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. 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. Evidence-based practice guidelines have 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 summarizes these developments, including an update on the definition of asthma, its epidemiology, natural history, cause, and pathogenesis. In addition, there is a discussion of the appropriate diagnostic evaluation of asthma and co-occurring conditions, management 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 asthma⁴: 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. The Expert Panel Report (EPR) 3 guidelines,⁵ issued in 2007, state that the immunohistopathologic features of asthma include inflammatory cell infiltration involving neutrophils (especially in sudden-onset, fatal asthma exacerbations; occupational asthma; and patients who smoke), eosinophils, and lymphocytes, with activation of mast cells and epithelial cell injury. Heterogeneity in the pattern of asthma inflammation has been recognized, consistent with the interpretation that phenotypic differences exist that influence treatment response. The inflammation of asthma leads to an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli.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.

Back to Top

Epidemiology and natural history

Several government 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 (CDC). Data published by the CDC indicate that approximately 20 million Americans have asthma. Estimates of 12-month period prevalence have found that approximately 3.0% of the U.S. population had asthma in 1970; more recent estimates indicated that the 12-month period prevalence had increased to 5.5% in 1996.⁶ In association with rising prevalence, patient encounters—via outpatient visits, emergency department use, and hospitalizations for asthma—also increased during this period. Asthma surveillance data in recent decades have revealed that a disparate burden of asthma exists in certain demographic subgroups: in children compared with adults, in women compared with men, in blacks compared with whites, and among Hispanics of Puerto Rican heritage compared with those of Mexican descent.⁶ The trend for increasing asthma mortality that began in 1978 and continued through the 1980s reached a plateau in the 1990s, and since 1999 annual rates in the United States have declined.⁶ These trends are reassuring, and they have been correlated with increasing rates of dispensed prescriptions for inhaled corticosteroids (ICS), implying that improved treatment of asthma may be responsible for these favorable developments. The overall annual economic burden for asthma care in the United States exceeds $11 billion.⁷

Back to Top

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 demonstrated disease risk from early environmental factors and susceptibility genes, subsequent disease induction and progression from inflammation, and response to therapeutic agents (Fig. 1).

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 or viruses, exercise, or inhalation of nonspecific irritants. 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 hyperplasia, and myofibroblast hyperplasia can lead to remodeling of the airway wall. 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 identify 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,⁸ 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 immunoglobulin E [IgE], CD23, interleukin-4 [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. A number of limitations have hindered our understanding of asthma obtained from these model systems: There are important differences between animal models of asthma and human disease, there are few longitudinal studies of human asthma with serial airway sampling, and 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 than in those with adult-onset asthma.

Immunopathogenesis and the Th2 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 Th2. The Th2 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 (GM-CSF).⁹ Recent study suggests that mutations in IL-4 receptor alpha (IL4Rα) are associated with a gain in receptor function and more IL-4 functional effect, which is associated with asthma exacerbations, lower lung function, and tissue inflammation, in particular to mast cells and IgE.¹⁰Eosinophils are often 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.

Knockout studies and anticytokine studies suggest that lipid mediators are products of arachidonic acid metabolism. They have been implicated in the airway inflammation of asthma and have been the target of pharmacologic antagonism by antileukotriene agents. Prostaglandins are generated by the cyclooxygenation of arachidonic acid, and leukotrienes are generated by the lipoxygenation of arachidonic acid. The proinflammatory prostaglandins (prostaglandin [PG]D₂, PGF₂, and TXB₂) cause bronchoconstriction, whereas other prostaglandins are considered protective and elicit bronchodilation (PGE₂ and PGI₂, or prostacyclin). Leukotrienes C₄, D₄, and E₄ compose the compound formerly known as slow-reacting substance of anaphylaxis, a potent stimulus of smooth muscle contraction and mucus secretion. Ultimately, mediators lead to degranulation of effector or 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 hygiene hypothesis has been proposed to explain the epidemiologic observation that asthma prevalence is much greater in industrialized Western societies than in less technologically advanced societies.^11,12 This hypothesis maintains that airway infections and early exposure to animal allergens (e.g., farm animals, cats, dogs) is important in affecting the propensity for persons to become allergic or asthmatic. Specifically, early exposure to the various triggers that can occur with higher frequency in a rural setting might protect against the allergic diathesis that is characteristic of the Th2 paradigm. In a “cleaner” urban Western society, such early childhood exposure is lacking, and this encourages a higher incidence of allergy and asthma. The hygiene hypothesis has become the basis for a number of emerging therapies.

Whether airway hyperresponsiveness is a symptom of airway inflammation or airway remodeling, or whether it is the cause of long-term loss of lung function, remains controversial. Some investigators have hypothesized that aggressive treatment with anti-inflammatory therapies improves the long-term course of asthma beyond their salutary effects on parameters of asthma control and rates of exacerbation over time.¹³ This contention has been supported by an observational study¹⁴ that found long-term exposure to ICS 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 (early-phase and late-phase events) and the concept of airway remodeling, or the chronic nonreversible changes that can happen in the airways, remains a source of intense research.⁴ The natural history of airway remodeling is poorly understood, and although airway remodeling occurs in some patients with asthma, it does not appear to be a universal finding.

Clinically, airway remodeling may be defined as persistent airflow obstruction despite aggressive anti-inflammatory therapies, including ICS and systemic corticosteroids. Pathologically, airway remodeling appears to have a variety of features that include increases of smooth muscle mass, mucous gland hyperplasia, persistence of chronic inflammatory cellular infiltrates, release of fibrogenic growth factors along with collagen deposition, and elastolysis.¹⁵ Increased numbers and size of vessels in the airway wall is a long-recognized characteristic and one of the most consistent features of asthma remodeling occurring in mild, moderate and severe asthmatic lungs.^16-19 (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).

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 colleagues²⁰ 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 (TGF)-β to perpetuate remodeling. On the other hand, one of the most striking features reported in early detailed histopathologic studies of asthmatic lungs was the increased amount and size of submucosal vessels, and this has been repeatedly confirmed in other, more recent, reports.^17,19,21-24

Although understanding of new vessel formation and its genesis in asthma is still in its early stages, it has been suggested that vascular remodeling may be a critical component in the pathophysiology of asthma and a determinant of asthma severity. Asosingh and colleagues showed that angiogenesis is a very early event, with onset during the initiation of acute airway inflammation in asthma.²¹ It is linked to mobilization of bone marrow–derived endothelial progenitor cells, which, together with Th1 and Th2 cells, lead to a proangigogenic lung environment in asthma, which is sustained long after acute inflammation is resolved.²¹ The enlarged airway vascular bed may contribute to the airflow limitation either through the vascular tissue’s itself increasing airway wall thickness or through edema formation. Angiogenesis itself may play a role in the disease progression through recruitment of inflammatory cells, effects that alter airway physiology, or by secretion of proinflammatory mediators.

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.^25-29 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.²⁶ High levels of ROS are produced in the lungs of asthmatic patients by activated inflammatory cells (i.e., eosinophils, alveolar macrophages, and neutrophils).²⁷ The 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. Other investigators have measured products of arachidonic acid metabolism in exhaled breath condensate.³⁰ 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 (LTE₄)-like immunoreactivity is increased in exhaled breath condensate of steroid-naïve patients who have mild asthma, with levels about threefold to fourfold higher than those in healthy subjects. Concomitant with increased oxidants, antioxidant protection of the lower airways is decreased in lungs of asthmatic patients.^28,29

Another reactive species, nitric oxide (NO), is increased in the asthmatic airway.²⁶ 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 studies have suggested cytotoxic consequences associated with tyrosine nitration induced by reaction products of NO.³¹ Based on the high levels of NO in exhaled breath of asthmatics and the decrease of NO that occurs in response to treatment with corticosteroids, measurement of NO has been proposed as a noninvasive way to detect airway inflammation, diagnose asthma, and monitor the response to anti-inflammatory therapy.^32-34 The development of NHANES (National Health and Nutrition Examination Survey) normative levels for the fractional excretion of NO (FE_NO) will facilitate more widespread application of this exhaled gas measure in the clinical care of asthmatics.

The β-Agonist Controversy

Short-Acting β Agonists

Much controversy has surrounded the excessive or regular use of β-agonist preparations and the contention that this could lead to worsening of asthma control and pose a risk for untoward outcomes, including near-fatal and fatal episodes of asthma.

Several studies from New Zealand suggested that the use of inhaled β agonists increases the risk of death in severe asthma.^6,35-37 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.³⁸ Data were based on matching 129 case patients who had fatal or near-fatal asthma with 655 controls. The use of a 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 other case-controlled studies, relates to the comparability of cases and controls 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.³⁹ 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.

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.⁴⁰ 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 (FEV₁), 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 meta-analysis of pooled results from 22 randomized, placebo-controlled trials that studied at least 1 week of a 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.

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.⁴¹ 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 (relative risk [RR], 2.16; 95% confidence interval [CI], 1.06-4.41) and asthma-related deaths (RR, 4.37; 95% CI, 1.25-15.34) and in combined asthma-related deaths or life-threatening experiences (RR, 1.71; 95% CI, 1.01-2.89) 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.

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 before 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, 1.25-25.26) and combined asthma-related deaths or life-threatening experiences (RR, 10.46; 95% CI, 1.34-81.58).

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 behavior 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 subsequent label changes for LABA and LABA-containing medications.

Data from SMART, combined with other recent reports,⁴² have fueled a controversy regarding the role of LABAs 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-to-benefit standpoint. This will require additional studies to fully clarify; however, asthma care providers should also be mindful that use of a LABA in combination with ICS has been associated with a 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.⁴³

Previously published meta-analyses have shown that low-dose ICS combined with LABA is associated with superior outcomes compared with higher-dose ICS.^44-46These data led to the recommendation in the EPR-2 update of the NAEPP guidelines to prescribe the combination of ICS and LABA for patients with moderate persistent asthma and severe persistent asthma. The update categorized this management recommendation as based on level A evidence.² Based on safety concerns, the EPR-3 guidelines⁵ recommend that medium-dose ICS be regarded as equivalent to adding LABA to low-dose ICS, and state “the established, beneficial effects of LABA for the great majority of patients who have asthma that is not sufficiently controlled with ICS alone should be weighed against the increased risk for severe exacerbations, although uncommon, associated with daily use of LABA.” At this time, 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 ADRβ₂ gene for the β₂-adrenergic receptor can influence clinical response to β agonists. For the ADRB2, 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., Gly16Gly, Arg16Arg, Glu27Glu, and Gln27Gln). 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.

In the presence of a polymorphism, the acute bronchodilator response to a β agonist, or protection from a bronchoconstrictor, may be affected. Studies indicate that in patients with Arg16Arg variant, the resulting β₂-adrenergic receptor 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 Gly16Gly, the β₂-adrenergic receptor is downregulated by endogenous catecholamines; therefore, the acute bronchodilator response is reduced or blunted. In relation to prolonged β-agonist therapy (e.g., >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 patients, 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 currently unclear. There are conflicting data regarding whether Arg/Arg homozygotes are prone to experience reflex morbidity with inhaled LABA,⁴³ but the weight of evidence, particularly from more-recent studies,^47,48 indicates that response to LABA when used in combination with ICS does not vary based on β₂-adrenergic genotypes at codon 16.

There are limited data on mutations involving the leukotriene cascade or corticosteroid metabolism. Polymorphisms of the 5-lipoxygenase (5-LO) gene promoter and the LTC₄ synthase gene (LTC4S) have been described. Asthmatics with the wild-type allele 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 gene promoter occur only in about 5% of asthmatic patients; for this reason, it is unlikely to play an important role in most patients. An SNP in LTC4S 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.

Back to Top

Diagnostic evaluation, comorbid disease, and peak expiratory flow monitoring

The history and physical examination are important to confirm a diagnosis and exclude conditions such as hyperventilation syndrome, vocal cord adduction, heart failure, and others that can masquerade as asthma; to assess the severity of airflow obstruction and the need for aggressive intervention including inpatient management; to identify risk factors for poor outcomes; and 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 chest tightness, wheezing, episodic dyspnea, and cough. Some patients 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 FEV₁ and the PEF 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 NAEPP has set forth the grading of asthma severity into four categories based on frequency of daytime and nocturnal symptoms, peak flows, and as-needed use of inhaled short-acting β agonists: intermittent, mild persistent, moderate persistent, and severe persistent.⁵ The mildest category, designated mild intermittent in EPR-2, was changed to intermittent in EPR-3 to emphasize that even patients with this level of asthma severity may have serious or even life-threatening asthma exacerbations.⁵

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 less than 25% of the predicted value. Hypercapnia in the setting of acute asthma does not necessarily mandate intubation or suggest a poor prognosis.⁴⁹ 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 can 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 it is not recommended for routine clinical practice. The methacholine challenge test, which is most commonly 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 inhalation challenge with methacholine (or histamine) excludes active, symptomatic asthma. Measurement of FE_NO has been associated with a negative predictive value of 92%⁵⁰ for ruling out presence of asthma; however, additional studies are required for this more-convenient and less-costly test to supplant methacholine challenge, which is still regarded as the gold standard for the diagnosis of asthma.

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.⁴⁹ Over the past decade, 6 of 10 randomized trials have failed to show an advantage for the addition of PEF monitoring beyond symptom-based intervention for the control group.⁵¹ Regular PEF monitoring allows early detection of worsening airflow obstruction, which may be of particular value in a subset of poor perceivers—persons 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.

Back to Top

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:

• Education of primary health care providers
• Education programs for asthma patients
• Longitudinal outpatient follow-up with easy access to providers
• Emphasis on chronic maintenance therapy rather than acute episodic care
• Emphasis on daily anti-inflammatory therapy

Organized approaches to improving care have included dissemination of clinical practice guidelines, disease state management, and case management.⁵²

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, rather than 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 it is a chronic disease suitable for self-management and patient education; it can be managed largely on an outpatient basis, thus avoiding costly inpatient care; there is a consensus on what constitutes optimal care; and 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 a prestudy and post-study design has typically been employed, usually with no control group; the choice of outcome measures varies; and 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 have been disseminated 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. Possible mechanisms by which practice guidelines can improve patient care include 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 achieve favorable clinical outcomes.⁵³ 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 3

In 1991, the coordinating committee of NAEPP, along with the NHLBI, convened an expert panel to develop extensive and detailed guidelines for the diagnosis and management of asthma.¹ The EPR-2 was published in 1997² and EPR-3 guidelines were released in 2007.⁵ Overall, the published guidelines highlight the significant role of airway inflammation in the pathogenesis of asthma, an emphasis on the role of anti-inflammatory maintenance therapy for persistent asthma, and 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: maintain normal activity level, including exercise; maintain near-normal parameters of pulmonary function; prevent chronic and troublesome exacerbations of asthma by maintaining a chronic baseline maintenance therapy; and 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. A second component involves measures to minimize or avoid exposure to clinically relevant aeroallergens and irritants that can exacerbate asthma. A third component is pharmacotherapy.

The NAEPP guidelines recommend that asthma should be managed in an algorithmic manner, based on asthma severity; EPR-3 guidelines introduced the concept of asthma control and its importance in management. Patients are to be classified as having intermittent, mild persistent, moderate persistent, or 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 recommendation, described in EPR-2 would have resulted in patients with asthma receiving pharmacotherapeutic agents associated with favorable asthma care outcomes that are also appropriate from both cost and risk-to-benefit standpoints. In the real world, however, this paradigm was imperfect, because it relied on the correct categorization of patients for pharmacotherapy to be prescribed appropriately. Both health care providers and patients are prone to underestimate asthma severity,⁵⁴ and for this reason, many patients managed based on this paradigm were undertreated.

A new paradigm was proposed in EPR-3 guidelines, based on the assessment of asthma control.⁵⁵ 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.⁵⁵ This follows from the understanding that a patient with severe persistent asthma who is treated appropriately with multiple controllers and who adheres to orders regarding medications and recommended avoidance strategies can achieve well-controlled (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-persistent to moderate-persistent asthma who either does not receive appropriate instructions for avoidance measures and controller medications, or both, or who is poorly adherent to therapy, 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.

Another limitation of EPR-2 was that the categorization of asthma severity was proposed at a time before long-term therapy was initiated; however, many patients are already taking controller medications when they are initially seen. EPR-3 guidelines⁵ stipulate that the asthma severity level can be inferred, based upon response, or lack thereof, to asthma pharmacotherapy. This concept, responsiveness, is defined as the ease with which asthma control can be achieved by therapy.

EPR-3 guidelines recommend that asthma should be categorized based on level of severity at the initial visit, and at subsequent visits the focus of providers should be on asthma control (Fig. 6). At the initial visit, severity is assigned based on assessment of both impairment and risk domains, as illustrated in Table 1, for patients who are not taking regular controller medication, and for patients on regular pharmacotherapy for asthma.

For all patients with asthma, regardless of severity classification, the goal of asthma management as described in EPR-3⁵ is the same: to achieve control by reducing both impairment and risk (see Table 2). The impairment domain is focused on the present and entails assessments of frequency and intensity of asthma symptoms, functional limitation, lung function, and meeting expectations of, and satisfaction with, asthma treatment. The risk domain is focused on the future and includes preventing asthma exacerbations and severe exacerbations, minimizing the need for using health services (emergency department visits or hospitalization), reducing the tendency for progressive decline in lung function, and providing pharmacotherapy that offers minimal or no risk for untoward effects. The impairment and risk domains might respond differently to treatment.

Asthma control is a multidimensional construct. Asthma control can be assessed by use of validated instruments, including the Asthma Control Questionnaire (ACQ), Asthma Therapy Assessment Questionnaire (ATAQ), and the Asthma Control Test (ACT). These instruments include assessment of asthma symptoms, frequency of use of as-needed rescue medication, the impact of asthma on everyday functioning, and, in the case of the ACQ, the impact of asthma on lung function. The ACT is highlighted herein as an example of a validated instrument that can be used in routine asthma management as a gauge of asthma control. The ACT is reliable and responsive to asthma control over time.^56,57 The process of accomplishing the ACT entails a patient’s accurately responding to five questions (using a 1-5 scale) pertaining to the previous 4 weeks: activity restriction at work, school, or home; frequency of shortness of breath episodes; frequency of nocturnal awakening; as-needed use of rescue bronchodilator; and overall assessment of asthma control. The lowest possible score is 5 and the highest possible is 25. The higher the score, 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 asthma as poorly controlled or well controlled.⁵⁷ 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, which 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.⁵⁸

The current paradigm for asthma management (see Fig 6), recommends that asthma care providers categorize asthma severity at the initial visit based on the criteria mentioned earlier, and subsequent visits should proceed with assessment of asthma control. If asthma is well controlled (ACT = 20), the provider, in collaboration with the patient, may consider maintaining current management or a step down. If asthma is not well controlled, it is appropriate to step up management or carry out an assessment to determine whether factors such as poor adherence or a comorbid condition is present that is complicating response to therapy. If asthma is not well-controlled, data indicate that such patients are at elevated risk for exacerbation of asthma, and on this basis they are clearly candidates for intervention.⁵⁹

Although the concept of expert practice guidelines that have become increasingly evidence based 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. Because asthma research is rapidly evolving and new pharmacotherapeutics are anticipated, continued periodic revision of guidelines for asthma can be anticipated.

Allergy, Allergen Avoidance, and Allergen Immunotherapy

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 EPR-3 guidelines⁵point out that “sensitivity to a perennial indoor allergen is usually not possible with a patient’s medical history alone.”

Clinical relevance of inhalant allergens can be demonstrated by immediate hypersensitivity skin testing or radioallergosorbent (RAST) assay. Of these, skin testing is more sensitive, is 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. EPR-3⁵ also recommends that diagnostic allergy testing may be indicated for “selected patients who have asthma at any level of severity … as a basis for education about the role of allergens for avoidance and for immunotherapy.” 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 can provoke and perpetuate asthma symptoms are listed in Box 1. Persons with asthma are usually 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,⁶⁰ the usefulness of air conditioning for improving asthma symptoms should not be underestimated.

Dust mites are microscopic, and they rely on heat and humidity to survive and proliferate.⁶¹ Allergy to dust mites is common in patients with asthma. Recommended avoidance measures to reduce exposures to dust mite allergen include encasing the mattress, box spring, and pillows in impermeable covers; reducing indoor relative humidity; washing bedding weekly in the hot cycle (130°F); and, if possible, removing carpets in favor of tiled or hardwood flooring.⁶¹

For patients who are allergic to cat or dog dander and who own pets, no avoidance strategy can rival the benefit that will occur with eliminating the pet from the home. If a cat or dog is removed from the home, however, the allergen can persist for several months. For this reason, clinical benefit cannot be expected promptly.⁶² When it is not possible to eliminate pets from the home, second-best measures include restricting the pet from the bedroom, using high-efficiency particulate or electrostatic air cleaners, and removing carpets and other furnishings that 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.⁶³

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.^64,65 As shown in Figure 7, the EPR-3 guidelines recommend considering allergen immunotherapy for patients who have mild or moderate persistent asthma (steps 2-4) and who have a clinically relevant component of allergic potential to inhalant allergens. 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 since 1954 have shown statistically and clinically significant dose-dependent benefits with administration of allergen immunotherapy in properly selected patients with asthma.⁶⁴

The immunologic changes that develop with administration of allergen immunotherapy are complex. Successful immunotherapy results in generation of a population of CD4⁺/CD25⁺ T lymphocytes producing IL-10 and/or TGF-β. Allergen immunotherapy has been shown to block the immediate and late-phase allergic response; decrease recruitment of mast cells, basophils, and eosinophils upon provocation or natural exposure to allergens in the skin, nose, eye, and bronchial mucosa; blunt the seasonal rise in specific IgE; and suppress late-phase inflammatory responses in the skin and respiratory tract.⁶⁶ However, the efficacy of immunotherapy in relation to these immunologic changes is not completely understood.

In contrast to medication that affects only symptoms, immunotherapy can favorably affect the disease process that underlies asthma symptoms. Numerous randomized, double-blind, placebo-controlled trials have shown that allergen immunotherapy is associated with benefit for reducing symptoms and reducing reliance on medication.⁶⁶ A meta-analysis of 75 randomized, placebo-controlled studies confirmed the effectiveness of immunotherapy in asthma, with a significant reduction in asthma symptoms and medication, and with improvement in bronchial hyperreactivity.⁶⁷This meta-analysis included 36 trials for dust mites, 20 for pollens, and 10 for animal dander. Immunotherapy is efficacious for pollen, mold, dust mite, cockroach, and animal allergens; however, its effectiveness is more established for dust mite, animal dander, and pollen allergens, because fewer studies have been published demonstrating efficacy using mold and cockroach allergens.

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.⁵⁵ The decision to begin allergen immunotherapy should be individualized and based on severity of symptoms, relative benefit with pharmacotherapy, and whether the patient has comorbid conditions such as cardiovascular conditions or is using beta blockers.⁶⁸ These factors increase the risk for (serious) anaphylaxis, which is the major risk of allergen immunotherapy.

Aspirin Intolerance and Desensitization

Aspirin (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs) can provoke bronchospasm (with or without nasal and ocular congestion or flushing) in a subgroup of asthmatic patients.⁶⁹ 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 subtherapeutic dosage of ASA in this setting can lead to potentially life-threatening bronchospasm. ASA and NSAIDs, including ibuprofen, naproxen, sulindac, indomethacin, and etodolac, inhibit cyclooxygenases 1 and 2 (COX-1 and COX-2) and are 100% cross-reactive in ASA-sensitive asthmatic patients. In AERD patients, cross-reaction can 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.⁶⁹

COX inhibition downregulates the enzyme PGE₂, leading, in turn, to excessive production of sulfidopeptide leukotrienes (LTC₄, LTD₄, and LTE₄). These mediators participate in acute bronchospastic reaction provoked by ASA ingestion and also contribute to the ongoing airways obstruction and inflammation that persist in AERD patients despite avoidance of ASA and other COX-inhibiting drugs.⁶⁹ Administration of antileukotriene agents, which either selectively block leukotriene receptors or inhibit leukotriene synthesis by blocking 5-LO or its activator, 5-LO 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 montelukast⁷⁰ or zileuton.⁷¹

Antileukotriene agents also attenuate bronchospastic reaction provoked by ASA challenge in AERD.^72,73 For this reason, antileukotriene drugs are useful for reducing severity of reaction in patients undergoing desensitization, although respiratory reaction is not blocked completely.⁶⁹ Biosynthesis of leukotrienes is upregulated in AERD; a key enzyme, LTC₄ synthase, is overexpressed in bronchial mucosa.⁶⁹ AERD patients have increased expression of the Cys-LT₁ receptor on inflammatory leukocytes,⁷⁴ thereby enhancing their ability to respond to leukotrienes. Downregulation of Cys-LT₁ receptor expression might explain the mechanism for benefit with ASA desensitization treatment.⁷⁴

Desensitization can be performed for patients who require administration of ASA or ASA-like drugs 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.⁷⁵ Improvement included reduced level of symptoms, lower reliance on medication, and less morbidity (as reflected in fewer annual episodes of upper respiratory infection or sinusitis and reduced rates of sinus surgery procedures). Based on these findings and previous experience with ASA desensitization⁵⁰ 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 can occur during desensitization, this procedure should only be carried out in settings with experienced physicians and appropriate equipment to treat such reactions.

Pharmacotherapy

The pharmacotherapy for asthma, as recommended by current NAEPP guidelines, is summarized in Figure 7 and Tables 3 through 5. The overall strategy is a stepwise approach based on level of severity. Inhaled short-acting β agonists (relievers) used on an as-needed basis are recommended for patients who have intermittent asthma and 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 cost effective in the management of asthma, with an incremental cost-effectiveness ratio for a symptom-free day of approximately $5.00 to $6.00.⁷⁶ Regular use of ICS can reduce rates of asthma exacerbation⁷⁷ and prevent increases in bronchial hyperresponsiveness⁷⁸ and accelerated loss of lung function.¹⁴ A large retrospective case-control study from Canada associated regular use of ICS with statistically significant reductions in rates of mortality from asthma.⁷⁹

Evidence indicates that patients with moderate persistent asthma who remain symptomatic on low-dose ICS monotherapy experience greater benefit from LABA added to low-dose ICS compared with doubling the dose of ICS.⁴³ Several studies have examined the usefulness of ICS taken in combination with other agents such as theophylline⁸⁰ and leukotriene antagonists.⁸¹ These agents are also a rational alternative, taken in combination with ICS, to doubling the dose of ICS 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 LABA.⁸² A study from the Asthma Clinical Research Network found that monotherapy with salmeterol is not adequate replacement therapy for asthma controlled on triamcinolone 400 µg twice a day.⁸³ As noted earlier, LABA monotherapy can improve symptoms and lung function, but has no effect on airways inflammation.⁴³

The molecular mechanism of action of glucocorticoids involves binding to a specific intracellular glucocorticoid receptor (GCR). This binding dissociates heat-shock proteins and creates an active glucocorticoid and receptor (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 might also suppress gene expression by interfering with the interaction of transcription factors (i.e., nuclear factor-κB) with promoter regions of proinflammatory cytokines. Through these mechanisms, glucocorticoids 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 barrier to wider use of these agents despite several reassuring long-term studies and recommendations from evidence-based practice guidelines. One landmark study⁸⁴ included 1041 children from ages 5 years through 12 years with mild-to-moderate asthma for a study duration of 4 to 6 years. The children were randomized into three groups: 200 µg of budesonide twice a day, 8 mg 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 among 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.⁸⁵

Practical approaches to minimize or eliminate systemic toxicity from ICS include using the lowest dose needed by proactively stepping down the dose after several months of optimal asthma control, 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 adding LABA or another controller agent to facilitate dose reduction of ICS.

Antileukotrienes

The sulfidopeptide or cysteinyl leukotrienes (LTC₄, LTD₄, and LTE₄) are formed by the lipoxygenation of arachidonic acid by the enzyme 5-LO. These compounds, released by mast cells, 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.^69,73Placebo-controlled clinical trials have shown salutary effects in asthmatics treated with antileukotriene drugs.⁸⁶

Churg-Strauss vasculitis (CSS) has been reported in patients receiving antileukotriene drugs. In most cases, patients with severe asthma who improved and were able to suspend or taper oral corticosteroids developed CSS.^87,88 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 antileukotriene drug. Similar cases of CSS have also been reported in association with other asthma drugs, including cromolyn, fluticasone, and omalizumab.

Antileukotrienes have been associated with statistically significant improvement in mild-to-moderate asthma compared with placebo.^89,90 A 3-month, double-blind, parallel-group study of 681 subjects with FEV₁ 50% to 80% showed significant improvement with montelukast. Asthma exacerbation decreased by 31%, and asthma-free days increased by 37%.⁸⁹ Another randomized trial involving 226 adults with moderate-to-severe asthma showed that montelukast 10 mg allowed significant tapering of inhaled steroids in patients requiring moderate to high doses.⁹⁰ 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.⁷¹

A current scientific controversy surrounding antileukotrienes 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.⁹¹ Whether these findings are relevant to human disease awaits performance of additional studies.

EPR-3⁵ guidelines recommend a role for antileukotrienes 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 who were randomized to ICS or antileukotrienes, ICS have been associated with superior efficacy.⁹² Antileukotrienes facilitate reduction in the need for inhaled β agonists and ICS, and they may be associated with improved compliance compared with inhaled medications. Antileukotriene 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 antileukotriene 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_2α that is critical in this subgroup.⁶⁹

Anti-IgE Therapy

Omalizumab (Xolair), is a humanized monoclonal anti-IgE antibody that binds with high affinity to the FcεRI receptor-binding site on IgE. Omalizumab reduces the amount of free IgE available to bind to FcεRI receptors on mast cells and basophils. 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.

Humbert and colleagues⁹³ studied 419 patients whose asthma was not adequately controlled on high-dose ICS combined with LABA. The subjects were 12 to 75 years old and had reduced lung function and history of recent asthma exacerbation. These subjects were randomized to treatment with omalizumab or placebo. Omalizumab was associated with a statistically significant reduction in the rate of asthma exacerbations and severe asthma exacerbations, as well as statistically significant improvements in asthma-related quality of life, morning peak expiratory flow rate, and asthma symptom scores. These data provide support for the recommendation to consider a trial of omalizumab in properly selected patients with severe persistent allergic asthma.

In pivotal trials,^94,95 omalizumab was associated with a substantial rate of local reactions. A rate of anaphylaxis of slightly less than 1 in 1000 was observed, and this has been confirmed by surveillance data recorded since approval of the drug in June 2003. Based on the observed risk of anaphylaxis, in July 2007 the FDA added a black box warning to the omalizumab label. The warning states that health care providers administering omalizumab should be prepared to manage anaphylaxis, and patients should be closely observed for an appropriate period after omalizumab administration.

A numerical, but not statistically significant, increase in the rate of malignancy in patients receiving omalizumab was also observed. Malignancies developed in 0.5% of patients receiving omalizumab compared with 0.2% of patients who received placebo. Because these malignancies were diagnosed over a shorter period than the time oncogenesis requires to develop (i.e., 6 months in 60% of cases), and because a heterogeneity of tumors was observed, there is reason to suspect these tumors were not causally related to omalizumab. Postmarketing surveillance studies are in progress that will provide more definitive data on the possible relationship between malignancy and omalizumab.

The EPR-3⁵ guidelines state that omalizumab is the only adjunctive therapy to demonstrate added efficacy to high-dose ICS plus LABA in patients with severe persistent allergic asthma and to stipulate that evidence does not support use of certain agents, which in some cases are FDA-approved for management of other conditions and have been advocated for management of severe, refractory asthma. These agents include methotrexate, soluble IL-4 receptor, anti–IL-5, anti–IL-12, cyclosporine A, intravenous immune globulin, gold, troleandomycin, and colchicine. The data supporting use of macrolides were characterized as “encouraging but insufficient to support a recommendation.”

Back to Top

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, certain limitations to these approaches warrant continued development of new therapeutics. Poor adherence with inhaled devices can contribute to poor asthma care outcomes. Despite evidence to the contrary, patients, parents, and clinicians have lingering questions about the long-term safety of ICS. There are insufficient data for the concept that chronic long-term therapy with the existing agents, including ICS, has a disease-modifying effect or an effect that prevents or reverses airway remodeling. A small subset of patients have inadequately treated asthma despite maximal doses of ICS, and these patients likely have some form of relative steroid resistance. Finally, older nonspecific, systemic, alternative anti-inflammatory agents (methotrexate, gold, cyclosporine) have significant and unacceptable side effects.⁹⁶ For these reasons, the pharmaceuticals industry and various investigators have been aggressively pursuing novel therapies for asthma.

Anticytokine Therapies

Th2 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.^97,98Although 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.⁹⁷ 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.⁹⁸ 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.⁹⁹ One approach is development of on-site-activated steroids such as ciclesonide, which is a nonhalogenated ICS prodrug that requires endogenous cleavage by esterases for activity. Soft steroids are also being developed; these have improved local, topical selectivity and have much less steroid effect outside the target area. They may be inactivated by esterases or other enzymes (for example a lactone–glucocorticosteroid conjugate). Another approach is using 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.

Back to Top

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 might eventually translate into practical and clinically useful tools at point of care. The availability of such tools will encourage more precise management of anti-inflammatory therapy. Further development of pharmacogenetics might 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.

Back to Top

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.
• There is no cure for asthma, but in the overwhelming majority of cases, well-controlled asthma can be achieved with proper management.
• Pharmacogenetics holds promise for identifying subsets of patients who might 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.

Back to Top

References