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Although much progress has been made in our understanding of bronchialasthma over the past decade, asthma remains a frequently encounteredcondition challenging physicians in the office setting as well as in acute caresettings.1,2,3Although the 1980s were characterized by increases in asthmamorbidity and mortality, the most recent data indicate a plateauing of thesetrends occurred in the 1990s, and that asthma mortality rates have declined

from 1998-2002.4

In recent decades, a surge in asthma prevalence alsooccurred in the United States and other "Western" countries; whether this trendis also plateauing is unclear. Tremendous progress has been made in thefundamental understanding of asthma pathogenesis by virtue of invasiveresearch tools such as bronchoscopy, bronchoalveolar lavage, airway biopsy,and measurement of airway gases, although the etiology of airway inflammationremains obscure. The knowledge that asthma is an inflammatory disorder hasbecome fundamental to our definition of asthma, beyond a simplebronchospastic disorder worthy of bronchodilators alone. In fact, the pastdecade has been characterized by a proliferation of expert practice guidelines,all with a goal of disseminating scientific knowledge to the practicing clinicianwith a goal of widespread implementation of anti-inflammatory therapy toimprove asthma outcomes. To this extent, there has been much emphasis onearly diagnosis and longitudinal care of patients with asthma, along withensuring adherence to the recommended therapies. In this context, there havebeen many advancements in the available pharmacologic armamentarium inboth chronic and acute therapy with the development and approval of novelmedications. Yet, as exciting as this revolution has been in asthma researchand practice, many controversies abound, and further fundamentaldevelopments in novel therapeutics are imminent.

This review of asthma for the practicing clinician will summarize thesedevelopments, including an updated definition of asthma, review of theepidemiology and natural history, and current thinking regarding etiology andpathogenesis. In addition, there will be an update on the diagnostic evaluationof comorbid disease, serial monitoring of asthma, and the most recent update ofthe expert panel guidelines and management algorithms. The authors will offera critique of these guidelines, including their limitations. Finally, there will bediscussion of newer therapies for the future.

Definitions

Epidemiology andNatural History

Etiology andPathogenesis

Diagnostic Evaluation,Comorbid Disease and Pe

Expiratory Flow Monitorin

Part 2:Asthma Therapy

DEFINITIONS

Asthma is a chronic, episodic disease of the airways, and it is best viewed as asyndrome. In 1997, the National Heart, Lung, and Blood Institute (NHLBI)included the following features as integral to the definition of asthma1,2: recurrentepisodes of respiratory symptoms; variable airflow obstruction that is oftenreversible, either spontaneously or with treatment; presence of airwayhyperreactivity; and, importantly, chronic airway inflammation in which manycells and cellular elements play a role, in particular, mast cells, eosinophils, Tlymphocytes, macrophages, neutrophils, and epithelial cells. All of these

features need not be present in any given asthmatic patient. Although theabsolute "minimum criteria" to establish a diagnosis of asthma is not known orwidely agreed upon, the presence of airway hyperreactivity is a common findingin patients with current symptoms and active asthma.

EPIDEMIOLOGY AND NATURAL HISTORY

Several governmental agencies have been charged with surveillance forasthma, including the NHLBI's National Asthma Education and PreventionProgram (NAEPP), the Department of Health and Human Services (Healthy
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People 2010), and the Centers for Disease Control. The latest data on asthmaoutcomes published by the Centers for Disease Control indicates that about 15million American adults suffer from asthma.4 The trend for increasing asthma-associated morbidity and mortality reported between 1980 and 1995 has notcontinued between 1995 and 1999. The annual rates of patients reportingasthma attacks during 1997-1999 were lower than previously reported rates.

Since 1995, the rate of outpatient visits for asthma increased, whereas the ratesof hospital admissions decreased (from 19.5 per 10,000 population in 1995 to15.7 in 1998). Importantly, annual rates of asthma mortality which increasedduring the 1980s have plateaued in the 1990s and have decreased from 1998-2002. These trends are reassuring and indicate that perhaps the aggressivestrategies of asthma management finally seem to be reaching fruition. However,

African Americans continue to have higher rates of asthma emergencydepartment visits, hospitalizations, and deaths than do Caucasians. The overalleconomic 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 manyforms. This heterogeneity has been amply established by a variety of studies

which have indicated disease risk from early environmental factors andsusceptibility genes; and subsequent disease induction and progression frominflammation as well as response to therapeutic agents(Figure 1). Recentevidence suggests that asthma is an inflammatory disease, and not simply dueto excessive smooth muscle contraction. Inflammation is the proximate cause ofairway hyperreactivity and variable airflow obstruction in asthma, and is auniversal finding in all asthmatic individuals. Increased airway inflammationfollows exposure to inducers such as allergens, viruses, exercise, or nonspecificirritant inhalation. Increased inflammation leads to exacerbations characterizedby dyspnea, wheezing, cough, and chest tightness. Abnormal histopathologiclesions including edema, epithelial cell desquamation, and inflammatory cellinfiltration are found not only in autopsy studies of severe asthma cases buteven 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 wallremodeling. 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), andintrinsic abnormalities of the arachidonic acid pathway and smooth muscle cells.While these types of descriptive studies have revealed a composite picture ofasthma (Figure 2), they have failed to provide a basic unifying defect.

Advances have been made in our understanding of asthmatic airwayinflammation through the use of invasive technology such as bronchoscopy withairway sampling in both mild and severe asthma at baseline state, 6as well as

study of the airway biology with experimental provocation that includes allergenchallenge as well as response to anti-inflammatory therapies. Further insightshave been obtained through transgenic murine models with deletion or "knockout" of specific genes (ie, those for IgE, CD23, IL-4, or IL-5) or overexpressionof other putative genes. Also, specific monoclonal antibodies or cytokineantagonists have been utilized in various asthma models. Several important andtechnical limitations have hindered our understanding of asthma obtained fromthese model systems: (1) there are important differences between animalmodels of asthma and the human disease; (2) there are few longitudinal studiesof human asthma with serial airway sampling; and (3) it is often difficult to
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determine the cause and effect from multiple mediator studies.

Despite the explosion of information about asthma, the nature of the basicpathogenesis has not been established. Studies suggest a genetic basis forairway hyperresponsiveness, including linkage to chromosomes 5q and 11q.

However, asthma clearly does not result from a single genetic abnormality, butis 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 asasthmatic adults whose asthma began in childhood, compared with adult-onsetasthmatics.

Immunopathogenesis and the TH2 PhenotypeBased upon animal studies and limited bronchoscopic studies in adults, theimmunologic processes involved in the airway inflammation of asthma arecharacterized by the proliferation and activation of helper T lymphocytes (CD4+)of the subtype TH2. The TH2 lymphocytes mediate allergic inflammation in atopicasthmatics 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.7Eosinophilsare frequently present in the airways of asthmatics (more commonly in allergicbut also in nonallergic patients), and these cells produce mediators that canexert damaging effects on the airways. Recent knockout studies andanticytokine studies suggest that lipid mediators are products of arachidonicacid metabolism. They have been implicated in the airway inflammation ofasthma, and therefore have been the target of pharmacologic antagonism by anew class of agents called antileukotrienes. Prostaglandins (PGs) aregenerated by the cyclooxygenation of arachidonic acid, and leukotrienes aregenerated by the lipoxygenation of arachidonic acid. The proinflammatoryprostaglandins (PGD2, PGF2, and TXB2) cause bronchoconstriction, whereasother prostaglandins are considered protective and elicit bronchodilation (PGE2

and PGI2, or prostacyclin). Leukotrienes C4, D4, and E4 compose the compoundcalled "slow-reacting substance of anaphylaxis," a potent stimulus of smoothmuscle contraction and mucus secretion. Ultimately, mediators lead todegranulation of effector/proinflammatory cells in the airways that release othermediators and oxidants, a common final pathway that leads to the chronic injuryand inflammation noted in asthma.

Hypotheses Related to "Hygiene" and Airway HyperresponsivenessMost studies of airway inflammation in human asthma have been in adultsbecause of safety and convenience. However, asthma often occurs in earlychildhood, and persistence of the asthmatic syndrome into later childhood andadulthood has been the subject of much speculation. The epidemiologicobservation that asthma prevalence is much greater in industrialized Westernsocieties than in less technologically advanced societies has been explained bythe so-called "hygiene hypothesis."8,9 This hypothesis proposes that airwayinfections 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 TH2airway immunologic profile. Specifically, early exposure to the various triggersthat may occur with higher frequency in a rural setting may tilt this balance to aTH1 paradigm and hence be protected against the allergic diathesis that ischaracteristic of the TH2 paradigm. In a "cleaner" urban Western society, suchearly childhood exposure is lacking, and the paradigm therefore shifts closer tothe allergic diathesis of TH2, which results in a higher incidence of asthma and
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other allergic diseases. Although this notion remains speculative, it is the basisfor emerging therapeutic options that attempt to shift the balance in favor of theTH1 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 thisnatural history are sources of much speculation. Whether airwayhyperresponsiveness is a symptom of airway inflammation or airwayremodeling, or is the cause of long-term loss of lung function, is being activelydebated. Some investigators have hypothesized that aggressive therapy withanti-inflammatory therapies to improve airway hyperreactivity (above andbeyond their effects on conventional parameters of asthma control) may haveadditional long-term benefits.10

Concept of Airway RemodelingThe relation between the several types of airway inflammation (both early-phaseand late-phase events) and the concept of airway remodeling, or the chronic

nonreversible changes that may happen in the airways, remains a source ofintense research.11The natural history of airway remodeling is poorlyunderstood, and although airway remodeling may occur in some patients withasthma, it may not be a universal finding. Clinically, airway remodeling may bedefined as persistent airflow obstruction despite aggressive anti-inflammatorytherapies, including inhaled corticosteroids (ICs) and systemic corticosteroids.Pathologically, airway remodeling appears to have a variety of features thatinclude an increase in smooth muscle mass, mucus gland hyperplasia,persistence of chronic inflammatory cellular infiltrates, release of fibrogenicgrowth factors along with collagen deposition, and elastolysis(Figure 3). Manybiopsy studies show these pathologic features from the airways of patients withchronic asthma. However, there are many unanswered questions, includingwhether features of remodeling are related to an inexorable progression ofacute or chronic airway inflammation or whether remodeling is a phenomenonseparate from inflammation altogether(Figure 4andFigure 5).

Recent research has confirmed that the airway epithelium is an active regulatorof local events, and the relation between the airway epithelium and thesubepithelial mesenchyma is thought to be a key determinant in the concept ofairway remodeling. A recent hypothesis by Holgate et al12indicates that airwayepithelium in asthma functions in an inappropriate "repair phenotype" in whichthe epithelial cells produce proinflammatory mediators as well as transforminggrowth factor- to perpetuate remodeling.

Exhaled Gases and Oxidative StressAsthma is characterized by specific biomarkers in expired air that reflect an

altered airway redox chemistry, including lower levels of pH and increasedreactive oxygen and nitrogen species during asthmatic exacerbations.13-18

Reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, andhydroxyl radicals cause inflammatory changes in the asthmatic airway. Insupport of this concept are the high levels of ROS and oxidatively modifiedproteins in airways of patients with asthma.14High levels of ROS are producedin the lungs of asthmatic patients by activated inflammatory cells (ie,eosinophils, alveolar macrophages, and neutrophils).15 Increased ROSproduction of asthmatic patients' neutrophils correlates with the severity ofreactivity of airways in these patients, and severe asthma is associated with
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neutrophilic airway infiltrates. Concomitant with increased oxidants, antioxidantprotection of the lower airways is decreased in asthmatic lungs.16,17

Another reactive species, nitric oxide (NO), is increased in the asthmaticairway.14Nitric 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 NOSI and NOS II genotype and expression are associated with asthma. Recent invitro studies have suggested cytotoxic consequences associated with tyrosinenitration induced by reaction products of NO. Other investigators havemeasured products of arachidonic acid metabolism in exhaled breathcondensate.18 Specifically, 8-isoprostane, a PGF2 analog that is formed byperoxidation of arachidonic acid, is increased in patients with asthma of differentseverities, and leukotriene E4-like immunoreactivity is increased in exhaledbreath condensate of steroid-nave patients with mild asthma with levels aboutthreefold to fourfold higher than in healthy subjects.

The-Agonist Controversy

There has been much controversy surrounding the potential role of-agonistpreparations in asthma mortality.19The hypothesis is that excessive or regularuse of-adrenergic bronchodilators can actually worsen asthma, perhapscontributing to morbidity and mortality. A variety of epidemiologic studies havefound conflicting findings. Several studies from New Zealand suggested that theuse of inhaled-agonists increases the risk of death in severe asthma.20-22

Spitzer and coworkers conducted a matched, case-controlled study using ahealth insurance database from Saskatchewan, Canada, of a cohort of 12,301patients for whom asthma medications had been prescribed.23Data were basedon matching 129 case patients who had fatal or nearly fatal asthma with 655controls. The use of -agonist administered by a metered-dose inhaler (MDI)was associated with an increased risk of death from asthma, with an odds ratioof 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 thisstudy, and indeed case-controlled studies in general, is concern regarding thecomparability of the two groups in terms of the severity of the underlyingdisease.24 A large, placebo-controlled trial of salmeterol, a long-acting2-receptor agonist, was recently stopped prematurely due to concerns with interimanalysis that suggested salmeterol may be associated with excess mortality dueto life-threatening asthma. This Salmeterol Multiple-Center Asthma ResearchTrial (SMART) was a 28-week safety study comparing salmeterol 42 mcgmetered dose inhaler twice a day with placebo, in addition to other asthmatherapies. Of over 26,000 patients randomized, a higher number of asthma-related deaths or life-threatening experiences (36 v. 23) and a higher number ofasthma-related deaths (13 v. 4) occurred in the patients treated with salmeterol.

Although there was no statistically significant difference for this primary endpointfor the total population, a subset analysis indicated that asthma-related deathsor life-threatening episodes were higher in African-Americans using salmeterol.Interestingly, 50% of Caucasian and 38% African-American patients were usingconcurrent inhaled corticosteroid at baseline. Among the patients using inhaledcorticosteroids, there was no significant difference between the two groupsimplying that greater riskfor controlled outcomes was related to salmeterolmonotherapy. A rate of asthmatic exacerbation equivalent to placebo haspreviously been reported in patients with mild persistent asthma receivingsalmeterol monotherapy.63
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Sears and coworkers conducted a placebo controlled, crossover study inpatients with mild stable asthma to evaluate the effects of regular versus on-demand inhaled fenoterol therapy for 24 weeks.25In the 57 patients who didbetter with one of the two regimens, only 30% had better asthma control whenreceiving regularly administered bronchodilators, whereas 70% had better

asthma control when they employed the bronchodilators only as needed. Morerecently, a study by Drazen and coworkers randomly assigned 255 patients withmild asthma to inhaled albuterol either on a regular basis (two puffs four timesper day) or only on an as-needed basis for 16 weeks.26There were nosignificant differences between the two groups in a variety of outcomes,including morning peak expiratory flow, diurnal peak flow variability, forcedexpiratory volume in one second, number of puffs of supplemental as-neededalbuterol, asthma symptoms, or airway reactivity to methacholine. Since neitherbenefit nor harm was seen, it was concluded that inhaled albuterol should beprescribed for patients with mild asthma on an as-needed basis. A recent meta-analysis of pooled results from 22 randomized, placebo-controlled trials thatstudied at least one week of regularly administered2-agonist in patients withasthma compared to a placebo group (that did not permit "as-needed" 2

agonist use) concluded that regular use results in tolerance to the drug'sbronchodilator and non-bronchodilator effects and maybe associated withpoorer disease control compared to placebo. However, there was no decline inthe mean FEV1 after regular treatment with2-agonists.

PharmacogeneticsPolymorphisms of the gene for the2-adrenergic receptor (AR) may beimportant in determining the clinical response to beta-agonists. For the2-ARgene, single nucleotide polymorphisms (SNPs) have been defined at condons16 and 27. The normal or "wild type" pattern is arginine-16-glycine andglutamine-27-glutamic acid, but SNPs have been described with homozygouspairing (eg, Gly16 Gly, Arg16 Arg, Glu27 Glu, and Gln27 Gln). Importantly, thefrequency 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 notappear to influence baseline lung function. However, in the presence of apolymorphism the acute bronchodilator response to a beta agonist, or protectionfrom a bronchoconstrictor, is affected. Studies indicate that patients with Arg16

Arg variant, the resulting2AR is resistant to endogenous circulatingcatecholamines (eg, receptor density and integrity is preserved) with asubsequent ability to produce an acute bronchodilator response to an agonist.In patients with Gly16 Gly, the2AR is down regulated by endogenouscatecholamines, therefore the acute bronchodilator response is reduced orblunted. In relation to prolonged beta agonist therapy (eg, greater than 2 weeks)it appears that only patients who are homozygous for Arg16 who were receivingregularly scheduled beta-agonist aerosol had a persistent decrease in lungfunction over time (eg, tachyphylaxis). These same individuals, when switchedto as needed albuterol, had no decrease in lung function, as is the case forhomozygous Gly16. Polymorphisms at the 27 loci are of unclear significance.

Also, the impact of haplotypes (eg, variant genes linked at > 2 loci) is presentlyunclear.

A recent study with transgenic mouse models using2AR knock-out as well asoverexpression of2AR has suggested an alternative molecular mechanism forthe effects of chronic exposure to-agonists and effects on airwaybronchodilator response. Interestingly and unexpectedly, the mice with absent

2AR had markedly reduced bronchoconstrictive response to methacholine. The
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overexpressors of2AR who had continuous2AR signaling activitydemonstrated an enhanced constrictive response. In addition, theoverexpressors showed increased expression of a phospholipase C1 enzymewhich 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 orcorticosteroid metabolism. Polymorphisms of the 5-lipoxygenase (5-LO)promoter gene and the leukotriene C4 (LTC4) synthase gene have beendescribed. Asthmatics with the "wild type" genotype at 5-LO have a greaterresponse with 5-LO inhibitor therapy compared to asthmatics with a mutantgene. However, mutations of the 5-LO promoter occur only in about 5% of theasthmatic patients so it is unlikely to play an important role in most patients. ASNP in the LTC4 synthase promoter gene (A-444C) is associated with increasedleukotriene production and has a lower response to leukotriene modifyingagents. Far less is known about genetic variability in the corticosteroid pathway.

Polymorphisms in the glucocorticoid receptor gene have been identified, whichappear to affect steroid binding and downstream pathways in various in vitrostudies. However, polymorphisms in the glucocorticoid pathways have not beenassociated with the asthma phenotype or clinical steroid resistance.

DIAGNOSTIC EVALUATION, COMORBID DISEASE, ANDPEAK EXPIRATORYFLOW MONITORING

The history and physical examination are important for several reasons: (1) toconfirm a diagnosis and exclude mimics such as hyperventilation syndrome,vocal cord adduction, heart failure, and others; (2) to assess the severity ofairflow obstruction and the need for admission to the hospital; (3) to identifyfactors 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 cardinalsymptoms of asthma include episodic dyspnea, chest tightness, wheezing, andcough. Some patients may present with atypical symptoms, such as coughalone (cough-equivalent asthma) or only dyspnea on exertion. It is essential tospecifically inquire about nocturnal symptoms because these are often ignored.

The most objective indicator of asthma severity is the measurement of airflowobstruction by spirometry or peak expiratory flow (PEF). The PEF and the FEV 1yield comparable results. For initial diagnostic purposes in most patients,spirometry rather than a simple PEF should be performed, although PEF maybe a reasonable tool for long-term monitoring. The National Asthma Educationand Prevention Program (NAEPP) and its Expert Panel Report 2 (EPR 2) have

set forth the grading of asthma severity into four categories based on thefrequency 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 nodiagnostic or therapeutic value. A chest radiograph should not be obtainedunless complications of pneumonia, pneumothorax, or an endobronchial lesionare suspected. The correlation of severity between acute asthma and arterialblood gases is poor. Mild-to-moderate asthma is typically associated withrespiratory alkalosis and mild hypoxemia on the basis of ventilation-perfusion
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mismatching. Severe hypoxemia is quite uncommon in asthma. Normocapniaand hypercapnia do imply severe airflow obstruction, with FEV1 usually


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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 statemanagement, and case management.29The thesis of disease state management is a global approach to chronicdiseases such as asthma by integrating various components of the health care delivery system. It is hoped thatmanaging all costs of care comprehensively, rather than seeking to minimize the costs of each component, willimprove health and save money. This approach relies heavily on information technology to identify patients, moncare, and assess outcomes and costs. Asthma is thought to be an ideal disease for the disease managementapproach because: 1) it is a chronic disease suitable for self-management and patient education; 2) it is a diseascan be managed largely on an outpatient basis, thus avoiding costly inpatient care; 3) there is a consensus on wconstitutes 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 manylimitations to the published asthma disease management studies. These studies typically have a pre- and post-sdesign, usually with no control group. The choice of outcome measures varies. Many interventions are oftenperformed at the same time and it is difficult to tease out the essential components of a program. They often useproprietary data systems and algorithms that make reproducing the studies difficult. There are many other desiglimitations, 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 ogoal of practice guidelines is to improve the quality of care while reducing inappropriate care and helping to contrrising costs. These guidelines are of interest to many groups including specialty medical societies, state and fedegovernment, insurers and managed care organizations, commercial enterprises, and hospitals. There are severamethods used to develop practice guidelines including informal consensus development, formal consensusdevelopment, evidence-based guideline development, and explicit guideline development.30 Informal consensusdevelopment, which is based largely on expert opinion with some general support from the literature, is the stratemost frequently used, as in the asthma practice guidelines (discussed below). Several possible mechanisms by practice guidelines may improve patient care have been described: improve clinician knowledge; affect clinicianattitudes to agree with and accept the guidelines as a "new standard of care"; and modify clinician behavior andpractice patterns.

There is only limited evidence, however, that practice guidelines can achieve favorable clinical outcomes.31 In fasome data suggest that simply disseminating guidelines may not affect physician behavior or clinical outcomes. have advocated additional strategies to include removing disincentives, adding a variety of incentives, and includthe 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 developedextensive and detailed guidelines for the diagnosis and management of asthma.1 The EPR 2 was published in 1Overall, the published guidelines highlight the following: 1) a new appreciation for the significant role of airwayinflammation in the pathogenesis of asthma; 2) a change in the emphasis for treatment, to include anti-inflammamaintenance therapy; 3) a focus on establishing risk factors for the development of asthma and identifying appro
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programs for control and prevention.

The NAEPP guidelines for classifying the severity of asthma are based on two parameters: the frequency ofsymptoms and the severity of airflow obstruction as assessed by objective measurements such as PEF or a spirin 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 asby maintaining a chronic baseline maintenance therapy; and 4) avoid the toxicity of some of the medications thatused to treat asthma. To facilitate these goals, the NAEPP outlined a number of key components for managemeFirst, patient education and self-management skills are critical. This education would involve some knowledge ofdisease, the proper use of medications, the proper metered-dose inhaler technique, and a written crisis plan formanaging exacerbations. The second component is the use of a home peak-flow device to monitor disease seveespecially for patients with moderate or severe disease. The third component involves measures to minimize or exposure to known environmental triggers that can exacerbate asthma, including the home environment as well 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 classifiespatients into four levels of severity: mild intermittent, and mild, moderate, or severe persistent disease. A dailymaintenance therapy is suggested for persistent disease. The EPR 2 classifies asthma medications as "long-tercontrollers" or "quick-relief medications." The medication list is updated to include salmeterol (Serevent), fluticas(Flovent), and antileukotrienes (all approved since 1991). EPR 2 provides a specific conversion table comparingequipotent doses of the inhaled steroids. The 1997 EPR 2 report places special emphasis on "step-down" therapafter a period of good control. EPR 2 recommends PEF monitoring for moderate and severe asthma, but only onper day (in the morning, pre-bronchodilator).

The 2002 Update3 to the NAEPP EPR 2 adds several additional points: 1) Long-term management of asthma inchildren has been revised with a strong emphasis on using ICs as the preferred agents in mild or moderate persasthma. 2) For patients >5 years old with moderate persistent asthma on ICs, addition of long-acting beta agonisimproves asthma control and outcomes. 3) Addition of antibiotics is not recommended for acute asthma exacerb4) 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 recommendations are not truly "evidence based" (ie, are not supported by randomized controlled trials) and repran expert opinion. It is important to stress that the differences between the published guidelines are small and thoverall consensus is remarkable. These general guidelines were developed to assist the clinician with patientmanagement and treatment decisions. Specific treatment regimens must be tailored to individual patient needs. since asthma research is a rapidly evolving area and new therapeutics are anticipated, these guidelines will be rperiodically. 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 a

other insects, as well as outdoor pollens, is common among asthmatic patients. The 1997 Expert Panel Report 2Guidelines for the Diagnosis and Management of Asthma differed from the 1991 Expert Panel Report inrecommending cutaneous orin vitro testing "for at least those patients with persistent asthma exposed to perennindoor allergens."1,2Clinical relevance of inhalant allergens can be demonstrated by immediate hypersensitivity stesting and/or radioallergosorbent (RAST) assay. Of these, skin testing is more sensitive, less costly, and entailsdelay in yielding results; for these reasons, skin testing is preferred. The information that these diagnostic testsprovide, whether the asthmatic patient exhibits IgE-mediated (allergic) potential to inhalant allergens, and to whiallergens the patient can be said to be "allergic", is used to direct relevant avoidance measures. Avoidance of clrelevant allergens can lead to substantial reduction of symptoms and medication reliance, and for some patientsbe the most important element of asthma management. The inhalant allergens that may provoke and perpetuate
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asthma symptoms are listed in Table 4. Individuals with asthma are frequently sensitized to more than one allerg

Table 4:

Inhalant Allergens

Indoor Outdoor Dust Mites Tree

Cockroach Grass

Pets (cat, dog, etc) Ragweed/Other weeds

Mold Spores Mold Spores

Air conditioning can be associated with dramatic reduction in exposures to outdoor pollens and mold spores whiindoors. Because we now spend the majority of our time indoors, the utility of air conditioning for improving asthmsymptoms 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 tosurvive and proliferate.33Allergy to dust mites is common in patients with asthma. Recommended avoidancemeasures to reduce exposures to dust mite allergen include: encasement of mattress/box spring and pillows inimpermeable covers, reducing indoor relative humidity, washing bedding weekly in hot cycle (130F) and if possremoval 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 occur with elimination of the pet from the home. If a cat or dog is removed from the home, however, the allergenpersist for several months. For this reason, clinical benefit cannot be expected promptly.34 When elimination of pfrom the home is not possible, second best measures include restricting the pet from the bedroom, use of highefficiency particulate or electrostatic air cleaners, and removal of carpets and other furnishings which otherwise as an allergen reservoir. Washing the cat or dog, if recommended as an avoidance strategy, needs to be carriedfrequentlyat least twice a week.35

When a regimen of avoidance measures combined with appropriate pharmacotherapy is undesirable, not feasibineffective to achieve optimal asthma control, administration of allergen immunotherapy vaccines ("allergy shotsbe considered.36-38 Allergen immunotherapy entails the incremental administration of inhalant allergens for the puof inducing immune system changes in host response with natural exposure to these allergens. Numerous studiecarried out during the past 5 decades have shown statistically and clinically significant dose-dependent benefit wadministration of allergen immunotherapy in properly selected patients with asthma.37 Recent studies demonstraimmunotherapy can inhibit late-phase response and appears to work through induction of T-cell tolerance36-38; incontrast to medication which affects only symptoms, immunotherapy can favorably impact upon the disease procthat underlies asthma symptoms. The therapeutic utility of inhalant allergen immunotherapy has also been suppby findings of a meta-analysis of randomized, double-blinded studies of allergen immunotherapy for asthma repoby Abramson and colleagues39, in which statistically significant benefit was reported as manifested in reduced assymptoms, 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 overestimaeffect size because of a well-recognized reporting bias (eg, negative studies tend to not get published), the authcalculated 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 systemicreactions are not uncommon, immunotherapy should only be given in a setting in which adequate precautions artaken and life-threatening anaphylaxis can be treated.37 The decision to begin allergen immunotherapy should beindividualized, and based on symptom severity, relative benefit with pharmacotherapy, and whether co-morbidconditions such as beta-blocker use40 are present which increase risk for (serious) anaphylaxisthe major risk o
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allergen immunotherapy.

Aspirin Intolerance and Desensitization:

Aspirin (ASA) and non-steroidal anti-inflammatory drugs can provoke bronchospasm (with/without nasal-ocularcongestion or flushing) in a subgroup of asthmatic patients.41In ASA sensitive asthmatics, potentially seriousbronchospastic reaction occurs up to several hours after exposure to ASA or an ASA-like drug; even a sub-theradosage of ASA in this setting can lead to potentially life-threatening bronchospasm. 41 ASA and non-steroidal antinflammatory drugs, including ibuprofen, naproxen, sulindac, indomethacin, etodolac, etc., share the action ofinhibition of cycloxygenase COX-1 and COX-2 and are 100% cross-reactive in ASA sensitive asthmatic patients

ASA sensitive asthmatics, cross reaction may also occur with higher doses of salsalate42 or acetaminophen,43 ware weak inhibitors of COX-1 and COX-2. Selective inhibitors of COX-2, rofecoxib, valdecoxib, and celecoxib, docross-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, leadingturn to excessive production of sulfidopeptide leukotrienes (LTC4, LTD4, and LTE4). These mediators, formerly kas slow reacting substance of anaphylaxis (SRS-A), not only participate in acute bronchospastic reaction provok

ASA ingestion but also contribute to the ongoing airways obstruction and inflammation that persists in ASA-sensasthmatic patients despite avoidance of ASA and other COX-inhibiting drugs.41Administration of anti-leukotrieneagents, which either selectively block leukotriene receptors or inhibit leukotriene synthesis by blocking 5-lipoxygeor its activator, 5-lipoxygenase activating protein (FLAP), are efficacious in management of chronic persistent asin patients who are ASA-sensitive. Added benefit has been reported in double-blind placebo-controlled studies i

ASA-sensitive asthmatic patients receiving inhaled (and/or oral) corticosteroids treated with montelukast46orzileuton.47

Anti-leukotriene agents also attenuate bronchospastic reaction provoked by ASA challenge in ASA-sensitiveasthmatics.48 For this reason, anti-leukotriene drugs have utility for reducing severity of reaction in patients undedesensitization, although bronchospastic reaction is unlikely to be blocked completely.49,50 Biosynthesis of leukotis upregulated in ASA sensitive asthmatics;41,51 a key enzyme, LTC4 synthase, is overexpressed in bronchial mu

ASA sensitive rhinosinusitis/asthma patients have increased expression of the CysLT1 receptor on inflammatoryleukocytes,51thereby enhancing their ability to respond to leukotrienes. Down regulation of Cys-LT 1 receptorexpression may explain the mechanism for ASA desensitization.51

Desensitization can be performed for patients who require administration of ASA or ASA-like drug for managemeco-occurring conditions, eg, arthritis, thromboembolism, orcoronary artery disease. Clinical benefit in patients w

ASA sensitive respiratory disease - particularly for polypoid rhinosinusitis - may be expected in 2/3 of patients wdesensitized and then take ASA regularly.52Improvement includes reduced level of symptoms, lower medicationreliance, and less morbidity (as reflected in fewer annual episodes of URI/sinusitis, and reduced rates of sinus suprocedures). Based on these findings and previous experience with ASA desensitization,41 this intervention can be considered for patients with corticosteroid-dependency and/or refractory rhinosinusitis who require repeated surgery procedures. Because of potentially serious bronchospastic reaction that may occur during this procedurdesensitization should only be carried out in settings where experienced physicians and appropriate equipment treat such reactions are present.

Pharmacotherapy:

The pharmacotherapy for asthma, as recommended by current NAEPP guidelines, is summarized in theaccompanying Tables 1,2, 3,and5. The overall strategy is to use a stepwise approach based on the level of seInhaled beta agonists ("relievers") used on an as-needed basis are recommended for patients with mild intermittasthma who are asymptomatic between episodes. Patients with persistent asthma, as defined above, with morefrequent symptoms, are treated with the addition of an anti-inflammatory agent ("controller") used on a scheduledbasis in addition to an inhaled beta agonist on an as-needed basis. For patients with more severe disease and d
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acute exacerbations, addition of oral corticosteroids as a short-term burst is appropriate.

Inhaled corticosteroidsWith the current paradigm of asthma as a chronic inflammatory disorder of the airways, ICs have become first-lintherapy for all patients with persistent asthmamild, moderate, or severe. Over the past 5 to 10 years, the trend

use of inhaled steroids has been to use more potent ICs topically at higher doses, especially for the more severecases. This is predicated on the hypothesis of a dose-response effect for these agents. Although many studiessupport this hypothesis, there is continued debate and reevaluation of this by inhaled-steroid-sparing approachediscussed below. It is well documented that higher doses of ICs facilitate a reduction in systemic corticosteroids severe asthma. Another trend has been the use of ICs at an earlier stage of asthma. Limited data suggest that eaddition of ICs might improve the long-term FEV1 by preventing subepithelial fibrosis, although this hypothesis isuniversally accepted. Several studies with follow-up over 10 years indicate that ICs do not cure asthma, and cesof therapy often results in prompt relapse. Some studies suggest that in stable asthmatics less-frequent dosing, as bid or qd, may be equally effective. Less-frequent dosing has clear-cut benefits in terms of improved complianInhaled steroids are also cost-effective in management of asthma, with an incremental cost-effectiveness ratio fosymptom-free day of approximately $5.00 - $6.00.53 Finally, regular use of inhaled steroids can prevent asthmatiexacerbation,54increases in bronchial hyperresponsiveness,55 and accelerated loss of lung function.56 A largeretrospective case-control study from Canada associated regular use of ICs with statistically significant reduction

rates of mortality.57

Currently, five specific inhaled corticosteroids are approved for maintenance therapy for asthma in the United StaThe two newest agents include fluticasone and budesonide (Pulmicort Turbuhaler). In general, the more topicallpotent agents such as fluticasone and budesonide have the advantage of dosing with far fewer puffs per day toaccomplish the same clinical benefit.

A recent development in chronic asthma maintenance therapy is the concept of combination therapy to produceadditive or synergistic effects. A variety of studies indicate that groups of mild-to-moderate asthmatics who remasymptomatic on low-to-intermediate doses of ICs experience greater benefit from a long-acting inhaled bronchodtaken in combination with inhaled steroid compared with doubling the dose of inhaled steroid. 58,59A natural extenof this concept has been the development of a new inhaled product that combines fluticasone and salmeterol intosingle device. This has recently become available as a diskus device (Advair Diskus) with the medication packag

a non-chlorofluorocarbon dry-powder preparation. This product is now available in three different steroid dosestrengths, Advair 100 g fluticasone/50 g salmeterol (green), 250/50 (yellow), and 500/50 (red). Several pivotastudies indicate that the combination product is superior to the individual components in patients with mild andmoderately 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 weecompared 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 theophylline 60 aleukotriene antagonists.61 These agents are also a rational alternative, taken in combination with inhaled steroid,doubling the dose of inhaled steroid, in patients who remain symptomatic on low - intermediate inhaled steroidtreatment. The benefits of combination therapy, as measured by symptom scores, prn use of beta agonists, lungfunction, and exacerbation rates, with these other agents are not as dramatic, however, as with the addition of thlong-acting inhaled bronchodilator.62A study from the Asthma Clinical Research Network of the NHLBI found tha

monotherapy with salmeterol is not adequate replacement therapy for patients controlled on triamcinolone (Azm400 g twice per day.63 The exact molecular mechanism whereby the combination of inhaled steroids and long-abeta agonists synergistically improve asthma control is not fully known. Preliminary data indicate that long-actingagonists may facilitate the steroid effect whereas the steroids upregulate the beta-agonist receptors. Preliminaryalso do not support the contention that long-acting bronchodilators have a "masking effect" on underlying airwayinflammation.

The molecular mechanism of action of glucocorticoids (GCs) involves binding to a specific intracellular glucocortreceptor (GCR). This binding dissociates heat-shock proteins and creates an active GC-GCR complex. The GC-
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complex translocates to the nucleus and binds to specific GCR-responsive elements on genomic DNA that inducspecific gene expression (ie, beta-adrenergic receptors). The GC-GCR complex may also suppress gene expresby interfering with the interaction of transcription factors (ie, nuclear factor-kB) with promoter regions ofproinflammatory cytokines. Through these mechanisms, GCs inhibit the production of a wide range of cytokinesimportant in asthma. In addition to inhibiting cytokine production, glucocorticoids also inhibit production of

inflammatory leukotrienes and eicosanoids through effects on phospholipase A2. In contrast, genes for anti-inflammatory or bronchodilatory products (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 molecularmechanisms remain poorly understood. There is likely only one type of human glucocorticoid receptor; thereforepolymorphisms of the human steroid receptor have not been established. Two discrete types of relative steroidresistance have been described. Type 1 steroid resistance is a relative lack of steroid responsiveness in the airwalthough there is evidence for steroid effect in other tissues of the body, usually manifest as clinical steroid side (i.e., cushingoid effects). Type 1 steroid resistance is acquired and more common. On the other hand, type 2 steresistance is due to a generalized lack of steroid responsiveness in the airways and other organ systems on a gebasis. Patients with type 2 resistance have poor asthma control despite systemic corticosteroids and no systemisteroid side effects. Type 2 steroid resistance is rare. The relative contribution of this concept of steroid resistanc

suboptimal asthma control and poor outcomes remains unknown. Patients with such a molecular basis for steroiresistance 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 apractical barrier to wider use of these agents despite several reassuring long-term studies and expert practiceguidelines. One landmark study64 randomized 1,041 children from ages 5 through 12 with mild-to-moderate astha study duration of 4 to 6 years into three groups (200 g budesonide bid, 8 mg of nedocromil (Tilade) bid, orplacebo). This robust study noted that the asthma clinical outcomes improved most for the budesonide group (fehospitalizations, fewer urgent visits, and decreased airway hyperresponsiveness to methacholine). However, thewas no significant difference in the degree of change in FEV1 after bronchodilator use between any of the threegroups. Long-term budesonide was well tolerated, and even though there was a 1.1 cm smaller increase in heighcompared with the placebo group during the first year, this reduction in linear growth velocity was absent by thesecond year, and the projected height in the budesonide-treated group was no different than in the nedocromil o

placebo groups. Also, there were no significant differences in bone density or the incidence of cataracts betweenthree groups. Although a number of other short-term studies have noted a reduction in height and linear growthvelocity over 6 to 12 months with ICs, longer-term studies have consistently noted that the final adult height is noinfluenced by ICs.65Practical approaches to minimize or eliminate systemic toxicity from ICs include: (1) using thlowest 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 toropharynx after each use; and (3) adding a long-acting beta agonist or, more simply, using a combination IC anlong-acting beta-agonist inhaler to facilitate a reduction of IC for a steroid-sparing effect.

AntileukotrienesThe sulfidopeptide or cysteinyl leukotrienes (LTC4, LTD4, and LTE4), formerly known as the "slow-reacting substaof anaphylaxis," are formed by the lipoxygenation of arachidonic acid by the enzyme 5-lipoxygenase. Thesecompounds, 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 yeasuggest that the cysteinyl leukotrienes are involved in the pathogenesis of chronic human asthma, and these datsatisfy Koch's postulates which represent a series of experimental observations that establishes cause and effecbiologic phenomena. Leukotrienes can be recovered from nasal secretions, bronchoalveolar lavage fluid, and urpatients with asthma. Potent leukotriene antagonists inhibit asthmatic responses to allergens, exercise, cold dry and aspirin. Finally, placebo-controlled clinical trials have shown salutary effects in asthmatics treated with anti-leukotriene drugs.

Within the past few years, three agents that antagonize the leukotriene pathway have been approved by the FDA
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use as maintenance therapy for mild persistent asthma. Zafirlukast and montelukast studies will be reviewed, anzileuton 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 doublblind, randomized, placebo-controlled, 13-week studies in 1,380 patients with mild to moderate asthma have shothat treatment with zafirlukast improves daytime asthma symptoms, nighttime awakenings, mornings with asthm

symptoms, rescue albuterol use, FEV1, and morning PEF.66 Zafirlukast is administered as 20 mg bid and is wellabsorbed. It should be given on an empty stomach; otherwise, drug levels would be reduced by 40%. At the currrecommended dose, the risk of liver function abnormalities is thought to be quite low. Cases of hepatotoxicity habeen described with use of zafirlukast but not montelukast, for which routine monitoring is not felt to be necessarChurg-Strauss vasculitis (CSS) has been reported in patients receiving anti-leukotriene drugs, in most cases patwith severe asthma who improved and were able to suspend or taper oral corticosteroid developed CSS. 67,68Itappears 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 drugMoreover, similar cases of CSS have also been reported in association with inhaled cromolyn and more recentlyinhaled fluticasone.

Montelukast (Singulair) is a specific cysteinyl leukotriene (cysLT, or LTD4) receptor antagonist that received FDAapproval in 1998. Preliminary data suggest that montelukast may have several advantages compared with zafirl

or zileuton (Zyflo). These include ease of dosing (once a day; no significant change in absorption by food) and aabsence of significant drug interactions. Early experience shows an excellent safety profile with no effect on the 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 yeaasthmatic children with efficacy and safety.

Several published studies indicate that montelukast 10 mg given once daily at bedtime causes significantimprovement in chronic mild-to-moderate asthma compared with placebo. 69-71 A 3-month, double-blind, parallel-study (n = 681 with FEV1 50% to 80%) showed significant improvement in the montelukast group (asthmaexacerbation decreased by 31%, asthma-free days increased by 37%).69 Another randomized trial involving aduwith moderate-to-severe asthma (n = 226) showed that montelukast 10 mg allowed significant tapering of inhalesteroids in patients requiring moderate-to-high doses.70 A 4-week, controlled trial in 80 aspirin-intolerant adultasthmatics 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 asthmacan prevent airway remodeling. Even though these agents affect a single pathway, data from animal models indbroader effect on eosinophilia and collagen deposition.72Whether these findings are relevant to the human disearemains to be determined.

The exact place for antileukotrienes in chronic maintenance therapy for asthma remains to be established. The Eindicates a possible role for these agents in the initial therapy for mild persistent asthma as an alternative to ICs cromolyn or nedocromil). These agents have effects on early and delayed asthma responses; therefore, they actbronchodilators within 1 to 3 hours after administration as well as anti-inflammatory agents with response in 2 to weeks. The magnitude of increase in FEV1 at 4 weeks is about 14% above that of placebo. It is likely that the inhsteroids have more potent effects, especially in patients with moderate to severe disease. One head-to-headcomparative trial clearly indicated that beclomethasone (Qvar, Vanceril, and others) is superior to montelukast.73

antileukotrienes do facilitate a reduction in the need for inhaled beta agonists and ICs, therefore, risk for untowar

effects from these medication exposures. Also, these oral agents may improve compliance compared with themetered-dose inhalers. A subset of patients respond much more dramatically to the antileukotrienes, usually witfirst 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 bronchoprovocatchallenge, and exhibit greater end-organ responsiveness to leukotrienes compared with aspirin tolerant asthmatOn this basis, patients with aspirin-sensitive asthma warrant a trial of anti-leukotriene pharmacotherapy, althougrate of response in this subgroup is similar to rates reported among aspirin tolerant asthmatics. That the data shoabout the same rate of benefit in ASA sensitive asthmatics compared with ASA tolerant asthmatics is consistentthe hypothesis that it is the balance between PGE2 and PGF2 alpha that is critical in this subgroup. Anti-leukotri
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agents may also attenuate exercise-induced bronchospasm.

Anti-IgE TherapyOmalizumab (Xolair), the first selective anti-IgE therapy, is a unique humanized monoclonal anti-IgE antibody thabinds with high affinity to the FcRI receptor-binding site on IgE. Omalizumab was approved by the FDA in 2003

Omalizumab reduces the amount of free IgE available to bind to FcRI receptors on mast cells, basophils, and ocells. This agent is being evaluated as a drug for subcutaneous administration either every 2 or every 4 weeks foallergic asthmatic patients with serum IgE levels in the range of 30 to 700 IU/ml. Experimental studies indicated tweekly therapy with omalizumab attenuated both the early and late asthmatic responses evaluated at days 28 anand the dose of aerosolized allergen required to decrease FEV 1 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 moderatesevere perennial allergic asthma who required daily use of inhaled and/or oral corticosteroids was conducted insubjects ages 11 to 50 for 20 weeks.74The active-treatment arm included two different doses of intravenouslyadministered omalizumab (2.5 mg/kg/ng IgE/mL) or a high dose (5.8 mg/kg/ng IgE/mL). At 12 weeks, there was 50% improvement in asthma symptom scores in one-half of the patients treated with either dose of omalizumabcompared with 24% of patients in the placebo group. A 50% or greater reduction in dose of oral corticosteroids wreported in 78% of subjects in the high-dose group and 57% of those in the low-dose group versus 33% of subjethe placebo group (P = 0.04). More than one third of the subjects in the omalizumab groups were able to discont

oral corticosteroids. One fifth of the subjects taking ICs for control of asthma symptoms were able to completelydiscontinue steroid use after being treated with omalizumab. During the 20-week study period, 45% of patientsreceiving placebo reported an exacerbation, compared with only 28% of patients in the low-dose group and 30%patients in the high-dose group. Finally, asthma-specific quality of life questionnaire scores also improved sign

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