Although much progress has been made in our understanding of bronchial asthma in recent years, asthma remains a commonly encountered condition that challenges physicians in the office setting as well as in acute care settings. ^1–3 Although the 1980s were characterized by increases in asthma morbidity and mortality in the United States, these trends reached a plateau in the 1990s, and asthma mortality rates have declined since 1999. ⁴ In recent decades, a surge in asthma prevalence also occurred in the United States and other Western countries; data suggest this trend may also be reaching a plateau.

Tremendous progress has been made in our fundamental understanding of asthma pathogenesis by virtue of invasive research tools such as bronchoscopy, bronchoalveolar lavage, airway biopsy, and measurement of airway gases, although the cause of airway inflammation remains obscure. The knowledge that asthma is an inflammatory disorder has become fundamental to our definition of asthma. A proliferation of evidence-based practice guidelines has been disseminated with a goal of encouraging more frequent use of anti-inflammatory therapy to improve asthma outcomes. To this extent, there has been much emphasis on early diagnosis and longitudinal care of patients with asthma, along with ensuring adherence to recommended therapies. In this context, there have been advances in our pharmacologic armamentarium in both chronic and acute therapy with the development and approval of novel medications. Yet, as exciting as this revolution has been in asthma research and practice, a number of controversies persist, and further fundamental developments in novel therapeutics are imminent.

This review of asthma for the practicing clinician will summarize these developments, including an update on the definition of asthma, its epidemiology, natural history, cause, and pathogenesis. In addition, there will be discussion of the appropriate diagnostic evaluation of asthma and co-occurring conditions, serial monitoring of asthma, and newer therapies for the future.

Definitions

Asthma is a chronic, episodic disease of the airways that is best viewed as a syndrome. In 1997, the National Heart, Lung, and Blood Institute (NHLBI) included the following features as integral to the definition of asthma: ¹² recurrent episodes of respiratory symptoms; variable airflow obstruction that is often reversible, either spontaneously or with treatment; presence of airway hyperreactivity; and, importantly, chronic airway inflammation in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells. All of these features need not be present in any given asthmatic patient. Although the absolute “minimum criteria” to establish a diagnosis of asthma are not widely agreed on, the presence of airway hyper-reactivity can be regarded as a sine qua non for patients with current symptoms and active asthma.

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Epidemiology and natural history

Several governmental agencies have been charged with surveillance for asthma, including the NHLBI's National Asthma Education and Prevention Program (NAEPP), the Department of Health and Human Services (Healthy People 2010), and the Centers for Disease Control and Prevention. Data published by the Centers for Disease Control and Prevention indicate that approximately 15 million American adults have asthma. ⁴ The trend for increasing asthma—mortality that began in 1978 through the 1980s—reached a plateau in the 1990s and, since 1999 annual rates have declined. Annual rates of patients reporting “asthma attacks” from 1997 to 1999 were lower than previously reported rates. Since 1995, the rate of outpatient visits for asthma increased, whereas the rates of hospital admissions declined (from 19.5 per 10,000 population in 1995 to 15.7 in 1998). These trends are reassuring, and have been correlated with increasing rates of dispensed prescriptions for inhaled corticosteroids—implying that improved treatment of asthma may be responsible for these favorable developments. African Americans continue to have higher rates of asthma emergency department visits, hospitalizations, and deaths than whites. The overall annual economic burden for asthma care in the United States exceeds $6 billion. ⁵

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Etiology and pathogenesis

Clinicians have long known that asthma is not a single disease; it exists in many forms. This heterogeneity has been well established by a variety of studies that have indicated disease risk from early environmental factors and susceptibility genes, subsequent disease induction and progression from inflammation, and response to therapeutic agents (Fig. 1). Recent evidence indicates asthma is an inflammatory disease and not simply a result of excessive smooth muscle contraction. Increased airway inflammation follows exposure to inducers such as allergens, viruses, exercise, or nonspecific irritant inhalation. Increased inflammation leads to exacerbations characterized by dyspnea, wheezing, cough, and chest tightness. Abnormal histopathology including edema, epithelial cell desquamation, and inflammatory cell infiltration are found not only in autopsy studies of severe asthma cases but even in patients with very mild asthma. Reconstructive lesions, including goblet cell hyperplasia, subepithelial fibrosis, smooth muscle cell and myofibroblast hyperplasia may lead to airway wall remodeling. Many studies have emphasized the multifactorial nature of asthma, with interactions between neural mechanisms, inflammatory cells (mast cells, macrophages, eosinophils, neutrophils, and lymphocytes), mediators (interleukins, leukotrienes, prostaglandins, and platelet-activating factor), and intrinsic abnormalities of the arachidonic acid pathway and smooth muscle cells. Although these types of descriptive studies have revealed a composite picture of asthma (Fig. 2), they have failed to provide a basic unifying defect.

Advances have been made in our understanding of asthmatic airway inflammation through the use of invasive technology such as bronchoscopy with airway sampling at baseline state, ⁶ and with experimental provocation (e.g., allergen challenge) and following administration of interventions, such as anti-inflammatory pharmacotherapy. Further insights have been obtained through transgenic murine models with deletion or “knockout” of specific genes (i.e., those for IgE, CD23, IL-4, or IL-5) or overexpression of other putative genes. Also, specific monoclonal antibodies or cytokine antagonists have been used in various asthma models. The following limitations have hindered our understanding of asthma obtained from these model systems: (1) there are important differences between animal models of asthma and human disease; (2) there are few longitudinal studies of human asthma with serial airway sampling; and (3) it is often difficult to determine cause and effect from multiple mediator studies.

Despite the explosion of information about asthma, the nature of its basic pathogenesis has not been established. Studies suggest a genetic basis for airway hyperresponsiveness, including linkage to chromosomes 5q and 11q. Asthma clearly does not result from a single genetic abnormality; rather it is a complex multigenic disease with a strong environmental contribution. For example, allergic potential to inhaled allergens (e.g., dust mites, mold spores, cat dander) is found more commonly in asthmatic children or asthmatic adults whose asthma began in childhood versus those with adult-onset asthma.

Immunopathogenesis and the T_H2 Phenotype

Based on animal studies and limited bronchoscopic studies in adults, the immunologic processes involved in the airway inflammation of asthma are characterized by the proliferation and activation of helper T lymphocytes (CD4+) of the subtype T_H2. The T_H2 lymphocytes mediate allergic inflammation in atopic asthmatics by a cytokine profile that involves IL-4 (which directs B lymphocytes to synthesize IgE), IL-5 (which is essential for the maturation of eosinophils), and IL-3 and granulocyte-macrophage colony-stimulating factor. ⁷ Eosinophils are frequently present in the airways of asthmatics (more commonly in allergic but also in nonallergic patients), and these cells produce mediators that can exert damaging effects on the airways. Recent knockout studies and anti-cytokine studies suggest that lipid mediators are products of arachidonic acid metabolism. They have been implicated in the airway inflammation of asthma, and therefore have been the target of pharmacologic antagonism by a class of agents termed anti-leukotrienes. Prostaglandins (PGs) are generated by the cyclooxygenation of arachidonic acid, and leukotrienes are generated by the lipoxygenation of arachidonic acid. The proinflammatory prostaglandins (PGD₂, PGF₂, and TXB₂) cause bronchoconstriction, whereas other prostaglandins are considered protective and elicit bronchodilation (PGE₂ and PGI₂, or prostacyclin). Leuko-trienes C₄, D₄, and E₄ compose the compound “slow-reacting substance of anaphylaxis,” a potent stimulus of smooth muscle contraction and mucus secretion. Ultimately, mediators lead to degranulation of effector/proinflammatory cells in the airways that release other mediators and oxidants—a common final pathway that leads to the chronic injury and inflammation noted in asthma.

The “Hygiene” Hypothesis, Airway Hyperresponsiveness, and Disease Progression

Most studies of airway inflammation in human asthma have been conducted in adults because of safety and convenience. However, asthma often occurs in early childhood, and persistence of the asthmatic syndrome into later childhood and adulthood has been the subject of much investigation. The epidemiologic observation that asthma prevalence is much greater in industrialized Western societies than in less technologically advanced societies has been explained by the so-called “hygiene hypothesis.” ^8,9 This hypothesis proposes that airway infections and higher levels of exposure to animal allergens (e.g., farm animals, cat, dog) is important in affecting the propensity for individuals to become allergic and/or asthmatic. Specifically, early exposure to the various triggers that may occur with higher frequency in a rural setting may be protective against the allergic diathesis that is characteristic of the T_H2 paradigm. In a “cleaner” urban Western society, such early childhood exposure is lacking, and this encourages a higher incidence of allergy and asthma. This hypothesis has become the basis for a number of emerging therapies.

Whether airway hyperresponsiveness is a symptom of airway inflammation or airway remodeling, or is the cause of long-term loss of lung function, remains controversial. Some investigators have hypothesized that aggressive therapy with anti-inflammatory therapies improves the long-term course of asthma—above and beyond their salutary effects on parameters of asthma control and rates of exacerbation over time. ¹⁰ This contention has been supported by an observational study ¹¹ that found long-term inhaled steroid exposure was associated with an attenuation of the accelerated decline in lung function previously reported in asthmatics; more studies are required to substantiate these findings.

Concept of Airway Remodeling

The relation between the several types of airway inflammation (both early-phase and late-phase events) and the concept of airway remodeling, or the chronic nonreversible changes that may happen in the airways, remains a source of intense research.¹² The natural history of airway remodeling is poorly understood, and although airway remodeling may occur in some patients with asthma, it may not be a universal finding. Clinically, airway remodeling may be defined as persistent airflow obstruction despite aggressive anti-inflammatory therapies, including inhaled corticosteroids (ICs) and systemic corticosteroids. Pathologically, airway remodeling appears to have a variety of features that include an increase in smooth muscle mass, mucus gland hyperplasia, persistence of chronic inflammatory cellular infiltrates, release of fibrogenic growth factors along with collagen deposition, and elastolysis (Fig. 3). Many biopsy studies show these pathologic features in the airways of patients with chronic asthma. However, there are many unanswered questions, including whether features of remodeling are related to an inexorable progression of acute or chronic airway inflammation or whether remodeling is a phenomenon separate from inflammation altogether (Figs. 4 and 5).

Recent research has confirmed that the airway epithelium is an active regulator of local events, and the relation between the airway epithelium and the subepithelial mesenchyma is believed to be a key determinant in the concept of airway remodeling. A hypothesis by Holgate and colleagues ¹³ proposes that airway epithelium in asthma functions in an inappropriate “repair phenotype” in which the epithelial cells produce proinflammatory mediators as well as transforming growth factor-β to perpetuate remodeling.

Exhaled Gases and Oxidative Stress

Asthma is characterized by specific biomarkers in expired air that reflect an altered airway redox chemistry, including lower levels of pH and increased reactive oxygen and nitrogen species during asthmatic exacerbations. ^14–18 Reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and hydroxyl radicals cause inflammatory changes in the asthmatic airway. In support of this concept are the high levels of ROS and oxidatively modified proteins in airways of patients with asthma. ¹⁵ High levels of ROS are produced in the lungs of asthmatic patients by activated inflammatory cells (i.e., eosinophils, alveolar macrophages, and neutrophils). ¹⁶ Increased ROS production of neutrophils in asthmatic patients correlates with the severity of reactivity of airways in these patients; severe asthma is associated with neutrophilic airway infiltrates. Concomitant with increased oxidants, antioxidant protection of the lower airways is decreased in lungs of asthmatic patients. ^17,18 Another reactive species, nitric oxide (NO), is increased in the asthmatic airway. ¹⁵ Nitric oxide is produced by nitric oxide synthase (NOS), all isoforms of which—constitutive (neuronal, or type I, and endothelial, or type III enzymes) and inducible (type II enzymes)—are present in the lung. Abnormalities of NOS I and NOS II genotype and expression are associated with asthma. Recent in vitro studies have suggested cytotoxic consequences associated with tyrosine nitration induced by reaction products of NO. Other investigators have measured products of arachidonic acid metabolism in exhaled breath condensate. ¹⁹ Specifically, 8-isoprostane, a PGF_2a analogue that is formed by peroxidation of arachidonic acid, is increased in patients with asthma of different severities, and leukotriene E₄–like immunoreactivity is increased in exhaled breath condensate of steroid-naïve patients with mild asthma with levels about threefold to fourfold higher than those in healthy subjects.

The β-Agonist Controversy

Short-Acting β Agonists

There has been much controversy surrounding the potential role of β-agonist preparations in asthma mortality. The hypothesis is that excessive or regular use of β-adrenergic bronchodilators can actually worsen asthma, perhaps contributing to morbidity and mortality. A variety of epidemiologic studies have found conflicting findings. Several studies from New Zealand suggested that the use of inhaled β agonists increases the risk of death in severe asthma. ^4,20–22 Spitzer and coworkers conducted a matched, case-controlled study using a health insurance database from Saskatchewan, Canada, of a cohort of 12,301 patients for whom asthma medications had been prescribed. ²³ Data were based on matching 129 case patients who had fatal or nearly fatal asthma with 655 controls. The use of β agonist administered by a metered-dose inhaler (MDI) was associated with an increased risk of death from asthma, with an odds ratio of 5.4 per canister of fenoterol, 2.4 per canister of albuterol, and 1.0 for background risk (e.g., no fenoterol or albuterol). The primary limitation of these data, and a number of case-controlled studies, relates to the comparability of the two groups in terms of severity of their underlying disease. Sears and coworkers conducted a placebo-controlled, crossover study in patients with mild stable asthma to evaluate the effects of regular versus on-demand inhaled fenoterol therapy for 24 weeks. ²⁴ In the 57 patients who did better with one of the two regimens, only 30% had better asthma control when receiving regularly administered bronchodilators, whereas 70% had better asthma control when they employed the bronchodilators only as needed.

More recently, a study by Drazen and coworkers randomly assigned 255 patients with mild asthma to inhaled albuterol either on a regular basis (two puffs four times per day) or on an as-needed basis for 16 weeks. ²⁵ There were no significant differences between the two groups in a variety of outcomes, including morning peak expiratory flow, diurnal peak flow variability, forced expiratory volume in 1 second, number of puffs of supplemental as-needed albuterol, asthma symptoms, or airway reactivity to methacholine. Because neither benefit nor harm was seen, it was concluded that inhaled albuterol should be prescribed for patients with mild asthma on an as-needed basis. A recent meta-analysis of pooled results from 22 randomized, placebo-controlled trials that studied at least 1 week of regularly administered β₂ agonist in patients with asthma compared with a placebo group (that did not permit “as-needed” β₂-agonist use) concluded that regular use results in tolerance to bronchodilator and nonbronchodilator effects of the drug and may be associated with poorer disease control compared with placebo. However, there was no decline in the mean FEV₁ after regular treatment with β₂ agonists.

Long Acting β Agonists

The Salmeterol Multiple-Center Asthma Research Trial (SMART) was an observational 28-week study comparing salmeterol 42 μg metered-dose inhaler twice a day with placebo, in addition to usual asthma therapies. ²⁶ More than 26,000 subjects were enrolled. SMART found that in the salmeterol group there was a statistically significant increase in risk for asthma-related deaths and life-threatening experiences compared with placebo. There were statistically significant differences for respiratory-related deaths (RR = 2.16, 95% CI = 1.06 to 4.41) and asthma-related deaths (RR = 4.37, 95% CI = 1.25 to 15.34), and in combined asthma-related deaths or life-threatening experiences (RR = 1.71, 95% CI = 1.01 to 2.89) in subjects randomized to salmeterol compared with placebo. There were 13 asthma-related deaths and 37 combined asthma-related deaths or life-threatening experiences in the salmeterol group, compared with 3 and 22, respectively, in those randomized to placebo. However, of the 16 cases of asthma fatality in subjects enrolled in the study, 13 (81%) occurred in the initial phase of SMART, when subjects were recruited via print, radio, and television advertising; following this, subjects were recruited directly by investigators. These differences in outcomes occurred largely in African American subjects. In African Americans not taking ICs prior to randomization, salmeterol was associated with statistically significant increases in the risk for combined respiratory-related deaths or life-threatening experiences (RR = 5.61, 95% CI = 1.25 to 25.26) and combined asthma-related deaths or life-threatening experiences (RR = 10.46, 95% C I = 1.34 to 81.58). Medication exposures were not tracked during the study, and allocation to ICs combined with a long-acting β agonist (LABA) was not randomized, so the effect of concomitant ICs use cannot be determined from these data. Whether the statistically significant risk in untoward outcomes reflects genetic predisposition, risk associated with LABA monotherapy, or health maintenance behaviors cannot be determined definitively at this time. Based on findings of SMART, the U.S. Food and Drug Administration (FDA) issued a “black box” warning, public health advisory, and subsequently label changes for long-acting β agonists and long-acting β-agonist–containing medications.

Data from SMART, combined with other recent reports ²⁷ have fueled a controversy regarding the role of LABA in asthma management, such that an honest difference of opinion currently exists regarding the appropriate level of asthma severity at which regular use of LABA combined with ICs is favorable from a risk-benefit standpoint. This will require additional studies to fully clarify; however, asthma care providers should also be mindful that use of LABA in combination with ICs has been associated with the following range of favorable outcomes: reduction of symptoms—including nocturnal awakening; improvement in lung function; improvement in quality of life; reduced use of “rescue” medication; and reduced rate of exacerbations and severe exacerbations compared with ICs at the same or higher dose. ²⁸ Previously published meta-analyses have shown that low-dose ICs combined with LABA is associated with superior outcomes compared with higher dose ICs. ^29–31 These data led to the recommendation in the EPR2 update of the NAEPP guidelines to prescribe the combination of ICs and LABA for patients with moderate persistent asthma and severe persistent asthma, and categorized this management recommendation as based on level A evidence. ² The decision to prescribe, or continue to prescribe, LABA should be based on an individualized determination of risk relative to benefit made by each asthmatic patient in partnership with his or her physician.

Pharmacogenetics

Polymorphisms of the gene for the β₂-adrenergic receptor (AR) can influence clinical response to β agonists. For the β₂ AR gene, single nucleotide polymorphisms (SNPs) have been defined at codons 16 and 27. The normal or “wild type” pattern is arginine-16-glycine and glutamine-27-glutamic acid, but SNPs have been described with homozygous pairing (e.g., Gly16 Gly, Arg16 Arg, Glu27 Glu, and Gln27 Gln). The frequency of these polymorphisms is the same in the normal population as in asthmatics. Presence of a gene variant itself does not appear to influence baseline lung function. However, in the presence of a polymorphism, the acute bronchodilator response to a β agonist, or protection from a bronchoconstrictor, may be affected. Studies indicate in patients with Arg16 Arg variant, the resulting β₂AR is resistant to endogenous circulating catecholamines (i.e., receptor density and integrity are preserved) with a subsequent ability to produce an acute bronchodilator response to an agonist. In patients with Gly16 Gly, the β₂ AR is downregulated by endogenous catecholamines; therefore, the acute bronchodilator response is reduced or blunted. In relation to prolonged β-agonist therapy (e.g., greater than 2 weeks) patients who are homozygous for Arg16 were found to exhibit a decline in lung function and an increase in exacerbation rates in association with regular inhaled short-acting β agonists. These same individuals, when switched to as needed albuterol, had no decrease in lung function, as is the case for homozygous Gly16. Polymorphisms at the 27 loci are of unclear significance. Also, the impact of haplotypes (e.g., variant genes linked at > 2 loci) is presently unclear. There are conflicting data regarding whether Arg/Arg homozygotes are prone to experience reflex morbidity with inhaled long-acting β agonists. ²⁸ and further studies will be required to clarify this matter.

There are limited data on mutations involving the leukotriene cascade or corticosteroid metabolism. Polymorphisms of the 5-lipoxygenase (5-LO) promoter gene and the leukotriene C₄ (LTC₄) synthase gene have been described. Asthmatics with the “wild type” genotype at 5-LO have a greater response with 5-LO inhibitor therapy compared with asthmatics with a mutant gene. However, mutations of the 5-LO promoter occur only in about 5% of the asthmatic patients; for this reason, it is unlikely to play an important role in most patients. An SNP in the LTC₄ synthase promoter gene (A-444C) is associated with increased leukotriene production and has a lower response to leukotriene-modifying agents. Far less is known about genetic variability in the corticosteroid pathway. Polymorphisms in the glucocorticoid receptor gene have been identified that appear to affect steroid binding and downstream pathways in various in vitro studies. However, polymorphisms in the glucocorticoid pathways have not been associated with the asthma phenotype or clinical steroid resistance.

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Diagnostic evaluation, comorbid disease, and peak expiratory flow monitoring

The history and physical examination are important for the following reasons: (1) to confirm a diagnosis and exclude mimics such as hyperventilation syndrome, vocal cord adduction, heart failure, and others; (2) to assess the severity of airflow obstruction and the need for aggressive intervention including hospitalization; (3) to identify risk factors for poor outcomes; and (4) to identify comorbid conditions that can make asthma refractory to treatment, including sinusitis, gastroesophageal reflux, and ongoing aeroallergen exposure. The cardinal symptoms of asthma include episodic dyspnea, chest tightness, wheezing, and cough. Some patients may present with atypical symptoms, such as cough alone (cough-equivalent asthma) or primarily dyspnea on exertion. The most objective indicator of asthma severity is the measurement of airflow obstruction by spirometry or peak expiratory flow (PEF). The PEF and the FEV₁ yield comparable results. For initial diagnostic purposes in most patients, spirometry rather than a simple PEF should be performed, although PEF may be a reasonable tool for long-term monitoring. The National Asthma Education and Prevention Program (NAEPP) and its Expert Panel Report 2 (EPR 2) have set forth the grading of asthma severity into the following four categories based on frequency of daytime and nocturnal symptoms, peak flows, and as-needed use of inhaled short-acting β agonists: (1) mild intermittent, (2) mild persistent, (3) moderate persistent, and (4) severe persistent. ² Hyperinflation, the most common finding on a chest radiograph, has no diagnostic or therapeutic significance. A chest radiograph should not be obtained unless complications of pneumonia, pneumothorax, or an endobronchial lesion are suspected. The correlation of severity between acute asthma and arterial blood gases is poor. Mild-to-moderate asthma is typically associated with respiratory alkalosis and mild hypoxemia on the basis of ventilation-perfusion mismatching. Severe hypoxemia is quite uncommon in asthma. Normocapnia and hypercapnia imply severe airflow obstruction, with FEV₁ usually <25% of the predicted value. Recent data suggest that hypercapnia in the setting of acute asthma does not necessarily mandate intubation or suggest a poor prognosis. ³² Spirometry in an asthmatic patient typically shows obstructive ventilatory impairment with reduced expiratory flows that improve with bronchodilator therapy. Typically, there is an improvement in either FEV₁ or forced vital capacity (FVC) with acute administration of an inhaled bronchodilator (12% and 200 mL). However, the absence of a bronchodilator response does not exclude asthma. The shape of the flow volume loop may provide insight into the nature and location of airflow obstruction.

In patients with atypical chest symptoms of unclear etiology (cough or dyspnea alone), a variety of challenge tests can identify airway hyperreactivity as the cause of symptoms. By far, the most commonly used agents are methacholine or histamine, which give comparable results. Exercise, cold air, and isocapnic hyperventilation—other approaches that require complex equipment—have a lower sensitivity. In a patient with clinical features typical for asthma, along with reversible airflow obstruction, there is no need for a provocation procedure to establish a diagnosis. The use of measures of airway hyperreactivity has been proposed as a tool to guide anti-inflammatory therapy, but is not recommended for routine clinical practice. The methacholine challenge test, which is most frequently used in the United States, is very sensitive; a positive test result is defined as a 20% decline in FEV₁ during incremental methacholine aerosolization. However, methacholine responsiveness is nonspecific, and it can occur in a variety of other conditions, including allergic rhinitis, chronic obstructive pulmonary disease, and airway infection. For practical purposes, a negative inhalational challenge with methacholine (or histamine) excludes active, symptomatic asthma as a cause for the patient's symptoms.

PEF monitoring has been advocated as an objective measure of airflow obstruction in patients with chronic asthma. Despite a sound theoretical rationale for PEF monitoring, as advocated by all published asthma guidelines, clinical trials that examined the use of PEF monitoring in ambulatory asthma patients show conflicting results. ³² Over the past decade, 6 of 10 randomized trials have failed to show an advantage for the addition of PEF monitoring above and beyond symptom-based intervention for the control group. ³³ Regular PEF monitoring allows early detection of worsening airflow obstruction, which may be of particular value in a subset of “poor perceivers”—individuals with a blunted awareness of ventilatory impairment. PEF monitoring also has value for risk stratification. Excessive diurnal variation and a morning dip of PEF imply poor control and a need for careful re-evaluation of the management plan. PEF alone is never appropriate; rather, PEF should be part of a comprehensive patient education program. Asthma therapy is discussed later in this chapter.

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Asthma management algorithms

General Concepts Regarding Guidelines

There are many organizational and social barriers to optimal asthma care. Studies suggest that a small subset of patients uses a large percentage of health care resources. A major challenge in improving outcomes for asthma is implementing basic asthma management principles widely at the community level. Key issues include:

1. Education of primary health care providers
2. Programs for asthma patient education
3. Longitudinal outpatient follow-up with easy access to providers
4. Emphasis on chronic maintenance therapy rather than acute episodic care
5. Emphasis on daily anti-inflammatory therapy

Organized approaches to improving care have included dissemination of clinical practice guidelines, disease state management, and case management. ³⁴ The thesis of disease state management is a global approach to chronic diseases such as asthma by integrating various components of the health care delivery system. It is hoped that managing all costs of care comprehensively versus seeking to minimize the costs of each component, will improve health outcomes and be cost beneficial. This approach relies on information technology to identify patients, monitor care, and assess outcomes and costs. Asthma is viewed as an ideal disease for the disease management approach because (1) it is a chronic disease suitable for self-management and patient education; (2) it can be managed largely on an outpatient basis, thus avoiding costly inpatient care; (3) there is a consensus on what constitutes optimal care; and (4) optimal care implementation can promptly lead to measurable reduction in costs and improved outcomes. Although many studies have reported interventions that reduce costs and improve outcomes, there are limitations to published asthma disease management studies because (1) a pre- and poststudy design has typically been employed, usually with no control group; (2) the choice of outcome measures varies; (3) several interventions have often been performed at the same time and it is difficult to identify the essential components linked with success. These studies have often used proprietary data systems and algorithms that make reproducing them difficult. Other design limitations include control of cofactors such as severity and season.

Practice Guidelines

Guidelines for medical practice are being disseminated with increasing frequency for a wide range of conditions. The overall goal of practice guidelines is to improve quality of care, reduce costs, and enhance health care outcomes. These guidelines are of interest to many groups including specialty medical societies, state and federal government, insurers and managed care organizations, commercial enterprises, and hospitals. There are several methods used to develop practice guidelines including informal consensus development, formal consensus development, evidence-based guideline development, and explicit guideline development. Informal consensus development, which is based largely on expert opinion with support from the literature, is the strategy most frequently used, as in the asthma practice guidelines discussed later. Possible mechanisms by which practice guidelines may improve patient care include the following: improved clinician knowledge; encouraging clinicians to agree with and accept the guidelines as “standard of care”; and influencing clinician asthma care behavior.

There is limited evidence, however, that practice guidelines can achieve favorable clinical outcomes. ³⁵ Some clinicians have advocated additional strategies to include removing disincentives, adding a variety of incentives, and including the guidelines in a broader program that addresses translation, dissemination, and implementation in the local community.

Asthma Practice Guidelines: Expert Panel Report 2

In 1991, the coordinating committee of NAEPP convened an expert panel along with the NHLBI, to develop extensive and detailed guidelines for the diagnosis and management of asthma. ¹ The EPR 2 was published in 1997. ² Overall, the published guidelines highlight the following: (1) a new appreciation for the significant role of airway inflammation in the pathogenesis of asthma; (2) a change in the emphasis for treatment to include anti-inflammatory maintenance therapy; and (3) a focus on establishing risk factors for the development of asthma and identifying appropriate programs for control and prevention.

The NAEPP outlined four goals of therapy for asthma: (1) maintain normal activity level, including exercise; (2) maintain near-normal parameters of pulmonary function; (3) prevent chronic and troublesome exacerbations of asthma by maintaining a chronic baseline maintenance therapy; and (4) avoid untoward effects of medications used to treat asthma. To facilitate these goals, the NAEPP outlined a number of key components for management. First, patient education and self-management skills are critical. This education includes knowledge of the disease, proper use of medications, including appropriate metered-dose inhaler technique, and a written action plan for managing exacerbations. The second component is the use of a home peak-flow device to monitor disease severity, especially for patients with moderate or severe disease. The third component involves measures to minimize or avoid exposure to known aeroallergens and irritants that can exacerbate asthma, including indoor and outdoor factors. The final component is pharmacotherapy.

There are several differences between the EPR 2 and the NAEPP 1991 report. ^1,2 The EPR 2 report classifies patients into four levels of severity: (1) mild intermittent; (2) mild; (3) moderate; or (4) severe persistent disease. A daily maintenance therapy is suggested for persistent disease. The EPR 2 classifies asthma medications as “long-term controllers” or “quick-relief medications.” The medication list is updated to include salmeterol (Serevent), fluticasone (Flovent), and anti-leukotrienes (all approved since 1991). EPR 2 provides a specific conversion table comparing equipotent doses of the inhaled steroids. The 1997 EPR 2 report places special emphasis on “step-down” therapy after a period of optimal control. EPR 2 recommends PEF monitoring for moderate and severe asthma, but only once per day (in the morning, pre-bronchodilator). The 2002 Update ³ to the NAEPP EPR 2 adds the following additional points: (1) long-term management of asthma in children has been revised with a strong emphasis on using ICs as the preferred agents for mild persistent and moderate persistent asthma; (2) for patients older than 5 years of age with moderate persistent asthma on low-dose ICs, addition of long-acting β agonists improves asthma control and outcomes; (3) addition of antibiotics is not recommended for acute asthma exacerbation; and (4) written action plans are de-emphasized because they have not shown benefit over medical management alone.

The NAEPP guidelines recommend that asthma should be managed in an algorithmic manner, based on asthma severity. As noted earlier, patients are to be classified in the following four categories ( Table 1 ): mild intermittent, mild persistent, moderate persistent, and severe persistent asthma, based on assessment of the level of symptoms (day or night), reliance on “reliever” medication, and lung function at time of presentation, with pharmacologic management (see later) then being prescribed in an evidence-based fashion according to each respective categorization. In an ideal world, this would result in patients with asthma receiving pharmacotherapeutic agents associated with favorable asthma care outcomes that are also appropriate from both cost- and risk-benefit standpoints. In the real world, however, this paradigm is imperfect because it relies on the correct categorization of patients for pharmacotherapy to be prescribed appropriately. Both health care providers and patients are prone to underestimate asthma severity, ³⁶ and for this reason, many patients who are managed based on this paradigm are undertreated.

A new paradigm, based on assessment of asthma control, has been encouraged. ³⁷ Asthma severity and asthma control are not synonymous. Asthma severity is clearly a determinant of asthma control, but its impact is affected by a variety of factors, including patterns of therapeutic adherence and the degree to which recommended avoidance measures for clinically relevant aeroallergens are pursued. Patterns of health service use, including hospitalization and emergency department visits, correlate more closely with asthma control than with asthma severity. ³⁷ This follows from the understanding that a patient with severe persistent asthma who is treated appropriately with multiple controllers, and is adherent with not only medications but also recommended avoidance strategies, can achieve well- (or totally) controlled asthma. This patient will not require hospitalization or emergency department management, will not miss school or work days, and will not experience nocturnal awakening or limitation in routine activities because of asthma. This patient has severe persistent asthma that is well controlled. In contrast, a patient with mild-to-moderate persistent asthma who either does not receive appropriate instructions for avoidance measures and controller medication(s), or both, or is poorly adherent, will likely have poor control of asthma. This patient is more likely to require hospitalization or emergency department management, miss school or work days, and experience nocturnal awakening or limitation in routine activities because of asthma. This patient has mild-to-moderate persistent asthma that is poorly controlled.

Asthma control is a multidimensional construct. Asthma control can be assessed by use of the Asthma Control Test (ACT), which includes assessment of asthma symptoms, frequency of use of as-needed “rescue” medication, and the impact of asthma on everyday functioning. The ACT was designed for use as a patient-completed screening tool for gauging asthma control over time in a “user-friendly” fashion. The ACT is a valid and reliable instrument that is responsive to asthma control over time. ^38,39 The process of accomplishing the ACT entails a patient (or parent of an asthmatic child) accurately responding to five questions pertaining to symptoms and as-needed use of “rescue” medication during the previous 4 weeks. In general, the higher the score from 5 to 25, the better the control of asthma; however, using a “cut-point” of 19 yields the best balance of sensitivity (71%) and specificity (71%) for classifying patients as “poorly-controlled” or “well-controlled.” ³⁹ Use of serial ACT scores in asthma management can objectify the degree to which the goals of management as described in NAEPP guidelines are being achieved, and in so doing can encourage optimal asthma care outcomes. A randomized controlled trial demonstrated that asthma management guided by assessment of asthma control leads to improved control of asthma over time. ⁴⁰

Although the concept of expert practice guidelines merits widespread support, specific treatment regimens must be determined by the physician and patient based on consideration of risk relative to benefit, and tailored to individual patient needs. As asthma research is rapidly evolving and new pharmacotherapeutics are anticipated, these guidelines will be revised periodically. Release of NAEPP EPR 3 guidelines is expected at the time this is being written.

The Role of Allergy and Allergen Avoidance

Sensitization to inhalant allergens such as dust mites, mold spores, cat, dog, or other animal proteins, cockroach and other insect allergens, and outdoor pollens is common among asthmatic patients. The 1997 Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma differed from the 1991 Expert Panel Report in recommending cutaneous or in vitro testing “for at least those patients with persistent asthma exposed to perennial indoor allergens.” ^1,2 Clinical relevance of inhalant allergens can be demonstrated by immediate hypersensitivity skin testing or radioallergosorbent (RAST) assay. Of these, skin testing is more sensitive, less costly, and entails no delay in yielding results; for these reasons, skin testing is preferred. The information that these diagnostic tests provide, whether the asthmatic patient exhibits IgE-mediated (allergic) potential to inhalant allergens, and which allergens the patient can be said to be “allergic” to, is used to direct relevant avoidance measures. Avoidance of clinically relevant allergens can lead to substantial reduction of symptoms and medication reliance, and for some patients, this can be the most important element of asthma management. The inhalant allergens that may provoke and perpetuate asthma symptoms are listed in Box 1. Individuals with asthma are frequently sensitized to more than one allergen.

Air conditioning can be associated with a dramatic reduction in exposures to outdoor pollens and mold spores while indoors. Because we now spend the majority of our time indoors, the usefulness of air conditioning for improving asthma symptoms should not be under-estimated. ³⁶

Dust mites are a major source of allergen in house dust. They are microscopic, and rely on heat and humidity to survive and proliferate. ⁴² Allergy to dust mites is common in patients with asthma. Recommended avoidance measures to reduce exposures to dust mite allergen include: encasement of mattress and box spring and pillows in impermeable covers, reducing indoor relative humidity, washing bedding weekly in the hot cycle (130°F) and, if possible, removal of carpets in favor of tiled or hardwood flooring. ⁴²

For individuals allergic to cat or dog dander who are pet owners, no avoidance strategy can rival the benefit that will occur with elimination of the pet from the home. If a cat or dog is removed from the home, however, the allergen may persist for several months. For this reason, clinical benefit cannot be expected promptly. ⁴³ When elimination of pets from the home is not possible, second-best measures include restricting the pet from the bedroom, use of high efficiency particulate or electrostatic air cleaners, and removal of carpets and other furnishings, which otherwise serve as an allergen reservoir. Washing the cat or dog, if recommended as an avoidance strategy, needs to be carried out frequently—at least twice a week. ⁴⁴

When a regimen of avoidance measures combined with appropriate pharmacotherapy is undesirable, not feasible, or ineffective to achieve optimal asthma control, administration of allergen immunotherapy vaccines (“allergy shots”) can be considered. ^45,46 Allergen immunotherapy entails the incremental administration of inhalant allergens for the purpose of inducing immune system changes in the host response with natural exposure to these allergens. Numerous studies carried out during the past five decades have shown statistically and clinically significant dose-dependent benefits with administration of allergen immunotherapy in properly selected patients with asthma. ⁴⁵ Recent studies demonstrate that immunotherapy can inhibit late-phase response and appears to work through induction of T cell tolerance. ^40–42 In contrast to medication that affects only symptoms, immunotherapy can favorably affect the disease process that underlies asthma symptoms. The therapeutic usefulness of inhalant allergen immunotherapy has also been supported by findings of a meta-analysis of randomized, double-blinded studies of allergen immunotherapy for asthma reported by Abramson and colleagues, ⁴⁷ in which statistically significant benefit was reported as manifested in reduced asthma symptoms, diminished medication reliance, and improvements in specific and nonspecific bronchial hyper-responsiveness. Although there is a tendency in this and other areas of the asthma literature to overestimate efficacy because of a well-recognized reporting bias (e.g., negative studies tend to not get published), the authors calculated that 33 negative studies would need to be published to overturn their findings. ⁴⁷

In the United States, 7 to 10 million immunotherapy injections are administered annually. Because systemic reactions are not uncommon, immunotherapy should be given only in a setting in which adequate precautions are taken and life-threatening anaphylaxis can be treated. ³⁷ The decision to begin allergen immunotherapy should be individualized and based on symptom severity, relative benefit with pharmacotherapy, and whether comorbid conditions such as beta-blocker use ⁴⁸ are present. These factors increase the risk for (serious) anaphylaxis—the major risk of allergen immunotherapy.

Aspirin Intolerance and Desensitization

Aspirin (ASA) and non-steroidal anti-inflammatory drugs can provoke bronchospasm (with or without nasal-ocular congestion or flushing) in a subgroup of asthmatic patients. ⁴⁹ In patients with aspirin-exacerbated respiratory disease (AERD), potentially serious bronchospastic reaction occurs up to several hours after exposure to ASA or an ASA-like drug; even a sub-therapeutic dosage of ASA in this setting can lead to potentially life-threatening bronchospasm. ASA and nonsteroidal anti-inflammatory drugs, including ibuprofen, naproxen, sulindac, indomethacin, and etodolac, share the action of inhibition of cyclooxygenases COX-1 and COX-2 and are 100% cross-reactive in ASA-sensitive asthmatic patients. In AERD patients, cross-reaction may also occur with higher doses of salsalate or acetaminophen, which are weak inhibitors of COX-1 and COX-2. Selective inhibitors of COX-2 (e.g., celecoxib) do not cross-react with ASA and can be tolerated without bronchospastic reaction. ⁴⁹

Studies carried out in the last decade have shown that COX inhibition downregulates the enzyme PGE₂, leading, in turn, to excessive production of sulfidopeptide leukotrienes (LTC₄, LTD₄, and LTE₄). These mediators not only participate in acute bronchospastic reaction provoked by ASA ingestion but also contribute to the ongoing airways obstruction and inflammation that persist in AERD patients despite avoidance of ASA and other COX-inhibiting drugs. ⁴⁹ Administration of anti-leukotriene agents, which either selectively block leukotriene receptors or inhibit leukotriene synthesis by blocking 5-lipoxygenase or its activator, 5-lipoxygenase activating protein (FLAP), are efficacious in the management of chronic persistent asthma in patients with AERD. Added benefit has been reported in double-blind, placebo-controlled studies in AERD patients receiving inhaled (and oral) corticosteroids treated with montelukast ⁵⁰ or zileuton. ⁵¹

Anti-leukotriene agents also attenuate bronchospastic reaction provoked by ASA challenge in AERD. ^52,53 For this reason, anti-leukotriene drugs are useful for reducing severity of reaction in patients undergoing desensitization, although respiratory reaction is not blocked completely. ⁴⁹ Biosynthesis of leukotrienes is upregulated in AERD; a key enzyme, LTC₄ synthase, is overexpressed in bronchial mucosa. ⁴⁹ AERD patients have increased expression of the Cys-LT₁ receptor on inflammatory leukocytes, ⁵⁴ thereby enhancing their ability to respond to leukotrienes. Downregulation of Cys-LT₁ receptor expression may explain the mechanism for ASA desensitization. ⁵⁴

Desensitization can be performed for patients who require administration of ASA or ASA-like drug for management of co-occurring conditions (e.g., arthritis, thromboembolism, or coronary artery disease). Clinical benefit in patients with AERD—particularly for polypoid rhinosinusitis—was observed in 87% of patients who were desensitized and then took ASA regularly for more than 1 year. ⁵⁵ Improvement included reduced level of symptoms, lower medication reliance, and less morbidity (as reflected in fewer annual episodes of URI/sinusitis, and reduced rates of sinus surgery procedures). Based on these findings and previous experience with ASA desensitization, ⁴¹ this intervention can also be considered for patients with corticosteroid-dependency, poorly-controlled asthma, or refractory rhinosinusitis who require repeated sinus surgery procedures. Because of potentially serious bronchospastic reaction that may occur during this procedure, desensitization should only be carried out in settings where experienced physicians and appropriate equipment to treat such reactions are present.

Pharmacotherapy

The pharmacotherapy for asthma, as recommended by current NAEPP guidelines, is summarized in Tables 1 through 4 . The overall strategy is to use a stepwise approach based on level of severity. Inhaled short-acting β agonists (“relievers”) used on an as-needed basis are recommended for patients with mild intermittent asthma who are asymptomatic between episodes. Patients with persistent asthma, with more frequent symptoms, are treated with the addition of an anti-inflammatory agent (“controller”) used on a scheduled basis in addition to an inhaled short-acting β agonist on an as-needed basis. For patients with more severe disease and during acute exacerbations, addition of oral corticosteroids as a short-term burst is appropriate.

Inhaled Corticosteroids.

With the current paradigm of asthma as a chronic inflammatory disorder of the airways, ICs have become the preferred therapy for all patients with persistent asthma—mild, moderate, and severe. Recent data indicate that ICs do not “cure” asthma, and cessation of therapy often results in prompt relapse. Inhaled steroids are also cost effective in the management of asthma, with an incremental cost-effectiveness ratio for a symptom-free day of approximately $5.00 to $6.00. ⁵⁶ Regular use of ICs can reduce rates of asthma exacerbation ⁵⁷ and prevent increases in bronchial hyper-responsiveness ⁵⁸ and accelerated loss of lung function. ¹¹ A large retrospective case-control study from Canada associated regular use of ICs with statistically significant reductions in rates of mortality from asthma. ⁵⁹

Evidence indicates that patients with moderate persistent asthma who remain symptomatic on low-dose ICS monotherapy experience greater benefit from a long-acting inhaled bronchodilator added to low-dose ICS compared with doubling the dose of inhaled steroid. ²⁸ Several studies have examined the usefulness of ICS taken in combination with other agents such as theophylline ⁶⁰ and leukotriene antagonists. ⁶¹ These agents are also a rational alternative, taken in combination with ICS, to doubling the dose of inhaled steroid in patients who remain symptomatic on low-dose ICS monotherapy. The benefits of combination therapy, as measured by symptom scores, as-needed use of β agonists, lung function, and exacerbation rates, with these other agents are not as dramatic as with the addition of a long-acting inhaled bronchodilator. ⁶² A study from the Asthma Clinical Research Network of the NHLBI found that monotherapy with salmeterol is not adequate replacement therapy for patients controlled on triamcinolone 400 μg twice a day. ⁶³ As noted, LABA monotherapy may improve symptoms and lung function, but it has no effect on airways inflammation. ²⁸

The molecular mechanism of action of glucocorticoids (GCs) involves binding to a specific intracellular glucocorticoid receptor (GCR). This binding dissociates heat-shock proteins and creates an active GC-GCR complex. The GC-GCR complex translocates to the nucleus and binds to specific GCR-responsive elements on genomic DNA that induce specific gene expression (i.e., β-adrenergic receptors). The GC-GCR complex may also suppress gene expression by interfering with the interaction of transcription factors (i.e., nuclear factor-kB) with promoter regions of proinflammatory cytokines. Through these mechanisms, GCs inhibit the production of a wide range of cytokines important in asthma. In addition to inhibiting cytokine production, glucocorticoids also inhibit production of inflammatory leukotrienes and eicosanoids through effects on phospholipase A₂. In contrast, genes for anti-inflammatory or bronchodilatory products (i.e., β receptors and lipocortin) are increased by corticosteroids. Lipocortin, a protein that inhibits phospholipase A₂, further dampens inflammation. The concept of “resistance” to corticosteroids has received much attention, although the exact molecular mechanisms remain poorly understood. There is likely only one type of human glucocorticoid receptor; therefore, polymorphisms of the human steroid receptor have not been established. Two discrete types of relative steroid resistance have been described. Type 1 steroid resistance is a relative lack of steroid responsiveness in the airways, although there is evidence for steroid effect in other tissues of the body, usually manifesting as clinical steroid side effects (i.e., cushingoid effects). Type 1 steroid resistance is acquired and more common. Type 2 steroid resistance is caused by a generalized lack of steroid responsiveness in the airways and other organ systems on a genetic basis. Patients with type 2 resistance have poor asthma control despite systemic corticosteroids and no systemic steroid side effects. Type 2 steroid resistance is rare. The relative contribution of this concept of steroid resistance in suboptimal asthma control and poor outcomes remains unknown. Patients with such a molecular basis for steroid resistance may be a subset who would benefit from alternative anti-inflammatory approaches.

Steroid “phobia,” or excess concern over the systemic effects of ICs by both patients and clinicians, remains a practical barrier to wider use of these agents despite several reassuring long-term studies and expert practice guidelines. One landmark study ⁶⁴ randomized 1041 children from ages 5 through 12 with mild-to-moderate asthma for a study duration of 4 to 6 years into three groups (200 μg budesonide twice a day, 8 μg of nedocromil (Tilade) twice a day, or placebo). This robust study noted that the asthma clinical outcomes improved most for the budesonide group (fewer hospitalizations, fewer urgent visits, and decreased airway hyperresponsiveness to methacholine). However, there was no significant difference in the degree of change in FEV₁ after bronchodilator use between any of the three groups. Long-term budesonide was well tolerated, and although there was a 1.1 cm smaller increase in height compared with the placebo group during the first year, this reduction in linear growth velocity was absent by the second year, and the projected height in the budesonide-treated group was no different than in the nedocromil or placebo groups. Also, there were no significant differences in bone density or the incidence of cataracts between the three groups. Although a number of other short-term studies have noted a reduction in height and linear growth velocity over 6 to 12 months with ICs, longer-term studies have consistently noted that the final adult height is not influenced by ICs. ⁶⁵ Practical approaches to minimize or eliminate systemic toxicity from ICs include the following: (1) using the lowest dose needed by proactively stepping down the dose after several months of optimal asthma control; (2) routinely using a spacer extension device (if metered-dose inhalers are used) or a dry-powder device and rinsing the oropharynx after each use; and (3) adding a long-acting β agonist to facilitate a reduction of ICs.

Anti-leukotrienes.

The sulfidopeptide or cysteinyl leukotrienes (LTC₄, LTD₄, and LTE₄), formerly known as the “slow-reacting substance of anaphylaxis,” are formed by the lipoxygenation of arachidonic acid by the enzyme 5-lipoxygenase. These compounds, released by mast cells and eosinophils and airway epithelial cells, have a variety of potent effects including bronchoconstriction, increased permeability, and enhanced airway reactivity. Cysteinyl leukotrienes are involved in the pathogenesis of human asthma. Leukotrienes can be recovered from nasal secretions, bronchoalveolar lavage fluid, and urine of patients with asthma. Potent leukotriene antagonists attenuate asthmatic responses to allergens, exercise, cold dry air, and aspirin. ^49,53 Placebo-controlled clinical trials have shown salutary effects in asthmatics treated with anti-leukotriene drugs. ⁶⁶

Churg-Strauss vasculitis (CSS) has been reported in patients receiving anti-leukotriene drugs; in most cases, patients with severe asthma who improved and were able to suspend or taper oral corticosteroids developed CSS. ^67,68 It appears that rather than a causal association, this likely reflects an unmasking of extrapulmonary features of preexisting CSS with a tapering of oral steroids following symptomatic improvement on a trial of an anti-leukotriene drug. Moreover, similar cases of CSS have also been reported in association with inhaled cromolyn and with inhaled fluticasone.

Anti-leukotrienes have been associated with statistically significant improvement in mild-to-moderate asthma compared with placebo. ^69–70 A 3-month, double-blind, parallel-group study (n = 681 with FEV₁ 50% to 80%) showed significant improvement in the montelukast group (asthma exacerbation decreased by 31%, asthma-free days increased by 37%). ⁶⁹ Another randomized trial involving adults with moderate-to-severe asthma (n = 226) showed that montelukast 10 mg allowed significant tapering of inhaled steroids in patients requiring moderate-to-high doses. ⁷⁰ A 4-week, controlled trial in 80 AERD patients with high medication reliance at baseline, showed that montelukast 10 mg given at bedtime significantly improved asthma control. ⁵¹

A current scientific controversy surrounding anti-leukotrienes is whether they affect the natural history of asthma and can prevent airway remodeling. Data from animal models indicate an effect on eosinophilia and collagen deposition. ⁷¹ Whether these findings are relevant to human disease awaits performance of additional studies.

EPR 2 guidelines recommend a role for anti-leukotrienes for mild persistent asthma as an alternative to ICs (or cromolyn or nedocromil). These agents have effects on early and delayed asthma responses; therefore, they act as bronchodilators within 1 to 3 hours after administration as well as anti-inflammatory agents with a response in 2 to 4 weeks. The magnitude of increase in FEV₁ at 4 weeks is about 14% above that of placebo. In comparator trials in patients with mild persistent asthma, randomized to ICs or anti-leukotrienes, ICs have been associated with superior efficacy. ⁷² Anti-leukotrienes facilitate reduction in the need for inhaled β agonists and ICs, and may be associated with improved compliance compared with inhaled medications. Anti-leukotriene agents also have been shown to attenuate exercise-induced bronchospasm. Patients with AERD, compared with aspirin-tolerant asthmatics, release higher levels of leukotrienes with aspirin-provoked respiratory reaction, and exhibit greater end-organ responsiveness to leukotrienes. On this basis, patients with AERD warrant a trial of anti-leukotriene pharmacotherapy, although the rate of response in this subgroup is similar to rates reported among aspirin-tolerant asthmatics. That the data show about the same rate of benefit in AERD compared with ASA-tolerant asthmatics is consistent with the hypothesis that it is the balance between PGE₂ and PGF_2a that is critical in this subgroup. ⁴⁹

Anti-IgE Therapy.

Omalizumab (Xolair), the first selective anti-IgE therapy, is a humanized monoclonal anti-IgE antibody that binds with high affinity to the FceRI receptor-binding site on IgE. Omalizumab was approved by the FDA in 2003. ^73,74 Omalizumab reduces the amount of free IgE available to bind to FceRI receptors on mast cells, basophils, and other cells. This agent is administered subcutaneously every 2 or 4 weeks for asthmatic patients with objective evidence of IgE-mediated (allergic) potential to perennial allergen(s) with serum IgE levels of 30 to 700 IU/mL. Experimental studies demonstrated that omalizumab attenuated both early and late asthmatic responses evaluated at days 28 and 56, and the dose of aerosolized allergen required to decrease FEV₁ by 15% was increased by 2.7 doubling doses, indicating a reduction in airway reactivity. A large placebo-controlled study of 317 patients with moderate-to-severe perennial allergic asthma who required daily use of inhaled and/or oral corticosteroids was conducted in subjects ages 11 to 50 for 20 weeks. ⁷⁴ The active-treatment arm included two different doses of intravenously administered omalizumab (2.5 mg/kg/ng IgE/mL) or a high dose (5.8 mg/kg/ng IgE/mL). At 12 weeks, there was a 50% improvement in asthma symptom scores in 50% of the patients treated with either dose of omalizumab compared with 24% of patients in the placebo group. A 50% or greater reduction in dose of oral corticosteroids was reported in 78% of subjects in the high-dose group and 57% of those in the low-dose group versus 33% of subjects in the placebo group (P = 0.04). More than one third of subjects in the omalizumab group were able to discontinue oral corticosteroids. One fifth of the subjects taking ICs were able to completely discontinue steroid use after being treated with omalizumab. During the 20-week study period, 45% of patients receiving placebo reported an exacerbation, compared with only 28% of patients in the low-dose group and 30% of patients in the high-dose group. More recent studies have confirmed that in properly selected patients with severe persistent asthma that is poorly controlled despite use of combination controller therapy, omalizumab is efficacious for reducing exacerbations over time and improving quality of life. ⁷⁵

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Experimental therapies

Inhaled drugs administered by some form of a handheld device (most often a dry-powder device or a pressurized metered-dose inhaler) are generally acceptable, adequate, and effective. This will likely be the therapy for the majority of asthmatics for the foreseeable future. However, the following limitations to these approaches warrant continued development of new therapeutics: (1) poor adherence with inhaled devices may contribute to poor asthma care outcomes; (2) despite evidence to the contrary, patients, parents, and clinicians have lingering questions about the long-term safety of ICs; (3) there are insufficient data for the concept that chronic long-term therapy with the existing agents, including corticosteroids, has a disease-modifying effect or an effect that prevents or reverses airway remodeling; (4) a small subset of patients have inadequately treated asthma despite maximal doses of inhaled corticosteroids, and these patients likely have some form of relative steroid resistance; and (5) older nonspecific, systemic, alternative anti-inflammatory agents (methotrexate, gold, cyclosporine) have significant and unacceptable side effects. ⁷⁶ For these reasons, the pharmaceutical industry and various investigators have been aggressively pursuing novel therapies for asthma.

Anti-cytokine Therapies

T_H2 cells and their derived cytokines IL-4, IL-5, and IL-13 play a critical role in orchestrating eosinophilia and asthmatic airway inflammation in various models of asthma. Over the past few years, there have been several early-phase human studies with pharmacologic approaches to antagonize these pathways, with mixed results. ^77,78 Although the animal studies had been promising, an important study using intravenous humanized monoclonal antibody to IL-5 (SB-240563) at doses of 2.5 mg/kg or 10 mg/kg was disappointing in a double-blind, placebo-controlled trial using an inhaled allergen-challenge model. ⁷⁷ Even though a single intravenous dose of anti-IL-5 decreased blood eosinophilia for 16 weeks and sputum eosinophilia for 4 weeks, there was no significant effect on the late asthmatic response or airway hyperresponsiveness to allergen challenge.

Several studies with an inhaled soluble IL-4 receptor antagonist, altrakincept (Nuvance) found modest benefit, but further development was discontinued by the manufacturer. In a placebo-controlled, parallel-group study of 62 moderate-persistent asthmatics dependent on moderate doses of ICs, subjects were randomized to placebo or three different doses of IL-4R by once-weekly nebulization for 12 weeks. ⁷⁸ There were modest improvements in symptom scores and FEV₁ in the highest-dose group, but the asthma exacerbation rate was not significantly different than in the placebo group. An IL-13 antagonist has also shown promise in a primate model of asthma, and clinical studies are being initiated in human patients.

Novel Steroids

Steroids, either systemic or inhaled, are exquisitely active and effective in asthma, but their mechanism of action is broad, and concern for toxicity even with topical steroids has limited their wider use. A variety of approaches are being pursued to maximize local activity within the airways and at the same time to minimize systemic absorption and toxicity. ⁷⁹ These approaches include the following: (1) development of “on-site-activated steroids” such as ciclesonide, which is a nonhalogenated ICS prodrug that requires endogenous cleavage by esterases for activity; (2) development of “soft steroids,” which have improved local, topical selectivity and have much less steroid effect outside the target area; these agents may be inactivated by esterases or other enzymes (for example a lactone-glucocorticosteroid conjugate); and (3) use of “dissociated steroids,” or agents that favor monomeric glucocorticoid receptor complexes (i.e., they produce “transrepression”) and avoid dimerization or “transactivation,” which is undesirable in asthma. Agents from each of these categories are undergoing clinical trials.

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Conclusion

Further progress in asthma care will require better understanding of the molecular and genetic basis for the clinical heterogeneity seen in this disorder. The relation between acute and chronic inflammation as well as airway hyperresponsiveness and airway remodeling is still unclear. Research in exhaled noninvasive markers of inflammation may eventually be translated into a practical and clinically useful tool. The availability of such a tool would be essential to more precisely manage anti-inflammatory therapy. Further development of pharmacogenetics may identify subsets of patients who may preferentially respond to one class of anti-inflammatory agents as opposed to others, thereby eliminating some of the trial and error that often occurs in normative asthma management. Finally, the specific pharmacotherapeutic approaches to block unique pathways offer hope for major new advances in the next 5 to 10 years.

Summary

• Asthma is a chronic, episodic disease of the airways, which is best viewed as a syndrome.
• Prevalence and severity of asthma have increased dramatically in recent decades.
• Although there is no cure for asthma, with proper management well-controlled asthma can be achieved in the overwhelming majority of cases.
• Pharmacogenetics holds promise for identifying subsets of patients who may preferentially respond to select asthma medications and encourage more favorable asthma care outcomes.
• Specific pharmacotherapeutic approaches to block unique pathways involved in asthma inflammation offer hope for major new advances in asthma management in the near future.

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Suggested Readings

• Is allergen immunotherapy effective in asthma? A meta-analysis of randomized controlled trials. Am J Respir Crit Care Med. 151: 1995; 969-974.
• Allergen immunotherapy: A practice parameter. Ann Allergy Asthma Immunol. 90: 2003 Jan; 1-40.
• Can guideline-defined asthma control be achieved?. Am J Resp Crit Care Med. 170: 2004; 836-844.
• Asthma: From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med. 161: 2000; 1720-1745.
• Guidelines for the Diagnosis and Management of Asthma—Update on Selected Topics 2002. U.S. Department of Health and Human Services, National Institutes of Health; 2002. NIH Publication No. 02-5075 (http://www.nhlbi.nih.gov/guidelines/asthma/index.htm).
• Attaining optimal asthma control: A practice parameter. J Allergy Clin Immunol. 116: 2005; S3-11.
• Surveillance for asthma—United States, 1980-1999. In Surveillance Summaries, March 29, 2002. MMWR. 51: 2002; 1-14.
• National Asthma Education and Prevention Program. Expert panel report guidelines for the diagnosis and management of asthma. J Allergy Clin Immunol. 88: 1991; 425-534.
• National Heart, Lung, and Blood Institute: National Asthma Education Program Expert Panel Report II: Guidelines for the diagnosis and management of asthma; 1997, NIH Publication No. 97-4051A.
• Pharmacological management to reduce exacerbations in adults with asthma. A systematic review and meta-analysis. JAMA. 292: 2004; 367-376.