Monitoring asthma with FeNO

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; 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

Inhaled steroids vs. bronchodilators

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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Safety of LABA use

Nelson HS, Weiss ST, Bleecker ER, et al, SMART Study Group. The salmeterol multicenter asthma research trial. Chest 2006; 129:15-26. The SMART trial, a randomized, double-blinded, placebo-controlled trial (N= 26,355) showed a small, but statistically significant increase in respiratory-related and asthma-related deaths for the population receiving salmeterol. Subgroup analyses suggested the risk may be greater in African Americans compared with Caucasians. 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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Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs long-acting β-agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial. JAMA. 2015; 1720-1730. This randomized, open-label study compared adding either a long-acting beta-agonist or long-acting anticholinergic to inhaled corticosteroids in 1070 African-American patients with asthma with a mean follow up of 310 days. The authors found no difference in time-to-exacerbation or adverse events between the two groups. The authors found no excess risk with using a combination of long-acting beta-2 agonists and inhaled corticosteroids in an African American population.

PMID: 26505596

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The following are the first two in a series of four FDA-mandated trials on patients with persistent asthma comparing the safety of inhaled corticosteroid compared with combined inhaled corticosteroid and long-acting beta agonist. The trials are large (~11,700 patients) and have similar protocols. In both trials the combined endpoint of death, intubation, and admission was rare (0.3-0.6%) and not different between the two groups. The absolute risk reduction in exacerbations were 1.6% and 2% with combination therapy. Potential treatment limitations include unusually high treatment adherence and exclusion of patients with uncontrolled asthma.

Peters SP, Bleecker ER, Canonica GW, et al. Serious asthma events with budesonide plus formoterol vs. budesonide alone. N Engl J Med. 2016; 850-860.

PMID: 27579635

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Stempel DA, Raphiou IH, Kral KM, et al. Serious asthma events with fluticasone plus salmeterol versus fluticasone alone.  N Engl J Med. 2016; 1822-1830.

PMID: 26949137

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As needed use of ICS/LABA for mild asthma

The following 2 large, randomized studies among patients with mild asthma are noteworthy for finding ICS/LABA inhaler used only on a prn basis resulted in an exacerbation rate similar to use of bid ICS maintenance therapy but with substantially lower overall steroid exposure. However, daily asthma symptom scores were better among subjects receiving ICS maintenance therapy.  

O'Byrne PM, FitzGerald JM, Bateman ED et al. Inhaled Combined Budesonide-Formoterol as Needed in Mild Asthma. N Engl J Med. 2018 May 17;378(20):1865-1876.

PMID: 29768149

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Bateman ED, Reddel HK, O'Byrne PM et al. As-Needed Budesonide-Formoterol versus Maintenance Budesonide in Mild Asthma. N Engl J Med. 2018 May 17;378(20):1877-1887.

PMID: 29768147

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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

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

Combination therapies

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 1-year, randomized study (n=3,421) of patients with uncontrolled asthma compared the addition of LABA vs escalating steroid in 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

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 adding long-acting beta-agonist therapy. However, the study was not powered to compare the effect on exacerbations.

PMID: 20979471

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Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med. 2012; 367:1198-207. 48 week randomized study of 912 patients with poorly controlled asthma despite receiving ICS/LABA combination therapy found that the addition of tiotropium (Respimat soft-mist inhaler rather than dry powder) demonstrated a statistically significant improvement in FEV1 (230ml) that was less than the minimal clinically important difference, but also a 21% reduction in severe exacerbations.


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Azithromycin to reduce asthma exacerbations

Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017; 12;390: 659-668. Randomized double-blind trial of 420 patients with uncontrolled persistent asthma on medium-to-high dose ICS plus a LABA.  Azithromycin 500 mg three times per week reduced moderate/severe exacerbations (1.07 per patient year vs 1.86 per patient year, p<0.0001) and improved asthma QOL.

PMID: 28687413

Difficult to Control Asthma

Chung KF, Wenzel SE, Brozek JL. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014;43: 343–373. These guidelines provide an updated definition of severe asthma and are noteworthy for recommending against the use of exhaled nitric oxide for guiding therapy and the use of bronchial thermoplasty outside of a clinical trial.

PMID: 24337046

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Anti-IgE Therapy

Hanania NA, Alpan O, Hamilos, et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med 2011;154:573-82. In this multicenter RCT (n=850), of patients with inadequately controlled asthma despite high-dose ICS and LABA, the addition of omalizumab reduced the one-year exacerbation rate (NNT of 5 to prevent one exacerbation/year) and reduced use of rescue albuterol by 0.27 puffs/day.

PMID: 21536936

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Anti-IL5 Therapy

Prior studies of the IL-5 antagonist mepolizumab in unselected patients with clinical asthma did not show significant benefit. Subsequent studies demonstrated efficacy in patients with increased sputum eosinophils, but access to this test is not widely available. The following 2 RCTs of mepolizumab in severe asthma with peripheral eosinophilia (at least > 150 cell/microL depending on study) found mepolizumab decreased the frequency of exacerbations by roughly 30 to 50%. All patients in the Bel et al study were on oral corticosteroids at baseline and median dose decreased from 10 mg to 3 mg/day with mepolizumab.  Of note, in the Ortega study, exacerbations in the control group decreased from 3.6 to 1.75/year, raising concerns about suboptimal baseline asthma treatment.

Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014; 371: 1198-1207.  

PMID: 25199059

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Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014; 371: 1189-1197.

PMID: 25199060

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Anti-IL4 and IL13 Therapy

Dupilumab is an anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. The following RCTs compared dupilumab to placebo in patients receiving chronic oral steroids (Rabe) or uncontrolled asthma despite an aggressive inhaler regimen (Castro). Rabe et al found a 70% reduction in oral glucocorticoid use while Castro et al found a 47% (200 mg dose) and 65% (300 mg dose) reduction in severe exacerbations. Of note, neither trial had peripheral eosinophilia as an inclusion criteria but Castro et al did note greater benefits in patients with higher baseline levels of eosinophils.

Rabe KF, Nair P, Brusselle G et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med. 2018; 378:2475-2485.

PMID: 29782224

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Castro M, Corren J, Pavord ID et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018; 378:2486-2496.

PMID: 29782217

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The role of nonadherence in refractory asthma

Gamble J, Stevenson M, McClean E, et al. The prevalence of nonadherence in difficult asthma. Am J Respir Crit Care Med 2009;180:817-22. In a patient population referred for specialist care in the setting of refractory asthma, 35% of patients filled fewer than half of their prescriptions for inhaled corticosteroids. Nonadherent patients had significantly lower asthma-specific quality of life. This study highlights an important and often overlooked factor in asthma refractoriness.

PMID: 19644048

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 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% of patients in the treatment group were hospitalized for respiratory symptoms compared to 2.0% in the sham group.

PMID: 19815809

Exercise-induced bronchoconstriction

Parsons JP, Hallstrand TS, Mastronarde JG, et al. An official American Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction. Am J Respir Crit Care Med 2013; 187:1016-1027. This guideline offers a succinct, practical overview of EIB management, including the strength of evidence supporting various options for diagnosis and treatment.

PMID: 23634861

**See also Invasive Mechanical Ventilation and Occupational Medicine