Literature Review |

Top Ten List in Asthma* FREE TO VIEW

Jay Peters, MD, FCCP
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*From the Division of Pulmonary/Critical Care, Department of Medicine, University of Texas Health Science Center at San Antonio, TX.

Correspondence to: Jay Peters, MD, FCCP, University of Texas Health Science Center at San Antonio, 7702 Floyd Curl Dr, Department of Medicine, Division of Pulmonary/Critical Care, San Antonio, TX 78229; e-mail: peters@uthscsa.edu

Chest. 2003;123(2):593-595. doi:10.1378/chest.123.2.593
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1. Rytila P, Metso T, Heikkinen K, et al. Airway inflammation in patients with symptoms suggesting asthma but with normal lung function. Eur Respir J 2000; 16:824–830

This study evaluated and observed patients who had symptoms of asthma but did not have significant airflow variability or hyperresponsiveness. This group of patients had a higher number of blood and sputum eosinophils than did healthy control subjects, but had less pronounced eosinophil counts than did the asthmatic control subjects. Three months of treatment with inhaled beclomethasone resulted in significant improvement in the total symptom score and cough score. Over 1 year of follow-up, 13% of patients developed asthma, 55% had asthmatic symptoms with normal lung function, and 32% became symptom-free. This study helps to characterize a subgroup of patients who are left without an accurate diagnosis, often leading to repeated courses of antibiotic, antitussive, and β-agonist agents. It raises the question of whether the early treatment of eosinophilic inflammation might have an impact on disease progression.

2. Htut T, Higenbottam TW, Gill GW, et al. Eradication of house dust mite from homes of atopic asthmatic subjects: a double-blind trial. J Allergy Clin Immunol 2001; 107:55–60

Active heat-steam treatment of homes caused a sustained reduction in house dust-mite antigen compared to no change in the sham-treated group. A single treatment reduced the mite allergen load below the risk level for sensitization and improved bronchial hyperresponsiveness by fourfold over a 9-month period. The addition of a ventilation system above the patient’s bedroom sustained the improvements in bronchial hyperresponsiveness and allergen levels for 12 months. The results of this well-controlled study add support to the concept that the prevention of exacerbations of asthma should be possible by the limitation of exposure to allergens.

3. Kolbe J, Fergusson W, Vamos M, et al. Case-control study of severe life threatening asthma (SLTA) in adults: demographics, health care, and management of the acute attack. Thorax 2000; 55:1007–1015

This case-control study compared 77 patients who had severe life-threatening asthma (SLTA) with 239 matched control subjects who were hospitalized for acute asthma. Patients with SLTA were more likely to have had prior SLTA or hospital admissions in the prior year. The SLTA group had no evidence of increased physical, economic, or other barriers to health care, but they had a demonstrable deficiency in their self-management skills. Contrary to previous reports, this study found few differences in areas of sociodemographic factors in patients with SLTA and recommended educational interventions that focus on providing individual patients with better advice on the self-management of acute exacerbations of asthma.

4. Lazarus SC, Boushey HA, Fahy JV, et al. Long-acting β2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized trial. JAMA 2001; 285:2583–2593

One hundred sixty-four patients with persistent asthma that was well-controlled with triamcinolone therapy were randomly assigned to receive salmeterol alone or to receive continued therapy with low-dose triamcinolone. Patients who switched to salmeterol monotherapy had a greater increase in sputum eosinophils, more treatment failures, and more asthmatic exacerbations compared to the group receiving low-dose inhaled corticosteroids (ICSs). The results of this study emphasized the importance of combining antiinflammatory therapy with long-acting β-agonist therapy and should be a warning to patients who rely on bronchodilators alone.

5. Coreno A, Skowronski M, Kotaru C, et al. Comparative effects of long-acting β2-agonists, leukotriene receptor antagonists, and a 5-lipoxygenase inhibitor on exercise-induced asthma. J Allergy Clin Immunol 2000; 106:500–506

This randomized, double-blinded, placebo- controlled study compared the effectiveness of long-acting β-agonist therapy to therapy with leukotriene inhibitors and the relative potencies of the antileukotriene agents on exercise-induced asthma. Salmeterol acted quickly and significantly blunted the obstructive response for 12 h. The leukotriene inhibitors produced an effect within 1 h of ingestion that was equal to the effect of long-acting β-agonists. Zileuton provided equivalent prophylaxis for the first 4 h, but by 8 h it was less efficacious than montelukast or zafirlukast. Although the sample size was small, this well-designed study provides comparative data regarding therapy for patients with exercise-induced asthma.

6. Busse W, Corren J, Lanier BQ, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 2001; 108:184–190

This study evaluated the efficacy of a recombinant humanized anti-IgE, omalizumab, in 525 patients with allergic asthma requiring daily therapy ICSs. Omalizumab treatment resulted in a lower number of asthmatic patients experiencing exacerbations (14.6% vs 23.3%, respectively; p = 0.009) during the initial 16 weeks while receiving a stable steroid dose as well as fewer exacerbations (21.3% vs 32.3%, respectively; p = 0.004) during the 12-week steroid-reduction phase. Therapy with ICSs was more likely to be discontinued with omalizumab (39.6% vs 19.1%, respectively; p < 0.001). The adverse-event profile with omalizumab was similar to that of placebo. Because IgE is an early and central mediator that is responsible for the induction and amplification of allergic reactions, recombinant anti-IgE is a promising therapeutic agent in the treatment of asthma. Future studies will clarify its role in patients with poorly controlled or steroid-resistant asthma.

7. Borish LC, Nelson HS, Corren J, et al. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol 2001; 107:963–970

Interleukin (IL)-4 has a unique biological activity in its ability to drive the differentiation of naïve T lymphocytes into the T-helper 2 phenotype and may play a key role in chronic asthma. In this study, 62 patients with moderate persistent asthma who had documented dependence on ICSs were randomized to weekly doses of nebulized, recombinant, human, soluble IL-4 receptor (IL-4R) or placebo. After a period of stabilization, therapy with ICSs was withdrawn. By 28 days, 50% of patients receiving placebo vs only 33% of patients receiving 3.0 mg IL-4R discontinued the study secondary to the exacerbations of symptoms. Over 3 months of treatment, this IL-4R group maintained the FEV1 after corticosteroid discontinuation (a decline of only 2%) compared to significant worsening in the placebo group (decline, 13%; p = 0.05). No significant adverse effects accompanied the use of nebulized IL-4R. Although there were no significant differences in the number of circulating eosinophils or the total IgE level over the duration of this study, patients receiving nebulized soluble IL-4R maintained better control of their asthma after corticosteroid withdrawal.

8. 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

This multicenter study evaluated the efficacy of adding salmeterol or montelukast to patients whose conditions were suboptimally controlled by ICS therapy. Four hundred forty-seven patients were randomized to receive 12 weeks of therapy with fluticasone, 100 μg, plus either salmeterol, 50 μg twice daily, or oral montelukast, 10 mg daily, in a double-blind, double-dummy protocol. The combination of a therapy with a long-acting β-agonist and ICSs resulted in significantly greater morning peak expiratory flow (24.9 vs 13.0 L/min, respectively; p < 0.001), FEV1 at clinic visits (0.34 vs 0.20 L, respectively; p < 0.001), and the percentage of days with no albuterol use (26.3% vs 19.1%, respectively; p = 0.032). Asthma exacerbation rates were also significantly lower in the salmeterol/fluticasone group (p = 0.031). Of note, patients in the salmeterol/fluticasone group still used > 2 puffs per day albuterol after 12 weeks of treatment.

9. Rodrigo GJ, Rodrigo C. First-line therapy for adult patients with acute asthma receiving a multiple-dose protocol of ipratropium bromide plus albuterol in the emergency department. Am J Respir Crit Care Med 2000; 161:1862–1868

This double-blinded study randomized 180 patients presenting to the emergency department with a severe exacerbation of asthma (FEV1, < 50% of baseline) to receive high-dose albuterol (2,800 μg/h) or a combination of high-dose albuterol and ipratropium bromide (2,800 and 504 μg/h, respectively). The medications were administered through a metered-dose inhaler with a valved spacer device in a dose of 4 puffs at 10-min intervals for 3 h. Therapy with aminophylline and systemic corticosteroids were excluded in all patients. Patients receiving the combination of ipratropium and albuterol had an overall 20.5% greater improvement in peak flow (95% confidence interval [CI], 2.6 to 38.4%) and a 48.1% greater improvement in FEV1 (95% CI, 19.8 to 76.4%). The objective criteria for hospital admission were established in the study protocol. The addition of ipratropium to albuterol therapy reduced the relative risk of hospital admission by 49% (relative risk, 0.51; 95% CI, 0.31 to 0.83). This single-center study suggests that aggressive therapy with combined high-dose β-agonists and ipratropium results in improved lung function and reduced hospital admission rates in patients with severe exacerbations of asthma.

10. Israel E, Banerjee TR, Fitzmaurice GM, et al. Effects of inhaled glucocorticoids on bone density in premenopausal women. N Engl J Med 2001; 345:941–947

ICS therapy is the most effective antiinflammatory treatment for asthma. However, the effects of the long-term use of ICSs on bone metabolism and the associated risk of osteoporosis remain controversial. Although some studies have shown a reduction in bone mineral density, others have not. Most of these studies have been conducted in a cross-sectional fashion. This 3-year prospective study by Israel et al evaluated 109 premenopausal women with asthma and no known conditions that cause bone loss who were treated with inhaled triamcinolone. Supplemental dietary calcium and vitamin D intake were standardized, and physical activity scores were monitored. ICS therapy was associated with a dose-related decline in bone density at both the total hip and trochanter of 0.00044 g/cm2 per puff per year of treatment (p ≤ 0.01). Even after the exclusion of all women who received systemic corticosteroids at any time during the study, there was still an association between the decline in bone density and the number of puffs per year. This study suggests a real, but very low, risk of osteoporosis with higher doses of inhaled corticosteroids.

Abbreviations: CI = confidence interval; ICS = inhaled corticosteroid; IL = interleukin; IL-4R = interleukin 4 receptor; SLTA = severe life-threatening asthma




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