View the Disease Management Project
Table of Contents

Revised
February 28, 2005

Mani S.
Kavuru, MD

Department of
Pulmonary, Allergy, and Critical Care
Medicine

David M.
Lang, MD

Department of
Pulmonary, Allergy, and Critical Care
Medicine

Serpil C.
Erzurum, MD

Print Chapter

Copyright 2005
The Cleveland Clinic Foundation

Part 2:

Asthma Management Algorithms

Experimental Therapies

Summary

References

Part 1:

Asthma definition, epidemiology, etiology, pathogenesis, and diagnostic evaluation

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.

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 (130°F) 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 frequently—at 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 tolerance^36-38; 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) anaphylaxis—the 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 anti-inflammatory 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 asthma—mild, 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 µg fluticasone/50 µg 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 µg, 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 µg 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 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 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 µg 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 anti-leukotriene 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 double-blind, 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 pre-existing 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 aspirin-exacerbated 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 FcεRI 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 FcεRI 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.

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 disease-modifying 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, T_H2 cells and their derived cytokines IL-4, IL-5, and IL-13 play a critical role in orchestrating eosinophilia and asthmatic airway inflammation in various models of asthma. Over the past few years, there have been several early-phase human studies with pharmacologic approaches to antagonize these pathways, with mixed results.^77,78 Although the animal studies had been 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-IL-5 decreased blood eosinophilia for 16 weeks and sputum eosinophilia for 4 weeks, there was no significant effect on the late asthmatic response or airway hyperresponsiveness to allergen challenge. 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 lactone-glucocorticosteroid 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.

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.

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