Although much progress has been made in our understanding of bronchial asthma over the past decade, asthma

remains a frequently encountered condition challenging physicians in the office setting as well as in acute care settings.1,2,3 Although the 1980s were characterized by increases in asthma morbidity and mortality, the most recent data indicate a plateauing of these trends occurred in the 1990s, and that asthma mortality rates have declined from 1998-2002.4 In recent decades, a surge in asthma prevalence also occurred in the United States and other "Western" countries; whether this trend is also plateauing is unclear. Tremendous progress has been made in the 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 etiology of airway inflammation remains obscure. The knowledge that asthma is an inflammatory disorder has become fundamental to our definition of asthma, beyond a simple bronchospastic disorder worthy of bronchodilators alone. In fact, the past decade has been characterized by a proliferation of expert practice guidelines, all with a goal of disseminating scientific knowledge to the practicing clinician with a goal of widespread implementation 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 the recommended therapies. In this context, there have been many advancements in the available 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, many controversies abound, and further fundamental developments in novel therapeutics are imminent. 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

DEFINITIONS
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 asthma1,2: 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.

EPIDEMIOLOGY AND NATURAL HISTORY

Several governmental agencies have been charged with surveillance for asthma, including the NHLBI's National Asthma Education and Prevention Program (NAEPP), the Department of Health and Human Services (Healthy

People 2010), and the Centers for Disease Control. 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 asthmaassociated 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 19982002. 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

ETIOLOGY AND PATHOGENESIS

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 TH2 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 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.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 TH1 versus the TH2 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 TH1 paradigm and hence be protected against the allergic diathesis that is characteristic of the TH2 paradigm. In a "cleaner" urban Western society, such early childhood exposure is lacking, and the paradigm therefore shifts closer to the allergic diathesis of TH2, 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 TH1 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- 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 whichconstitutive (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 PGF2 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-nave patients with mild asthma with levels about threefold to fourfold higher than in healthy subjects. The -Agonist Controversy There has been much controversy surrounding the potential role of -agonist preparations in asthma mortality.19 The hypothesis is that excessive or regular use of -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 -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 -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 2receptor 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 asthmarelated 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 ondemand 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 metaanalysis of pooled results from 22 randomized, placebo-controlled trials that studied at least one week of regularly administered 2-agonist in patients with asthma compared to a placebo group (that did not permit "as-needed" 2 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 2-agonists. Pharmacogenetics Polymorphisms of the gene for the 2-adrenergic receptor (AR) may be important in determining the clinical response to beta-agonists. For the 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 2AR 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 2AR 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 2AR knock-out as well as overexpression of 2AR has suggested an alternative molecular mechanism for the effects of chronic exposure to -agonists and effects on airway bronchodilator response. Interestingly and unexpectedly, the mice with absent 2AR had markedly reduced bronchoconstrictive response to methacholine. The

overexpressors of 2AR who had continuous 2AR signaling activity demonstrated an enhanced constrictive response. In addition, the overexpressors showed increased expression of a phospholipase C 1 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 -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.

DIAGNOSTIC EVALUATION, COMORBID DISEASE, AND PEAK EXPIRATORY FLOW MONITORING

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 hyperventilationother approaches that require complex equipmenthave 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.

General Concepts Regarding Guidelines:

There are many organizational and social barriers to optimal asthma care. Studies suggest that a small subset of patients utilizes 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; Programs for asthma patient education; Longitudinal outpatient follow-up care 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 include the dissemination of clinical practice guidelines, disease state management, and case management.29 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 and save money. This approach relies heavily on information technology to identify patients, monitor care, and assess outcomes and costs. Asthma is thought to be an ideal disease for the disease management approach because: 1) it is a chronic disease suitable for self-management and patient education; 2) it is a disease that can be managed largely on an outpatient basis, thus avoiding costly inpatient care; 3) there is a consensus on what constitutes optimal care, and; 4) optimal care can reduce morbidity and costs and improve outcomes. Many studies have proposed formal interventions that can reduce costs and improve outcomes. There are many limitations to the published asthma disease management studies. These studies typically have a pre- and post-study design, usually with no control group. The choice of outcome measures varies. Many interventions are often performed at the same time and it is difficult to tease out the essential components of a program. They often use proprietary data systems and algorithms that make reproducing the studies difficult. There are many other design limitations, including control of cofactors such as severity, season, and so forth.

Practice Guidelines:
Guidelines for medical practice are being disseminated with increasing frequency for a variety of diseases. The overall goal of practice guidelines is to improve the quality of care while reducing inappropriate care and helping to control rising costs. These guidelines are of interest to many groups including specialty medical societies, state and federal government, insurers and managed care organizations, commercial enterprises, and hospitals. There are several methods used to develop practice guidelines including informal consensus development, formal consensus development, evidence-based guideline development, and explicit guideline development.30 Informal consensus development, which is based largely on expert opinion with some general support from the literature, is the strategy most frequently used, as in the asthma practice guidelines (discussed below). Several possible mechanisms by which practice guidelines may improve patient care have been described: improve clinician knowledge; affect clinician attitudes to agree with and accept the guidelines as a "new standard of care"; and modify clinician behavior and practice patterns. There is only limited evidence, however, that practice guidelines can achieve favorable clinical outcomes.31 In fact, some data suggest that simply disseminating guidelines may not affect physician behavior or clinical outcomes. Some have advocated additional strategies to include removing disincentives, adding a variety of incentives, and including the guidelines in a broader program that addresses translation and implementation in the local community.

Asthma Practice Guidelines: Expert Panel Report 2:

In 1991, the coordinating committee of NAEPP convened an expert panel along with the NHLBI and developed extensive and detailed guidelines for the diagnosis and management of asthma.1 The EPR 2 was published in 1997.2 Overall, the published guidelines highlight the following: 1) a new appreciation for the significant role of airway inflammation in the pathogenesis of asthma; 2) a change in the emphasis for treatment, to include anti-inflammatory maintenance therapy; 3) a focus on establishing risk factors for the development of asthma and identifying appropriate

programs for control and prevention. The NAEPP guidelines for classifying the severity of asthma are based on two parameters: the frequency of symptoms and the severity of airflow obstruction as assessed by objective measurements such as PEF or a spirogram in the physician's office. By this scheme, there are four levels of asthma severity (Table 1): The NAEPP outlined four goals of therapy for asthma: 1), maintain normal activity level, including exercise; 2) maintain near normal parameters of pulmonary function; 3) prevent chronic and troublesome exacerbations of asthma by maintaining a chronic baseline maintenance therapy; and 4) avoid the toxicity of some of the medications that are 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 would involve some knowledge of the disease, the proper use of medications, the proper metered-dose inhaler technique, and a written crisis plan for managing exacerbations. The second component is the use of a home peak-flow device to monitor disease severity, especially for patients with moderate or severe disease. The third component involves measures to minimize or avoid exposure to known environmental triggers that can exacerbate asthma, including the home environment as well as outdoor exposure. The final component is pharmacotherapy. There are only minor differences between the EPR 2 and the NAEPP 1991 report.1,2 The EPR 2 report classifies patients into four levels of severity: mild intermittent, and mild, moderate, or severe persistent disease. A daily maintenance therapy is suggested for persistent disease. The EPR 2 classifies asthma medications as "long-term controllers" or "quick-relief medications." The medication list is updated to include salmeterol (Serevent), fluticasone (Flovent), and antileukotrienes (all approved since 1991). EPR 2 provides a specific conversion table comparing equipotent doses of the inhaled steroids. The 1997 EPR 2 report places special emphasis on "step-down" therapy after a period of good control. EPR 2 recommends PEF monitoring for moderate and severe asthma, but only once per day (in the morning, pre-bronchodilator). The 2002 Update3 to the NAEPP EPR 2 adds several additional points: 1) Long-term management of asthma in children has been revised with a strong emphasis on using ICs as the preferred agents in mild or moderate persistent asthma. 2) For patients >5 years old with moderate persistent asthma on ICs, addition of long-acting beta agonists improves asthma control and outcomes. 3) Addition of antibiotics is not recommended for acute asthma exacerbation. 4) Written action plans are de-emphasized, as not having shown benefit over medical management alone. In general, we support the concept of expert practice guidelines and widespread dissemination. However, many of the recommendations are not truly "evidence based" (ie, are not supported by randomized controlled trials) and represent an expert opinion. It is important to stress that the differences between the published guidelines are small and the overall consensus is remarkable. These general guidelines were developed to assist the clinician with patient management and treatment decisions. Specific treatment regimens must be tailored to individual patient needs. Also, since asthma research is a rapidly evolving area and new therapeutics are anticipated, these guidelines will be revised periodically. Finally, as controlled studies become available, hopefully expert dogma will be replaced by data.

The Role of Allergy and Allergen Avoidance:

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

asthma symptoms are listed in Table 4. Individuals with asthma are frequently sensitized to more than one allergen. Table 4: Inhalant Allergens Indoor Dust Mites Cockroach Pets (cat, dog, etc) Mold Spores Outdoor Tree Grass Ragweed/Other weeds Mold Spores

Air conditioning can be associated with dramatic reduction in exposures to outdoor pollens and mold spores while indoors. Because we now spend the majority of our time indoors, the utility of air conditioning for improving asthma symptoms should not be underestimated.32 Dust mites are a major source of allergen in house dust. They are microscopic, and rely on heat and humidity to survive and proliferate.33 Allergy to dust mites is common in patients with asthma. Recommended avoidance measures to reduce exposures to dust mite allergen include: encasement of mattress/box spring and pillows in impermeable covers, reducing indoor relative humidity, washing bedding weekly in hot cycle (130F) and if possible removal of carpets in favor of tiled or hardwood flooring.33 For individuals allergic to cat or dog dander who are pet owners, no avoidance strategy can rival the benefit that will occur with elimination of the pet from the home. If a cat or dog is removed from the home, however, the allergen may persist for several months. For this reason, clinical benefit cannot be expected promptly.34 When elimination of pets from the home is not possible, second best measures include restricting the pet from the bedroom, use of high efficiency particulate or electrostatic air cleaners, and removal of carpets and other furnishings which otherwise serve as an allergen reservoir. Washing the cat or dog, if recommended as an avoidance strategy, needs to be carried out frequentlyat least twice a week.35 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.36-38 Allergen immunotherapy entails the incremental administration of inhalant allergens for the purpose of inducing immune system changes in host response with natural exposure to these allergens. Numerous studies carried out during the past 5 decades have shown statistically and clinically significant dose-dependent benefit with administration of allergen immunotherapy in properly selected patients with asthma.37 Recent studies demonstrate that immunotherapy can inhibit late-phase response and appears to work through induction of T-cell tolerance36-38; in contrast to medication which affects only symptoms, immunotherapy can favorably impact upon the disease process that underlies asthma symptoms. The therapeutic utility of inhalant allergen immunotherapy has also been supported by findings of a meta-analysis of randomized, double-blinded studies of allergen immunotherapy for asthma reported by Abramson and colleagues39, in which statistically significant benefit was reported as manifested in reduced asthma symptoms, diminished medication reliance, and improvements in specific and non-specific bronchial hyperresponsiveness. Although there is a tendency in this and other areas of the asthma literature to overestimate effect size because of a well-recognized reporting bias (eg, negative studies tend to not get published), the authors calculated that 33 negative studies would need to be published to overturn their findings. 39 Seven to ten million immunotherapy injections are administered annually in the United States. Because systemic reactions are not uncommon, immunotherapy should only be given in a setting in which adequate precautions are taken and life-threatening anaphylaxis can be treated.37 The decision to begin allergen immunotherapy should be individualized, and based on symptom severity, relative benefit with pharmacotherapy, and whether co-morbid conditions such as beta-blocker use40 are present which increase risk for (serious) anaphylaxisthe major risk of

allergen immunotherapy.

Aspirin Intolerance and Desensitization:

Aspirin (ASA) and non-steroidal anti-inflammatory drugs can provoke bronchospasm (with/without nasal-ocular congestion or flushing) in a subgroup of asthmatic patients.41 In ASA sensitive asthmatics, potentially serious bronchospastic reaction occurs up to several hours after exposure to ASA or an ASA-like drug; even a sub-therapeutic dosage of ASA in this setting can lead to potentially life-threatening bronchospasm.41 ASA and non-steroidal antiinflammatory drugs, including ibuprofen, naproxen, sulindac, indomethacin, etodolac, etc., share the action of inhibition of cycloxygenase COX-1 and COX-2 and are 100% cross-reactive in ASA sensitive asthmatic patients. In ASA sensitive asthmatics, cross reaction may also occur with higher doses of salsalate42 or acetaminophen,43 which are weak inhibitors of COX-1 and COX-2. Selective inhibitors of COX-2, rofecoxib, valdecoxib, and celecoxib, do not cross-react with ASA and can be tolerated without bronchospastic reaction.44,45 Studies carried out in the last decade have shown that COX inhibition downregulates the enzyme PGE2, leading in turn to excessive production of sulfidopeptide leukotrienes (LTC4, LTD4, and LTE4). These mediators, formerly known as slow reacting substance of anaphylaxis (SRS-A), not only participate in acute bronchospastic reaction provoked by ASA ingestion but also contribute to the ongoing airways obstruction and inflammation that persists in ASA-sensitive asthmatic patients despite avoidance of ASA and other COX-inhibiting drugs.41 Administration of anti-leukotriene agents, which either selectively block leukotriene receptors or inhibit leukotriene synthesis by blocking 5-lipoxygenase or its activator, 5-lipoxygenase activating protein (FLAP), are efficacious in management of chronic persistent asthma in patients who are ASA-sensitive. Added benefit has been reported in double-blind placebo-controlled studies in ASA-sensitive asthmatic patients receiving inhaled (and/or oral) corticosteroids treated with montelukast46 or zileuton.47 Anti-leukotriene agents also attenuate bronchospastic reaction provoked by ASA challenge in ASA-sensitive asthmatics.48 For this reason, anti-leukotriene drugs have utility for reducing severity of reaction in patients undergoing desensitization, although bronchospastic reaction is unlikely to be blocked completely.49,50 Biosynthesis of leukotrienes is upregulated in ASA sensitive asthmatics;41,51 a key enzyme, LTC4 synthase, is overexpressed in bronchial mucosa.41 ASA sensitive rhinosinusitis/asthma patients have increased expression of the CysLT1 receptor on inflammatory leukocytes,51 thereby enhancing their ability to respond to leukotrienes. Down regulation of Cys-LT1 receptor expression may explain the mechanism for ASA desensitization.51 Desensitization can be performed for patients who require administration of ASA or ASA-like drug for management of co-occurring conditions, eg, arthritis, thromboembolism, or coronary artery disease. Clinical benefit in patients with ASA sensitive respiratory disease - particularly for polypoid rhinosinusitis - may be expected in 2/3 of patients who are desensitized and then take ASA regularly.52 Improvement includes reduced level of symptoms, lower medication reliance, and less morbidity (as reflected in fewer annual episodes of URI/sinusitis, and reduced rates of sinus surgery procedures). Based on these findings and previous experience with ASA desensitization,41 this intervention can also be considered for patients with corticosteroid-dependency and/or refractory rhinosinusitis who require repeated sinus surgery procedures. Because of potentially serious bronchospastic reaction that may occur during this procedure, desensitization should only be carried out in settings where experienced physicians and appropriate equipment to treat such reactions are present.

Pharmacotherapy:
The pharmacotherapy for asthma, as recommended by current NAEPP guidelines, is summarized in the accompanying Tables 1, 2, 3, and 5. The overall strategy is to use a stepwise approach based on the level of severity. Inhaled beta agonists ("relievers") used on an as-needed basis are recommended for patients with mild intermittent asthma who are asymptomatic between episodes. Patients with persistent asthma, as defined above, 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 beta 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 first-line therapy for all patients with persistent asthmamild, moderate, or severe. Over the past 5 to 10 years, the trend in the use of inhaled steroids has been to use more potent ICs topically at higher doses, especially for the more severe cases. This is predicated on the hypothesis of a dose-response effect for these agents. Although many studies support this hypothesis, there is continued debate and reevaluation of this by inhaled-steroid-sparing approaches, as discussed below. It is well documented that higher doses of ICs facilitate a reduction in systemic corticosteroids in severe asthma. Another trend has been the use of ICs at an earlier stage of asthma. Limited data suggest that earlier addition of ICs might improve the long-term FEV1 by preventing subepithelial fibrosis, although this hypothesis is not universally accepted. Several studies with follow-up over 10 years indicate that ICs do not cure asthma, and cessation of therapy often results in prompt relapse. Some studies suggest that in stable asthmatics less-frequent dosing, such as bid or qd, may be equally effective. Less-frequent dosing has clear-cut benefits in terms of improved compliance. Inhaled steroids are also cost-effective in management of asthma, with an incremental cost-effectiveness ratio for a symptom-free day of approximately $5.00 - $6.00.53 Finally, regular use of inhaled steroids can prevent asthmatic exacerbation,54 increases in bronchial hyperresponsiveness,55 and accelerated loss of lung function.56 A large retrospective case-control study from Canada associated regular use of ICs with statistically significant reduction in rates of mortality.57 Currently, five specific inhaled corticosteroids are approved for maintenance therapy for asthma in the United States.2 The two newest agents include fluticasone and budesonide (Pulmicort Turbuhaler). In general, the more topically potent agents such as fluticasone and budesonide have the advantage of dosing with far fewer puffs per day to accomplish the same clinical benefit. A recent development in chronic asthma maintenance therapy is the concept of combination therapy to produce either additive or synergistic effects. A variety of studies indicate that groups of mild-to-moderate asthmatics who remain symptomatic on low-to-intermediate doses of ICs experience greater benefit from a long-acting inhaled bronchodilator taken in combination with inhaled steroid compared with doubling the dose of inhaled steroid.58,59 A natural extension of this concept has been the development of a new inhaled product that combines fluticasone and salmeterol into a single device. This has recently become available as a diskus device (Advair Diskus) with the medication packaged as a non-chlorofluorocarbon dry-powder preparation. This product is now available in three different steroid dose strengths, Advair 100 g fluticasone/50 g salmeterol (green), 250/50 (yellow), and 500/50 (red). Several pivotal studies indicate that the combination product is superior to the individual components in patients with mild and moderately severe chronic asthma.58 A randomized, controlled trial with Advair 100/50 g, one puff twice a day, markedly improved several outcomes, including FEV1 and the probability of an asthma exacerbation over 12 weeks compared with placebo or each of the individual components separately.58 Several studies have examined the utility of ICs taken in combination with other agents such as theophylline60 and leukotriene antagonists.61 These agents are also a rational alternative, taken in combination with inhaled steroid, to doubling the dose of inhaled steroid, in patients who remain symptomatic on low - intermediate inhaled steroid treatment. The benefits of combination therapy, as measured by symptom scores, prn use of beta agonists, lung function, and exacerbation rates, with these other agents are not as dramatic, however, as with the addition of the long-acting inhaled bronchodilator.62 A study from the Asthma Clinical Research Network of the NHLBI found that monotherapy with salmeterol is not adequate replacement therapy for patients controlled on triamcinolone (Azmacort) 400 g twice per day.63 The exact molecular mechanism whereby the combination of inhaled steroids and long-acting beta agonists synergistically improve asthma control is not fully known. Preliminary data indicate that long-acting beta agonists may facilitate the steroid effect whereas the steroids upregulate the beta-agonist receptors. Preliminary data also do not support the contention that long-acting bronchodilators have a "masking effect" on underlying airway inflammation. The molecular mechanism of action of glucocorticoids (GCs) involves binding to a specific intracellular glucocorticoid receptor (GCR). This binding dissociates heat-shock proteins and creates an active GC-GCR complex. The GC-GCR

complex translocates to the nucleus and binds to specific GCR-responsive elements on genomic DNA that induce specific gene expression (ie, beta-adrenergic receptors). The GC-GCR complex may also suppress gene expression by interfering with the interaction of transcription factors (ie, nuclear factor-kB) with promoter regions of proinflammatory cytokines. Through these mechanisms, GCs inhibit the production of a wide range of cytokines important in asthma. In addition to inhibiting cytokine production, glucocorticoids also inhibit production of inflammatory leukotrienes and eicosanoids through effects on phospholipase A2. In contrast, genes for antiinflammatory or bronchodilatory products (ie, beta 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 a lot of 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 manifest as clinical steroid side effects (i.e., cushingoid effects). Type 1 steroid resistance is acquired and more common. On the other hand, type 2 steroid resistance is due to a generalized lack of steroid responsiveness in the airways and other organ systems on a genetic basis. Patients with type 2 resistance have poor asthma control despite systemic corticosteroids and no systemic steroid side effects. Type 2 steroid resistance is rare. The relative contribution of this concept of steroid resistance in suboptimal asthma control and poor outcomes remains unknown. Patients with such a molecular basis for steroid resistance may be a subset who would benefit from alternative anti-inflammatory approaches. Steroid "phobia," or excess concern over the systemic effects of ICs by both patients and clinicians, remains a practical barrier to wider use of these agents despite several reassuring long-term studies and expert practice guidelines. One landmark study64 randomized 1,041 children from ages 5 through 12 with mild-to-moderate asthma for a study duration of 4 to 6 years into three groups (200 g budesonide bid, 8 mg of nedocromil (Tilade) bid, or placebo). This robust study noted that the asthma clinical outcomes improved most for the budesonide group (fewer hospitalizations, fewer urgent visits, and decreased airway hyperresponsiveness to methacholine). However, there was no significant difference in the degree of change in FEV1 after bronchodilator use between any of the three groups. Long-term budesonide was well tolerated, and even though there was a 1.1 cm smaller increase in height compared with the placebo group during the first year, this reduction in linear growth velocity was absent by the second year, and the projected height in the budesonide-treated group was no different than in the nedocromil or placebo groups. Also, there were no significant differences in bone density or the incidence of cataracts between the three groups. Although a number of other short-term studies have noted a reduction in height and linear growth velocity over 6 to 12 months with ICs, longer-term studies have consistently noted that the final adult height is not influenced by ICs.65 Practical approaches to minimize or eliminate systemic toxicity from ICs include: (1) using the lowest dose needed by proactively stepping down the dose after several months of optimal asthma control; (2) routinely using a spacer extension device (if metered-dose inhalers are used) or a dry-powder device and rinse the oropharynx after each use; and (3) adding a long-acting beta agonist or, more simply, using a combination IC and long-acting beta-agonist inhaler to facilitate a reduction of IC for a steroid-sparing effect. Antileukotrienes The sulfidopeptide or cysteinyl leukotrienes (LTC4, LTD4, and LTE4), formerly known as the "slow-reacting substance of anaphylaxis," are formed by the lipoxygenation of arachidonic acid by the enzyme 5-lipoxygenase. These compounds, released by mast cells and eosinophils and airway epithelial cells, have a variety of potent effects including bronchoconstriction, increased permeability, and enhanced airway reactivity. Data over the past 10 years suggest that the cysteinyl leukotrienes are involved in the pathogenesis of chronic human asthma, and these data satisfy Koch's postulates which represent a series of experimental observations that establishes cause and effect in biologic phenomena. Leukotrienes can be recovered from nasal secretions, bronchoalveolar lavage fluid, and urine of patients with asthma. Potent leukotriene antagonists inhibit asthmatic responses to allergens, exercise, cold dry air, and aspirin. Finally, placebo-controlled clinical trials have shown salutary effects in asthmatics treated with antileukotriene drugs. Within the past few years, three agents that antagonize the leukotriene pathway have been approved by the FDA for

use as maintenance therapy for mild persistent asthma. Zafirlukast and montelukast studies will be reviewed, and zileuton will be omitted since this agent is rarely used. Zafirlukast (Accolate) is a selective, competitive receptor antagonist at the LTD4 and LTE4 level. Three US doubleblind, randomized, placebo-controlled, 13-week studies in 1,380 patients with mild to moderate asthma have shown that treatment with zafirlukast improves daytime asthma symptoms, nighttime awakenings, mornings with asthma symptoms, rescue albuterol use, FEV1, and morning PEF.66 Zafirlukast is administered as 20 mg bid and is well absorbed. It should be given on an empty stomach; otherwise, drug levels would be reduced by 40%. At the currently recommended dose, the risk of liver function abnormalities is thought to be quite low. Cases of hepatotoxicity have been described with use of zafirlukast but not montelukast, for which routine monitoring is not felt to be necessary. Churg-Strauss vasculitis (CSS) has been reported in patients receiving anti-leukotriene drugs, in most cases patients with severe asthma who improved and were able to suspend or taper oral corticosteroid developed CSS. 67,68 It appears that rather than a causal association, this likely reflects an unmasking of extrapulmonary features of preexisting CSS with taper of oral steroids following symptomatic improvement on a trial of an anti-leukotriene drug. Moreover, similar cases of CSS have also been reported in association with inhaled cromolyn and more recently with inhaled fluticasone. Montelukast (Singulair) is a specific cysteinyl leukotriene (cysLT, or LTD4) receptor antagonist that received FDA approval in 1998. Preliminary data suggest that montelukast may have several advantages compared with zafirlukast or zileuton (Zyflo). These include ease of dosing (once a day; no significant change in absorption by food) and an absence of significant drug interactions. Early experience shows an excellent safety profile with no effect on the liver function test. Also, the 5-mg, chewable tablets have been used in 6- to 14-year-old, and a 4 mg tablet for 3-5 year old asthmatic children with efficacy and safety. Several published studies indicate that montelukast 10 mg given once daily at bedtime causes significant improvement in chronic mild-to-moderate asthma compared with placebo. 69-71 A 3-month, double-blind, parallel-group study (n = 681 with FEV1 50% to 80%) showed significant improvement in the montelukast group (asthma exacerbation decreased by 31%, asthma-free days increased by 37%).69 Another randomized trial involving adults with moderate-to-severe asthma (n = 226) showed that montelukast 10 mg allowed significant tapering of inhaled steroids in patients requiring moderate-to-high doses.70 A 4-week, controlled trial in 80 aspirin-intolerant adult asthmatics showed that montelukast 10 mg given at bedtime significantly improved asthma control.71 A current scientific controversy surrounding anti-leukotrienes is whether they affect the natural history of asthma and can prevent airway remodeling. Even though these agents affect a single pathway, data from animal models indicate a broader effect on eosinophilia and collagen deposition.72 Whether these findings are relevant to the human disease remains to be determined. The exact place for antileukotrienes in chronic maintenance therapy for asthma remains to be established. The EPR 2 indicates a possible role for these agents in the initial therapy 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 response in 2 to 4 weeks. The magnitude of increase in FEV1 at 4 weeks is about 14% above that of placebo. It is likely that the inhaled steroids have more potent effects, especially in patients with moderate to severe disease. One head-to-head comparative trial clearly indicated that beclomethasone (Qvar, Vanceril, and others) is superior to montelukast.73 The antileukotrienes do facilitate a reduction in the need for inhaled beta agonists and ICs, therefore, risk for untoward effects from these medication exposures. Also, these oral agents may improve compliance compared with the metered-dose inhalers. A subset of patients respond much more dramatically to the antileukotrienes, usually within the first 30 days. If there is no response during this period, it is reasonable to stop these agents. Patients with aspirinexacerbated respiratory disease have been shown to release higher levels of leukotrienes with bronchoprovocation challenge, and exhibit greater end-organ responsiveness to leukotrienes compared with aspirin tolerant asthmatics. On this basis, patients with aspirin-sensitive asthma warrant a trial of anti-leukotriene pharmacotherapy, although the rate of response in this subgroup is similar to rates reported among aspirin tolerant asthmatics. That the data show about the same rate of benefit in ASA sensitive asthmatics compared with ASA tolerant asthmatics is consistent with the hypothesis that it is the balance between PGE2 and PGF2 alpha that is critical in this subgroup. Anti-leukotriene

agents may also attenuate exercise-induced bronchospasm. Anti-IgE Therapy Omalizumab (Xolair), the first selective anti-IgE therapy, is a unique humanized monoclonal anti-IgE antibody that binds with high affinity to the FcRI receptor-binding site on IgE. Omalizumab was approved by the FDA in 2003.74,75 Omalizumab reduces the amount of free IgE available to bind to FcRI receptors on mast cells, basophils, and other cells. This agent is being evaluated as a drug for subcutaneous administration either every 2 or every 4 weeks for allergic asthmatic patients with serum IgE levels in the range of 30 to 700 IU/ml. Experimental studies indicated that weekly therapy with omalizumab attenuated both the early and late asthmatic responses evaluated at days 28 and 56, and the dose of aerosolized allergen required to decrease FEV1 by 15% was increased by 2.7 doubling doses, indicating a decrease in airway reactivity. The initial large placebo-controlled study of 317 patients with moderate to severe perennial allergic asthma who required daily use of inhaled and/or oral corticosteroids was conducted in subjects ages 11 to 50 for 20 weeks.74 The active-treatment arm included two different doses of intravenously administered omalizumab (2.5 mg/kg/ng IgE/mL) or a high dose (5.8 mg/kg/ng IgE/mL). At 12 weeks, there was a 50% improvement in asthma symptom scores in one-half of the patients treated with either dose of omalizumab compared with 24% of patients in the placebo group. A 50% or greater reduction in dose of oral corticosteroids was reported in 78% of subjects in the high-dose group and 57% of those in the low-dose group versus 33% of subjects in the placebo group (P = 0.04). More than one third of the subjects in the omalizumab groups were able to discontinue oral corticosteroids. One fifth of the subjects taking ICs for control of asthma symptoms were able to completely discontinue steroid use after being treated with omalizumab. During the 20-week study period, 45% of patients receiving placebo reported an exacerbation, compared with only 28% of patients in the low-dose group and 30% of patients in the high-dose group. Finally, asthma-specific quality of life questionnaire scores also improved significantly for the active-treatment group.

EXPERIMENTAL THERAPIES
With our current paradigm of asthma, the mainstays of therapy include maintenance therapy with ICs for mild persistent asthma, and combination therapy using inhaled long-acting beta agonists, oral leukotriene antagonists, oral theophylline, inhaled cromolyn/nedocromil, oral long-acting beta agonists, along with short-acting inhaled beta agonists as "relievers" to be taken on a prn basis. 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, there are a number of limitations to these approaches that warrant continued development of new therapeutics: 1) Poor adherence with inhaled devices may contribute to poor asthma outcomes. 2) Despite evidence to the contrary, patients, parents, and clinicians have lingering questions about the long-term safety of ICs. 3) There are insufficient data for the concept that chronic long-term therapy with the existing agents, including corticosteroids, has a diseasemodifying effect or an effect that prevents airway remodeling. 4) A small subset of patients have inadequately treated asthma despite maximal doses of inhaled corticosteroids, and these patients likely have some form of relative steroid resistance. 5) The older nonspecific, systemic, alternative anti-inflammatory agents (methotrexate, gold, cyclosporin) have significant and unacceptable side effects.76 For these reasons, the pharmaceutical industry and various investigators have been aggressively pursuing novel therapies for asthma. Anticytokine Therapies As previously discussed, 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.77,78 Although the animal studies had been very promising, an important study using intravenous humanized monoclonal antibody to IL-5 (SB-240563) at doses of 2.5 mg/kg or 10 mg/kg was disappointing in a double-blind, placebo-controlled trial using an inhaled allergen-challenge model.77 Even though a single intravenous dose of anti-IL5 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. This study raises serious questions about the relative importance of the eosinophil in mediating human asthma, contrary to prior animal studies. Several studies with an inhaled soluble IL-4 receptor antagonist, altrakincept (Nuvance) found modest benefit, but

further development was discontinued by the manufacturer. In a placebo-controlled, parallel-group study of 62 moderate-persistent asthmatics dependent on moderate doses of ICs, subjects were randomized to placebo or three different doses of IL-4R by once-weekly nebulization for 12 weeks.78 There were modest improvements in symptom scores and FEV1 in the highest-dose group, but the asthma exacerbation rate was not significantly different than in the placebo group. An IL-13 antagonist has also shown promise in a primate model of asthma, and clinical studies are being initiated in human patients. Novel Steroids Steroids, either systemic or inhaled, are exquisitely active and effective in asthma, but their mechanism of action is very broad, and concern for toxicity even with topical steroids has limited their wider use. A variety of approaches are being pursued to maximize local activity within the airways and at the same time to minimize systemic absorption and toxicity.79 These approaches include the following: 1) development of "on-site-activated steroids" such as ciclesonide, which is a nonhalogenated inhaled steroid prodrug that requires endogenous cleavage by esterases for activity; 2) development of "soft steroids," which have improved local, topical selectivity and have much less steroid effect outside the target area; these agents may be inactivated by esterases or other enzymes, for example a lactoneglucocorticosteroid conjugate; and 3) "dissociated steroids," or agents that favor monomeric glucocorticoid receptor complexes (produce "transrepression") and avoid dimerization or "transactivation," which is undesirable in asthma. Agents from each of these categories are undergoing clinical trials.

SUMMARY
Further progress in asthma care will require better understanding of the molecular and genetic basis for the clinical heterogeneity seen in this disorder. The relation between acute and chronic inflammation as well as airway hyperresponsiveness and airway remodeling is still unclear. Research in exhaled noninvasive markers of inflammation may eventually be translated into a practical and clinically useful tool. The availability of such a tool would be essential to more precisely titrate anti-inflammatory therapy. Further development of pharmacogenetics may identify subsets of patients who may preferentially respond to one class of anti-inflammatory agents as opposed to others, eliminating some of the trial and error that often occurs in clinical medicine. Clear identification of when asthma truly begins in childhood and the concept of early intervention may allow modification of the subsequent natural history of the disease. Finally, the specific pharmacotherapeutic approaches to block unique pathways offer hope for major new advances in the next 5 to 10 years. Return to Medicine Index

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26. Martin AJ, McLennan LA, Landau LI, et al. The natural history of childhood asthma to adult life. Br Med J.
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27. Mountain RD, Sahn SA. Clinical features and outcome in patients with acute asthma presenting with
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28. Jain P, Kavuru MS, Emerman C, Ahmad M. Utility of peak expiratory flow monitoring in asthma. Chest.
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29. Lomas J, Anderson GM, Domnick-Pierre K, et al. Do practice guidelines guide practice? N Engl J Med.
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30. Tarlov AR, Ware JE, Greenfield S, Nelson EC, Perrin E, Zubkoff M. The medical outcomes study: an
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31. Woolf SH. Practice guidelines: a new reality in medicine; part III: Impact on patient care. Arch Intern Med.
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32. Samet JM, Marbury MC, Spengler JD. Health effects and sources of indoor air pollution. Part I. Am Rev Resp
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33. Arlian LG, Platts-Mills TA. The biology of dust mites and the remediation of mite allergens in allergic disease.
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34. Wood RA, Chapman MD, Adkinson NF Jr, Eggleston PA. The effect of cat removal on allergen content in
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35. Hodson T, Custovic A, Simpson A, Chapman M, Woodcock A, Green R. Washing the dog reduces allergen
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36. Platts-Mills TA. Allergen-specific treatment for asthma. Am Rev Resp Dis. 1993;148:553-555. 37. Allergen immunotherapy: a practice parameter. American Academy of Allergy, Asthma and Immunology.
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38. Durham SR, Walker SM, Varga EM, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J
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39. Abramson MJ, Puy RM, Weiner JM. Is allergen immunotherapy effective in asthma? A meta-analysis of

randomized controlled trials. Am J Respir Crit Care Med. 1995;151:969-74.

40. Lang DM. Anaphylactoid and anaphylactic reactions: Hazards of beta-blockers. Drug Saf. 1995;12(5):299304.

41. Szczeklik A, Stevenson DD. Aspirin-induced asthma: Advances in pathogenesis, diagnosis, and
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42. Stevenson DD, Hougham AJ, Schrank PJ, Goldlust MB, Wilson RR. Salsalate cross-sensitivity in aspirinsensitive patients with asthma. J Allergy Clin Immunol. 1990;86:749-58.

43. Settipane R, Stevenson D. Cross sensitivity with acetaminophen in aspirin sensitive subjects with asthma. J
Allergy Clin Immunol. 1989;84:26-33.

44. Stevenson DD, Simon RA. Lack of cross-reactivity between rofecoxib and aspirin in aspirin-sensitive patients
with asthma. J Allergy Clin Immunol. 2001;108:47-51.

45. Dahlen B, Szczeklik A, Murray JJ; Celecoxib in Aspirin-Intolerant Asthma Study Group. Celecoxib in patients
with asthma and aspirin intolerance. N Engl J Med. 2001;344:142.

46. Dahlen SE, Malmstrom K, Nizankowska E, et al. Improvement of aspirin-tolerant asthma by montelukast, a
leukotriene antagonist. Am J Resp Crit Care Med. 2002;165:9-14.

47. Dahlen B, Nizankowska E, Szczeklik A. Benefits from adding the 5-lipoxygenase inhibitor zileuton to
conventional therapy in aspirin intolerant asthmatics. Am J Resp Crit Care Med. 1998;157:1187-94.

48. Lang DM. Anti-Leukotriene agents and Aspirin-sensitive asthma - Are we removing the second bassoonist or
skating to where the puck is gonna be? Ann Allergy Asthma Immunol. 2000;85:5-8.

49. Stevenson DD, Simon RA, Mathison DA, Christiansen SC. Montelukast is only partially effective in inhibiting
aspirin responses in aspirin sensitive asthmatics. Ann Allergy Asthma Immunol. 2000;85:477-82.

50. Pauls JD, Simon RA, Daffern PJ, Stevenson DD. Lack of effect of the 5-lipoxygenase inhibitor zileuton in
blocking oral aspirin challenges in aspirin sensitive asthmatics. Ann Allergy Asthma Immunol. 85: 40; 2000.

51. Sousa AR, Parkih A, Scadding G, Corrigan CJ, Lee TH. Leukotriene-receptor expression in nasal mucosal
inflammatory cells in aspirin sensitive rhinosinusitis. N Engl J Med. 2002;347:1493-9.

52. Berges-Gimeno MP, Simon RA, Stevenson DD. Long-term treatment with aspirin desensitization in asthmatic
patients with aspirin exacerbated respiratory disease. J Allergy Clin Immunol. 2003;111:180-6.

53. Rutten-van Molken MP, Feenstra TL. The burden of asthma and chronic obstructive pulmonary disease: Data
from the Netherlands. Pharmacoeconomics. 2001;19 Suppl 2:1-6.

54. Juniper EF, Kline PA, Vanzieleghem MA, Ramsdale EH, O'Byrne PM, Hargreave FE. Effect of long-term
treatment with an inhaled corticosteroid (budesonide) on airway responsiveness and clinical asthma in nonsteroid dependent asthmatics. Am Rev Respir Dis. 1990;142:832-836.

55. Haahtela T, Jarvinen M, Kava T, et al. Comparison of a b2-agonist, terbutaline, with an inhaled corticosteroid,

budesonide, in newly detected asthma. N Engl J Med. 1991;325:388-392.

56. Dompeling E, van Schayck CP, van Grunsven PM, et al. Slowing the deterioration of asthma and chronic
obstructive pulmonary disease observed during bronchodilator therapy by adding inhaled corticosteroids: a 4year prospective study. Ann Intern Med. 1993;118:770-778.

57. Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B.

Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med. 2000;343:332-336.

58. Kavuru M, Melamed J, Gross G, et al. Salmeterol and fluticasone propionate combined in a new powder
inhalation device for the treatment of asthma: A randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2000;105:1108-1116.

59. Pauwels R, Lofdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations in
asthma: Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med. 1997;337:1405-1411.

60. Evans DJ, Taylor DA, Zetterstrom O, Chung KF, O'Connor BJ, Barnes PJ. A comparison of low-dose inhaled
budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med. 1997;337:1412-1418.

61. Laviolette M, Malmstrom K, Lu S, et al. Montelukast added to inhaled beclomethasone in treatment of asthma.
Am J Respir Crit Care Med. 1999;160:1862-1868.

62. Nelson H, Busse WW, Kerwin E, et al. Fluticasone propionate/salmeterol combination provides more effective
asthma control than low-dose inhaled corticosteroid plus montelukast. J Allergy Clin Immunol. 2000;106:10881095.

63. Lazarus SC, Boushey HA, Fahy JV, et al. Long-acting beta2-agonist monotherapy vs. continued therapy with
inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial. JAMA. 2001;285(20):2583-2593.

64. Szefler S, Weiss S, Tonascia J, et al. Long-term effects of budesonide or nedocromil in children with asthma.
The CAMP Research Group. N Engl J Med. 2000;343:1054-1063.

65. Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with
asthma. N Engl J Med. 2000;343:1064-1069.

66. Zafirlukast for asthma. Med Lett Drugs Ther. 1996;38:111-112. 67. Jamaleddine G, Diab K, Tabbarah Z, Tawil A, Arayssi T. Leukotriene antagonists and the Churg-Strauss
syndrome. Semin Arthritis Rheum. 2002;31:218-227.

68. Wechsler ME, Finn D, Gunawardena D, et al. Churg-Strauss syndrome in patients receiving montelukast as
treatment for asthma. Chest. 2000;117:708-713.

69. Reiss TF, Chervinsky P, Dockhorn RJ, Shingo S, Seidenberg B, Edwards TB. Montelukast, a once daily
leukotriene receptor antagonist in the treatment of chronic asthma: a multicenter randomized double-blind trial. Arch Intern Med. 1998;158:1213-1220.

70. Leff JA, Israel E, Noonan MJ, et al. Montelukast (MK-0476) allows tapering of inhaled corticosteroids in
asthmatic patients while maintaining clinical stability (abstract). Am J Respir Crit Care Med. 1997;155:A976.

71. Dahlen B, Nizankowska E, Szczeklik A, et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to
conventional therapy in aspirin-intolerant asthmatics. Am J Respir Crit Care Med. 1998;157:1187-1194.

72. Henderson WR Jr, Tang LO, Chu SJ, et al. A role for cysteinyl leukotrienes in airway remodeling in a mouse
asthma model. Am J Respir Crit Care Med. 2002;165:108-116.

73. Malmstrom K, Rodriguez-Gomez G, Guerra J, et al. Oral montelukast, inhaled beclomethasone, and placebo
for chronic asthma. Ann Intern Med. 1999;130:487-495.

74. Milgrom H, Fick RB, Su JQ, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. N Engl J
Med. 1999;341:1966-1973.

75. Soler M, Matz J, Townley R, et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid
requirement in allergic asthmatics. Eur Respir J. 2001;18(2):254-261.

76. Erzurum SC, Leff JA, Cochran JE, et al. Lack of benefit of methotrexate in severe, steroid-dependent asthma.
A double-blind, placebo-controlled study. Ann Intern Med. 1991;114:353-360.

77. Leckie MJ, ten Brinkei A, Kahn J, et al. Effects of an interleukin-5 blocking monoclonal antibody on
eosinophils, airway hyperresponsiveness, and the late asthmatic response. Lancet. 2000;356:2144-2148.

78. Borish LC, Nelson HS, Corren J, et al. Efficacy of soluble IL-4 receptor for the treatment of adults with
asthma. J Allergy Clin Immunol. 2001;107:963-970. 79. Dahl R, Nielsen LP. Steroids: an overview. In: Hansel TT, Barnes PJ (eds): New Drugs for Asthma, Allergy, and COPD. Karger, Basel, 2001, p. 86-90.

KETERANGAN DARI MAKALAH 2. OCREEE

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Natural History of Asthma. Reproduced from Holgate ST. The cellular and mediator basis of asthma in relation to natural history. Lancet 1997;350(suppl 2):5-9. Reprinted in Szefler SJ. The natural history of asthma and early intervention. .J Allergy Clin Immunol 2002;109:S550. Figure 1
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Schematic showing airway inflammation in patients with asthma. Reproduced from Spahn J, Covar R, Stempel DA. Asthma: addressing consistency in results from basic science, clinical trials, and observational experience. J Allergy Clin Immunol 2002;109:S492. Figure 2

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Clinical consequences of airway remodeling in asthma. RBM = respiratory bronchiolar mucosa; ECM = extracellular mucosa Reproduced from Bousquet J, et al.11 Figure 3

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Links between pathologic mechanisms and clinical consequences in asthma. Reproduced from Bousquet J, et al.11 Figure 4

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Mechanisms of acute and chronic inflammation in asthma and remodeling processes. Reproduced from Bousquet J, et al.11 Figure 5 Table 1: Stepwise Approach for Managing Asthma in Adults and Children Older Than 5 Years of Age: Treatment Classify Severity: Medications Required to Maintain Clinical Features Before Treatment or Adequate Control Long-Term Control Symptoms/Day Symptoms/Night PEF or FEV1 PEF Variability

Daily Medications

Preferred Treatment Step 4 Severe Persistent

High-dose inhaled corticosteroids AND Long-Acting beta2-agonists AND, if needed, Corticosteroid tablets or syrup long term (2 mg/kg/day, generally do not exceed 60 mg per day). (Make repeat attempts to reduce systemic corticosteroids and maintain control with high-dose inhaled corticosteroids.)

Continual Frequent

< 60% > 30%

Step 3 Moderate Persistent

Daily > 1 night/week

> 60% - <80% Preferred Treatment Low-to-medium dose inhaled > 30% Alternative Treatment

corticosteroids and long-acting beta2agonists. Increase inhaled corticosteroids within medium-dose range OR Low-to-medium dose inhaled corticosteroids and either leukotriene modifier or theophylline.

If needed (particularly in patients with recurring severe exacerbations):

Preferred Treatment
Increase inhaled corticosteroids within medium-dose range and add long-acting beta2-agonists.

Alternative Treatment
Increase inhaled corticosteroids within medium-dose range and add either leukotriene modifier or theophylline.

Step 2 Mild Persistent > 2/week but < 1x/day > 2 nights/month > 80% 20 - 30%

Preferred Treatment
Low-dose inhaled corticosteroids

Alternative Treatment (listed alphabetically): cromolyn, leukotriene

modifier, nedocromil, OR sustained release theophylline to serum concentration of 5-15 g/mL.

No daily medication needed.

Step 1 Mild Intermittent

< 2 days/week < 2 nights/month

> 80% < 20%

Severe exacerbations may occur, separated by long periods of normal long function and no symptoms. A course of systemic corticosteroids is recommended.

Quick Relief All Patients

Short-acting bronchodilator: 2-4 puffs short-acting beta2-agonists as needed for symptoms. Intensity of treatment will depend on severity of exacerbation; up to 3 treatments at 20-minute intervals or a single nebulizer treatment as needed. Course of systemic corticosteroids may be needed. Use of short-acting beta2-agonists > 2 times a week in intermittent asthma (daily, or increasing use in persistent asthma) may indicate the need to initiate (increase) long-term control therapy.

Step down Review treatment every 1 to 6 months; a gradual stepwise reduction in treatment may be possible. Step up If control is not maintained, consider step up. First, review patient medication technique, adherence, and environmental control.

Note The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs. Classify severity: assign patient to most severe step in which any feature occurs (PEF is % of personal best; FEV1 is % predicted). Gain control as quickly as possible (consider a short course of systemic corticosteroids); then step down to the least medication necessary to maintain control. Provide education on self-management and controlling environmental factors that make asthma worse (eg, allergens and irritants). Refer to an asthma specialist if there are difficulties controlling asthma or if step 4 care is required. Referral may be considered if step 3 care is required.

Goals of Therapy: Asthma Control Minimal or no Maintain (near)

chronic symptoms day or night Minimal or no exacerbations No limitations on activities; no school/work missed

normal pulmonary function Minimal use of short-acting inhaled beta2agonist (< 1x per day, < 1 canister/month Minimal or no adverse effects from medication

Keterangan dari : Baca Yang teliti pastiu ketemu, kalau pusing gak usah dimasukin ya NES . ocreee VENOUS THROMBOEMBOLISM
Deep vein thrombosis (DVT) and pulmonary embolism represent different manifestations of the same clinical entity, which is referred to as venous thromboembolism. In patients with this condition, venous thrombosis occurs when red blood cells, fibrin, and to a lesser extent platelets and leukocytes form a mass within an intact cardiovascular system. A proximal DVT in the leg is one that is located within the popliteal, femoral (including the superficial femoral), or iliac veins. A pulmonary embolism occurs when a segment of a thrombus within the deep venous system detaches from the vessel, travels to the lungs, and lodges within the pulmonary arteries. The pelvic and deep veins of the lower extremities are the source of more than 70% of all pulmonary emboli.1 The superior vena cava, upper extremity veins, and right chambers of the heart are less common sources.

INCIDENCE
It is difficult to determine the incidence of venous thromboembolic disease. Clinical signs and symptoms are nonspecific, and screening tests are not always sensitive enough to detect disease in asymptomatic patients. According to population studies, the overall age- and sex-adjusted annual incidence of venous thromboembolic disease is 1 to 2 per 1,000 people.2,3 More than one-third of these cases represent recurrent disease.2 Extrapolation of these data suggests that more than 250,000 cases of venous thromboembolism are diagnosed annually in the United States. At least 50,000 of these cases are fatal, although available autopsy data suggest that this figure is probably a significant underestimation of actual mortality.

PATHOPHYSIOLOGY
Deep Vein Thrombosis Venous thrombi typically develop within a deep vein at a site of vascular trauma and in areas of sluggish blood flow (eg, in the venous sinuses of the calf and within a valve cusp). An accumulation of fibrin and platelets causes rapid growth in the direction of the blood flow, potentially reducing venous return. Endogenous fibrinolysis results in a partial or complete resolution of the thrombus. Residual thrombus will organize and the vein may incompletely recanalize, which often results in narrowing of the lumen and valvular incompetency. An extensive collateral network can develop. Pulmonary Embolism Thrombi that embolize to the lungs will lodge within either the lobar arteries or the distal main pulmonary artery;

occasionally they will straddle the pulmonary artery bifurcation (saddle embolus). Smaller thrombi can travel more distally. A pulmonary embolism causes several physiologic changes. Stimulation of irritant receptors causes alveolar hyperventilation, which increases the respiratory rate. Gas exchange becomes impaired because the affected lung tissue is ventilated but not perfused. Initially, this alveolar "dead space," and later the development of intrapulmonary shunting, causes bronchoconstriction and hypoxemia. Atelectasis and edema caused by the loss of alveolar surfactant can develop within hours. A decrease in the cross-sectional area of the pulmonary arterial bed, hypoxia, and the release of humoral factors by activated platelets (eg, serotonin and thromboxane) increase pulmonary vascular resistance. Even so, an acute embolic event in a healthy individual will not generate a mean pulmonary artery pressure greater than 40 mm Hg.4 Pulmonary hypertension can result in right ventricular failure and, infrequently, decrease cardiac output. The severity of hemodynamic compromise, and hence symptoms, is dependent on the extent of arterial obstruction and the presence or absence of pre-existing cardiopulmonary disease.

ETIOLOGY
More than 150 years ago, German pathologist Rudolf Virchow identified a triad of factors-stasis, endothelial injury, and alterations in blood coagulability-that predispose an individual to the development of thrombosis (Table 1). His finding is still valid today. Thrombophilia (the tendency to develop thrombosis) can be inherited, acquired, or both. Prior to 1993, a heritable cause of thrombophilia was identified in fewer than 20% of affected patients. However, since the discovery of factor V Leiden (Arg506Gln mutation) and the prothrombin gene mutation G20210A, this percentage has risen dramatically. Still, many cases of venous thromboembolism remain idiopathic. Extensive testing for the presence of a thrombophilic state can be quite costly. Screening should be reserved for patients who sustain their first event prior to 50 years of age, have a history of recurrent events, or who have a first-degree relative with a venous thromboembolic event that also occurred prior to the age of 50.5

SIGNS AND SYMPTOMS

Deep Vein Thrombosis The typical symptoms of DVT include leg pain, edema, erythema, and warmth in the affected area. Physical examination might also reveal distention of collateral veins and a palpable cord if there is an associated superficial vein thrombosis. Homans's sign (calf pain upon sudden dorsiflexion of the foot) and Lowenberg's sign (calf pain in response to lower pressure than expected upon inflation of a sphygmomanometer cuff) are insensitive and nonspecific findings.6 Using a clinical model in a symptomatic patient can help the clinician estimate the probability that DVT is present.7 However, it is still necessary to perform an objective test because similar findings can be seen in patients with a musculoskeletal disorder (eg, a muscle or tendon tear, muscle strain, or knee injury), edema due to inactivity, a lymphatic disorder, venous reflux, Baker's cyst, or cellulitis.8 Moreover, objective testing should be performed on patients in whom there is a high clinical suspicion because DVT is often asymptomatic. Pulmonary Embolism Pulmonary embolism is also characterized by a constellation of nonspecific signs and symptoms that are associated with other diseases (Table 2). The most common symptoms in individuals without preexisting cardiopulmonary disease are dyspnea, pleuritic chest pain, cough, leg edema, leg pain, hemoptysis, and palpitations.9 The most common findings on physical examination are tachypnea, rales (crackles), tachycardia, a fourth heart sound, accentuation of the second heart sound (closure of the pulmonic valve), DVT, and diaphoresis.9 Nearly 50% of patients with DVT have an asymptomatic pulmonary embolism at the time of their diagnosis.10 Table 2: Differential Diagnosis of Pulmonary Embolism Exacerbation of Angina chronic obstructive Anxiety pulmonary disease Aortic dissection Malignancy Asthma Musculoskeletal pain Congestive heart Pericarditis failure Pneumonia Costochondritis Pneumothorax Esophageal spasm Rib fracture

DIAGNOSIS

Deep Vein Thrombosis:

D-dimers D-dimers are formed when plasmin degrades cross-linked fibrin. They can be measured by enzyme-linked immunosorbent assay (ELISA), a whole-blood agglutination test (eg, SimpliRED), or a latex agglutination test. Elevated levels of D-dimers are found in nearly all patients with venous thromboembolic disease as well as in patients with active cardiopulmonary disease or malignancy and in those who have experienced recent surgery or trauma. Therefore, D-dimer measurement is most useful in excluding a diagnosis of venous thromboembolic disease. In patients who are clinically suspected of having DVT, a D-dimer level of less than 500 ng/mL on ELISA testing has a negative predictive value of 95%.11 Duplex Ultrasonography Duplex ultrasonography combines two modalities: B-mode imaging (brightness modulation) and color Doppler techniques (Figure 1). It is used to detect the presence of intraluminal echoes (the visual representation of a thrombus) and to assess blood-flow characteristics (including its presence, direction, and variation with respiration). In a symptomatic patient, an inability to fully compress a vein and thereby obliterate its lumen is a clear sign (> 95% sensitivity and specificity) of proximal DVT.12 This test is less sensitive for the detection of calf vein thrombosis. The advantages of duplex ultrasonography are its wide availability and its noninvasiveness. Its drawbacks include the fact that it is operator-dependent and can be difficult to perform on obese patients, patients with significant tenderness or edema, and patients whose limbs are in a cast or other immobilizing device. Moreover, duplex ultrasonography cannot always accurately distinguish between an acute and chronic thrombus. Contrast Venography Contrast venography remains the gold standard for diagnosing DVT, but it is rarely used as the initial diagnostic test because of patient discomfort, exposure to contrast material, and limitations of availability. During this procedure, a tourniquet is placed around the limb distally to occlude only the superficial veins. Contrast material is injected into a superficial vein on the dorsum of the foot, and it travels through perforating veins to reach the deep system. An intraluminal filling defect or an abrupt cut-off of contrast is consistent with DVT (Figure 2). Venography is more sensitive than duplex ultrasonography in detecting calf vein thrombosis, and Right common iliac vein with filling defect. it can be used to demonstrate the presence of reflux. Contrast-induced Figure 2 thrombosis can occur. Other Tests Impedance plethysmography uses electrodes placed around the calf to measure changes in blood volume (proximal venous obstruction increases blood volume and decreases electrical impedance). Although this test is highly sensitive and specific for detecting proximal DVT, it has become less popular since duplex ultrasonography has become widely available. Radioactive fibrinogen (I125) has only historical importance since it was withdrawn from the market. A new test (Acutect) is based on 99mTc-apcitide, which binds to glycoprotein IIb/IIIa receptors on activated platelets; because this test requires further validation, it is not widely used. Magnetic resonance venography has a sensitivity and specificity approaching that of contrast venography, but it is cost-prohibitive as a screening test.13

Pulmonary Embolism:
Electrocardiography In patients with pulmonary embolism, the electrocardiogram might be normal or it might reveal sinus tachycardia. In patients with a large embolus, patterns consistent with right heart strain are often seen. Patterns include right-axis deviation, right bundle branch block, P-wave pulmonale, an S1Q3T3 pattern (a prominence of S waves in lead I, Q waves in lead III, and T-wave inversion in lead III), nonspecific ST-T-wave changes, and arrhythmias (Figure 3). Chest Radiography Findings on chest radiographs are also nonspecific. Pleural effusions, atelectasis, elevation of a hemidiaphragm, and

THERAPY

Heparin Heparin is an animal-derived large polysaccharide that binds to endogenous antithrombin. This heparin-antithrombin complex catalyzes the inactivation of several activated coagulation factors, including factor Xa and IIa (thrombin). Heparin can be administered by either intravenous infusion or subcutaneous injection. Its plasma half-life is generally 1 to 2 hours, although the duration lengthens with higher doses. Heparin is primarily cleared from the circulation by the reticuloendothelial system. A baseline complete blood count with platelets and an activated partial thromboplastin time (aPTT) should be documented prior to initiating therapy. Weight-based dosing (an 80 U/kg bolus followed by 18 U/kg/h) is associated with a lower risk of recurrent thromboembolism.17 The appropriate dose is determined by the aPTT value. The target value is 1.5 to 2.5 times the mean control value (which corresponds to 0.3 to 0.6 U/mL on the amidolytic anti-factor Xa assay) and should be checked 6 hours after a dose adjustment. Adverse drug reactions include bleeding, heparin-induced thrombocytopenia, and osteoporosis with prolonged use. Low-Molecular-Weight Heparin (LMWH) A LMWH is a small heparin fragment whose mechanism of action is similar to that of unfractionated heparin. However, LMWH has less nonspecific binding to proteins, which results in a longer plasma half-life (4 h) and a more predictable dose-response relationship. Laboratory monitoring is usually not necessary, but it must be performed with a chromogenic anti-Xa assay (rather than the aPTT measurement) 4 hours after a dose has been given (therapeutic range: 0.6 to 1.0 IU/mL in most laboratories). LMWH is as effective as unfractionated heparin for the treatment of DVT, and it might be associated with a lower risk of bleeding.18 Studies have demonstrated that LMWH is similarly efficacious and safe in treating pulmonary embolism.19,20 In appropriate patients, LMWH can facilitate the outpatient treatment of venous thromboembolic disease because it is administered subcutaneously.21,22 Although the incidence of heparin-induced thrombocytopenia and osteoporosis is lower with LMWH than with unfractionated heparin, caution should be used in obese patients and in those with renal insufficiency because of the renal clearance of LMWH.

Two drugs approved by the Food and Drug Administration (FDA) for the treatment of venous thromboembolism are enoxaparin sodium (Lovenox) and tinzaparin sodium (Innohep). The dose of enoxaparin sodium is 1 mg/kg twice daily, and the dose of tinzaparin sodium is 175 anti-Xa U/kg daily; both are administered subcutaneously. Dalteparin sodium (Fragmin) is FDA-approved only for prophylaxis of DVT. Warfarin Warfarin is an oral drug that inhibits gamma-carboxylation of the vitamin K-dependent coagulation factors II, VII, IX, and X. Although a prolongation of the prothrombin time (PT) can begin in 5 to 7 hours after drug administration due to the short half-life of factor VII, warfarin's ability to fully exert its anticoagulant effect can take as long as 72 hours, which is the half-life of factor II. Warfarin and heparin can be started on the same day, but concomitant administration of these drugs for 4 or 5 days is recommended.23 Warfarin also inhibits carboxylation of natural anticoagulant proteins C and S resulting in a rapid decline of their levels. This poses a theoretical risk for a venous thromboembolic event in patients who have a deficiency of proteins C and S at baseline or who have a hypercoagulable state. Starting the patient on the expected daily dose (eg, 5mg) rather than administering a loading dose can minimize excess anticoagulation (and potential bleeding) and avoid an extreme decline in protein C levels without significantly prolonging hospitalization.24 Historically, the appropriate dose of warfarin was determined by monitoring the PT. The international normalized ratio (INR) was developed in response to the significant variability in thromboplastin reagents. The target INR in the treatment of venous thromboembolic disease is 2.0 to 3.0.25 Higher-intensity anticoagulation is associated with an increase in bleeding. Cytochrome P-450 enzymes in the liver metabolize warfarin. Multiple drug interactions have been reported due to alterations in intestinal absorption, interference with cytochrome P-450 enzyme metabolism, and effect on plasma protein binding. Limiting the use of aspirin, nonsteroidal anti-inflammatory medications, and alcohol is recommended. Patients must also be instructed to avoid consumption of foods that contain a significant amount of vitamin K (eg leafy green vegetables, soybean, green tea, and a wide variety of herbal supplements). Recommendations regarding the duration of therapy are still evolving, although some general guidelines do exist. Therapy should be individualized for each patient according to their personal preference, age, comorbidities, and

OUTCOMES

Thromboprophylaxis is important in decreasing morbidity and mortality in hospitalized patients. Patients who undergo orthopedic surgery, who have a history of venous thromboembolism, or who have one of several medical comorbidities (malignancy, cardiopulmonary, or neurologic disease) have an increased risk of venous thromboembolism. Risk stratification for each patient is necessary to determine the need for and modality of prophylaxis. Mechanical devices (eg, elastic graduated stockings and intermittent pneumatic compression) and chemical regimens (eg, low-dose unfractionated heparin and low-molecular-weight heparin) reduce, but do not eliminate, the risk of venous thromboembolism.30 Many patients who are diagnosed with venous thromboembolic disease recover completely. However, morbidity is associated with two long-term complications: chronic thromboembolic pulmonary hypertension and post-thrombotic syndrome. Chronic pulmonary thromboembolism with pulmonary hypertension is seen in up to 5% of patients as a result of the incomplete resolution of a thrombus.31 These patients are functionally limited because of progressive exertional dyspnea, chest pain, syncope, and lower-extremity edema. Surgical thromboendarterectomy may be considered in patients with hemodynamic compromise, accessible disease, and few comorbid conditions. Post-thrombotic syndrome is characterized by leg pain, edema, other signs of venous insufficiency, and eventually leg ulceration as a result of prolonged venous hypertension. At least 30% of patients with venous thromboembolism develop this chronic debilitating disease.32 The risk of developing post-thrombotic syndrome depends on the speed of vein recanalization and development of ipsilateral recurrent events, but not necessarily the extent of thrombosis. Sized-to-fit compression stockings are the mainstay of therapy, which may decrease the risk of post-thrombotic syndrome by 50%.33 Return to Medicine Index

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