF] and/or FEV1 less than 40% of normal predicted values. Decreased arterial O2 (PaO2), and O2 saturations by pulse oximetry (SaO2 less than 90% [0.90] on room air is severe). Decreased arterial or capillary CO2 if mild, but in the normal range or increased in moderate to severe obstruction.

Other Diagnostic Tests

    • Blood gases to assess metabolic acidosis (lactic acidosis) in severe obstruction. Complete blood count if there are signs of infection (fever and purulent sputum). Serum electrolytes as therapy with β2-agonist and corticosteroids can lower serum potassium, magnesium, and phosphate, and increase glucose. Chest radiograph if signs of consolidation on auscultation.

Exercise-Induced Bronchospasm

During vigorous exercise, pulmonary function measurements (FEV1 and PEF) in patients with asthma increase during the first few minutes but then begin to decrease after 6 to 8 minutes (Fig. 15-3).2 EIB is defined as a drop in FEV1 of 15% or greater from baseline (pre-exercise value).2 Most studies suggest that many patients with persistent asthma experience EIB.2 The exact pathogenesis of EIB is unknown, but heat loss and/or water loss from the central airways appears to play an important role.13 EIB is provoked more easily in cold, dry air; alternatively, warm, humid air can blunt or block it.13 Studies have demonstrated increased plasma histamine, cysteinyl LTs, prostaglandins, and tryptase concentrations during EIB, suggesting a role for mast cell degranulation.13 These findings have led to the development of inhaled mannitol, an osmotic agent, as an indirect pharmacologic bronchoprovocation test to assist in the diagnosis of asthma.17


FIGURE 15-3 Typical responses to exercise in a normal subject and an asthmatic subject. Note the initial bronchodilation. (PEF, peak expiratory flow.)

A refractory period following EIB lasts up to 3 hours after exercise in some patients. During this period, repeat exercise of the same intensity produces either no decrease in pulmonary function or a drop of less than 50% of the initial response.13 This refractory period is thought to be caused by an acute depletion of mast cell mediators and time required for their repletion. Patients with known refractoriness to exercise will still respond to histamine, so acute hyporesponsiveness of airway smooth muscle does not appear to be a factor.13

EIB is believed to be a reflection of increased BHR associated with asthma. A correlation, though not perfect, exists between EIB and reactivity to histamine, methacholine, and mannitol.13,17 Other patient groups with BHR (e.g., after viral infection, cystic fibrosis, or allergic rhinitis) show bronchoconstriction after exercise to a lesser degree (5% to 10% drops) than patients with asthma (15% to 40% drops).13Patients will not always demonstrate the same sensitivity. During periods of remission, a decreased sensitivity to the same degree of exercise is often observed. Finally, a number of children and adults with EIB are otherwise normal, without symptoms or abnormal pulmonary function except in association with exercise.2 Elite athletes have a higher prevalence of EIB than the general population.13

Nocturnal Asthma

Images Worsening of asthma during sleep is referred to as nocturnal asthma. Patients with nocturnal asthma exhibit significant falls in pulmonary function between bedtime and awakening.2 Typically, their lung function reaches a nadir at 3 to 4 AM. Although the pathogenesis of this phenomenon is unknown, it has been associated with diurnal patterns of endogenous cortisol secretion and circulating epinephrine.2Direct evidence for an inflammatory component to nocturnal asthma includes increased circulating histamine and activated eosinophils and LT excretion at night associated with increased BHR to methacholine.2

Numerous other factors that may affect nocturnal worsening of asthma, including allergies and improper environmental control, gastroesophageal reflux, obstructive sleep apnea, and sinusitis, also must be considered when evaluating these patients.2 Most experts consider nocturnal symptoms to be a sign of inadequately treated persistent asthma.2 Awakening from nocturnal asthma is a sensitive indicator of both severity and inadequate control.2


Viral Respiratory Infections

Viral respiratory infections are primarily responsible for exacerbations of asthma, particularly in children under age 10.9,10 Infants are particularly susceptible to airway obstruction and wheezing with viral infections because of their small airways. The most common cause of exacerbations in both children and adults is the rhinovirus, which is the most frequent virus associated with the common cold and distributed worldwide.10 Other viruses isolated include RSV, parainfluenza virus, adenoviruses, coronavirus, and influenza viruses. Certain viruses (RSV and parainfluenza virus) are capable of inducing specific IgE antibodies, and rhinovirus can activate eosinophils directly in asthmatics.10 The increase in asthma symptoms and BHR that occurs may last for days or weeks following resolution of the symptoms of the viral infection. Evidence does not support a beneficial effect of influenza vaccine for preventing asthma exacerbations from subsequent influenza infections.2

Environmental and Occupational Factors

Agents and events and the mechanisms that are known to trigger asthma are listed in Table 15-1.2 The general mechanisms are unknown but presumably are the result of epithelial damage and inflammation in the airway mucosa. Ozone and sulfur dioxide, common components of air pollution, have been used to induce BHR in animals. Exposure to 0.2 ppm ozone for 2 to 3 hours can induce bronchoconstriction and increase BHR in asthmatics.2,8 Sulfur dioxide in the ambient atmosphere is highly irritating and presumably induces bronchoconstriction through mast cell or irritant-receptor involvement.2 Asthma produced by repeated prolonged exposure to industrial inhalants is a significant health problem. It has been estimated that occupational asthma accounts for 2% of all asthmatic persons.8 Persons with occupational asthma have the typical symptoms of asthma with cough, dyspnea, and wheeze. Typically, the symptoms are related to workplace exposure and improve on days off and during vacations.8 In some instances, symptoms may persist even after termination of exposure.8

Stress, Depression, and Psychosocial Factors in Asthma

Observational studies demonstrate an association between increased stress and worsening asthma, but the role is not clearly defined.2 Bronchoconstriction from psychological factors appears to be mediated primarily through excess parasympathetic input. Atropine has been shown to block experimental psychogenic bronchoconstriction. It is most important to emphasize to both patients and parents that asthma is not an emotional disease; however, coping skills may benefit the patient who becomes emotionally distraught during an asthma attack.


Disorders of the upper respiratory tract, particularly rhinitis and sinusitis, have been linked with asthma for many years. As many as 40% to 50% of asthmatics have abnormal sinus radiographs.2 However, chronic sinusitis may just represent a nonbacterial coexisting condition with allergic asthmatics because the histologic changes in the paranasal sinuses are similar to those seen in the lung and nose.2 Treatment of upper airway disease may optimize overall asthma control. The mechanism by which sinusitis aggravates asthma is unknown. The treatment of allergic rhinitis with intranasal corticosteroids and cromolyn but not antihistamines will reduce BHR in asthmatic patients.2 It has been postulated that transport of mucus chemotactic factors and inflammatory mediators from nasal passages during allergic rhinitis into the lung may accentuate BHR.

Gastroesophageal Reflux Disease

Symptoms of gastroesophageal reflux disease (GERD) as well as asymptomatic reflux are common in both children and adults who have asthma.2 Nocturnal asthma may be associated with nighttime reflux.2Reflux of acidic gastric contents into the esophagus is thought to initiate a vagally mediated reflex bronchoconstriction.2 Also of concern is that most medications that decrease airway smooth muscle tone may have a relaxant effect on gastroesophageal sphincter tone. However, treatment of reflux in asthma patients has produced inconsistent results on asthma control.2,18 The current recommendation is to initiate standard antireflux therapy in those patients exhibiting symptoms of reflux.2

Female Hormones and Asthma

Premenstrual worsening of asthma has been reported in as many as 30% to 40% of women in some studies, whereas worsening of pulmonary functions has been reported even in women not aware of worsening symptoms.19 The pathophysiology is uncertain because estrogen replacement in postmenopausal women has been shown to worsen asthma, whereas estradiol and progesterone administration has been variably reported to improve or have no effect on asthma in women with premenstrual asthma.19,20 Asthma symptoms may vary significantly during different stages of the menstrual cycle. The clinical significance of menstruation-related asthma is still unclear because some studies have reported that up to 50% of ED visits by women were premenstrual, whereas others have reported no association with menstrual phase.19,20 In general, BHR and symptoms improve in asthmatic women during pregnancy.2,19


Documentation in the literature of food allergens as triggers for asthma is not available.2 However, additives, specifically sulfites used as preservatives, can trigger life-threatening asthma exacerbations. Beer, wine, dried fruit, and open salad bars, in particular, have high concentrations of metabisulfites.2 Severe oral corticosteroid-dependent patients should be warned about ingesting foods processed with sulfites. Another additive producing bronchospasm is benzalkonium chloride, which is found as a preservative in some nebulizer solutions of antiasthmatic drugs.21

Aspirin and other nonsteroidal antiinflammatory drugs can precipitate an attack in up to 20% of adults and 5% of children with asthma.22 The mechanism is related to cyclooxygenase inhibition, and 5-lipoxygenase inhibition can alter dose–response but not completely block the symptoms.22 The prevalence increases with age and severity of asthma.2 The greatest frequency occurs in severe corticosteroid-resistant asthmatics in their fourth and fifth decades who also have perennial rhinitis and nasal polyposis (presence of several polyps).22 Other drugs that do not precipitate bronchospasm but that prevent its reversal are the nonselective β-blocking agents.2

Nutritional Factors

Epidemiologic data suggest that obesity increases the prevalence of asthma and may reduce asthma control.23 Lung volume and tidal volume are reduced in obesity, promoting airway narrowing. Obesity also produces low-grade systemic inflammation that may act on the lung to worsen asthma.23 The mechanism is likely the release of adipose-derived proinflammatory mediators such as IL-6, IL-10, eotaxin, tumor necrosis factor-α, transforming growth factors-β1, C-reactive protein, leptin, and adiponectin or a result of common predisposing dietary factors. Although not all studies find relationship between body mass index and asthma control, management of asthma in obese patients should include weight loss measures.24

More recently it has been shown that children with vitamin D insufficiency are at greater risk of uncontrolled asthma (increased hospitalizations, BHR, and eosinophil counts).25 Vitamin D helps regulate T cells and improves their secretion of antiinflammatory cytokines in response to corticosteroids.25 Clinical trials defining the potential therapeutic role of vitamin D supplementation in asthma management are underway.



Aerosol Therapy for Asthma

Images Images Aerosol delivery of drugs for asthma has the advantage of being site specific and thus enhancing the therapeutic ratio.2,26 Inhalation of short-acting β2-agonists provides more rapid bronchodilation than either parenteral or oral administration, as well as the greatest degree of protection against EIB and other challenges.2 Inhaled corticosteroids (ICSs) have been developed with rapid oral and systemic clearance to enhance lung activity and reduce systemic activity. Specific agents (e.g., cromolyn, formoterol, salmeterol, and ipratropium bromide) are only effective by inhalation.2 Therefore, an understanding of aerosol drug delivery is essential to optimal asthma therapy. Table 15-4 lists the factors determining lung deposition of therapeutic aerosols.

TABLE 15-4 Factors Determining Lung Deposition of Aerosols


Device Determinants of Delivery

Devices used to generate therapeutic aerosols include jet nebulizers, ultrasonic nebulizers, metered-dose inhalers (MDIs), and dry powder inhalers (DPIs). The single most important device factor determining the site of aerosol deposition is particle size.26 Devices for delivering therapeutic aerosols generate particles with aerodynamic diameters from 0.5 to 35 μm.26 Particles larger than 10 μm deposit in the oropharynx, particles between 5 and 10 μm deposit in the trachea and large bronchi, particles 1 to 5 μm in size reach the lower airways, and particles smaller than 0.5 μm act as a gas and are exhaled. In asthma, the airways, not the alveoli, are the target for delivery. Respirable particles are deposited in the airways by three mechanisms: (a) inertial impaction, (b) gravitational sedimentation, and (c) Brownian diffusion.26 The first two mechanisms are the most important for therapeutic aerosols and probably are the only factors that can be manipulated by patients.

Each delivery device within a classification generates specific aerosol characteristics, so extrapolation of delivery data from one device cannot be applied to the other devices in the class. For instance, MDIs can deliver 15% to 50% of the actuated dose; DPIs, 10% to 30% of the labeled dose; and nebulizers, 2% to 15% of the starting dose.26 MDIs and DPIs are portable and convenient, unlike jet nebulizers. Small portable ultrasonic nebulizers have also been developed. MDIs consist of a pressurized canister with a metering valve; the canister contains active drug, low-vapor-pressure propellants such as hydrofluoroalkane (HFA), cosolvents, and/or surfactants.26 The international ban on the production and use of chlorofluorocarbon (CFC) propellant (due to their ozone layer–depleting properties) has resulted in no CFC-propelled MDIs available in the United States with the exception of pirbuterol Autohaler until December 31, 2013. With any change in the components of an MDI, the FDA considers it to be a new drug that requires stability, safety, and efficacy studies prior to approval. The drug is either in solution or a suspended micronized powder. In order to disperse the suspension for accurate delivery, the canister must be shaken. The metering chamber measures a liquid volume, and, therefore, the device must be held with the valve stem downward so that the chamber is covered with liquid26 (Fig. 15-4). When the canister is actuated, the device releases the propellant and drug in a forceful spray whose particles are large (mass median aerodynamic diameter [MMAD] = 45 μm)26(see Fig. 15-4). As evaporation occurs, the particle size is reduced to a final MMAD of 0.5 to 5.5 μm depending on the MDI. The aerosol cloud extends about 6 in beyond the MDI at the lowest MMAD.26 Each MDI has different conditions for storage and durations to expiration, so the pharmacist must become familiar with and counsel the patient on these factors.


FIGURE 15-4 Illustration of a metered-dose inhaler demonstrating the particle size difference as the aerosol cloud extends outward.

The breath-actuated MDI Autohaler is cocked with a lever to “load” the dose of medication, a baffle is opened by inspiratory pressure, and the dose is expelled from the canister metering chamber.26 While the need for hand–lung coordination for proper actuation is reduced significantly with breath-actuated MDIs, these devices do not accommodate the use of a spacer device.

Spacer devices are used frequently with an MDI to decrease oropharyngeal deposition and enhance lung delivery.2 However, not all spacer devices produce similar effects. The design of spacers varies from simple open-ended tubes that separate the MDI from the mouth to valved holding chambers (VHCs) with one-way valves that open during inhalation (the preferred system). A VHC allows evaporation of the propellant prior to inhalation permitting a greater number of drug particles to achieve a respirable droplet size. VHC use also allows inhalation after actuation of the MDI, obviating the need for good hand–lung coordination.26 Additionally, the large particles that normally would deposit in the oropharynx “rain out” in the spacer.26 All the available spacers significantly reduce oropharyngeal deposition from MDIs, with the VHCs being superior to the open-ended tubes.26 This reduction in oropharyngeal deposition is an important factor in reducing local adverse effects (e.g., hoarseness and thrush) from ICSs.26The change in lung delivery depends on both the MDI and the drug, where one spacer device may enhance delivery with one MDI preparation and decrease delivery with others.26 The use of VHCs is less likely to enhance delivery from HFA-propelled MDIs. Finally, over time, holding chambers can build up static electricity that attracts small particles to the sides of the chamber, significantly reducing aerosol availability. Some spacers should be washed weekly with household detergent with a single rinse and allowed to drip dry.2 Other VHCs have been developed with antistatic materials.

Dry micronized powders can be inhaled directly into the lung. A number of DPIs are now available for use in the United States.26 Currently, there are no generic DPIs as each drug plus device has its own patent. Each DPI has unique characteristics with advantages and disadvantages (Table 15-5). The primary advantage of DPIs is that they are breath actuated and require minimal hand–lung coordination, and it is thus easier to teach patients proper technique.26 Some DPIs are more flow dependent than others.26 Thus, similar to MDIs and spacers, delivery data from one DPI cannot be extrapolated to another.

TABLE 15-5 Characteristics of Various Inhalation Devices


Nebulizers come in two basic types, the jet nebulizer and the ultrasonic nebulizer. Jet nebulizers produce an aerosol from a liquid solution or suspension placed in a cup. A tube connected to a stream of compressed air or O2 flows up through the bottom and draws the liquid up an adjacent open-ended tube.26 The air and liquid strike a baffle, creating a droplet cloud that is then inhaled.26 Ultrasonic nebulizers produce an aerosol by vibrating liquid lying above a transducer at speeds of about 1 mHz.26 Both produce similar degrees of lung deposition, with the exception that ultrasonic nebulizers are ineffective for nebulizing currently available micronized suspensions.26 The aerosol output and lung delivery vary significantly among the commercially available jet nebulizers even when operated in the same manner.26Increasing fill volume will increase the total amount of drug delivered; however, it also will take longer for the patient to nebulize the dose.26 The MMAD of the droplets is related directly to the gas flow, with flows of 5 to 12 L/min providing an aerosol cloud with an MMAD of 4 to 8 μm for most jet nebulizers.26 Each jet nebulizer comes with its optimal operating instructions.

Patient Determinants of Delivery

Images Images The most important patient factor determining aerosol deposition is inspiratory flow (see Table 15-4).2,26 High inspiratory flows increase the degree of deposition owing to impaction of particles of any size, thereby increasing deposition centrally (i.e., throat and large airways) and decreasing peripheral deposition. Optimal inspiratory flow for most MDIs is slow and deep (approximately 30 L/min or 5 seconds for a full inhalation).2 In general, DPIs require higher inspiratory flows (≥60 L/min) and a change in inhalation technique (i.e., deep, forceful inspiration) for optimal dispersion of the powder, which, in turn, increases the amount of drug delivered to the larger central airways.26 However, this difference in delivery may not produce clinically significant differences.26 Patients should be cautioned not to exhale into DPIs because this causes loss of dose and moistens the dry powder, causing aggregation into larger particles. Patient factors that cannot be controlled include interpatient variability in airway geometry (particularly the differences between children and adults)26 and the effects of bronchospasm, edema, and mucus hypersecretion. Mild obstruction increases aerosol deposition; however, severe obstruction probably leads to increased central deposition from impaction.26 The absolute delivery to the lung is not as important as consistency of delivery, assuming that a sufficient dose to produce the desired therapeutic effect is achieved. No single inhalation device is the best for all patients. Table 15-5 lists the differing characteristics of inhalation devices.

Appropriate inhalation technique is essential to achieve optimal drug delivery and therapeutic effect.2 The components are illustrated in Figure 15-5. Approximately 50% to 80% of a dose from MDIs and DPIs impacts on the oropharynx and is then swallowed; the rest is either left in the device or exhaled.26 It is important that actuation occurs during inhalation, although the time during inspiration is unimportant.2,26 Although radiolabeled studies with MDIs indicate improved delivery by holding the actuator 2 to 3 cm in front of an open mouth to allow more evaporation and less impaction, physiologic studies with bronchodilators have failed to document an advantage for this method.2,26 Many patients do not use their MDIs optimally, and patient instruction with demonstration is the most effective means of improving inhaler technique.2,26 Even with instruction, up to 30% of patients, particularly young children and the elderly, cannot master the use of an MDI. For these patients, attachment of a VHC to the MDI or use of a breath-actuated MDI can improve efficacy significantly.2,26 However, addition of a VHC offers no advantage in patients who can use an MDI optimally alone.26 Mouth rinsing following treatment with MDI- and DPI-ICSs is important to minimize local adverse effects and oral absorption.2,26


FIGURE 15-5 Instructions for inhaler use from the adapted NAEPP Expert Panel Report 2.

Delivery from high-resistance DPIs is more flow dependent than from low-resistance DPIs. Thus, younger children and possibly elderly adults will have more variability in delivery from high-resistance devices.26 Most children younger than 4 years of age cannot generate a sufficient inspiratory flow to use DPIs. Young children (<4 years) and infants generally require the use of a face mask attached to either an MDI plus VHC or nebulizer. The use of a face mask results in a reduction in lung delivery due to the portion of the aerosol inhaled nasally, so the doses of drugs used in these patients are often not decreased.


Acute Severe Asthma

The primary goal is prevention of life-threatening asthma by early recognition of signs of deterioration and early intervention. As such, the principal goals of treatment include2:

   1. Correction of significant hypoxemia

   2. Rapid reversal of airflow obstruction

   3. Reduction of the likelihood of relapse of the exacerbation or future recurrence of severe airflow obstruction

   4. Development of a written asthma action plan in case of a further exacerbation

These goals are best achieved by early initiation or intensification of treatment and close monitoring of objective measures of oxygenation and lung function.2 Early response to treatment as measured by the improvement in FEV1at 30 minutes following inhaled β2-agonists is the best predictor of outcome.2,27 Providing adequate O2 supplementation to maintain O2 saturations above 90% (0.90) (or >95% [0.95] in pregnant women and those who have coexistent heart disease) is essential. In children younger than 6 years of age, in whom lung function measures are difficult to obtain, a combination of objective (e.g., O2saturation, capillary CO2, respiratory rate, and heart rate) and subjective measures may be used to assess severity.2,28

The primary therapy of acute exacerbations is pharmacologic, which includes short-acting inhaled β2-agonists and, depending on the severity, systemic corticosteroids, inhaled ipratropium, and O2 (Figs. 15-6and 15-7).2 It is important that therapy not be delayed, so the history and physical examination should be obtained while initial therapy is being provided. Patients at risk for life-threatening exacerbations require special attention. Risk factors include a history of previous severe asthma exacerbations (e.g., hospitalizations, intubations, or hypoxic seizures), difficulty perceiving asthma symptoms or severity of exacerbations, comorbidities (e.g., cardiac disease, other chronic lung disease, illicit drug use, or major psychosocial/psychiatric history), use of more than two canisters per month of short-acting inhaled β2-agonists, and current intake of oral corticosteroids or recent withdrawal from oral corticosteroids.2


FIGURE 15-6 Home management of acute asthma exacerbation. Patients at risk for asthma-related death should receive immediate clinical attention after initial treatment. Additional therapy may be required. (From reference 2.)


FIGURE 15-7 Emergency department and hospital care of acute asthma exacerbations. (From reference 2.)

A complete blood count may be appropriate for patients with fever or purulent sputum, but modest leukocytosis is common in asthma exacerbations due to viral infection or secondary to corticosteroid administration. Chest radiography is not recommended for routine assessment but should be obtained for patients suspected of a complicating cardiopulmonary process or another pulmonary process (pneumothorax or pulmonary consolidation).2 Serum electrolytes should be monitored if high-dose continuous inhaled or systemic β2-agonists are to be used because they can produce transient decreases in potassium, magnesium, and phosphate.2 Measurement of serum electrolytes is also prudent in patients who take diuretics regularly and in patients with coexistent cardiovascular disease. The combination of high-dose β2-agonists and systemic corticosteroids occasionally may result in excessive elevations of glucose and lactic acid.2

Initial response should be achieved within minutes, and most patients experience significant improvement within the first 30 to 60 minutes of therapy, with most patients doubling their FEV1 or PEF.2 In patients ultimately admitted to the hospital, only a 10% to 20% improvement is seen within the first 2 hours. Hypoxemia, primarily a result of ventilation–perfusion mismatch, is immediately correctable by low-flow O2.2 While reversal of lung function into the normal range may take 12 to 24 hours, complete restoration takes much longer—up to 3 to 7 days.2 A strategy to prevent recurrence includes systemic corticosteroids and symptom or PEF monitoring.2 It is essential to provide the patient with a written self-management action plan for dealing with exacerbations. Patients at risk for severe exacerbations should be taught how to use a peak flow meter and monitor morning peak flows at home.2 In young children, an increased respiratory rate, increased heart rate, and inability to speak more than one or two words between breaths are signs of severe obstruction.2 O2 saturations by pulse oximetry and peak flows should be measured in all patients not completely responding to initial intensive inhaled β2-agonist therapy. Initially, on admission, the peak flows or clinical symptoms should be monitored every 2 to 4 hours. Prior to discharge from the ED or hospital, the patient should be given a sufficient supply of prednisone, taught the purpose of the medications and proper inhaler technique, and referred to followup asthma care within 1 to 4 weeks; initiation of ICSs should also be considered.2

Images Early recognition of deterioration and aggressive treatment are the keys to successful treatment of acute asthma exacerbations. Thus, patient and/or parent education, teaching self-management skills, and written action plans for early institution of therapy for acute exacerbations improve outcomes.2 For more moderate to severe patients, this therapeutic plan also may include the availability of oral prednisone to begin at home.2 Easy access by telephone to healthcare providers is also needed. Because of the rapid progression to severe asthma that can occur, patients and parents should be encouraged to communicate promptly with their asthma care provider during an exacerbation.

Figures 15-6 and 15-7 illustrate the recommended therapies for the treatment of acute asthma exacerbations in home and ED/hospital settings, respectively.2 The dosages of the drugs for acute severe exacerbations are provided in Table 15-6.2,6 Institutions should strongly consider developing critical pathways/treatment algorithms for their EDs because their implementation has been shown to improve outcomes and decrease the cost of care.27 Finally, it is strongly recommended that an appointment with the patient’s primary care provider be made within 1 week of the ED visit.27

TABLE 15-6 Dosages of Drugs of Acute Severe Exacerbations of Asthma in the Emergency Department or Hospital


Nonpharmacologic and Ancillary Therapy

Infants and young children may be mildly dehydrated owing to increased insensible loss, vomiting, and decreased intake.2 Unless dehydration has occurred, increased fluid therapy is not indicated in acute asthma management because the capillary leak from cytokines and increased negative intrathoracic pressures may promote edema in the airways.2 Correction of significant dehydration is always indicated, and the urine specific gravity may help to guide therapy in young children, in whom the state of hydration may be difficult to determine.2 Chest physical therapy and mucolytics are not recommended in the therapy of acute asthma.2 Sedatives should not be given because anxiety may be a sign of hypoxemia, which could be worsened by central nervous system depressants. Antibiotics also are not indicated routinely because viral respiratory tract infections are the primary cause of asthma exacerbations.2Antibiotics should be reserved for patients who have signs and symptoms of pneumonia (e.g., fever, pulmonary consolidation, and purulent sputum from polymorphonuclear leukocytes). Mycoplasma and Chlamydia are infrequent causes of severe asthma exacerbations but should be considered in patients with high O2 requirements.2,28

Respiratory failure or impending respiratory failure as measured by rising PaCO2 (≥45 mm Hg [≥6 kPa]) or failure to correct hypoxemia with supplemental O2 therapy is treated with intubation and mechanical ventilation.27 In order to prevent barotrauma and pneumothoraces from excess positive pressure, it is recommended that controlled hypoventilation or permissive hypercapnia be used (correcting the hypoxemia, PaO2 >60 mm Hg [>8 kPa], but allowing the PaCO2 to rise to the high 60 mm Hg [8 kPa] range).27



Images The short-acting inhaled β2-agonists are the most effective bronchodilators and the treatment of first choice for the management of acute severe asthma.2,27 Up to 66% of adults presenting to an ED require only three doses of 2.5 mg nebulized albuterol to be discharged.27 Most well-controlled clinical trials have demonstrated equal to greater efficacy and greater safety of aerosolized β2-agonists over systemic administration regardless of the severity of obstruction.2,27 Systemic adverse effects, hypokalemia, hyperglycemia, tachycardia, and cardiac dysrhythmias are more pronounced in patients receiving systemic β2-agonist therapy. Children younger than 2 years of age achieve clinically significant responses from nebulized albuterol.2 Effective doses of aerosolized β2-agonists can be delivered successfully through mechanical ventilator circuits to infants, children, and adults in respiratory failure secondary to severe airway obstruction.29

Frequent administration of inhaled β2-agonists (every 20 minutes or continuous nebulization) has been found to be superior to the same dosage administered at 1-hour intervals.2 In the subset of more severely obstructed patients, continuous nebulization decreases the hospital admission rate, provides greater improvement in the FEV1 and PEF, and reduces duration of hospitalization when compared with intermittent (hourly) nebulized albuterol in the same total dose.2 Thus, continuous nebulization is recommended for patients having an unsatisfactory response (achieving less than 50% of normal FEV1 or PEF) following the initial three doses (every 20 minutes) of aerosolized β2-agonists and potentially for patients presenting initially with PEF or FEV1 values of less than 30% of predicted normal.2

The doses of inhaled β2-agonists for acute severe asthma exacerbations (see Table 15-6) have been derived empirically. The β2-agonists follow a log-linear dose–response curve.30 In addition, the dose–response curve is shifted to the right by more severe bronchospasm or by increased concentrations of bronchospastic mediators, which is characteristic of functional antagonists.30 The ability to increase the dose of the short-acting aerosolized β2-agonists by as much as 5- to 10-fold over doses producing adequate bronchodilation in chronic stable asthma is what contributes to their efficacy in reversing the bronchospasm of acute severe exacerbations. The nebulizer dose of inhaled β2-agonists for children often is listed on a weight basis (milligrams per kilogram). However, a fixed minimal dose (2.5 mg albuterol or equivalent), as opposed to a weight-adjusted dose, is more appropriate in younger children because children younger than 5 years of age receive a lower lung dose.2 Adults dosed on a weight basis demonstrate excessive cardiac stimulation, so they have fixed maximal doses2 (see Table 15-6). Initial doses of inhaled β2-agonists can produce vasodilation, worsening ventilation–perfusion mismatch, slightly lowering O2 saturation or PaO2.27 High doses of inhaled β2-agonists can produce a decrease in serum potassium concentration, an increase in heart rate, and an increase in serum glucose and lactic acid concentration.28 However, both children and adults receiving continuously nebulized β2-agonists have demonstrated decreased heart rates as their lung function improves.2 Thus, an elevated heart rate is not an indication to use lower doses or to avoid using inhaled β2-agonists.

The inhaled β2-agonists produce similar efficacy whether delivered by MDI plus VHC or nebulization in treating acute severe exacerbations in the ED and hospital; thus, the choice depends on the experience and comfort of the treating clinicians.2 The DPIs are currently not indicated for the treatment of acute severe asthma exacerbations due to the higher inspiratory flows required for adequate drug delivery.2


Systemic corticosteroids are indicated in all patients with acute severe asthma exacerbations not responding completely to initial inhaled β2-agonist administration (every 20 minutes for three to four doses).2IV therapy offers no therapeutic advantage over oral administration.2,31 This therapy usually is continued until hospital discharge. Tapering the systemic corticosteroid dose following discharge from the hospital appears unnecessary, provided that patients are prescribed ICSs for outpatient therapy.31 Most patients achieve 70% of predicted normal FEV1 within 48 hours and 80% of predicted by 6 days after plateauing by day 3. Thus, maintaining systemic corticosteroid courses for 10 to 14 days may be unnecessarily long in some patients. Indeed, many patients not admitted to the hospital respond to 3- to 5-day courses of systemic corticosteroids. Short courses of oral prednisone (3- to 10-day “bursts”) have been effective in preventing hospitalizations in infants and young children.2 It is recommended that a full dose of the corticosteroid be continued until the patient’s peak flow reaches 70% of predicted normal or personal best.2

Multiple daily dosing of systemic corticosteroids for the initial therapy of acute asthma exacerbations appears warranted because receptor binding affinities of lung corticosteroid receptors are decreased in the face of airway inflammation.31 However, patients with less severe exacerbations may be treated adequately with once-daily administration. High-dose and very-high-pulse-dose corticosteroid regimens have not been shown to enhance the outcomes in severe acute asthma but are associated with a higher likelihood of side effects.31

Studies of ICSs in acute exacerbations of asthma have provided conflicting results. Studies have demonstrated both greater and lesser efficacy than standard doses of oral corticosteroids.28,31 Currently, there is insufficient evidence supporting efficacy in the ED setting, although continued research appears warranted.28 There is evidence that prescribing ICSs on discharge from the ED reduces the risk of relapse.31This policy is rational because inflammation is the underlying cause of deterioration in most cases.2


Inhaled ipratropium bromide produces a further improvement in lung function of 10% to 15% over inhaled β2-agonists alone. In children and adults, multiple-dose ipratropium bromide added to initial therapy reduces hospitalization rate in the subset of patients with a baseline FEV1 of less than 30% of predicted.32 Ipratropium bromide, a quaternary amine, is poorly absorbed and produces minimal or no systemic effects.28 Care should be taken when administering ipratropium bromide by nebulizer. If a tight mask or mouthpiece is not used, the ipratropium bromide that deposits in the eyes may produce pupillary dilation and difficulty in accommodation.2 Ipratropium bromide is not a vasodilator, so unlike β2-agonists it will not worsen ventilation–perfusion mismatch.32

Alternative Therapies

The ED use of aminophylline, a moderate bronchodilator, for acute asthma has not been recommended for a number of years.2 Aminophylline in adults and children hospitalized with acute asthma does not enhance improvement in lung function or reduce length of hospitalization but has increased the risk of adverse effects.2 Adverse effects of theophylline include nausea and vomiting and potentiation of the cardiac effects of the inhaled β2-agonists.

Magnesium sulfate is a moderately potent bronchodilator, producing relaxation of smooth muscle and central nervous system depression. The use of IV magnesium sulfate in patients presenting to the ED is controversial (see below).28 The adverse effects of magnesium sulfate include hypotension, facial flushing, sweating, nausea, loss of deep tendon reflexes, and respiratory depression.28 Helium is an inert gas of low density with no pharmacologic properties that can lower resistance to gas flow and increase ventilation because the low density decreases the pressure gradient needed to achieve a given level of turbulent flow, converting turbulent flow to laminar flow.28 Helium is given as a mixture of helium and O2 (heliox), usually 60% to 70% helium with 30% to 40% O2.33 Heliox has been effective in some but not all clinical trials.33 Although heliox is free of adverse effects, its use is limited to patients with a low inspired O2 requirement because the decrease in density generally is insignificant clinically with less than 60% helium.28

The inhalational anesthetics halothane, isoflurane, and enflurane all have been reported to have a positive effect in children and adults with acute severe asthma that is unresponsive to standard medical therapy.2 The proposed mechanisms for inhalational anesthetics include direct action on bronchial smooth muscle, inhibition of airway reflexes, attenuation of histamine-induced bronchospasm, and interaction with β2-adrenergic receptors.2 Well-controlled trials with these agents have not been completed.27 Potential adverse effects include myocardial depression, vasodilation, arrhythmias, and depression of mucociliary function.27 In addition, the practical problem of delivery and scavenging these agents in the intensive care environment as opposed to the operating room is a concern. The use of volatile anesthetics cannot be recommended based on insufficient evidence of efficacy.

Ketamine has been recommended for rapid induction of anesthesia in patients with asthma who require intubation and mechanical ventilation.2 Although anecdotal reports have suggested that ketamine is useful as a short-term adjunct in acute severe asthma, controlled trials have not provided evidence of efficacy. Ketamine has several significant adverse effects, including the anesthesia emergence reaction, which can alter mood and cause delirium. These emergence phenomena occur in at least 25% of patients over 16 years of age; the incidence seems to be much lower in younger patients.2 Other risks include an increase in heart rate, arterial blood pressure, and cerebral blood flow because of its sympathetic effects.27

Special Populations

Images Infants and children younger than 4 years of age may be at greater risk of respiratory failure than older children and adults. Although treated with the same drugs, these younger children require the use of a face mask as opposed to a mouthpiece for delivery of aerosolized medication. Use of the face mask reduces delivery of drug to the lung by one half so that a minimal dose is recommended as opposed to a weight-adjusted dose.26 The face mask should be sized appropriately and should fit snugly over the nose and mouth. Use of the “blow-by” method, where the respiratory therapist or parent places the mask or extension tubing near the child’s nose and mouth, should be discouraged because holding the mask as few as 2 cm from the patient’s face reduces lung delivery of the aerosol by 80%.2,26

Drug Class Information

Short-Acting β2-Agonists

Images Images The β2-agonists are the most effective bronchodilators available. The β2-adrenergic receptors are transmembrane proteins consisting of clusters of seven helices of amino acids that form the ligand-binding core.30 The human β2-adrenergic receptors are polymorphic in structure, with the most common polymorphisms in the amino terminus of the receptor at amino acid positions 16 (encoding either arginine [Arg] or glycine [Gly]) and 27 (encoding either glutamine [Gln] or glutamic acid [Glu]).34 Some of the polymorphisms determine responsiveness to β2-agonists, whereas others may act as disease modifiers (see below).35 Stimulation of β2-adrenergic receptor activates cytoplasmic G proteins, which in turn activate adenylyl cyclase to produce cyclic adenosine monophosphate (cAMP), generally thought to be responsible for the bulk of activity through activation of various proteins by cAMP-dependent protein kinase A (PKA).30 This activation, in turn, decreases unbound intracellular calcium, producing smooth muscle relaxation, mast cell membrane stabilization, and skeletal muscle stimulation.30 Despite the fact that β2-agonists are potent inhibitors of mast cell degranulation in vitro, they do not inhibit the late asthmatic response to allergen challenge or the subsequent BHR.2,30 Long-term administration of β2-agonists does not reduce BHR, confirming a lack of significant antiinflammatory activity.34 β2-Adrenergic stimulation also activates Na+-K+-ATPase, produces gluconeogenesis, and enhances insulin secretion, resulting in a mild to moderate decrease in serum potassium concentration by driving potassium intracellularly.30 The chronotropic response to β2-agonists is mediated in part by baroreceptor reflex mechanisms as a result of the drop in blood pressure from vascular smooth muscle relaxation, as well as by direct stimulation of cardiac β2-receptors and some β1 stimulation at high concentrations.30 Table 15-7 lists the pharmacologic effects of adrenergic receptor stimulation. Because β1-receptor stimulation produces excessive cardiac stimulation, resulting in cardiac arrhythmias, and because the inotropic effect enhancing myocardial O2 consumption leads to myocardial necrosis, there is no rationale for using non–β2-selective agonists in the treatment of asthma.2

TABLE 15-7 Pharmacologic Responses to Sympathomimetic Agonists


Table 15-8 compares the various β-adrenergic agonists used in asthma in terms of selectivity, potency, oral activity, and duration of action. The β2-agonists are functional or physiologic antagonists in that they relax airway smooth muscle regardless of the mechanism for constriction.30 When administered in equipotent doses, all the short-acting drugs produce the same intensity of response; the only differences are in duration of action and cardiac toxicity.2,30 The catecholamine derivatives all have the disadvantage of rapid inactivation of their 3,4-hydroxyl catechol group from catechol-O-methyltransferase located in the GI tract, rendering them orally inactive. In addition, catecholamines are taken up rapidly into tissues by secondary uptake mechanisms that limit their receptor occupancy and thus have a shorter duration of action.30 All the β2-agonists are more bronchoselective when administered by the aerosol route. Aerosol administration of the short-acting β2-agonists provides more rapid response and greater protection against provocations that induce bronchospasm such as exercise and allergen challenges than does systemic administration.2,30 Differences in myocardial effects are discernible between selective and nonselective agents even when administered as aerosols, particularly at the higher doses used for acute severe asthma. The β2-agonists also differ in efficacy or ability to activate the β2-adrenergic receptors. Full agonists include the catecholamines while the synthetic β2-agonists all exhibit various levels of partial agonism in the following order of fuller agonism: formoterol > albuterol = terbutaline = pirbuterol > salmeterol.30 Although partial agonists by definition cannot produce maximum dilation or protection as full agonists and can potentially block the effect of a full agonist, these differences have not been proven to be clinically significant.

TABLE 15-8 Relative Selectivity, Potency, and Duration of Action of the β-Adrenergic Agonists


All synthetic β2-agonists are 1:1 racemic mixtures of two mirror images (enantiomers) owing to an asymmetric or chiral carbon.30 Since most physiologic functions (receptor occupancy and activation and enzymatic metabolism) are stereoselective, the (R)-enantiomers of the β2-agonists are the most pharmacologically active isomer.30 While it was felt initially that the (S)-enantiomers were essentially inactive owing to the 100- to 1,000-fold potency difference between the enantiomers, studies in animal models and isolated in vitro tissue preparations have suggested that the (S)-enantiomer of albuterol may be proinflammatory and could induce BHR.30 However, evidence that this occurs consistently in humans or is clinically relevant is lacking.30 The pharmacokinetics are stereoselective as well, although not predictable. (R)-Albuterol is metabolized more rapidly than (S)-albuterol, which could lead to accumulation of (S)-albuterol with continued dosing.30 On the other hand, (S)-terbutaline is eliminated more rapidly than (R)-terbutaline.34

Both the intensity and duration of response are dose dependent, and, more important, the dose–response relationship is dynamic.30,34 At increasing levels of baseline bronchoconstriction (irrespective of the stimulus), the dose–response curve is shifted to the right, and the duration of bronchodilation is decreased.30 This shift is reflected in the need for higher, more frequent doses in acute asthma exacerbations; the duration of protection against significant provocation is much less than the duration of bronchodilation in chronic stable asthma (see Table 15-8).30,34

Chronic administration of β2-agonists leads to downregulation (decreased number of β2-receptors) and a decreased binding affinity (desensitization) for these receptors.30 Systemic corticosteroid therapy can both prevent and partially reverse this phenomenon.2,30 However, the use of ICSs appears to have minimal ability to prevent tolerance to β2-agonists.30 Although in vitro differences in downregulation of the β2-receptors exist (Gly-16 homozygotes >Arg-16 homozygotes), clinical desensitization is seen in all polymorphisms.34 Tolerance primarily reduces duration of bronchodilation as opposed to peak response, although the latter can occur as well. A significantly greater tolerance develops in other tissues (e.g., lymphocytes and cardiac and skeletal muscle) compared with the lung, primarily as a result of the surplus β2-receptors found in respiratory smooth muscle.30 Tolerance to the extrapulmonary effects (cardiac stimulation and hypokalemia) may account for a lack of significant cardiac effects with retention of the bronchodilator response despite chronic inhaled β2-agonist therapy, whereas tolerance to mast cell stabilization may be a drawback to chronic use.30 Thus, chronic β2-agonist administration produces a tolerance of minimal clinical significance that is overcome easily by increasing the dose or by administering corticosteroids.2,30,34 Most of the tolerance occurs within a week of regular administration and does not worsen with continued administration. As would be expected from a receptor phenomenon, tolerance is a cross-tolerance to all β2-agonists.30 Regular use of short-acting inhaled β2-agonists may produce slight worsening of asthma in a subset of patients, but it does not appear to occur in the entire population.34 Regular treatment with short-acting β2-agonists can increase BHR and in homozygous Arg-16 patients reduces morning PEF and increases exacerbations.35 Regular treatment (four times daily) does not improve symptom control over as-needed use and is not indicated.2 Regular treatment with the long-acting inhaled β2-agonists (LABAs) is discussed in Chronic Asthma below.

In conclusion, the short-acting inhaled selective β2-agonists are indicated for the as-needed treatment of intermittent episodes of bronchospasm. They are the first treatment of choice for acute severe asthma and EIB.2,13 They inhibit EIB in a dose-dependent fashion and provide complete protection for a 2-hour period following inhalation with varying levels of patient-dependent protection over 4 hours.13Although the regular administration of β2-agonists slightly decreases the protective effect, two inhalations prior to exercise still essentially block EIB completely (1% vs. 5% drop in FEV1).30

Systemic Corticosteroids

Images The corticosteroids are the most effective antiinflammatories available to treat asthma.2 Actions useful in treating asthma include (a) increasing the number of β2-adrenergic receptors and improving the receptor responsiveness to β2-adrenergic stimulation, (b) reducing mucus production and hypersecretion, (c) reducing BHR, and (d) reducing airway edema and exudation.2,36 The glucocorticoid receptor is found in the cytoplasm of most body cells, explaining the multiple effects of systemic corticosteroids. There is no difference between glucocorticoid receptors found throughout the body; however, genetic differences between glucocorticoid receptors from different individuals may determine some of the variations in response.35 The corticosteroids are lipophilic, readily cross the cell membrane, and combine with the glucocorticoid receptor. The activated complex then enters the nucleus, where it acts as a transcription factor leading to gene activation or suppression.36 This leads to specific mRNA production, resulting in increased production of antiinflammatory mediators; suppression of several proinflammatory cytokines such as IL-1, GM-CSF, IL-4, IL-5, IL-6, and IL-8, reducing inflammatory cell activation, recruitment, and infiltration; and decreasing vascular permeability.36 In addition, the activated glucocorticoid receptor complex can act directly with cytoplasmic transcription factors, nuclear factor-κB, and activating protein 1 to prevent the action of proinflammatory cytokines on the cell.36

Owing to the mechanism that modifies gene expression, the time required to see a particular effect depends on the time required for new protein synthesis, decreased formation of the particular mediator, and resolution of the inflammatory response.36 Generally, the cellular and biochemical effects are immediate, but varying amounts of time are required to produce a clinical response. β2-Receptor density increases within 4 hours of corticosteroid administration.36 Improved responsiveness to β2-agonists occurs within 2 hours.36 In acute severe asthma, 4 to 12 hours may be required before any clinical response is noted.31,36 Reversal of seasonally increased BHR requires at least 1 week of therapy.36 The chronic use of corticosteroids does not induce a state of corticosteroid dependence, there is no evidence of tolerance produced by chronic administration.

The corticosteroids used in asthma are compared in Table 15-9.36,37 Besides acute severe asthma, systemic corticosteroids are also recommended for the treatment of impending episodes of severe asthma unresponsive to bronchodilator therapy.2,28 The effects of corticosteroids in asthma are dose and duration dependent. This pattern is true for the adverse effects as well (Table 15-10). The clinician must continually balance the toxicity of chronic systemic corticosteroid therapy with control of asthma symptoms. Because short-term (1 to 2 weeks) high-dose corticosteroids (1 to 2 mg/kg/day of prednisone) do not produce serious toxicities, the ideal use is to administer the systemic corticosteroids in a short “burst” and then to maintain the patient on appropriate long-term control therapy with ICSs (discussed below).2,28 In general, therapy for more than 5 days at doses that exceed the usual physiologic endogenous cortisol production will cause temporary aberration in adrenal cortisol release.36 However, this hypothalamic–pituitary–adrenal (HPA) axis suppression is short-lived (1 to 3 days) and readily reversible following short bursts (≤10 days) of pharmacologic doses.36 A maximum number of short bursts that a patient can receive probably exists, after which chronic corticosteroid side effects occur. Adult patients receiving at least eight bursts (≥10 days each) have a similar decrease in trabecular bone density as patients on daily or alternate-day corticosteroids over 1 year.36 Children who received four or more bursts per year of prednisone exhibited a subnormal response to hypoglycemic stress or adrenocorticotropic hormone (ACTH) administration.36 Just two or more bursts per year increase the risk for osteopenia in children with concomitant vitamin D insufficiency.38 Very short courses (3 to 5 days) have been effective in reducing hospitalization from acute exacerbations.2 Use of the shorter-acting corticosteroids such as prednisone will produce less adrenal suppression than the longer-acting dexamethasone.36

TABLE 15-9 Pharmacodynamic/Pharmacokinetic Comparison of the Corticosteroids


TABLE 15-10 Adverse Effects of Chronic Systemic Glucocorticoid Administration



The anticholinergic agents have a long history of use for asthma, but they do not have an FDA-labeled indication for asthma.2 Anticholinergics are competitive inhibitors of muscarinic receptors.39 Unlike β2-agonists, they are not functional antagonists; they only reverse cholinergic-mediated bronchoconstriction. Normal bronchial tone is maintained through parasympathetic innervation of the airways via the vagus nerve.39 A number of the triggers and mediators of asthma (i.e., histamine, prostaglandins, sulfur dioxide, exercise, and allergens) produce bronchoconstriction in part through vagal reflex mechanisms.39 Studies consistently demonstrate that anticholinergics are effective bronchodilators in asthma, although not as effective as β2-agonists. Anticholinergics attenuate but do not block allergen-induced asthma in a dose-dependent fashion and have no effect on BHR.39 Anticholinergics attenuate but do not block EIB.13

Ipratropium bromide is a nonselective muscarinic receptor blocker, and blockade of inhibitory muscarinic receptors theoretically could result in an increased release of acetylcholine and overcome the block on the smooth muscle receptors (M3).39 Only the quaternary ammonium derivatives such as ipratropium bromide should be used because they have the advantage of poor absorption across mucosae and the blood–brain barrier. This attribute contributes to negligible systemic effects with a prolonged local effect (i.e., bronchodilation). In addition, the quaternary compounds do not appear to produce a decrease in mucociliary clearance.39 Ipratropium bromide has a duration of action of 4 to 8 hours. Both intensity and duration of action are dose dependent. Tiotropium bromide, a long-acting inhaled anticholinergic with duration of 24 hours, is more selective for M1 and M3 receptors and less likely to affect the inhibitory M2 receptors.39 Time to reach maximum bronchodilation for ipratropium is considerably slower than for aerosolized short-acting β2-agonists (30 to 60 minutes vs. 5 to 10 minutes). However, this difference is of little clinical consequence because some bronchodilation is seen within 30 seconds; 50% of maximum response occurs within 3 minutes.39 Ipratropium bromide is only indicated as adjunctive therapy in acute severe asthma not completely responsive to β2-agonists alone because it does not improve outcomes in chronic asthma.2,31 Recent trials of tiotropium bromide in chronic asthma suggest that it may be as effective as LABAs added to ICSs and add additional control in severe asthma when added to ICS/LABA combinations.40,41


ED visits for asthma exceed the number of hospitalizations by approximately four times, yet the annual expenditures for ED visits remain significantly less than that spent on in-patient hospital services for patients with acute severe asthma.42 Thus, reducing the number of patients requiring hospitalizations is a primary goal of therapy. Since the primary drugs used to treat acute severe asthma are available generically, drug costs account for only a small portion of the overall costs of care. Few of these therapies have been evaluated formally for their pharmacoeconomic impact. One evaluation based on a meta-analysis of inhaled anticholinergics added to short-acting inhaled β2-agonists in children with acute severe asthma suggested that this approach was cost-effective and would reduce overall costs by reducing hospitalizations.32 In children with acute severe asthma admitted to an intensive care unit, the use of continuously nebulized albuterol resulted in a decreased cost of care compared with intermittent nebulization.2

Clinical Controversy…

Some clinicians believe that IV magnesium sulfate is effective for the treatment of acute severe asthma exacerbations unresponsive to standard doses of inhaled β2-agonists in the ED. This belief is based on subset analyses of two studies showing that patients with the most severe obstruction following initial inhaled β2-agonists demonstrated a reduction in hospitalizations with magnesium treatment compared with placebo.2 However, the subset with severe obstruction is the one demonstrating an improved response to the addition of ipratropium bromide and continuous nebulization of inhaled β2-agonists. In addition, a large, randomized trial failed to confirm a decrease in hospitalization even in the severe group.28 The 2007 NAEPP guidelines state that magnesium can be considered for use in patients with severe episodes with a poor response to initial inhaled β2-agonists.2


Figures 15-6 and 15-7 provide the monitoring parameters for acute severe asthma. Lung function, either spirometric or peak flow measurements, should be monitored 5 to 10 minutes after each treatment.2,28O2 saturations can be easily monitored continuously with pulse oximetry. For young children and infants, pulse oximetry, lung auscultation, and observation of the presence of supraclavicular retractions are useful.2,27 The majority of patients will respond within the first hour of initial inhaled β2-agonists regardless of history of pre-ED administration of drug.27 Patients not achieving an initial response should be monitored every 0.5 to 1 hour. Depending on whether there is a standard ED or a special unit for acute severe asthma, the decision to admit to the hospital should be made within 4 to 6 hours of entry to the ED.28 The mean duration of hospitalization following admission is 2 to 3 days. Frequency of monitoring depends on the severity of the exacerbation. With mild exacerbations, monitor lung function every 2 to 3 hours and with severe exacerbations every 0.5 to 1 hour.


Chronic Asthma

The diagnosis of chronic asthma is made primarily by history and confirmatory spirometry (see Clinical Presentation above).2 The NAEPP has provided a list of questions that would lead to the diagnosis of asthma2 (see Table 15-2). In the older child and adult patient in whom spirometric evaluations can be performed, failure of pulmonary functions to improve acutely does not necessarily rule out asthma. Patients with long-standing disease or substantial inflammation may require an intensive, prolonged course of bronchodilators and glucocorticoids before reversibility is detected.2 If baseline spirometry is normal, challenge testing with exercise, histamine, methacholine, or mannitol can be used to elicit BHR.2 Patients with significant symptoms and/or an FEV1 of less than 70% of predicted normal should not be challenged. Vocal cord dysfunction, particularly with exercise, may mimic asthma symptoms.2Studies for atopy such as serum IgE and sputum and blood eosinophil determinations are not necessary to make the diagnosis of asthma, but they may help differentiate asthma from chronic bronchitis in adults. Clinically, this distinction is often difficult to make. Some patients with chronic bronchitis may have a reversible component, and some patients with long-standing severe chronic asthma may have significant irreversible damage and obstruction. Very high peripheral blood eosinophil counts may point to the diagnosis of allergic bronchopulmonary aspergillosis (ABPA) or other hypereosinophilic syndromes.2 Skin testing is of no value in diagnosing asthma but is useful in identifying triggers.2 In small infants unable to perform spirometry, the diagnosis is more difficult. Hyperinflation may be demonstrated on the chest roentgenogram.2 Radiologic examination is helpful in ruling out other causes of wheezing (e.g., foreign-body aspiration, parenchymal lung disease, cardiac disease, and congenital anomalies).2 In place of pulmonary function measures, the parents should be given a diary card to record symptoms and precipitating events.

Desired Outcomes for the Long-Term Management of Asthma

The NAEPP has provided key points for managing asthma long term.2 The desired outcomes for therapy to control asthma are outlined below:

Reducing impairment:

   1. Prevent chronic and troublesome symptoms (e.g., coughing or breathlessness in the daytime, in the night, or after exertion).

   2. Require infrequent use (≤2 days a week) of short-acting inhaled β2-agonist for quick relief of symptoms2 (not including prevention of EIB).

   3. Maintain (near) normal pulmonary function.

   4. Maintain normal activity levels (including exercise and other physical activity and attendance at work or school).

   5. Meet patients’ and families’ expectations of and satisfaction with asthma care.

Reducing risk:

   1. Prevent recurrent exacerbations of asthma and minimize the need for ED visits or hospitalizations.

   2. Prevent loss of lung function; for children, prevent reduced lung growth.

   3. Minimal or no adverse effects of therapy.

Nonpharmacologic Therapy

Although the mainstay of the management of asthma is pharmacologic therapy, it is likely to fail without concurrent attention to relevant environmental control and management of comorbid conditions. Figure 15-8 depicts the stepwise approach for managing asthma recommended in the 2007 update by the NAEPP.2 Nonpharmacologic aspects of therapy are incorporated into the steps. The guidelines were designed to give primary healthcare providers a framework with which to develop the proper approach to the individualized therapy of patients. The heterogeneity of asthma demands an individualized approach to therapy with the basic goals of therapy as primary outcome measures.2 The focus of therapy is the prevention and suppression of the underlying inflammation.2 Thus, current therapeutic options in asthma consist of acute reliever medications used for acute symptoms and exacerbations and long-term control medications used for the prevention of symptoms and exacerbations and the suppression of inflammation and reduction of BHR.2



FIGURE 15-8 Stepwise approach for managing asthma in adults and children 0 to 4 and 5 to 11 years old. (From reference 2.)

Images The development of a partnership in care through patient education and the teaching of patient self-management skills should be the cornerstone of any treatment program.2 There are a number of published self-management programs for children and adults available through local American Lung Association chapters, as well as asthma treatment centers, and nationally through the NAEPP and the Asthma and Allergy Foundation of America.2 Asthma self-management programs have been shown to improve patient adherence to medication regimens, improve self-management skills, and improve use of healthcare services.2,43,44 Table 15-11 lists the key educational messages recommended by the NAEPP.2

TABLE 15-11 Key Educational Messages for Patients


Self-management programs instruct patients in the pathogenesis of asthma and the appropriate use of their medications but focus principally on teaching patients to recognize triggers for their asthma and how to recognize early signs of deterioration.43 Home PEF monitoring is part of some programs.2 However, routine PEF monitoring in and of itself does not improve patient outcomes.2

The NAEPP advocates the use of PEF monitoring only for patients with severe persistent asthma who have difficulty perceiving airway obstruction.2 It also has recommended a system based on a traffic light scenario (based on percentage of normal predicted values or personal best values): the green zone is equal to 80% to 100%, the yellow zone is equal to 50% to 79%, and the red zone is less than 50%. The yellow zone is cautionary and requires increasing as-needed bronchodilator use and possibly beginning prednisone if not improved, whereas the red zone warrants contacting the patient’s healthcare provider.2

Patient education is essential before monitoring can be effective. It has proved successful regardless of the health professional who provided the information (physician, nurse, or pharmacist). The NAEPP advocates significant involvement of all points of patient care in the educational process.2 The provision of written action plans enhances the success of education and is considered an essential component of care.2 Samples of clinically tested written action plans are available from NAEPP guidelines and other sources.2

In patients with known allergic triggers for their asthma, allergen avoidance has resulted in an improvement in symptoms, a reduction in medication use, and a decrease in BHR.2 A comprehensive approach to environmental control is advocated. For example, for patients with house dust mite allergy removing carpeting from bedrooms, washing sheets in hot water (>54.4°C [>130°F]) and using special dust-proof pillow and mattress covers can reduce symptoms and need for medications.2 Obvious environmental triggers (e.g., animal dander, cockroaches), if the patient is sensitive, should be avoided. Evidence for home air-filtering systems and chemicals for killing house dust mites is limited.2 Immunotherapy (allergy shots) with single antigens particularly has been beneficial and may be considered in patients with persistent asthma with documented sensitivity.2 Immunotherapy with multiple antigens has been less effective.

Patients who smoke should be encouraged to stop. Parents of children with asthma should stop or at least not smoke around their children.2

Pharmacologic Therapy

The current NAEPP recommendations for therapy of persistent asthma are illustrated in Figure 15-8.2 Therapy should be adjusted based on control status of the patient (refer to later section). Regardless of the long-term therapy, all patients need to have quick-relief medication in the form of short-acting inhaled β2-agonists available for acute symptoms. The ICSs are considered the preferred long-term control therapy for persistent asthma in all patients due to their potency and consistent effectiveness.2 Low- to medium-dose ICSs reduce BHR, improve lung function, and reduce severe exacerbations leading to ED visits and hospitalizations. They are more effective than cromolyn, theophylline, or the LT receptor antagonists.2 In addition, the ICSs are the only therapy that reduces the risk of dying from asthma.2 In the low to medium doses recommended by NAEPP guidelines (Table 15-12), ICSs are safe for long-term administration (see below).2,45 They do not appear to reduce airway remodeling and loss of lung function found in some patients with persistent asthma. The ICSs do not enhance lung growth in children with asthma, prevent the development of asthma in high-risk infants, or induce remission of asthma as BHR and other measures of inflammation return to pretreatment levels on discontinuation of therapy.46,47 The sensitivity and consequent clinical response to ICSs can vary among patients.2

TABLE 15-12 Available Inhaled Corticosteroid Products, Lung Delivery, and Comparative Daily Dosages


Although studies of the alternative long-term control therapies (e.g., cromolyn, LT receptor antagonists, and theophylline) demonstrate improvement in symptoms, lung function, and as-needed, short-acting inhaled β2-agonist use, they do not reduce BHR, suggesting minimal antiinflammatory activity.2 The evidence suggests minimal to no differences in efficacy between these alternatives. Therefore, NAEPP lists them in alphabetical order to show no preference of one over the other.2

For those patients inadequately controlled on low-dose ICSs either an increased dose of the ICS or the combination of ICS and LABA is the next step to gain control of more moderate persistent asthma.2Alternatives could be the addition of LT modifiers or theophylline to ICSs.2 The addition of theophylline or LT modifiers to ICSs is no more effective than doubling the dose of the ICS.2 The combination of ICS/LABA is more effective at reducing severe asthma exacerbations than doubling the dose of ICS in moderate persistent asthma; increasing the dose of ICSs fourfold also will result in a significant reduction in exacerbations.48,49 However, doses of ICSs in the high range significantly enhance the risk of toxicity.37,45,46 Thus, high doses of ICSs plus LABA are reserved for patients with severe persistent asthma.2

Although the addition of a third controller medication is often used clinically in patients with severe persistent asthma uncontrolled on high-dose ICS/LABA, there are few studies evaluating this practice.2 LT receptor antagonists or theophylline added to high-dose combination ICS/LABA do not improve outcomes.2 Omalizumab, a recombinant anti-IgE, has demonstrated significant activity in these severe uncontrolled atopic patients.2,50 More recently tiotropium bromide has shown promise as add-on to ICS/LABA combination but is not yet approved by the FDA for use in asthma.41,51

Special Populations

Images Children younger than 5 years of age have not been studied adequately. Thus, many of the recommendations in this age group are extrapolated from older children and adults.2 The studies of ICSs in this younger group demonstrate improvement in symptoms, as-needed bronchodilator use, and exacerbations. The nebulized suspension of budesonide gained FDA approval from three pivotal efficacy and safety trials.2 Recently, high-dose nebulized budesonide administered intermittently (1 mg twice a day for 7 days) at early signs of upper respiratory tract infections was as effective at preventing severe episodes of wheezing in infants 12 to 53 months of age with recurrent wheezing as low-dose (0.5 mg daily) continuous therapy.52 The FDA approval for montelukast in children younger than age 6 was based on safety and pharmacokinetic studies establishing doses but not on efficacy, although improvement in symptoms and as-needed bronchodilators was noted.2 Cromolyn nebulizer solution was approved down to age 2 years based on efficacy.2 Theophylline has not been evaluated adequately, except for pharmacokinetics.2 Combination therapy of any kind has not been studied sufficiently.2

The FDA approval of the fluticasone/salmeterol DPI 100/50 in patients 4 to 11 years of age was largely based on extrapolation of efficacy data from patients older than 12 years of age and by a single safety and efficacy study in children with asthma aged 4 to 11 years. In children 5 to 11 years old, the ICS/LABA combination has not yet been definitively shown to decrease exacerbations compared with medium-dose ICS, although impairment domains improved.2 More recently, the addition of a LABA to low-dose ICS improved overall asthma control compared with either doubling the dose of ICS or the addition of montelukast in children 6 to 17 years old.53

The elderly are at highest risk from dying of asthma.3 Owing to the increased risk of osteoporosis and cataracts in the elderly, patients requiring high doses of ICSs should have routine height measurements, bone mineral density determinations, and ophthalmic examinations.2,54 Appropriate therapies for prevention of osteoporosis should be instituted.2,54

Asthma affects 7% of pregnant women, making it potentially the most common serious medical condition to complicate pregnancy.19 Maternal asthma has been reported to increase the risk of perinatal mortality, preeclampsia, preterm birth, and low-birth-weight infants.19 More severe asthma is associated with increased risks, whereas better-controlled asthma is associated with decreased risks. A systematic review of the evidence on the safety of asthma medications has concluded that it is safer for pregnant women with asthma to be treated with effective medications than for them to have exacerbations.19 Proper monitoring and control of asthma should enable a woman with asthma to maintain a normal pregnancy with little or no risk to mother or her fetus. Regular visits are recommended and should include objective assessment of lung function and validated assessment of symptoms.

A stepwise approach to managing asthma during pregnancy and lactation has been published, with low-dose ICSs recommended as preferred treatment for mild persistent asthma with the addition of a LABA if not adequately controlled.19 Budesonide is considered the preferred ICS to initiate because it has the greatest amount of safety data, and the data are reassuring.19 Albuterol is considered the preferred rescue therapy.19 Conditions that may aggravate asthma such as allergic rhinitis and sinusitis should be aggressively treated.19

Drug Class Information

Inhaled Corticosteroids

The mechanism of action of the corticosteroids has been reviewed (see above). The principal advantage of the ICSs is their high topical potency to reduce inflammation in the lung and low systemic activity.37,46 The ICSs have high antiinflammatory potency, approximately 1,000-fold greater than endogenous cortisol, and differ from each other by as much as fourfold to sixfold.37 However potency differences, which are simply a measure of binding affinity to the receptor, can be overcome simply by giving different microgram dosages of drug. Aerosol delivery of the preparations is remarkably variable, ranging from 10% to 60% of the nominal dose (i.e., that dose which leaves an actuator for an MDI or, in the case of a DPI, that which is released on actuation of the inhaler).26,37 Different devices for the same chemical entity may result in twofold differences in delivery, so that delivery method can make a significant difference in the relative comparable dose or therapeutic index.2,37

The ICSs, beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate, and mometasone furoate, that are currently available for use are compared and listed in Table 15-12. The ICSs have pharmacokinetic differences that result in different topical/systemic activity.37 Most evidence is consistent with log-linear dose–response curves for both indirect and direct responses.46 The log-linear nature of the dose–response curve for ICS activity raises the issue of how much of a difference in dose (or lung delivery) or potency is detectable. The measures used to assess efficacy (lung function, BHR, symptoms, and as-needed short-acting inhaled β2-agonist use) are downstream events from the antiinflammatory activity.46 It takes a fourfold difference in potency or dose to detect clinically significant differences in efficacy.49 The table of comparable ICS doses (see Table 15-12) is based on extensive clinical trial data.2,37 Clinically comparable doses take into consideration drug potency differences as well as device delivery differences but not the potential for systemic activity.

Since the glucocorticoid receptors within the various tissues are the same, differences in the pharmacokinetic profile are required to produce differences in the topical/systemic effect ratio (therapeutic index).37Pharmacokinetic properties that enhance topical selectivity include rapid systemic clearance, poor oral bioavailability, and prolonged residence time in the lung.37 Owing to their high lipophilicity, systemic clearance of the available ICSs is very rapid, approaching the rate of liver blood flow with the exception of ciclesonide, which is inactivated by blood esterases as well.37 However, the ICSs differ markedly in their oral bioavailability, although they all undergo rather extensive first-pass metabolism to less active substances when absorbed37 (see Table 15-9). The ICSs produce dose-dependent systemic effects, contributed by the orally absorbed fraction and the fraction absorbed from the lung2,37,46(Table 15-13). Essentially all the drug that reaches the lung is absorbed systemically; thus, a slow absorption from the lung results in an apparent long elimination half-life and enhances topical selectivity by lowering the systemic concentration.37 Ciclesonide and beclomethasone dipropionate differ from the other ICSs in that the parent compounds are prodrugs that are metabolized in the lung to the active compounds des-ciclesonide and beclomethasone monopropionate.37 The potential advantage of the drugs with low oral bioavailability is obviated by using a spacer device with the MDI for the drugs with higher oral bioavailability because appropriate spacers reduce the oral dose by 80%.37 The use of VHCs also can increase systemic activity by increasing lung delivery of drugs not absorbed significantly orally.37 If this increase in lung deposition is twofold or less, it will increase systemic activity without producing a clinically important increase in efficacy, thus decreasing the therapeutic index.37 Mouth rinsing and spitting will also reduce the oral availability and are particularly useful for DPI devices.2,37 Although ciclesonide and its active metabolite have rapid systemic clearance suggesting an improved therapeutic index, it has not yet been clearly established in clinical trials.37

TABLE 15-13 Effects of Inhaled Corticosteroids


The response to ICSs is somewhat delayed. Most patients’ symptoms will improve in the first 1 to 2 weeks of therapy and will reach maximum improvement in 4 to 8 weeks.46 Improvement in baseline FEV1and PEF may require 3 to 6 weeks for maximum improvement, whereas improvement in BHR requires 2 to 3 weeks and approaches maximum in 1 to 3 months but may continue to improve over 1 year.46Most of the improvement in these parameters occurs at low to medium doses, and there is a large variability in response, with 10% of patients not demonstrating an improvement in either parameter.46 Whether these nonresponders also show no improvement in rates of exacerbations is unknown. Significant decreases in FeNO occur within 1 to 2 days with maximum effect in 2 to 3 weeks.16,46 Sensitivity to exercise challenge decreases after 4 weeks of therapy.46 Although single doses do not inhibit the immediate asthmatic response to antigen challenge or exercise, continued therapy for 1 week partially suppresses the response. The two latter effects are likely due to a reduction in mucosal mast cells.46

Local adverse effects from ICSs include oropharyngeal candidiasis and dysphonia that are dose dependent. The dysphonia (reported in 5% to 20% of patients) appears to be due to a local corticosteroid-induced myopathy of the vocal cords.2 The use of a spacer device with MDIs can decrease oropharyngeal deposition and thus decrease the incidence and severity of local side effects.2,46 In infants who require ICS delivery through a face mask, the parent should clean the nasal–perioral area with a damp cloth following each treatment to prevent topical candidal infections.

Systemic adverse effects can occur with any of the ICSs given in a sufficiently high dose.46 Long-term adverse effects of greatest concern include growth suppression in children, osteoporosis, cataracts, dermal thinning, and adrenal insufficiency and crisis.45,46 Of these, only growth retardation occurs in low to medium doses. However, the growth reduction appears to be transient in that growth velocity is reduced in the first 6 months to 2 years of therapy and then returns to normal.2,45 The effect is small (1 to 2 cm total) and not cumulative, but does persist into adulthood.55 The suppression of the HPA axis and decreased bone mineralization are dose dependent and do not appear to be significant clinically except at high doses.46 The risks therefore depend on the therapeutic index of each ICS and its delivery device. The effect of delivery device is illustrated by fluticasone propionate, which has both the greatest therapeutic index when administered by DPI and the lowest therapeutic index when administered by MDI plus VHC.37 Many of the ICSs, including fluticasone propionate, budesonide, ciclesonide, and mometasone furoate, are metabolized in the GI tract and liver by CYP3A4 isoenzymes. Potent inhibitors of CYP3A4 such as ritonavir and ketoconazole have the potential for increasing systemic concentrations of these ICSs by increasing oral availability and decreasing systemic clearance.37 Some cases of clinically significant Cushing’s syndrome and secondary adrenal insufficiency have been reported.37

Most patients with moderate disease can be controlled with twice-daily dosing of most ICSs.2,37 Twice-daily dosing produces less thrush than three- to four-times-daily dosing regimens. In milder asthma, once-daily dosing is often sufficient to maintain control.37,46 Some of the newer products have gained once-daily dosing indications, particularly in mild asthma once initial control is established.37 There is no specific pharmacologic or pharmacokinetic aspect of the current ICSs that allows for once-daily dosing because all the agents studied (both the older low-potency ICSs and newer high-potency ICSs) have been effective, provided that patients had relatively mild-to-moderate asthma.37 More severe patients require multiple daily dosing. The inflammatory response of asthma has been shown to inhibit corticosteroid-receptor binding.37 Once asthma is controlled, many patients are able to reduce the ICS dose and maintain control.37,46 There has been a recent interest in using ICSs as needed or intermittently in patients with mild persistent asthma; however, the as-needed use has shown inconsistent results with better overall control from regular use.56,57

Long-Acting Inhaled β2-Agonists

The two LABAs, formoterol and salmeterol, provide long-lasting bronchodilation (≥12 hours) when administered as aerosols34 (see Table 15-8). Unlike the more water-soluble short-acting β2-agonists, the long-acting agents are lipid soluble, readily partitioning into the outer phospholipid layer of the cell membrane.34 More recently, indacaterol, a 24-hour LABA, was developed and approved for use in COPD.58,59 However, due to concerns of safety of LABAs in asthma it has not yet been approved for asthma.58 The LABAs are more β2-selective than albuterol and more bronchoselective by virtue of their property of remaining in the lung tissue cell membrane, which produces its longer duration.30 However, all LABAs will produce dose-dependent systemic β2-agonist effects.30,58

The principal difference between formoterol and salmeterol is that formoterol has a more rapid onset of action. This is unlikely to produce a clinically significant advantage because both LABAs are recommended for chronic therapy only in combination with ICSs.2 LABAs are available singly and as fixed-dose combinations with ICSs (see below). Neither has approved FDA labeling for acute relief of asthma, although formoterol has an onset of activity similar to albuterol. Patients need to be counseled to continue to use their short-acting inhaled β2-agonists for acute exacerbations while receiving the LABA/ICS combination products.

The LABAs are preferred adjunctive therapy to ICSs in children 12 years and older and adults for step 3 and children 5 to 11 years of age for steps 4 and 5.2 Combination treatment with ICS/LABA provides greater asthma control than increasing the dose of ICS alone, while at the same time reducing the frequency of mild and severe exacerbations.48 Since they are devoid of antiinflammatory activity, LABAs should not be used as monotherapy for asthma. Patients treated with LABA monotherapy added to usual therapy are at an increased risk for severe, life-threatening exacerbations and asthma-related death.60,61This risk may be greater in African American patients. Whether this risk is obviated by concomitant ICS use is controversial at this time (see below).6163 A genotype stratified study failed to detect lung function deterioration or increased exacerbations in Arg-16 homozygotes receiving a LABA plus ICS.64

As with short-acting β2-agonists, tolerance is produced with chronic administration of LABAs. Long-term trials have shown no diminution in bronchodilator response but a partial loss of the bronchoprotective effect against methacholine, histamine, and exercise challenge.30 In particular, the duration of protection against EIB following a single dose of salmeterol is up to 9 hours but is reduced to less than 4 hours following regular treatment.30 Following regular treatment with LABAs, decreased protection against nonspecific bronchoprovocation with methacholine also occurs, although they continue to provide greater protection than placebo.30 Responsiveness to short-acting β2-agonists has been reported to be slightly decreased but easily overcome by increasing the dose (by 1–2 puff) following chronic therapy with LABAs.30

There is ample evidence that the use of a LABA in combination with ICS therapy does not mask inflammation.30 In children 4 to 11 years of age, LABAs added to ICS reduce impairment and improve asthma control but have yet to be adequately studied for reducing the risk domain of exacerbations over ICS alone.30,53


Methylxanthines have been used for asthma therapy for more than 50 years, but their use has declined markedly owing to the high risk of severe life-threatening toxicity and numerous drug interactions, as well as decreased efficacy compared with ICSs and LABAs. Theophylline, the primary methylxanthine of interest, is a moderately potent bronchodilator with mild antiinflammatory properties.2 Like the β2-agonists, the methylxanthines are functional antagonists of bronchospasm; however, their clinical utility is limited by their low therapeutic index.2 Theophylline as a sustained-release product is the preferred oral preparation, whereas its complex with ethylenediamine (aminophylline) is the preferred injectable product owing to increased solubility.2

The mechanism by which theophylline produces bronchodilation appears to be through nonselective phosphodiesterase (PDE) inhibition–producing increased cAMP and cyclic guanosine monophosphate (cGMP) concentrations.2The PDE isoenzymes currently thought to be important for theophylline’s clinical effects are isoenzymes III, predominant in airway smooth muscle, and IV, important in inflammatory cell regulation such as mast cells, neutrophils, eosinophils, and T lymphocytes.2 Selective PDE isoenzyme IV inhibitors, however, have no significant effects in clinical asthma. Theophylline also activates histone deacetylase that is involved in the corticosteroid-induced decrease in proinflammatory gene expression.65 It is a competitive antagonist of adenosine and stimulates endogenous catecholamine release, which are important determinants of toxic symptoms of excess theophylline.2

Theophylline has a log-linear dose–response curve.66 Most chronic stable patients with asthma will obtain significant bronchodilation when the serum theophylline concentration reaches 5 mcg/mL (28 μmol/L), and most patients will have no toxic symptoms with serum concentrations of less than 15 mcg/mL (83 μmol/L).2,66 The percentage of patients experiencing adverse effects increases sharply as concentrations exceed 15 mcg/mL (83 μmol/L). As with the β2-agonists, the dose–response curves for smooth muscle relaxation by theophylline are dynamic and shifted to the right in the face of increasing contractile stimuli.66 This property probably explains theophylline’s relative lack of bronchodilatory effect in acute severe asthma.2,66 The severity of theophylline’s toxicity precludes even doubling the usual dosage. Toxicities include caffeine-like effects of nausea, vomiting, tachycardia, jitteriness, and difficulty sleeping to more severe toxicities such as cardiac tachyarrythmias and seizures. Death has occurred in children receiving their usual doses of theophylline during acute systemic viral illnesses.66

Routine monitoring of serum concentrations is essential for the safe and effective use of theophylline.2 Theophylline is eliminated primarily by metabolism via the hepatic cytochrome P450 (CYP) mixed-function oxidase microsomal enzymes (primarily the CYP1A2 and CYP3A3 isozymes), with 10% or less excreted unchanged in the kidney.2 Theophylline clearance is age dependent, with 1- to 9-year-olds having the highest systemic clearances and therefore requiring the largest dosages (on a weight basis). However, even within the same age groups, theophylline clearance can vary twofold to threefold.2 Figure 15-9 outlines a dosing and monitoring schedule for theophylline. Factors affecting theophylline’s hepatic metabolism are listed in Table 15-14.2 Only drugs or diseases that produce a ≥20% inhibition or a ≥50% induction of theophylline metabolism are likely to result in clinically significant interactions.66


FIGURE 15-9 Algorithm for slow titration of theophylline dosage and guide for final dosage adjustment based on serum theophylline concentration measurement. For infants younger than 1 year of age, the initial daily dosage can be calculated by the following regression equation: Dose (mg/kg) = (0.2) (age in weeks) + 5. Whenever side effects occur, dosage should be reduced to a previously tolerated lower dose.

TABLE 15-14 Factors Affecting Theophylline Clearance


Sustained-release theophylline is less effective than ICSs and no more effective than oral sustained-release β2-agonists, cromolyn, or LT antagonists.2 The addition of theophylline to ICSs is similar to doubling the dose of the ICS and is overall less effective than the LABAs as adjunctive therapy.2 The addition of theophylline to patients with poorly controlled asthma receiving ICS/LABA combination does not improve outcomes.67

Cromolyn Sodium

Cromolyn is classified as a mast cell stabilizer and inhibits the early and late asthmatic response to allergen challenge, as well as inhibiting EIB.13,68 Long-term treatment produces minimal to no change in baseline BHR.2 Cromolyn inhibits neurally mediated bronchoconstriction through C-fiber sensory nerve stimulation in the airways, although it does not have a bronchodilatory effect.68

Cromolyn is only effective by inhalation, and available as a nebulizer solution.68 It is not bioavailable orally, but the portion of the dose that reaches the lung is absorbed completely.68 Absorption from the airway is significantly slower than elimination (hours vs. minutes). The short duration in the lung likely limits its efficacy. Both the intensity and duration of protection against various challenges are dose dependent.68

Cromolyn is remarkably nontoxic. No evidence of mutagenesis or teratogenesis has been found. Cough and wheeze have been reported following inhalation.2 Tolerance to cromolyn has not been demonstrated. It is not considered to be an ICS-sparing agent.

Cromolyn is no more or less effective than theophylline or the LT antagonists for persistent asthma.2,66 It is not as effective as the ICSs for controlling persistent asthma.66 Cromolyn is not as effective as the inhaled β2-agonists for preventing EIB but can be used in conjunction for patients not responding completely to the inhaled β2-agonists.13

Most patients will experience an improvement in 1 to 2 weeks, but it may take longer to achieve maximum benefit. Patients initially should receive cromolyn four times daily, and then only after stabilization of symptoms may the frequency be reduced to three times daily.

Leukotriene Modifiers

Two cysteinyl LT receptor antagonists (zafirlukast and montelukast) and one 5-lipoxygenase inhibitor (zileuton) are available in the United States.69 In challenge studies, they reduce allergen-, exercise-, cold-air hyperventilation–, irritant-, and aspirin-induced asthma.69 Clinical use of zileuton is limited due to the potential for elevated liver enzymes (especially in the first 3 months of therapy), and the potential inhibition of drugs metabolized by the CYP3A4 isoenzymes.66,69 They are not preferred alternatives in mild persistent asthma nor as alternative add-on therapy for moderate persistent asthma (Fig. 15-8).2

These drugs improve pulmonary function tests (FEV1 and PEF), decrease nocturnal awakenings and β2-agonist use, and improve asthma symptoms.69 A major advantage is that they are effective orally, and can be administered once or twice a day.69 However, they are less effective in asthma than low doses of ICSs.66,69 Although montelukast is approved for EIB in adults, it is significantly less effective than short-acting inhaled β2-agonists. In adults with severe uncontrolled asthma they do not improve outcomes.69 They are not as effective as LABAs when added to ICSs for moderate persistent asthma.69 It is not yet possible to predict which patients respond best to LT modifiers, although there is some evidence that patients with aspirin-sensitive asthma do well, as predicted by studies showing increased cysteinyl LT production in these patients.69 It is possible that genetic polymorphisms in the 5-lipoxygenase or LTC4 synthase pathways or in cys-LT1 receptors might predict better responders in the future.69 Anti-LTs also have modest efficacy in allergic rhinitis.

In general, the LTD4 receptor antagonists are well tolerated and do not appear to have serious class-specific effects.2 An idiosyncratic syndrome similar to the Churg-Strauss syndrome, with marked circulating eosinophilia, heart failure, and associated eosinophilic vasculitis, has been reported in a small number of patients treated with zafirlukast and montelukast.66 The majority of these patients had been receiving high-dose ICS or oral corticosteroids and were able to reduce the dose as a consequence of the LTD4 receptor antagonists. It is unclear whether the increased reports are due to increased case findings among patients with asthma prescribed a new drug or whether the syndrome is related to corticosteroid dose reduction or an idiosyncratic effect of LT modifiers in general. Whatever the cause, it appears to be a rare syndrome, with an estimated incidence of fewer than 1 case per 15,000 to 20,000 patient-years of treatment.66

Reports of adverse neuropsychiatric events have caused the manufacturers of the LT inhibitors to revise their labeling. However, evidence for causality of suicidal thoughts and suicide is lacking.70 Reports of fatal hepatic failure associated with zafirlukast have prompted a warning for patients to be made aware of signs and symptoms of hepatic dysfunction.2

Zileuton can be administered twice daily as controlled-release tablets.2 Efficacy data are more limited, liver function monitoring is recommended, and drug interactions are reported with warfarin and theophylline.

Anti-IgE (Omalizumab

Omalizumab is a recombinant anti-IgE antibody approved for the treatment of allergic asthma not well controlled on oral corticosteroids or ICSs.71 It is a composite of 95% human and 5% antihuman murine IgE sequences. Omalizumab binds to the Fc portion of the IgE antibody preventing the binding of IgE to its high-affinity receptor (FcεRI) on mast cells and basophils. The decreased binding of IgE on the surface of mast cells leads to a decrease in the release of mediators in response to allergen exposure. Omalizumab also decreases FcεRI expression on basophils and airway submucosal mast cells over 8 to 12 weeks.71

Omalizumab is administered subcutaneously and has a slow absorption rate; peak serum concentration is achieved in 3 to 14 days.71 Omalizumab is eliminated primarily through the reticuloendothelial system and has an elimination half-life of 17 to 22 days; serum free IgE levels return to previous level in about 3 weeks.71 Omalizumab should be administered under medical observation with drugs for treating anaphylaxis available.

The dosage of omalizumab is determined by the patient’s baseline total serum IgE level (international units per milliliter) and body weight (kilograms).71 Doses range from 150 to 375 mg and are given at either 2- or 4-week intervals. No further adjustments for variations in total serum IgE are required, and patients receive a consistent dose for the duration of treatment.71 Omalizumab is approved for patients greater than 12 years with allergic asthma.71Clinical trials in 5- to 12-year-olds are ongoing. Due to its significant cost, it is only indicated as step 5 or 6 care for patients who have allergies and severe persistent asthma that are inadequately controlled with the combination of high-dose ICS/LABA and at risk for severe exacerbations.2,72 It is the only adjunctive therapy that has demonstrated improved outcomes in patients uncontrolled on ICS/LABA and has allowed oral corticosteroid reduction in a number of studies.2,71 Omalizumab therapy is associated with a 0.2% rate of anaphylaxis prompting an FDA warning that patients should remain in the healthcare provider’s office for a reasonable period of time past the injection as 70% of reactions occur within 2 hours. In addition, patients should be counseled on the signs and symptoms of anaphylaxis because some reactions have occurred up to 24 hours following an injection.2,71

Miscellaneous Therapies (Immunomodulators)

The following therapies have been loosely categorized by the NAEPP with omalizumab as immunomodulators because they either affect the immune system or have antiinflammatory properties. Many have been used experimentally in severe persistent uncontrolled asthma for years to try to avoid or lower oral corticosteroid dosages.

Low-dose methotrexate (15 mg/wk) used for inflammatory diseases, psoriatic and rheumatoid arthritis, and polymyositis has been used to reduce the systemic corticosteroid dose in patients with severe steroid-dependent asthma.73 A meta-analysis of all studies determined that there was insufficient evidence to support its use, particularly in light of the risk for severe side effects.73 Low-dose weekly methotrexate is associated with hepatotoxicity and pulmonary fibrosis.73 The NAEPP has concluded that it should not be used in persistent asthma.2

A number of the drugs with antiinflammatory or immunomodulatory activity such as hydroxychloroquine, dapsone, gold, IV γ-globulin, cyclosporine, and colchicine have been studied in severe corticosteroid-dependent asthma with mixed and limited results.2,74 Routine use is not recommended.2

Future Therapies

In addition to a number of once-daily ICSs and ICS/LABA combinations, agents that are now in development for asthma focus on the treatment of allergic inflammation.75 Examples include inhibitors of eosinophilic inflammation, drugs that may inhibit allergen presentation, and inhibitors of Th2 cells. Multiple cytokines have been implicated in allergic inflammation, and several possible inhibiting approaches are being explored. These range from drugs that inhibit cytokine synthesis (cyclosporin A and tacrolimus), humanized blocking antibodies to cytokines or their receptors, soluble receptors to mop up secreted cytokines, receptor antagonists, and drugs that block the signal-transduction pathways activated by cytokines.75 Unfortunately specific anticytokine therapy against IL-5 and IL-4 has been disappointing to date.75

The FDA has approved Asthmatx, Inc’s Alair Bronchial Thermoplasty System to treat severe asthma in adult patients. This is the first nondrug treatment for asthma. The Alair treatment (three sessions of 30 minutes each) is performed via a bronchoscope that is inserted into the lungs. A tip of a small catheter then expands to deliver thermal energy to reduce the presence of airway smooth muscle that narrows the airways.76


Of the estimated $19.7 billion cost of asthma in the United States in 2004, direct medical expenditure accounted for $14.7 billion of the total, with emergency care (ED and in-patient hospital care) reaching $4.7 billion.4 A cost-of-illness approach takes in all measurable costs; both indirect costs or costs to society and direct medical costs are considered.77,78 Using this approach, indirect costs such as lost work and death accounted for 25% of total expenditures per patient. Although prescription drugs were the largest single direct medical expenditure at $6.7 billion,4 an increase in these costs secondary to improved patient adherence could significantly reduce other costs due to missed school days and lost productivity secondary to asthma morbidity and mortality.

The medication cost increase over the past years resulted from an increase in prescribed medications, as well as an increase in unit cost per medication. The latter may improve in the next few years as a number of existing products go off patent and become generic. Asthma severity affects cost of care as studies from health maintenance organizations suggest that up to 45% of the cost of asthma is accrued by 10% of the patients, primarily as a result of emergency care.78

Numerous studies have demonstrated the cost-effectiveness of patient education programs for asthma, particularly those providing guided self-management.2 Several studies have reported positive results from pharmacist interventions reducing overall cost of care.2 Similar studies have demonstrated the cost-effectiveness of specialist care compared with generalist care. However, the results of these trials may be confounded by changes in prescribing as part of the overall program.77 Indeed, use of ICSs reduces both morbidity, particularly hospitalizations, and mortality in asthma patients.2,77

The NAEPP recommendations provide numerous alternatives for long-term controllers in mild-to-moderate persistent asthma, and few studies have compared their relative cost-effectiveness. This comparison is important because outside the realm of randomized clinical trials that evaluate efficacy, other factors such as concern about adverse effects and adherence to therapy may alter the overall clinical effectiveness. Use of ICSs in children has produced a cost of $9.45 per symptom-free day gained and in adults $5 per symptom-free day.2 Retrospective analyses of large managed-care-linked pharmacy claims and healthcare utilization databases have allowed direct comparisons of the various long-term controllers in a general population to assess clinical effectiveness and cost-effectiveness. While these studies have confirmed comparative randomized clinical trials showing ICSs to be significantly more cost-effective than LT antagonists, many have flaws, including the short duration of followup for a chronic illness such as asthma.77

Clinical Controversy…

The potential for chronic use of inhaled β2-agonists to worsen asthma has been a concern for more than 40 years. A large multicenter clinical trial of the addition of LABA as monotherapy to patient’s usual therapy produced a significant increased risk of death from asthma.60 However, post hoc analysis from that study did not show an increased risk of death in those patients whose usual therapy included ICSs.60Other meta-analyses also failed to demonstrate an increased risk of death or hospitalizations from asthma in patients receiving ICS/LABA combination therapy.61,62 However, the FDA’s stance is that the number of patients in the trials was too low to detect rare events, so it has mandated the pharmaceutical companies to perform large clinical trials in both children and adults to determine whether ICSs protect against the risk of severe life-threatening asthma exacerbations in those on combination therapy.63 Those studies are underway. The LABAs should be used only in combination with ICSs where the risk of severe life-threatening exacerbations has not been demonstrated.61,62


Control of asthma is defined as reducing both impairment and risk domains.77 The stepwise approach to therapy should be used to achieve and maintain this control. The steps of care appropriate to the three age ranges of asthma have been outlined in Figure 15-8.2 Depending on the severity of the patient’s asthma, compromises from the ideal control are made, and the best possible outcome balancing disease control and possible adverse effects from the drugs is attempted. Regular followup contact is essential (at 1- to 6-month intervals, depending on control). A step-down in therapy can be considered, if well-controlled status has been achieved for at least 3 months.2

Components of control classification include symptoms, nighttime awakenings, interference with normal activities, pulmonary function, quality of life, exacerbations, medication adherence, treatment-related adverse effects, and satisfaction with care.77 The categories of well controlled, not well controlled, and very poorly controlled are recommended. Validated questionnaires such as the Asthma Therapy Assessment Questionnaire (ATAQ), the Asthma Control Questionnaire (ACQ), and the Asthma Control Test (ACT) can be regularly administered.77 The NAEPP minimally recommends spirometric tests at initial assessment, after treatment is initiated, and then every 1 to 2 years.2In moderate-to-severe persistent asthma, PEF monitoring is recommended. PEF monitoring should also be considered in patients who are poor symptom perceivers or those with a history of severe exacerbations.2 Patients should also be asked about exercise tolerance. All patients on inhaled drugs should have their inhalation delivery technique evaluated periodically—monthly initially and then every 3 to 6 months. Before stepping up therapy, adherence, environmental control, and comorbid conditions should be reviewed.2

Following initiation of antiinflammatory therapy or an increase in dosage, most patients should begin experiencing a decrease in symptoms in 1 to 2 weeks and achieve maximum symptomatic improvement within 4 to 8 weeks. The use of higher ICS doses or more potent agents may accelerate the process. Improvement in FEV1 and PEF should follow a similar time frame; however, a decrease in BHR, as measured by morning PEF, PEF variability, and exercise tolerance, may take longer and improve over 1 to 3 months.2 Patients should be informed that following a viral respiratory infection, they may experience decreased exercise tolerance for up to 4 weeks.

Initial visits with the patient should focus on the patient’s concerns, expectations, and goals of treatment. Basic education should focus on asthma as a chronic lung disease, the types of medications, and how they are to be used. Inhaler technique is taught, as is when to seek medical advice. Written action plans should be provided. Either peak flow–based or symptom-based self-monitoring can be effective, if taught and followed correctly.2 The first followup visit should be in 2 to 6 weeks, to evaluate control. At that time, the educational messages of the first visit should be repeated, as well as review of the patient’s current medications, adherence, and any difficulties related to the therapy.


Asthma is a complicated disease with a multitude of clinical presentations. The exact defect in asthma has not been defined, and it may be that asthma is a common presentation of a heterogeneous group of diseases. Asthma is defined and characterized by excessive reactivity of the bronchial tree to a wide variety of noxious stimuli. The reaction is characterized by bronchospasm, excessive mucus production, and inflammation. The central role of inflammation in inducing and maintaining BHR is now becoming widely appreciated. The goal of asthma therapy is to normalize, as much as possible, the patient’s life and prevent chronic irreversible lung changes. Drugs are the mainstay of asthma management. The goal of drug therapy is to use the minimum amount of medications possible to completely control the disease. In persistent asthma, therapy should be aimed at both bronchospasm and inflammation in order to produce the best results. Patients should be followed and monitored diligently for toxicities. Although death from asthma is an uncommon event, the most common cause of death is underassessment of the severity of obstruction either by the patient or by the clinician; the next common cause is undertreatment. A cornerstone of any therapy is education and the realization that most asthma deaths are avoidable.




    1. Rosenblatt MB. History of bronchial asthma. In: Weiss EB, Segal MS, Stein M, eds. Bronchial Asthma: Mechanisms and Therapeutics, 2nd ed. Boston: Little, Brown, 1976:5–17.

    2. National Institutes of Health, National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program. Full Report of the Expert Panel: Guidelines for the Diagnosis and Management of Asthma (EPR-3). July 2007,

    3. Akinbami LJ, Moorman JE, Bailey C, et al. Trends in asthma prevalence, health care use, and mortality in the United States, 2001-2010. NCHS Data Brief 2012;94:1–8.

    4. American Lung Association. Trends in Asthma Morbidity and Mortality. American Lung Association Epidemiology & Statistics Unit Research and Program Services. January 2009,

    5. Melén E, Pershagen G. Pathophysiology of asthma: Lessons from genetic research with particular focus on severe asthma. J Intern Med 2012;272:108–120.

    6. Gelfand EW. Pediatric asthma: A different disease. Proc Am Thorac Soc 2009;6:278–282.

    7. Busse WW, Lemanske RF Jr. Asthma. N Engl J Med 2001;344:350–362.

    8. Dykewicz MS. Occupational asthma: Current concepts in pathogenesis, diagnosis, and management. J Allergy Clin Immunol 2009;123:519–528.

    9. Sears MR. Epidemiology of asthma exacerbations. J Allergy Clin Immunol 2008;122:662–668.

   10. Busse WW, Lemanske RF Jr, Gern JE. Role of viral respiratory infections in asthma and asthma exacerbations. Lancet 2010;376(9743):826–834.

   11. Fixman ED, Stewart A, Martin JG. Basic mechanisms of development of airway structural changes in asthma. Eur Respir J 2007;29:379–389.

   12. Woodruff PG, Modrek B, Choy DF, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 2009;180:388–395.

   13. Weiler JM, Anderson SD, Randolph C, et al. Pathogenesis, prevalence, diagnosis, and management of exercise-induced bronchoconstriction: A practice parameter. Ann Allergy Asthma Immunol 2010;105(6 Suppl):S1–S47.

   14. Fahy JV. Eosinophilic and neutrophilic inflammation in asthma: Insights from clinical studies. Proc Am Thorac Soc 2009;6:256–259.

   15. An SS, Bai TR, Bates JHT, et al. Airway smooth muscle dynamics: A common pathway of airway obstruction in asthma. Eur Respir J 2007;29:834–860.

   16. Kharitonov SA, Barnes PJ. Exhaled biomarkers. Chest 2006; 130:1541–1546.

   17. Anderson SD, Charlton B, Weiler JM, et al. Comparison of mannitol and methacholine to predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma. Respir Res 2009;10:4.

   18. The American Lung Association Clinical Research Centers. Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med 2009;360:1487–1499.

   19. National Institutes of Health, National Heart, Lung and Blood Institute. NAEPP Expert Panel Report Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment—Update 2004. NIH Publication No. 04-5246. Bethesda, MD: National Heart, Lung and Blood Institute, National Institutes of Health, March 2004.

   20. Brenner BE, Holmes TM, Mazal B, Camargo CA Jr. Relation between phase of the menstrual cycle and asthma presentations in the emergency department. Thorax 2005;60: 806–809.

   21. Beasley R, Burgess C, Holt S. Call for a worldwide withdrawal of benzalkonium chloride from nebulizer solutions. J Allergy Clin Immunol 2001;107:222–223.

   22. Jenkins C, Costello J, Hodge L. Systematic review of the prevalence of aspirin induced asthma and its implications for clinical practice. BMJ 2004;328(7437):434.

   23. Dixon AE, Holguin F, Sood A, et al. An official American Thoracic Society workshop report: Obesity and asthma. Proc Am Thorac Soc 2010;7(5):325–335.

   24. Marcon A, Corsico A, Cazzoletti L, et al. Body mass index, weight gain, and other determinants of lung function decline in adult asthma. J Allergy Clin Immunol 2009;123: 1069–1074.

   25. Brehm JM, Schuemann B, Fuhlbrigge AL, et al. Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. J Allergy Clin Immunol 2010;126:52–58.

   26. Dolovich MB, Dhand R. Aerosol drug delivery: Developments in device design and clinical use. Lancet 2011;377(9770):1032–1045.

   27. Schatz M, Kazzi AAN, Brenner B, et al. American Thoracic Society documents: Joint task force report: Supplemental recommendations for the management and follow-up of asthma exacerbations. Proc Am Thorac Soc 2009;6: 353–393.

   28. Lazarus SC. Clinical practice. Emergency treatment of asthma. N Engl J Med 2010;363:755–764.

   29. Dhand R. Aerosol delivery during mechanical ventilation: From basic techniques to new devices. J Aerosol Med Pulm Drug Deliv 2008;21:45–60.

   30. Kelly HW. Risk versus benefit considerations for the beta(2)-agonists. Pharmacotherapy 2006;26:164S–174S.

   31. Rowe BH, Edmonds ML, Spooner CH, Diner B, Camargo CA Jr. Corticosteroid therapy for acute asthma. Respir Med 2004;98:275–284.

   32. Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: A systematic review with meta-analysis. Thorax 2005;60: 740–746.

   33. Rodrigo G, Pollack C, Rodrigo C, Rowe BH. Heliox for nonintubated acute asthma patients. Cochrane Database Syst Rev 2006;(4):CD002884.

   34. Kelly HW. What is new with the β2 agonists: Issues in the management of asthma. Ann Pharmacother 2005;39: 931–938.

   35. Tse SM, Tantisira K, Weiss ST. The pharmacogenetics and pharmacogenomics of asthma therapy. Pharmacogenomics J 2011;11:383–392.

   36. Green RH, Wardlaw AJ. Systemic corticosteroids in asthma. In: Li JT, ed. Pharmacotherapy of Asthma. New York, NY: Taylor and Francis, 2006:233–262.

   37. Kelly HW. Comparison of inhaled corticosteroids: An update. Ann Pharmacother 2009;43:519–527.

   38. Tse SM, Kelly HW, Litonjua AA, et al. Corticosteroid use and bone mineral accretion in children with asthma: Effect modification by vitamin D. J Allergy Clin Immunol 2012;130:53–60.

   39. Gross NJ. Anticholinergic bronchodilators. In: Li JT, ed. Pharmacotherapy of Asthma. New York, NY: Taylor and Francis, 2006:65–82.

   40. Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 2010;363:1715–1726.

   41. Kerstjens HA, Disse B, Schröder-Babo W, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: A randomized controlled trial. J Allergy Clin Immunol 2011;128:308–314.

   42. Rank MA, Liesinger JT, Ziegenfuss JY, et al. Asthma expenditures in the United States comparing 2004 to 2006 and 1996 to 1998. Am J Manag Care 2012;18:499–504.

   43. Boyd M, Lasserson TJ, McKean MC, Gibson PG, Ducharme FM, Haby M. Interventions for educating children who are at risk of asthma-related emergency department attendance. Cochrane Database Syst Rev 2009;(2):CD001290.

   44. Janson SL, McGrath KW, Covington JK, Cheng SC, Boushey HA. Individualized asthma self-management improves medication adherence and markers of asthma control. J Allergy Clin Immunol 2009;123:840–846.

   45. Pedersen S. Clinical safety of inhaled corticosteroids for asthma in children: An update of long-term trials. Drug Saf 2006;29:599–612.

   46. Masoli M, Shirtcliffe P, Weatherall M, Holt S, Beasley R. Inhaled corticosteroid therapy in the management of asthma in adults. In: Li JT, ed. Pharmacotherapy of Asthma. New York, NY: Taylor & Francis, 2006:83–115.

   47. Strunk RC, Sternberg AL, Szefler SJ, et al. Long-term budesonide or nedocromil treatment, once discontinued, does not alter the course of mild to moderate asthma in children and adolescents. J Pediatr 2009;154:682–687.

   48. Ducharme F, Ni Chroinin M, Greenstone I, Lasserson TJ. Addition of long-acting beta2-agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children. Cochrane Database Syst Rev 2010;(5):CD005535.

   49. Kelly HW. Inhaled corticosteroid dosing: Double for nothing? J Allergy Clin Immunol 2011;128:278–281.

   50. Casale TB, Stokes JR. Immunomodulators for allergic respiratory disorders. J Allergy Clin Immunol 2008;121: 288–296.

   51. Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012;367:1198–1207 [Epub ahead of print].

   52. Zeiger RS, Mauger D, Bacharier LB, et al. Continuous or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med 2011;365:1990–2001.

   53. Lemanske RF Jr, Mauger DT, Sorkness CA, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med 2010;362:975–985.

   54. Weldon D. The effects of corticosteroids on bone growth and bone density. Ann Allergy Asthma Immunol 2009;103:3–11.

   55. Kelly HW, Sternberg AL, Lescher R, et al. Effect of inhaled glucocorticoids in childhood on adult height. N Engl J Med 2012;367:904–912.

   56. Papi A, Canonica GW, Maestrelli P, et al. Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med 2007;356(20):2040–2052.

   57. Martinez FD, Chinchilli VM, Morgan WJ, et al. Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): A randomised, double-blind, placebo-controlled trial. Lancet 2011;377(9766):650–657.

   58. Chowdhury BA, Seymour SM, Michele TM, Durmowicz AG, Liu D, Rosebraugh CJ. The risks and benefits of indacaterol—The FDA’s review. N Engl J Med 2011;365:2247–2249.

   59. Ray SM, McMillen JC, Treadway SA, Helmer RS, Franks AS. Indacaterol: A novel long-acting β(2)-agonist. Pharmacotherapy 2012;32:456–474.

   60. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM. The Salmeterol Multicenter Asthma Research Trial: A comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129:15–26.

   61. McMahon AW, Levenson MS, McEvoy BW, Mosholder AD, Murphy D. Age and risks of FDA-approved long-acting β2-adrenergic receptor agonists. Pediatrics 2011;128: e1147–e1154.

   62. Jaeschke R, O’Byrne PM, Mejza F, et al. The safety of long-acting beta-agonists among patients with asthma using inhaled corticosteroids: Systematic review and meta-analysis. Am J Respir Crit Care Med 2008;178:1009–1016.

   63. Chowdhury BA, Seymour SM, Levenson MS. Assessing the safety of adding LABAs to inhaled corticosteroids for treating asthma. N Engl J Med 2011;364:2473–2475.

   64. Wechsler ME, Kunselman SJ, Chinchilli VM, et al. Effect of β2-adrenergic receptor polymorphism on response to longacting β2 agonist in asthma (LARGE trial): A genotype-stratified, randomized, placebo-controlled, crossover trial. Lancet 2009;374:1754–1764.

   65. Adcock IM, Barnes PJ. Molecular mechanisms of corticosteroid resistance. Chest 2008;134:394–401.

   66. Kelly HW. Non-corticosteroid therapy for the long-term control of asthma. Expert Opin Pharmacother 2007;8: 2077–2087.

   67. The American Lung Association Asthma Clinical Research Centers. Clinical trial of low-dose theophylline and montelukast in patients with poorly controlled asthma. Am J Respir Crit Care Med 2007;175:235–242.

   68. Lowery M, Kelly KJ. Cromolyn and nedocromil. In: Li JT, ed. Pharmacotherapy of Asthma. New York, NY: Taylor & Francis, 2006:195–231.

   69. O’Byrne PM, Gauvreau GM, Murphy DM. Efficacy of leukotriene receptor antagonists and synthesis inhibitors in asthma. J Allergy Clin Immunol 2009;124:397–403.

   70. Manalai P, Woo JM, Postolache TT. Suicidality and montelukast. Expert Opin Drug Saf 2009;8:273–282.

   71. Ledford DK. Omalizumab: Overview of pharmacology and efficacy in asthma. Expert Opin Biol Ther 2009;9:933–943.

   72. Wu AC, Paltiel AD, Kuntz KM, et al. Cost-effectiveness of omalizumab in adults with severe asthma: Results from the Asthma Policy Model. J Allergy Clin Immunol 2007;120:1146–1152.

   73. Davies H, Olson L, Gibson P. Methotrexate as a steroid sparing agent for asthma in adults. Cochrane Database Syst Rev 2000;(2):CD000391.

   74. Dykewicz MS. Immunosuppressive and other alternate treatments for asthma. In: Li JT, ed. Pharmacotherapy of Asthma. New York, NY: Taylor & Francis, 2006: 299–317.

   75. Barnes PJ. Drugs for asthma. Br J Pharmacol 2006; 147(Suppl 1):S297–S303.

   76. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: A multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med 2010;181:116–124.

   77. Reddel HK, Taylor DR, Bateman ED, et al. An official American Thoracic Society/European Respiratory Society statement: Asthma control and exacerbations: Standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med 2009;180: 59–99.

   78. Campbell JD, Spackman DE, Sullivan SD. Health economics of asthma: Assessing the value of asthma interventions. Allergy 2008;63:1581–1592.