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Table of Contents

Mani S.
Kavuru, MD

Department of
Pulmonary, Allergy, and Critical Care
Medicine

David M.
Lang, MD

Department of
Pulmonary, Allergy, and Critical Care
Medicine

Serpil C.
Erzurum, MD

Print Chapter

This review of asthma for the practicing clinician will summarize these developments, including an updated definition of asthma, review of the epidemiology and natural history, and current thinking regarding etiology and pathogenesis. In addition, there will be an update on the diagnostic evaluation of comorbid disease, serial monitoring of asthma, and the most recent update of the expert panel guidelines and management algorithms. The authors will offer a critique of these guidelines, including their limitations. Finally, there will be discussion of newer therapies for the future.

Definitions

Epidemiology and
Natural History

Etiology and
Pathogenesis

Diagnostic Evaluation, Comorbid Disease and Peak Expiratory Flow Monitoring

Part 2:
Asthma Therapy

Asthma is a chronic, episodic disease of the airways, and it 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^1,2: 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 is not known or widely agreed upon, the presence of airway hyperreactivity is a common finding in patients with current symptoms and active asthma.

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. The latest data on asthma outcomes published by the Centers for Disease Control indicates that about 15 million American adults suffer from asthma.⁴ The trend for increasing asthma-associated morbidity and mortality reported between 1980 and 1995 has not continued between 1995 and 1999. The annual rates of patients reporting asthma attacks during 1997-1999 were lower than previously reported rates. Since 1995, the rate of outpatient visits for asthma increased, whereas the rates of hospital admissions decreased (from 19.5 per 10,000 population in 1995 to 15.7 in 1998). Importantly, annual rates of asthma mortality which increased during the 1980s have plateaued in the 1990s and have decreased from 1998-2002. These trends are reassuring and indicate that perhaps the aggressive strategies of asthma management finally seem to be reaching fruition. However, African Americans continue to have higher rates of asthma emergency department visits, hospitalizations, and deaths than do Caucasians. The overall economic burden for asthma care in the United States exceeds $6 billion.⁵

Clinicians have long known that asthma is not a single disease; it exists in many forms. This heterogeneity has been amply established by a variety of studies which have indicated disease risk from early environmental factors and susceptibility genes; and subsequent disease induction and progression from inflammation as well as response to therapeutic agents (Figure 1). Recent evidence suggests that asthma is an inflammatory disease, and not simply due to excessive smooth muscle contraction. Inflammation is the proximate cause of airway hyperreactivity and variable airflow obstruction in asthma, and is a universal finding in all asthmatic individuals. 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 histopathologic lesions 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 who undergo research bronchoscopy. 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. While these types of descriptive studies have revealed a composite picture of asthma (Figure 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 in both mild and severe asthma at baseline state,⁶ as well as study of the airway biology with experimental provocation that includes allergen challenge as well as response to anti-inflammatory therapies. Further insights have been obtained through transgenic murine models with deletion or "knock out" of specific genes (ie, those for IgE, CD23, IL-4, or IL-5) or overexpression of other putative genes. Also, specific monoclonal antibodies or cytokine antagonists have been utilized in various asthma models. Several important and technical limitations have hindered our understanding of asthma obtained from these model systems: (1) there are important differences between animal models of asthma and the human disease; (2) there are few longitudinal studies of human asthma with serial airway sampling; and (3) it is often difficult to determine the cause and effect from multiple mediator studies.

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

Immunopathogenesis and the T_H2 Phenotype
Based upon 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 anticytokine 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 new class of agents called antileukotrienes. 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). Leukotrienes C₄, D₄, and E₄ compose the compound called "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.

Hypotheses Related to "Hygiene" and Airway Hyperresponsiveness
Most studies of airway inflammation in human asthma have been 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 speculation. 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 exposures to animal allergens (eg, farm animals, cat, dog) is important in affecting the relative balance of the T_H1 versus the T_H2 airway immunologic profile. Specifically, early exposure to the various triggers that may occur with higher frequency in a rural setting may tilt this balance to a T_H1 paradigm and hence be protected 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 the paradigm therefore shifts closer to the allergic diathesis of T_H2, which results in a higher incidence of asthma and other allergic diseases. Although this notion remains speculative, it is the basis for emerging therapeutic options that attempt to shift the balance in favor of the T_H1 immunologic profile.

Also, the overall concept of duration of asthma, the long-term effect on lung function as well as the decline in the forced expiratory volume in one second (FEV₁), the relative role of airway hyperreactivity or hyperresponsiveness to this natural history are sources of much speculation. Whether airway hyperresponsiveness is a symptom of airway inflammation or airway remodeling, or is the cause of long-term loss of lung function, is being actively debated. Some investigators have hypothesized that aggressive therapy with anti-inflammatory therapies to improve airway hyperreactivity (above and beyond their effects on conventional parameters of asthma control) may have additional long-term benefits.¹⁰

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.¹¹ 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 (Figure 3). Many biopsy studies show these pathologic features from 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 (Figure 4 and Figure 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 thought to be a key determinant in the concept of airway remodeling. A recent hypothesis by Holgate et al¹² indicates 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-ß 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.^13-18 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.¹⁴ High levels of ROS are produced in the lungs of asthmatic patients by activated inflammatory cells (ie, eosinophils, alveolar macrophages, and neutrophils).¹⁵ Increased ROS production of asthmatic patients' neutrophils correlates with the severity of reactivity of airways in these patients, and severe asthma is associated with neutrophilic airway infiltrates. Concomitant with increased oxidants, antioxidant protection of the lower airways is decreased in asthmatic lungs.^16,17

Another reactive species, nitric oxide (NO), is increased in the asthmatic airway.¹⁴ 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.¹⁸ Specifically, 8-isoprostane, a PGF_2α analog 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 in healthy subjects.

The β-Agonist Controversy
There has been much controversy surrounding the potential role of β-agonist preparations in asthma mortality.¹⁹ 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.^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 (eg, no fenoterol or albuterol). The primary limitation of this study, and indeed case-controlled studies in general, is concern regarding the comparability of the two groups in terms of the severity of the underlying disease.²⁴ A large, placebo-controlled trial of salmeterol, a long-acting β₂-receptor agonist, was recently stopped prematurely due to concerns with interim analysis that suggested salmeterol may be associated with excess mortality due to life-threatening asthma. This Salmeterol Multiple-Center Asthma Research Trial (SMART) was a 28-week safety study comparing salmeterol 42 mcg metered dose inhaler twice a day with placebo, in addition to other asthma therapies. Of over 26,000 patients randomized, a higher number of asthma-related deaths or life-threatening experiences (36 v. 23) and a higher number of asthma-related deaths (13 v. 4) occurred in the patients treated with salmeterol. Although there was no statistically significant difference for this primary endpoint for the total population, a subset analysis indicated that asthma-related deaths or life-threatening episodes were higher in African-Americans using salmeterol. Interestingly, 50% of Caucasian and 38% African-American patients were using concurrent inhaled corticosteroid at baseline. Among the patients using inhaled corticosteroids, there was no significant difference between the two groups—implying that greater risk for controlled outcomes was related to salmeterol monotherapy. A rate of asthmatic exacerbation equivalent to placebo has previously been reported in patients with mild persistent asthma receiving salmeterol monotherapy.⁶³

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.²⁵ 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 only on an as-needed basis for 16 weeks.²⁶ 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 one second, number of puffs of supplemental as-needed albuterol, asthma symptoms, or airway reactivity to methacholine. Since 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 one week of regularly administered β₂-agonist in patients with asthma compared to a placebo group (that did not permit "as-needed" β₂ agonist use) concluded that regular use results in tolerance to the drug's bronchodilator and non-bronchodilator effects and maybe associated with poorer disease control compared to placebo. However, there was no decline in the mean FEV₁ after regular treatment with β₂-agonists.

Pharmacogenetics
Polymorphisms of the gene for the β₂-adrenergic receptor (AR) may be important in determining the clinical response to beta-agonists. For the β_2-AR gene, single nucleotide polymorphisms (SNPs) have been defined at condons 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 (eg, Gly16 Gly, Arg16 Arg, Glu27 Glu, and Gln27 Gln). Importantly, the frequency of these polymorphisms is the same in the normal population as in a population of asthmatics. Also, the 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 beta agonist, or protection from a bronchoconstrictor, is affected. Studies indicate that patients with Arg16 Arg variant, the resulting β₂AR is resistant to endogenous circulating catecholamines (eg, receptor density and integrity is preserved) with a subsequent ability to produce an acute bronchodilator response to an agonist. In patients with Gly16 Gly, the β₂AR is down regulated by endogenous catecholamines, therefore the acute bronchodilator response is reduced or blunted. In relation to prolonged beta agonist therapy (eg, greater than 2 weeks) it appears that only patients who are homozygous for Arg16 who were receiving regularly scheduled beta-agonist aerosol had a persistent decrease in lung function over time (eg, tachyphylaxis). 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 (eg, variant genes linked at > 2 loci) is presently unclear.

A recent study with transgenic mouse models using β₂AR knock-out as well as overexpression of β₂AR has suggested an alternative molecular mechanism for the effects of chronic exposure to β-agonists and effects on airway bronchodilator response. Interestingly and unexpectedly, the mice with absent β₂AR had markedly reduced bronchoconstrictive response to methacholine. The overexpressors of β₂AR who had continuous β₂AR signaling activity demonstrated an enhanced constrictive response. In addition, the overexpressors showed increased expression of a phospholipase C β₁ enzyme which is thought to mediate the contractile response to methacholine. Overall, this study provides a new molecular mechanism to understand the effects of chronic β-agonist therapy on attenuated bronchodilator response (eg, tachyphylaxis).

To date there is 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 to asthmatics with a mutant gene. However, mutations of the 5-LO promoter occur only in about 5% of the asthmatic patients so it is unlikely to play an important role in most patients. A 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, which 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.

The history and physical examination are important for several 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 admission to the hospital; (3) to identify factors that might place a patient at particular risk for poor outcome; (4) to identify comorbid diseases that may complicate management, such as sinusitis, gastroesophageal reflux, and avoidable external triggers. 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 only dyspnea on exertion. It is essential to specifically inquire about nocturnal symptoms because these are often ignored.

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 four categories based on the frequency of symptoms, peak flows, and the need for inhaled beta agonists: mild intermittent, mild persistent, moderate persistent, and severe persistent.² Hyperinflation, the most common finding on a chest radiograph, has no diagnostic or therapeutic value. 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 do 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.²⁷ Spirometry in an asthmatic patient typically shows obstructive airway disease with reduced expiratory flows that improve with bronchodilator therapy (ie, reduced FEV₁/FVC ratio). Typically, there is an expected 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 by no means excludes 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 may help to identify airway hyperreactivity as the cause of the 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 this is not widely accepted in 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), but it is nonspecific and 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 chest 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 practice guidelines, clinical trials that study the usefulness of PEF monitoring in ambulatory asthma patients show conflicting results.²⁷ 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.²⁸ Regular PEF monitoring allows early detection of worsening airflow obstruction, which may be of particular value in a subset of "poor perceivers." Such poor perceivers are individuals who have a blunted respiratory symptom recognition despite an objective decline in lung function. PEF monitoring has some value in risk stratification. Excessive diurnal variation and a morning dip of PEF imply poor control and a need for careful reevaluation of the management plan. PEF alone is never appropriate; rather, PEF should be part of a comprehensive patient education program.

Asthma therapy is covered in Part 2 of this chapter.

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