Asthma

Web site for latest treatment guidelines:
http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf

Monitoring asthma control

Szefler SJ, Mitchell H, Sorkness CA, et al. Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults. Lancet 2008; 2008; 372:1065-72. 46-week randomized study of 546 patients with persistent asthma found adding measurement of exhaled nitric oxide to guideline-based care did not improve outcomes but increased inhaled steroid use compared to management based on guidelines alone.
PMID: 18805335
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Inhaled steroids vs. bronchodilators

Nelson HS, Weiss ST, Bleecker ER, et al, SMART Study Group. The salmeterol multicenter asthma research trial. Chest 2006; 129:15-26. This randomized, double-blinded, placebo-controlled, observational study (N= 26,355) showed a small, but statistically significant increase in respiratory-related and asthma-related deaths for the population receiving salmeterol. It is uncertain whether poor outcomes were due to physiologic treatment effects, genetic factors, lack of concomitant inhaled corticosteroid use, or patient behaviors.
PMID: 16424409
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Jaeschke R, O’Byrne PM, Mejza F, et al. The safety of long-acting beta-agonists among patients with asthma using inhaled corticosteroids: systematic review and metaanalysis. Am J Respir Crit Care Med. 2008; 178:1009-16. Results of the above SMART study have prompted greater scrutiny of long-acting beta-agonist use. This metaanalysis suggests these medications do not reduce or increase the risk of asthma-related admits or all-cause mortality when administered concomitantly with inhaled corticosteroids. The analysis was not able to address risk based on race or in children.
PMID: 18776152
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Haahtala T, Jarvinen M, Kava T, et al. Comparison of a beta 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. New Engl J Med 1991; 325:388-92. This randomized, blinded comparison of the above two drugs was important in establishing inhaled corticosteroids as the first line treatment for asthma.
PMID: 2062329
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As-needed use of inhaled steroids in mild asthma

Boushey HA, Sorkness CA, King TS, et al. Daily versus as-needed corticosteroids for mild persistent asthma. N Engl J Med 2005; 352:1519-28. A year-long RCT of 225 adults with mild persistent asthma compared prn inhaled corticosteroids based upon symptom-based action plan vs. daily treatment with ICS vs. daily leukotriene inhibitor and found no difference in morning peak expiratory flow and the rate of asthma exacerbations despite the prn corticosteroid group using an average of only 0.5 week of steroid per year. The ICS group had superior asthma control scores and lower markers of airway inflammation. Some attribute this relatively modest benefit of regular ICS use to the lower exacerbation rate in this study compared to its predecessors, which speaks to the challenge of identifying mild persistent asthmatics.
PMID: 15829533
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Papi A, Canonica GW, Maestrelli P, et al. Symptomatic use of beclomethasone plus albuterol and regular use of beclomethasone did not differ for control of mild asthma. N Engl J Med 2007; 356:2040-52. RCT of 466 patients of 6 months duration found PRN use of a single inhaler combination of beclomethasone and albuterol resulted in better peak flows and fewer exacerbations compared to PRN use of albuterol alone, as well as comparable peak flows, exacerbation rate, lung function, and symptoms to regular twice daily use of beclomethasone. The PRN beclomethasone group on average used < 125 mcg/day compared to 500 mcg/day in the regular twice daily groups.
PMID: 17507703
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Inhaled steroid vs. leukotriene receptor antagonists

Laviolette M, Malmstrom K, Lu S, et al. Montelukast added to inhaled beclomethasone in treatment of asthma. Am J Respir Crit Care Med 1999;160:1862-68. This randomized, double-blinded study supports the addition of a leukotriene inhibitor for asthmatics with inadequate symptom control with inhaled corticosteroid alone.
PMID: 10588598
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Malmstrom K, Rodriguez-Gomez G, Guerra J, et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. A randomized controlled trial. Ann Intern Med 1999;130:487-95. Both inhaled steroid and a leukotriene inhibitor were better than placebo. Beclomethasone was significantly better than montelukast in reducing exacerbations and symptoms.
PMID: 10075616
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Combination therapies

O’Byrne PM, Bisgaard H, Godard PP, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005: 171;129-36. This study included 2,760 asthmatics with a history of at least one exacerbation in the previous year and regular need for rescue bronchodilators despite baseline use of, on average, moderate doses of inhaled corticosteroid. Patients randomized to budesonide/formoterol (80/4.5) bid and prn had prolonged time to exacerbations requiring medical intervention compared to combination therapy with terbutaline prn or higher dose steroid (budesonide 320 bid) plus terbutaline prn. Subsequent RCTs have also shown favorable outcomes with this approach.
PMID: 15502112
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Bateman ED, Boushey HA, Bousquet J, et al. GOAL Investigators Group. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma Control study. Am J Respir Crit Care Med. 2004;170:836-44. This is a 1-year, randomized, stratified, double-blind, parallel-group study (n=3,421) of patients with uncontrolled asthma comparing the addition of LABA vs escalating steroidin achieving two rigorous, composite, guideline-based measures of control: totally and well-controlled asthma. Control was achieved more rapidly and at a lower corticosteroid dose with salmeterol/fluticasone versus fluticasone alone.
PMID: 15256389
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Peters SP, Kunselman SJ, Icitovic N, et al. for the National Heart, Lung, and Blood Institute Asthma Clinical Research Network. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 2010;363:1715-26. The TALC study showed that, in patients with asthma inadequately controlled by low-moderate dose inhaled corticosteroid therapy, the addition of long-acting anticholinergic therapy was superior to corticosteroid dose escalation and noninferior to long-acting beta-agonist therapy. However, the study was not powered to compare the effect on exacerbations.
PMID: 20979471

Anti-IgE therapy

Busse WW. Anti-immunoglobulin E (omalizumab) therapy in allergic asthma. Am J Respir Crit Care Med 2001;164(8Pt2):S12-7. Review summarizes several large RCTs studying the role of anti-IgE antibody in allergic asthma. The use of anti-IgE is associated with decreased frequency of exacerbations, reductions in corticosteroid dose, and improved quality of life in symptomatic patients with moderate to severe allergic asthma.
PMID: 11704612
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Proton pump inhibitors

Mastronade JG, Anthonisen NR, Castro M, et al. Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med 2009; 360:1487-99. 412 patients with minimal or no reflux symptoms and poorly controlled asthma despite moderate to high dose of inhaled corticosteroids to high-dose esomeprazole. Subjects underwent 24-hour esophageal pH studies prior to starting proton pump inhibitor. The study is noteworthy for finding no improvement in asthma control in this population, regardless of the presence of asymptomatic gastroesophageal reflux.
PMID: 19357404
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Bronchial thermoplasty

Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. (AIR2 Trial) Am J Respir Crit Care Med 2010;181:116-24. The AIR2 trial was the first large scale randomized study of bronchial thermoplasty to include a sham control. 288 patients with asthma symptoms despite standard therapy (high dose ICS + LABA) were included. During the 12 month follow up, the treatment group had a lower number of adverse respiratory events, severe exacerbations, emergency department visits, and hospitalizations, as well as a greater number (81%) of subjects reporting improvement in AQLQ. Notably, 63% of control subjects also reported clinically significant (>0.5) improvement in AQLQ. During treatment, 8.4% in treatment group were hospitalized for respiratory symptoms compared to 2.0% in the sham group.
PMID: 19815809
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Exercise-induced bronchoconstriction

Edelman JM, Turpin JA, Bronsky EA, et al. Oral montelukast compared with inhaled salmeterol to prevent exercise- induced bronchoconstriction. A randomized, double-blind trial. Ann Intern Med 2000;132:97-104. Study found leukotriene blockade has equal efficacy to a beta-agonist for the prevention of EIB and that daily administration is not associated with a reduction in efficacy that may be seen with daily dosing of long-acting beta agonists.
PMID: 10644288
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Airway remodeling

Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 1998;339:1194-200. Noteworthy for being one of the studies showing that a portion of patients with asthma go on to develop fixed airway obstruction.
PMID: 9780339
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