Highlights from the annual scientific assembly: patient-centered approaches to asthma management: strategies for treatment and management of asthma. * (Special Feature).

THE PURPOSE of this article is to review strategies for the outpatient treatment and management of asthma. In this review, we will examine the current recommendations for asthma treatment and focus on randomized, double-blind asthma pharmacotherapy trials published in 2001 that help us understand the role of the various asthma medications in the care of our patients. Although medical therapy is a cornerstone of asthma management, we will also detail current recommendations for nonpharmacologic approaches to asthma care and prevention.

Before focusing on asthma therapy and management, it is first useful to review the current definition of asthma to provide a rationale for our recommendations for asthma treatment. The most recent National Asthma Education and Prevention Program outlines several components to the definition of asthma, (1) including (1) "asthma, whatever the severity, is a chronic inflammatory disorder of the airways"; (2) "in susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and in the early morning"; and (3) that "atopy, the genetic predisposition for the development of an IgE-mediated response to common aeroallergens, is the strongest identifiable predisposing factor for developing asthma." (1) Obviously, other factors, such as tobacco smoke, air pollution, gastroesophageal reflux, and viral infections, can also contribute to inflammation of the airways and asthma symptoms; however, the fact that approximately 90% of children w ith asthma (2) and the majority of adult asthmatics have allergies (3) underscores the importance of allergic disease in asthma pathophysiology. Incumbent upon our recognition that inflammation and allergy are strongly related to asthma, minimizing the allergic inflammatory component in an overall asthma treatment strategy is, unfortunately, underutilized. Therefore, we propose a 4-step approach to asthma care: environmental control, pharmacologic management, immunotherapy, and vaccination.

ENVIRONMENTAL CONTROL

Many asthma patients can identify specific triggers that lead to the onset of chest tightness, wheezing, and shortness of breath. Such triggers might be seasonal, such as tree, grass, or weed pollens, or the triggers might be situational, such as exposure to animal dander. (4) In these instances, patients with mild symptoms when exposed to such allergens can either practice conscious allergen avoidance or increase medication use when exposure to known triggers is unavoidable. A subset of patients, however, experience seemingly random flares of asthma and are not aware of disease precipitants. Additionally, many patients experience perennial (year-round) symptoms and may or may not experience acute worsening of disease with specific triggers. It is these patients who are unaware of specific triggers or have perennial symptoms who may benefit most from allergen skin testing. (5) The presence of perennial symptoms does not rule out an allergic component to a person's disease; instead, the allergic triggers are m ore likely to be from indoor allergens, such as dust mites, cockroaches, molds (such as Cladosporium, Penicillium, and Alternaria), or animal dander. (5) Allergen skin testing is a highly sensitive and specific method of identifying environmental factors that elicit the IgE-mediated degranulation of mast cells and basophils that are the cornerstone of the subsequent eosinophilic inflammation characteristic of the allergic response. (6) Allergen avoidance measures have been proven to be effective for both allergic rhinitis and asthma. (7) In fact, treating allergic rhinitis with environmental avoidance measures, as well as medical therapy, greatly improves asthma control. Without skin testing to prove that an allergic component may be a factor in asthma, however, patients and their families may needlessly spend considerable sums of money engaging in modification of the home environment that may make no difference in symptom control.

PHARMACOLOGIC MANAGEMENT

Since most asthma medications are given by inhalation, proper technique must be taught and, in most cases, a spacer should be used inhaled medication delivery. Without proper technique and optimal medication delivery, no drug will be as effective as it could be, and the fault would not be necessarily be with the medication, but with the medical provider and patient for inadequate administration.

The classification of asthma severity and the recommended treatment for each level of illness as recommended by the National Asthma Education Panel is outlined in Table 1.1 For mild, intermittent asthma, the short-acting inhaled beta agonist remains the cornerstone of symptomatic control. (1) Beta agonists bronchodilate by relaxing smooth muscle that constricts the airways, and beta agonists are also reported to improve mucociliary function. The question of whether additional pharmacologic therapy is needed can be appropriately simplified by remembering the "rules of 2." If a patient has asthma symptoms and needs a short-acting beta agonist on more than 2 days per week, 2 nights per months, or needs more than 2 canisters of short-acting beta agonist per year, then a long-term controller medication is necessary. (1) A common error in asthma treatment is underestimating disease severity and not adding a controller medication when it is needed. Many randomized, double-blind studies indicate that inhaled cortico steroids are the initial controller medication of choice. (8-10) Other possible current choices for long-term controller medical therapy include leukotriene-receptor antagonists, such as montelukast or zafirlukast, long-acting beta agonists, such as formoterol or salmeterol, or the phosphodiesterase inhibitor, theophylline.

The choice of inhaled corticosteroids as first-line controller therapy has been supported by numerous randomized, controlled trials looking at the impact of these medications on lung function and short-term morbidity, as well as observational studies showing an effect on both morbidity and mortality. (11-19) In addition, 3 studies published in 2001 have examined the efficacy of long-term controller regimens, comparing inhaled corticosteroids with alternative therapies. (8-10) Busse et al (8) examined the efficacy and safety of an inhaled steroid (low-dose fluticasone proprionate) compared with a leukotriene-receptor antagonist (montelukast) for first-line maintenance therapy in patients who were using short-acting beta agonists alone for persistent asthma. In this 24-week study of 533 patients >15 years of age, there was no placebo control. Compared with baseline, improvement in pulmonary function, need for beta-agonist rescue medication, asthma symptom scores, and nocturnal awakening was found in both the g roup using the inhaled steroid and the group using the leukotriene-receptor antagonist. The patients treated with the inhaled steroid had statistically and clinically significantly greater improvement in all of the aforementioned parameters, however, compared with those treated with montelukast. (8)

Similarly, new evidence suggests that long-acting beta agonists should not be used as the sole first-line controller therapeutic agent. Lemanske et al (10) performed a randomized, controlled trial in 175 adolescent and adult asthmatics to determine whether the addition of a long-acting beta agonist might allow either elimination or dose reduction of inhaled corticosteroids. In this study, patients with persistent asthma who did not completely respond to 6 weeks of therapy with an inhaled corticosteroid (triamcinolone) were randomized to treatment with a long-acting beta agonist (salmeterol) or placebo, after which a trial of reduction in the inhaled steroid dose was attempted. Those patients treated with the long-acting beta agonist were able to reduce the corticosteroid dose safely, but there was an unacceptably high rate of treatment failure in the salmeterol group when inhaled steroids were totally discontinued. (10) Lazarus et al (9) tested a similar question in a trial designed to examine the effectiven ess of a long-acting beta agonist (salmeterol) versus an inhaled steroid (triamcinolone) for controller therapy. In that study, 166 patients with persistent asthma that was well controlled on an inhaled steroid were randomized to either continue their inhaled steroid or switch to the long-acting beta agonist. There were more treatment failures, a greater increase in eosinophilic inflammation, and increased sputum tryptase level in those randomized to the long-acting beta agonist, compared with those who continued taking the inhaled steroid. (9) These last 2 studies suggest that patients with persistent asthma that is controlled by inhaled corticosteroids cannot be switched to monotherapy with a long-acting beta agonist without the risk of losing asthma control. (9,10) Thus, inhaled corticosteroids are preferred over long-acting beta agonists and leukotriene-receptor antagonists for controller therapy.

The choice for additional therapy when a patient's asthma is not well controlled on a substantial dose of inhaled corticosteroids is more complex. Nelson et al (20) compared the efficacy and safety of a combination of inhaled steroid and long-acting beta agonist (fluticasone and salmeterol) with an inhaled steroid and a leukotriene-receptor antagonist (fluticasone and montelukast). In this multicenter, double-blind, double-dummy, parallel-group 12-week study, patients were enrolled who remained symptomatic on a low dose of inhaled corticosteroid. All patients were then treated for 12 weeks with the same dose of inhaled corticosteroid, but randomized to receive either a long-acting beta agonist (salmeterol) or a leukotriene-receptor antagonist (montelukast). The combination of the inhaled corticostertoid with the long-acting beta agonist significantly improved pulmonary function, rescue albuterol use, asthma exacerbation rate, and shortness-of-breath symptom score, compared with the group treated with both th e inhaled steroid and the leukotriene receptor; however, there were no differences between the groups in chest tightness, wheezing, and overall symptom scores. (20) Wilson et al (21) also examined addition of a leukotrienereceptor antagonist (montelukast) versus a long-acting beta agonist (salmeterol) to an inhaled steroid in patients whose asthma was not completely controlled with an inhaled steroid regimen. In this small (20 patient) placebo-controlled, double-dummy, crossover-design study, there were similar statistically significant improvements for both groups in rescue bronchodilator requirement and morning peak expiratory flow. There was a significant decrease in eosinophil count in the group treated with montelukast, suggesting that the addition of this drug decreased allergic inflammation. (21) Lofdahl et al(22) showed that the addition of a leukotriene-receptor antagonist also allows for reduction of inhaled steroid doses in patients requiring moderate to high doses of corticosteroid to maintain asthma control.

Based on the published data, our current recommendation is that short-acting beta agonists should be used as a rescue medication for patients with mild, intermittent asthma who have symptoms with unknown or unavoidable triggers. For those patients who need a short-acting beta agonist more than 2 days per week, 2 nights per month, or who need more than 2 canisters of short-acting beta agonist per year, a high-dose inhaled steroid should be added (Table 2). Given that inhaled steroids are first-line controller therapy, we choose a high dose of inhaled steroid for a practical reason based on patient compliance. If a low dose is initiated and is not effective, then it is much more difficult to convince patients to increase a medication in which they might have little faith, based on their immediately preceding experience, rather than tapering down a higher dose of an effective therapy to a lower dose that is still adequate for symptom control. If the patient continues to have symptomsdespite adequate inhaled-ster oid therapy, either a long-acting beta agonist or a leukotriene-receptor antagonist can be added, based on both patient and physician preferences. If the patient's asthma is still not completely controlled on this regimen, the addition of both the leukotriene-receptor antagonist and the long-acting beta agonist to inhaled corticosteroids is a reasonable alternative. Theophylline can also be considered after the leukotriene-receptor antagonist and the long-acting beta agonist have been added, since the leukotriene-receptor antagonist and the long-acting beta agonist have much better safety and side-effect profiles than theophylline. Finally, in cases of extremely severe asthma, the lowest possible dose of oral corticosteroids that still provides symptomatic relief may be necessary, though significant side effects occur with long-term use of this therapy.

ALLERGEN IMMUNOTHERAPY

In selected patients who have known triggers for asthma and who have allergy skin-test reactivity that match the triggers for asthma, allergen immunotherapy is a viable treatment option. (23) Allergen immunotherapy can also be considered for patients with positive immediate-phase skin-test reactions whose asthma is not well controlled with standard drug regimens. (23) A recent meta-analysis that included prospective, randomized, double-blind, placebo-controlled trials in the effectiveness of specific immunotherapy in the treatment of asthma revealed that patients treated with immunotherapy had significant improvement in symptoms, pulmonary function, and protection against bronchial challenge, and reduced need for medication compared with the subjects given placebos. (23) Caution should be advised in allergen immunotherapy administration, in that injections should be deferred to another day when patients are actively wheezing or have decreased peak expiratory flows on the planned day of injection. (24) In addi tion, cardiovascular disease and/or the use of beta-adrenergic antagonists may increase the risk of allergen immunotherapy. (24)

VACCINATION

Influenza is an important cause of asthma exacerbations in adults over 18 years of age. (25) The Centers for Disease Control Advisory Committee on Immunization Practices lists adults and children who have chronic disorders of the pulmonary or cardiovascular systems, including asthma, as one of the target groups for influenza vaccination because they are at increased risk for complications related to influenza. (26) Thus, influenza vaccination is an important adjunctive therapy in the treatment of asthma. Interestingly, the pneumococcal vaccine, though recommended for patients with chronic obstructive pulmonary diseases, such as emphysema, is not specifically recommended for asthmatic patients. (27)

SUMMARY

Asthma is a chronic inflammatory disease in which the genetic predisposition to allergic disease is the strongest identifiable predisposing factor. (1) Optimal outpatient treatment of asthma includes identifying and minimizing exposure to asthma triggers, whether they be allergens or irritants. When these triggers are not obvious, referral to an allergist may be appropriate to identify potential exacerbating factors. In addition, pulmonary consultation may be helpful in patients who do not have the typical features of asthma on chest radiograph or pulmonary function testing, or who are not responding well to standard therapy. The primary care physician is the most important component in the care of the asthmatic patient, however, managing acute exacerbations, determining long-term medical therapy, and providing preventive measures, such as yearly influenza vaccinations.

TABLE 1

Asthma Severity Classification

Step                   Daytime Symptoms     Nighttime Symptoms

4 Severe persistent    >1/day               4-7 times/wk
3 Moderate persistent  Daily                2-3 times/wk
2 Mild persistent *    >2-6 times/wk        >2 times/month

1 Mild intermittent    [less than or equal  [less than or equal to]2
                       to]2 time/week       times/month

Step                   [FEV.sub.1] or PEFR  PEFR Variability

4 Severe persistent    <60%                 >30%
3 Moderate persistent  60%-79%              >30%
2 Mild persistent *    [greater than or     20%-30%
                       equal to]80%
1 Mild intermittent    [greater than or     <20%
                       equal to]80%

[FFV.sub.1] = Forced expiratory volume in 1 second, PEFR = peak
expiratory flow rate.

* Controller medication should be started in persons with mild
persistent disease.

Rules of two: Controller medication should be used in persons who have
daytime symptoms more than twice a week, or night time symptoms more
than than twice a month. Controller medication should be increased in
persons already on these medications who have symptoms this often.
Medication can be stepped up or down depending on disease control.
TABLE 2

Inhaled Corticosteroids

          Drug                    Low-Dose

Beclomethasone                168-504 [micro]g
  42 [micro]g/puff            (4-12 puffs, 42 [micro]g)
  84 [micro]g/puff            (2-6 puffs, 84 [micro]g)

Budesonide                    200-400 [micro]g
  200 [micro]g/dose           (1-2 inhalations)

Flunisolide                   500-1,000 [micro]g
  250 mg/puff                 (2-4 puffs)

Fluticasone                   88-264 [micro]g
  MDI: 44,  110, 220          (2-6 puffs, 44 [micro]g, or
   [micro]g/puff               2 puffs, 110 [micro]g)
  DPI: 50, 100 250 [micro]g/  (2-6 inhalations, 50 [micro]g)
   puff

Triamcinolone                 400-1,000 [micro]g
  100 [micro]g/puff           (4-10 puffs)

          Drug                    Medium-Dose

Beclomethasone                504-840 [micro]g
  42 [micro]g/puff            (12-20 puffs, 42 [micro]g)
  84 [micro]g/puff            (6-10 puffs, 84 [micro]g)

Budesonide                    400-600 [micro]g
  200 [micro]g/dose           (2-3 inhalations)

Flunisolide                   1,000-2,000 [micro]g
  250 mg/puff                 (4-8 puffs)

Fluticasone                   264-660 [micro]g
  MDI: 44,  110, 220          (2-6 puffs,
   [micro]g/puff               110 [micro]g)
  DPI: 50, 100 250 [micro]g/  (3-6 inhalations, 100 [micro]
   puff                       g)

Triamcinolone                 1,000-2,000 [micro]g
  100 [micro]g/puff           (10-20 puffs)

          Drug                      High-Dose

Beclomethasone                >840 [micro]g
  42 [micro]g/puff            (>20 puffs, 42 [micro]g)
  84 [micro]g/puff            (>10 puffs, 84 [micro]g)

Budesonide                    >600 [micro]g
  200 [micro]g/dose           (>3 inhalations)

Flunisolide                   >2,000 [micro]g
  250 mg/puff                 (>8 puffs)

Fluticasone                   >660 [micro]g
  MDI: 44,  110, 220          (>6 puffs, 110 [micro]g or
   [micro]g/puff               >3 puffs, 220 [micro]g)
  DPI: 50, 100 250 [micro]g/  (>6 in halations, 100
   puff                        [micro]g)

Triamcinolone                 >2,000 [micro]g
  100 [micro]g/puff           (>20 puffs)

MDI = meter dose inhaler

DPI = dry powder inhaler

References

(1.) National Asthma Education and Prevention Program (National Heart Lung and Blood Institute): Guidelines for the Diagnosis and Management of Asthma: Expert Panel Report 2. Bethesda, Md, US Department of Health and Huamn Services, Public Health Service, National Institutes of Health, 1997. NIH publication No. 97-4051

(2.) Smith JM: Incidence of atopic tlisease. Med Clin North Am 1974; 58:3-24

(3.) Sibbald B: Familial inheritance of asthma and allergy. Allergy and Allergic Diseases. Kay AB (ed). Oxford, England, Blackwell Science, Ltd, Vol 2, 1997, pp 1177-1186

(4.) Platts-Mills TA, Vaughan JW, carter MC, et al: The role of intervention in established allergy: avoidance of indoor allergens in the treatment of chronic allergic disease. J Allergy Clin Immunol 2000; 106:787-804

(5.) Platts-Mills TA, Blumenthal K, Perzanowski M, et al: Determinants of clinical allergic disease, the relevance of indoor allergens to the increase in asthma. Am J Respir Crit Care Med 2000; 162 (suppl) :S128-S133

(6.) Norman PS, Peebles RS Jr: In vivo diagnostic allergy testing methods. Manual of Clinical Laboratory Immunology. Rose NR, deMacario EC, Folds JD, et al (eds). Washington, DC, American Society for Microbiology Press, 1997, pp 875-880

(7.) Woodcock A, Custovic A: Allergen avoidance: does it work? Br Med Bull 2000; 56:1071-1086

(8.) Busse W, Raphael GD, Galant 5, et al: Low-dose fluticasone propionate compared with montelukast for first-line treatment of persistent asthma: a randomized clinical trial. J Allergy Clin Immunol 2001; 107:461-468

(9.) Lazarus SC, Boushey HA, Fahy JV, et al: Long-acting beta-2 agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial. JAMA 2001; 285:2583-2593

(10.) Lemanske RF Jr, Sorkness CA, Mauger EA, et al: Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial. JAMA 2001; 285:2594-2603

(11.) Donahue, JG, Weiss ST. Livingston JM, et al: Inhaled steroids and the risk of hospitalization for asthma. JAMA 1997; 277:887-891

(12.) Ernst P, Spitzer WO, Suissa S, et al: Risk of fatal and near-fatal asthma in relation to inhaled corticosteroid use. JAMA 1992; 268:3462-3464

(13.) Haahtela T, Jarvinen M, Kava T, et al: Comparison of a beta-2 agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991; 325:388-392

(14.) Juniper EF, Kline PA, Vanzieleghem MA, et al: Long-term effects of budesonide on airway responsiveness and clinical asthma severity in inhaled steroid-dependent asthmatics, Eur Respir J 1990; 3:1122-1127

(15.) Juniper EF, Kline PA, Vanzieleghem MA, et al: Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics. Am Rev Respir Dis 1990; 142:832-836

(16.) Juniper EF, Kline PA, Vanzieleghem MA, et al: Reduction of budesonide after a year of increased use: a randomized controlled trial to evaluate whether improvements in airway responsiveness and clinical asthma are maintained. J Allergy Clin Immunol 1991; 87:483-489

(17.) Selroos O, Pietinalho A, Lofroos AB, et al: Effect of early vs late intervention with inhaled corticosteroids in asthma. Chest 1995; 108:1228-1234

(18.) Sont JK, Willems LN, Bel EH, et al: Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group. Am J Respir Crit Care Med 1999; 159:1043-1051

(19.) Suissa S, Ernst P, Benayoun S, et al: Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 2000; 343:332-336

(20.) Nelson HS, Busse WW, Kerwin E, et al: Fluticasone propionate/salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroid plus montelukast. J Allergy Clin Immunol 2000; 106:1088-1095

(21.) Wilson AM, Dempsey OJ, Sims EJ, et al: Evaluation of salmeterol or montelukast as second-line therapy for asthma not controlled with inhaled corticosteroids. Chest 2001; 119:1021-1026

(22.) Lofdahl CG, Reiss TF, Leff JA, et al: Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. BMJ 1999; 319:87-90

(23.) Ross RN, Nelson HS, Finegold I: Effectiveness of specific immunotherapy in the treatment of asthma: a meta-analysis of prospective, randomized, double-blind, placebo-controlled studies. C/in Ther 2000; 22:329-341

(24.) DuBuske LM: Appropriate and inappropriate use of immunotherapy. Ann Allergy Asthma Immunol 2001; 87:56-67

(25.) Folkerts G, Busse WW, Nijkamp FP, et al: Virus-induced airway hyperresponsiveness and asthma. Am J Respir Crit Care Med 1998; 57:1708-1 720

(26.) Bridges CB, Fukuda K, Cox NJ, et al: Prevention and control of influenza, recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal wkly Rep 2001; 50:1-44

(27.) Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1997; 46:1-24

* Presented as a Symposium at the 95th Annual Meeting of the Southern Medical Association, November 8-10, 2001, Nashville, Tenn.

From the center for Lung Research, Division of Allergy, Pulmonary, and critical care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.

This work was supported by K08-HL-03730, K08-AI-01582, the American Lung Association of Tennessee, and the American Academy of Allergy Asthma and Immunology ERT Award.

Southern Medical Association acknowledges Merck US Human Health for an unrestricted educational grant in support of this session and appreciates their interest in continuing medical education.