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(Chest. 1999;115:210-217.)
© 1999 American College of Chest Physicians

The 1997 Asthma Management Guidelines and Therapeutic Issues Relating to the Treatment of Asthma*

John W. Georgitis, MD, FCCP

* From the Department of Pediatrics, Division of Pediatric Allergy, Immunology, and Respiratory Medicine, Wake Forest University School of Medicine, Bowman Gray Campus, Winston-Salem, NC.


   Abstract
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 Abstract
Introduction
 Safety and Efficacy of...
 Clinical Efficacy Comparisons of...
 Comparative Risks Among Inhaled...
 Expectations With Different...
 Summary
 References
 
In 1997, the National Heart, Lung, and Blood Institute released the Second Expert Panel Report on the Guidelines for the Diagnosis and Management of Asthma as a follow-up to the first report issued in 1991. Implementation of the recommendations from this report could have a potentially huge impact on care and treatment of asthma in the United States. Even though the Guidelines are expansive, there are some areas related to the pharmacologic component that warrant further discussion and clarification. These are: (1) safety and efficacy of available asthma medications, (2) clinical efficacy comparisons of inhaled corticosteroids, (3) comparative risks among inhaled corticosteroids, and (4) expectations of different delivery systems used with inhaled corticosteroids.

Key Words: asthma guidelines • asthma management • inhaled corticosteroids


   Introduction
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 Abstract
 Introduction
Safety and Efficacy of...
 Clinical Efficacy Comparisons of...
 Comparative Risks Among Inhaled...
 Expectations With Different...
 Summary
 References
 
The Second Expert Panel Report on the Guidelines for the Diagnosis and Management of Asthma was distributed in spring 1997. Its goal was to link the practice of diagnosing and treating asthma with the most current knowledge about the disease. Although acknowledging that individualized treatment plans are the best course, the Expert Panel Report II outlines basic recommendations to help patients and clinicians make the most appropriate choices for optimal treatment of the disease. For example, the Report spells out six goals for asthma therapy to aid clinicians in the periodic assessment and monitoring of asthma patients (Table 1 ).1 These goals cover the important aspects for successfully managing the disease.


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  		Table 1. The Goals of Asthma Therapy

 
Another basic recommendation is the "stepwise" approach to pharmacologic therapy: gain control as quickly as possible, then gradually decrease (or increase) dosages to the least (or most) amount necessary to maintain control.1 This may be accomplished by either commencing treatment at the step most appropriate to the initial severity of the patient's asthma, or by starting at a higher level of therapy, such as with a higher dose of inhaled corticosteroids.

Of the four components in the report, the largest is devoted to pharmacologic therapy (component 3). This perhaps mirrors the increasingly major role of pharmacologic therapy in the management of asthma over the past 20 years.

This article will examine four areas in the pharmacologic component of the 1997 Expert Panel Report that warrant further clarification and discussion. They are: (1) safety and efficacy of the available asthma medications, (2) clinical efficacy comparisons of inhaled corticosteroids, (3) comparative risk among inhaled corticosteroids, and (4) expectations with different delivery systems used with inhaled corticosteroids.


   Safety and Efficacy of Available Asthma Medications
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 Abstract
 Introduction
 Safety and Efficacy of...
Clinical Efficacy Comparisons of...
 Comparative Risks Among Inhaled...
 Expectations With Different...
 Summary
 References
 
Nedocromil
One of the new asthma medications, nedocromil, has an anti-inflammatory action similar to that of cromolyn.1 2 The drug's mechanism of action appears to be inhibiting inflammation on the molecular level by blocking chloride channels and modulating mast cell mediator release and eosinophil recruitment.1 3 4 Nedocromil is effective in reducing bronchospasm brought on by cold, dry air,5 bradykinin aerosol,2 and exercise.6 It is also proven to reduce the need for quick-relief ß2-antagonists, improve morning peak flow, and reduce asthma symptoms.7 A few studies have shown that nedocromil used in conjunction with inhaled corticosteroids is efficacious,8 and may help reduce the inhaled corticosteroid dosing,7 9 but one study did not show a steroid-sparing effect.10

The Guidelines state that the response to "... nedocromil is less predictable than the response to inhaled corticosteroids."1 The therapeutic response with nedocromil may be similar to that with its counterpart, cromolyn sodium: allergic asthma and exercise-induced asthma are responsive to cromolyn and possibly to nedocromil. Only through continued clinical use of nedocromil will this be shown.

In clinical use, an important drawback to nedocromil is its unpleasant taste.8 In one study, over half of the nedocromil users (53%) recorded bad taste as the number one side effect in using the drug.10 Because side effects can potentially lead to noncompliance and the prevention of inflammation is now the focus of asthma management, noncompliance with a long-term controller medication such as nedocromil would be an issue.1

Inhaled Long-Acting ß2-Agonists
Introduced in 1995, salmeterol reduces bronchoconstriction by stimulating ß2-receptors and relaxing the smooth muscle in the airway.1 Indications for asthma therapy are limited to the prevention of exercise-induced bronchospasm and concomitant use with anti-inflammatory therapy for long-term control of symptoms, especially nocturnal symptoms.

Shortly after the introduction of salmeterol, patients mistakenly used it to treat acute exacerbations, sometimes with lethal results. In clinical use, constant, detailed patient education is needed when salmeterol is prescribed. Other reports of sudden, severe asthma attacks in patients using salmeterol raised concern that the drug may cause a sudden worsening of symptoms (under certain conditions and in certain patients).1 11 However, a recent, large-scale English study found that salmeterol users did not have a significant increase in death compared with those who used albuterol.12 The Expert Panel reports that current ongoing longitudinal studies are examining special populations to determine if they are at a higher risk of potentially lethal side effects with the use of salmeterol.1

Alternatively, recent clinical studies have demonstrated the effectiveness of adding a long-acting bronchodilator to inhaled corticosteroid therapy for asthma control.13 14 15 In one study, use of a lower inhaled corticosteroid dose with the long-acting bronchodilator resulted in better lung function and symptom control than did doubling of the inhaled corticosteroid dose.13 Similarly, the addition of a long-acting bronchodilator to patients whose asthma is poorly controlled by high-dose inhaled corticosteroids also improved lung function and symptom control.14

Leukotriene Modifiers
Three recent entries into the asthma armamentarium are the leukotriene modifiers montelukast, zafirlukast, and zileuton. These drugs specifically inhibit the steps in the inflammatory cascade mediated by cysteinyl leukotrienes.16 Montelukast and zafirlukast, leukotriene-receptor antagonists, work by blocking leukotriene D4 receptors.1 17 Zileuton, a 5-lipoxygenase inhibitor, blocks the production of many leukotrienes (eg, B4, C4, D4, and E4) in the inflammatory process by inhibiting the 5-lipoxygenase enzyme.1 17

However, clinical trials with montelukast, zafirlukast, and zileuton have shown only modest improvement based on increases in FEV1 of 10 to 15%, asthma symptom scores, and reduction in ß-agonist use for mild to moderate asthma.1 16 17 18 One study comparing zileuton and beclomethasone dipropionate (BDP) in moderate asthma showed twice the improvement in FEV1 with beclomethasone compared with zileuton (Zileuton New Drug Application, Phase III study of the effects of zileuton 600 mg qid compared to beclomethasone in moderate asthma; unpublished data).

In clinical practice, one of the main benefits of the leukotriene inhibitors is the ease of taking an oral medication over using an inhaler for asthma treatment. The downside to this delivery system is the attendant risk for significant drug-drug interactions and potentially serious systemic side effects. Zafirlukast and zileuton have been shown to inhibit the metabolism of warfarin and can affect liver function.1 Patients taking zileuton require regular liver transaminase monitoring (at least six times in the first year). In addition to warfarin, zileuton can also inhibit the metabolism of terfenadine and theophylline.1

Zafirlukast also has been implicated in causing or unmasking an atypical form of Churg-Strauss syndrome in eight patients following withdrawal of systemic corticosteroids.19 These patients have had clinical features consistent with Churg-Strauss syndrome, or allergic granulomatous angiitis, a rare vasculitis characterized by severe asthma, peripheral eosinophilia, mono- or polyneuropathy, pulmonary infiltrates, and sinus abnormalities. However, these eight cases have also had an acute dilating cardiomyopathy, and the authors speculate that this was an atypical presentation of Churg-Strauss syndrome that was unveiled after corticosteroid withdrawal facilitated by zafirlukast. The labeling of zafirlukast has changed to warn against the possible association of Churg-Strauss syndrome, a rare and sometimes fatal condition.20 The new labeling urges clinicians to monitor patients carefully when corticosteroids are being tapered or discontinued during asthma therapy with zafirlukast.

The Expert Panel notes that "... increased clinical experience and further study in a wide range of patients are needed to... establish a more specific role for leukotriene modifiers in asthma therapy."1

Anti-inflammatory Medications
Asthma has been well accepted as an inflammatory disease only in the past 5 to 10 years.21 Although research has identified most of the markers instrumental in the inflammatory cascade (cytokines, macrophages, mast cells, eosinophils, etc), it is still unknown which anti-inflammatory actions cause a therapeutic effect.1

Two of the new long-term control medications work by attenuating inflammation at specific points in the inflammatory process. The leukotrienes work specifically by inhibiting the leukotriene molecule late in the asthmatic response.21 22 23 Long-acting ß2-agonists work by stimulating ß2-receptors, which increases cyclic adenosine monophosphate and leads to reduced bronchoconstriction.1

The inhaled corticosteroids, although they are not new, have emerged as the cornerstone in anti-inflammatory therapy for asthma. Rather than working at a specific site in the inflammatory process, they have a broader mechanism of action, which may account for their efficacy as preventive therapy.1 24 In clinical use, they have been proved effective in diminishing airway hyperresponsiveness; preventing exacerbations; improving peak flow and spirometry; reducing symptom severity; possibly preventing airway wall remodeling in asthmatics; and exhibiting a prednisolone-sparing effect in patients with severe, chronic asthma.1 25 26 27 28 29 30 In clinical practice, the Expert Panel states, corticosteroids are the most "potent and consistently effective long-term-control medication for asthma."1


   Clinical Efficacy Comparisons of Inhaled Corticosteroids: Factors Influencing Efficacy
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The physiochemical properties of the glucocorticoid molecules determines the pharmacokinetics of inhaled corticosteroids. Due to the various properties of the different molecules, the Expert Panel points out that data suggest "... that different inhaled corticosteroid preparations are not equivalent on a per puff or microgram basis."1

Although not well defined, some of the factors thought to influence efficacy are topical potency; lipophilicity; the rate of dissolution; receptor-binding affinity; and receptor-binding half-life. While there have been important advances in the understanding of the molecular mechanisms of steroid action, other factors exist that influence efficacy and are yet unknown.

Topical Potency
The MacKenzie skin-blanching test, a topical vasoconstriction assay, measures topical potency. This test is believed to correlate with the binding affinities and binding half-lives for human lung corticosteroid receptors.31 32 33 Because of this correlation, the topical anti-inflammatory potency of inhaled corticosteroids can be ranked by measuring the amount of skin blanching in healthy subjects.32 34 35

However, not all inhaled corticosteroid preparations are metabolized the same when applied topically to the lungs. For example, BDP is a prodrug, which means it is converted to its active form (beclomethasone 17-monopropionate) once it enters bronchial tissue.28 36 The MacKenzie test measures the anti-inflammatory potency of beclomethasone dipropionate, not its more active form.

In addition, although the Expert Panel used topical potency to calculate dosing recommendations for oral inhaled corticosteroids, the validity of such comparisons remains controversial. Most clinicians would agree that all five of the currently available inhaled corticosteroid preparations work effectively. Yet, if judged by topical potency, the low values for triamcinolone and flunisolide would indicate they are less efficacious than other corticosteroids using a microgram per microgram basis (Table 2 ).1 This implies that lower-potency corticosteroids require higher doses to reach comparable clinical efficacy. The Expert Panel acknowledges the ambivalence of topical potency as a reliable standard for comparing efficacy by stating,,"The relationship between topical anti-inflammatory effect and clinical comparability in asthma management is not certain."1


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  		Table 2. Comparison of Topical Potency Among Corticosteroids

 
Receptor-Binding Affinity and Half-life
Because receptor-binding affinity and receptor-binding half-life correlate with topical potency, the Expert Panel used these two factors when estimating clinical comparable doses of inhaled corticosteroids (Table 3 ).28 32 Receptor-binding affinity refers to the amount of affinity the glucocorticoid molecule has for the steroid-finding site on the glucocorticoid receptor.32 This leads to activation of the receptor and dimerization of the active steroid receptor complex.32 Receptor-binding half-life is the measurement of how long it takes for the steroid receptor complex to be reduced by 50%.32 33 For clinical use, the pharmacokinetic profile of an ideal inhaled corticosteroid would be a high level of topical potency along with a prolonged receptor-binding affinity and half-life, presumably to obtain a more rapid clinical effect with the least amount of drug.


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  		Table 3. Pharmacodynamics/Pharmacokinetics of Inhaled Corticosteroids

 
However, as mentioned above, the validity of topical potency as a reliable comparative measure of efficacy remains uncertain for clinical use. By correlation, the validity of receptor-binding affinity and half-life is also uncertain. Does the questionable reliability of these pharmacokinetic factors undermine the dosing comparisons in the Expert Panel Report? This question stems from the biggest drawback to the current literature for inhaled corticosteroids: there is little reliable clinical data directly comparing all five inhaled corticosteroids in a similar clinical model.17 37 There are so many different factors to account for in inhaled corticosteroid dosing (eg, delivery systems, compliance, uniform drug distribution, etc) that realistic comparisons are not yet available.

There is reliable clinical data comparing two of the inhaled corticosteroids. The Expert Panel states, "BDP achieved effects similar to twice the dose of TAA [triamcinolone acetonide] on a microgram basis."1 The studies referred to in this statement compared the safety and efficacy of BDP (336 µg/d bid) without a spacer and triamcinolone acetonide (800 µg/d bid) with a built-in tube space [unpublished data from two studies, data on file at Key Pharmaceuticals: (1) Bronsky E, Korenblatt P, Harris AG, et al. A comparative clinical study of inhaled beclomethasone dipropionate and triamcinolone acetonide in persistent asthma. (2) Berkowitz R, Rachelefsky G, Harris A, et al. A comparison of triamcinolone acetonide MDI with a built-in tube extender and beclomethasone dipropionate MDI alone in adult asthmatics]. In the end, the Expert Panel relies on the common sense approach to comparative dosing: "The most important determination of appropriate dosing is the clinician's judgment of the patient's response to therapy."1

Lipophilicity and Dissolution Rate
These two factors—although not used by the Expert Panel to arrive at dosing recommendations—can be useful in comparing the efficacy of inhaled corticosteroids. A 1996 review article refers to lipophilicity as the most important factor and describes it as the index of lipid partitioning potential in the glucocorticoid molecules inversely related to water solubility.32 It is closely related to the rate of dissolution in that the most lipophilic steroid will dissolve quickly into biologic fluids, thus exhibiting a quicker anti-inflammatory effect.32

It is theorized that highly lipophilic corticosteroids have a prolonged duration of action because they are more easily deposited as micro-depots on the airway mucosa.32 Further benefits of high lipophilicity are increased lung tissue deposition leading to slow release from the lung lipid compartment, increased receptor-binding affinity, and prolonged receptor occupancy (half-life).32

For application in clinical use, pharmacokinetic studies have quantified the level of lipophilicity and dissolution rates among the various inhaled corticosteroids (Table 3) .32 BDP and fluticasone are the most lipophilic of all the inhaled corticosteroids.38


   Comparative Risks Among Inhaled Corticosteroids: Hypothalamic-Pituitary-Adrenal Axis Suppression
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For more than two decades, clinical investigators have questioned whether the use of inhaled corticosteroid therapy suppresses the hypothalamic-pituitary-adrenal (HPA) axis. The Expert Panel states that this issue is "complex and requires further study,"1 but two studies cited by the Expert Panel illustrate that not all inhaled corticosteroids carry the same amount of risk.

The first study found no HPA axis suppression in asthmatic children receiving BDP (mean dose, 490 µg/d) compared with controls who received no corticosteroid therapy.39 The second study found at least a twofold greater adrenal suppression in asthmatic patients taking fluticasone compared with those taking budesonide. This effect was found to be on a microgram-equivalent basis.40

Other studies not cited by the Expert Panel confirm these findings. Single and multiple doses over short time periods of a newer inhaled corticosteroid, fluticasone, have shown marked HPA axis suppression compared with budesonide and BDP.41 42 43 44 Ideally, an adjustment in dosing for potency of the corticosteroids would answer the question about possible adrenal suppression, yet such studies have yet to be done. One study showed the percentage of HPA axis suppression with a multiple-dose treatment of fluticasone propionate (1,000 µg bid) was more than double that seen with a single dose (65 vs 28%).44 In the same study, budesonide showed 16% suppression of plasma cortisol (Table 4 ).44 Another recent study confirms these findings. Multiple-dose treatment with fluticasone propionate (1,000 µg bid) showed triple the amount of HPA axis suppression compared with budesonide (84 vs 27%).45 It has been suggested that the more pronounced HPA axis suppression seen with fluticasone is related to its pharmacokinetic properties.40 45 Compared with other inhaled corticosteroids, fluticasone stays in the body longer because of the long plasma elimination half-life of the fluticasone propionate molecule (Table 5 ).45 46 47 48 49 50 51 Of all the inhaled corticosteroids, beclomethasone has the shortest half-life. Studies show that long-term treatment with BDP within recommended doses does not affect adrenocorticol function or growth.48 49 Future clinical studies using corticosteroids should pay particular attention to the potency, lipophilicity, and receptor binding characteristics.


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  		Table 4. HPA Axis Suppression47

 

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  		Table 5. Plasma Elimination Half-lives for Inhaled Corticosteroids

 

   Expectations With Different Delivery Systems Used With Inhaled Corticosteroids
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Other factors that can influence the efficacy of inhaled corticosteroids are the devices used to deliver the drug directly to the lungs via inhalation. When used properly, spacers or holding chambers decrease the amount of oropharyngeal deposition of the drug and increase the amount of deposition in the lung.37 The Expert Panel does not recommend one delivery device over another, but instead communicates the optimal technique and therapeutic issues with each device.

A majority of inhaled corticosteroids are available as metered-dose inhalers (MDIs), but certain patients (ie, the elderly and children) may have difficulty with coordinating the actuation and inhalation. For patients with poor MDI technique, the Expert Panel Report states that larger-volume spacers or holding chambers (> 600 cm3) may increase drug delivery to the lung over an MDI alone.1 Therefore, use of a spacer device/holding chamber or change to a dry-powder inhaler (DPI) may result in better patient compliance. More importantly, the guidelines stress the value of patient education, especially instituting an action plan and defining "controller" and "quick-relief" medications for asthma. Through patient education, patients will have a better understanding that inhaled corticosteroids are controller medications, and such knowledge is an important means of improving patient compliance.

There is still a need for greater understanding on the spacer/holding chamber issue because a recent review article by Newhouse52 states that a well-designed holding chamber must have a volume greater than 140 mL. Newhouse52 also found the same percentage of lung deposition with the Azmacort Tube Spacer (Rhone-Poulenc; Courbevoie, France) as with an MDI used with an open mouth or the two holding-chamber devices (Table 6 ). Nevertheless, no matter how large the spacer/holding chamber is, it still needs to be well designed. The Expert Panel cautions that "simple tubes do not obviate coordinating actuation and inhalation."1


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  		Table 6. MDI vs MDI Plus Accessory Devices: Volume and Percentage of Lung Deposition51

 
DPIs have been used for years in Europe and were recently introduced in the United States. Because the drug in a DPI is not aerosolized, it requires a rapid, deep, forceful inhalation rather than the slow, coordinated technique used with an MDI.1 Clinical studies have shown the DPI's efficacy in delivering drugs to the lungs.53 54

However, because of the special technique required to use DPIs, there may be drawbacks to their use. For one, proper drug delivery is dependent on optimal technique by the patient, but optimal technique can be difficult for patients to achieve for a variety of reasons. A minimum inspiratory flow rate is required for DPIs to work effectively. This may preclude the use of DPIs in young children,55 as indicated in the full prescribing information for the Pulmicort Turbuhaler. Also, as mentioned in the full prescribing information, DPIs have a lack of taste or sensation, unlike MDIs. If a patient cannot taste or feel the drug during delivery, it can hinder compliance. In addition, patients must perform two very different techniques when using both MDIs and DPIs.1 Even when patients do achieve optimal technique, studies have shown a wide variance in dose emissions with DPIs.56 57

In clinical use, a drawback of DPIs is their inconvenience. Storage can be a problem, as exposure to moisture can decrease the effectiveness of the drug. In addition, if the patient drops the device or exhales into it, the dose is lost.1 Also, DPIs cannot be used with holding chambers to decrease the level of oropharyngeal deposition.

Given the many issues regarding DPIs, it will be interesting to see if providers and patients in the United States accept them. Adults who are compliant and conscientious and can master all the techniques involved with taking their asthma medications may be the best candidates for these new delivery systems. The Expert Panel says, "Most [DPIs] appear to have similar delivery efficiency as MDI either with or without spacer/holding chamber... . "1


   Summary
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 Introduction
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 Clinical Efficacy Comparisons of...
 Comparative Risks Among Inhaled...
 Expectations With Different...
 Summary
References
 
In the 6 years since the 1991 Expert Panel Report was released, an increasing number of therapeutic choices have been introduced to treat and control asthma. The pharmacologic component of the 1997 Expert Panel Report provides clinicians with a detailed, annotated guide on how and when to use these medications.

It is hoped that clinical research will become available so that the next Expert Panel Report can include definitive data on the safety and efficacy of newer asthma medications (eg, long-term studies of the leukotriene modifiers); a reliable clinical model for comparing inhaled corticosteroids; a lengthier discussion on HPA axis suppression among oral inhaled corticosteroids; and the latest data pertaining to drug delivery devices. This information will be helpful to clinicians when they apply the Guidelines in practice.


   Footnotes
 
Correspondence to: John W. Georgitis, MD, FCCP, Medical Center Blvd, Winston-Salem, NC 27157; e-mail: jgeorgit@wfubmc.edu

Abbreviations: BDP = beclomethasone dipropionate; DPI = dry-powder inhaler; HPA = hypothalamic-pituitary-adrenal; MDI = metered-dose inhaler

Received for publication January 22, 1998. Accepted for publication July 22, 1998.


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