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SEVERE ASTHMA SERIES
Severe asthma: Current and future treatments
Eleftherios Zervas 1
,
 
Chris Brightling 2
,
 
Mina Gaga 1
 
 
 
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1
7th Pneumonology Department and Asthma Centre, Athens Chest Hospital, Athens, Greece
 
2
Institute for Lung Health, University of Leicester, Glenfield Hospital, UK
 
 
Corresponding author
Eleftherios Zervas   

7th Pneumonology Dept. and Asthma Centre, Athens Chest Hospital, Mesogion Ave. 152, 11527 Athens, Greece
 
 
Pneumon 2011;24(4):405-416
 
Article (PDF)
References (131)
 
KEYWORDS
severe asthma
 definition
 treatment
 
ABSTRACT
Most forms of asthma can be controlled by inhaled corticosteroids (ICS), but a substantial number of patients still experience symptoms and limitations in their personal and social life despite being on appropriate maintenance therapy. These patients with severe asthma account for almost half of the cost of the disease and most of its morbidity and mortality. To date, the use of ICS and long acting bronchodilators (LABAs) is the basis of severe asthma treatment, but the optimal use and dosage of these drugs should be determined based on the available evidence. Anti-immunoglobulin E (anti-IgE) has been recently established for the treatment of patients with severe allergic asthma whose symptoms are inadequately controlled with ICS/LABA. The use of long-acting anticholinergics (LAMA) as add-on therapy is currently under investigation in clinical trials. Alternative forms of treatment, such as macrolide therapy, have produced conflicting results, while an approach based on anti-tumour necrosis factor-α (anti-TNFα) has proven ineffective. The targeted inhibition of interleukin (IL) 2, IL 4, IL 5, IL-9 and IL 13 is currently being investigated. A nondrug treatment, bronchial thermoplasty (BT), has been reported to provide some benefits to patients with severe asthma, but the long-term benefit/risk ratio for BT is unknown at present. In view of the heterogeneity of severe asthma, the present challenge is to determine the appropriate phenotype for current and innovative forms of treatment. 
 
REFERENCES (131)
1.
Bateman ED, Boushey HA, Bousquet J et al. Can guidelinedefined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004;170:836- 844.
Google Scholar
 
 
2.
Rabe KF, Atienza T, Magyar P et al. Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet 2006;368:744-753.
Google Scholar
 
 
3.
Virchow JC, Mehta A, Ljungblad L, Mitfessel H. Add-on montelukast in inadequately controlled asthma patients in a 6-month open-label study: the MONtelukast In Chronic Asthma (MONICA) study. Respir Med 2010;104:644-651.
Google Scholar
 
 
4.
Demoly P, Gueron B, Annunziata K, Adamek L, Walters RD. Update on asthma control in five European countries: results of a 2008 survey. Eur Respir Rev 2010;19:150-157.
Google Scholar
 
 
5.
Gaga M, Papageorgiou N, Zervas E, Gioulekas D, Konstantopoulos S. Control of asthma under specialist care: is it achieved? Chest 2005;128:78-84.
Google Scholar
 
 
6.
Gianniou N, Rovina N. Poor asthma control in clinical practice: quantifying the perspective of improvement. Pneumon 2008;21:283-292.
Google Scholar
 
 
7.
Dockrell M, Partridge MR, Valovirta E. The limitations of severe asthma: the results of a European survey. Allergy 2007;62:134- 141.
Google Scholar
 
 
8.
Heaney LG, Brightling CE, Menzies-Gow A, Stevenson M, Niven RM. Refractory asthma in the UK: cross-sectional findings from a UK multicentre registry. Thorax 2010;65:787-794.
Google Scholar
 
 
9.
Chung KF, Godard P, Adelroth E et al. Difficult/therapy-resistant asthma: the need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies. ERS Task Force on Difficult/TherapyResistant Asthma. European Respiratory Society. Eur Respir J 1999;13:1198-1208.
Google Scholar
 
 
10.
Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. American Thoracic Society. Am J Respir Crit Care Med 2000;162:2341-2351.
Google Scholar
 
 
11.
Global Strategy for Asthma Management and Prevention. NIH Publication No 02-3659 Issued January, 1995 (updated 2009). Available on www.ginasthma.org.
Google Scholar
 
 
12.
Bousquet J, Mantzouranis E, Cruz AA et al. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol 2010;126:926-938.
Google Scholar
 
 
13.
Chanez P, Wenzel SE, Anderson GP et al. Severe asthma in adults: what are the important questions? J Allergy Clin Immunol 2007;119:1337-1348.
Google Scholar
 
 
14.
Loukides S, Kostikas K, Bakakos P. Severe refractory asthma: An asthma phenotype with multiple phenotypes? Pneumon 2011;24:232-234.
Google Scholar
 
 
15.
National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics--2007. J Allergy Clin Immunol 2002;110:S141-S219.
Google Scholar
 
 
16.
Tinkelman DG, Price DB, Nordyke RJ, Halbert RJ. Misdiagnosis of COPD and asthma in primary care patients 40 years of age and over. J Asthma 2006;43:75-80.
Google Scholar
 
 
17.
Oliveinstein R, Al JH, Alkhamis N et al. Challeges in the management of severe asthma: role of current and future therapies. Curr Pharm Des 2011;17:703-711.
Google Scholar
 
 
18.
Aaron SD, Vandemheen KL, Boulet LP et al. Overdiagnosis of asthma in obese and nonobese adults. CMAJ 2008;179:1121- 1131.
Google Scholar
 
 
19.
Gamble J, Stevenson M, McClean E, Heaney LG. The prevalence of nonadherence in difficult asthma. Am J Respir Crit Care Med 2009;180:817-822.
Google Scholar
 
 
20.
Kandane-Rathnayake RK, Matheson MC, Simpson JA et al. Adherence to asthma management guidelines by middle-aged adults with current asthma. Thorax 2009;64:1025-1031.
Google Scholar
 
 
21.
Bae YJ, Kim TB, Jee YK et al. Severe asthma patients in Korea overestimate their adherence to inhaled corticosteroids. J Asthma 2009;46:591-595.
Google Scholar
 
 
22.
Weinstein AG. Should patients with persistent severe asthma be monitored for medication adherence? Ann Allergy Asthma Immunol 2005;94:251-257.
Google Scholar
 
 
23.
Gaga M, Zervas E, Grivas S, Castro M, Chanez P. Evaluation and management of severe asthma. Curr.Med.Chem. 2007;14:1049- 1059.
Google Scholar
 
 
24.
Barnes PJ. How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol 2006;148:245-254.
Google Scholar
 
 
25.
Powell H, Gibson PG. Initial starting dose of inhaled corticosteroids in adults with asthma: a systematic review. Thorax 2004;59:1041-1045.
Google Scholar
 
 
26.
Szefler SJ, Martin RJ, King TS et al. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol 2002;109:410-418.
Google Scholar
 
 
27.
Reddel HK. Goals of asthma treatment: how high should we go? Eur Respir J 2004;24:715-717.
Google Scholar
 
 
28.
Haldar P, Pavord ID, Shaw DE et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008;178:218- 224.
Google Scholar
 
 
29.
Green RH, Brightling CE, Bradding P. The reclassification of asthma based on subphenotypes. Curr Opin Allergy Clin Immunol 2007;7:43-50.
Google Scholar
 
 
30.
Brightling CE, Green RH, Pavord ID. Biomarkers predicting response to corticosteroid therapy in asthma. Treat Respir Med 2005;4:309-316.
Google Scholar
 
 
31.
Rovina N, Baraldo S, Saetta M. Severe asthma: inflammation. Pneumon 2011;24:306-313.
Google Scholar
 
 
32.
Balzar S, Wenzel SE, Chu HW. Transbronchial biopsy as a tool to evaluate small airways in asthma. Eur Respir J 2002;20:254- 259.
Google Scholar
 
 
33.
Balzar S, Chu HW, Strand M, Wenzel S. Relationship of small airway chymase-positive mast cells and lung function in severe asthma. Am J Respir Crit Care Med 2005;171:431-439.
Google Scholar
 
 
34.
in ‘t Veen JC, Beekman AJ, Bel EH, Sterk PJ. Recurrent exacerbations in severe asthma are associated with enhanced airway closure during stable episodes. Am J Respir Crit Care Med 2000;161:1902-1906.
Google Scholar
 
 
35.
Lahzami S, King GG. Targeting small airways in asthma: the new challenge of inhaled corticosteroid treatment. Eur Respir J 2008;31:1145-1147.
Google Scholar
 
 
36.
Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129:15-26.
Google Scholar
 
 
37.
Bateman E, Karpel J, Casale T, Wenzel S, Banerji D. Ciclesonide reduces the need for oral steroid use in adult patients with severe, persistent asthma. Chest 2006;129:1176-1187.
Google Scholar
 
 
38.
Johnson M. The beta-adrenoceptor. Am J Respir Crit Care Med 1998;158:S146-S153.
Google Scholar
 
 
39.
Loukides S. Long acting β2-agonists in asthma: friend or foe? Pneumon 2007;20:120-122.
Google Scholar
 
 
40.
Weatherall M, Wijesinghe M, Perrin K, Harwood M, Beasley R. Meta-analysis of the risk of mortality with salmeterol and the effect of concomitant inhaled corticosteroid therapy. Thorax 2010;65:39-43.
Google Scholar
 
 
41.
Wijesinghe M, Weatherall M, Perrin K, Harwood M, Beasley R. Risk of mortality associated with formoterol: a systematic review and meta-analysis. Eur Respir J 2009;34:803-811.
Google Scholar
 
 
42.
Beasley R, Perrin K, Weatherall M, Wijesinghe M. Call for withdrawal of LABA single-therapy inhaler in asthma. Lancet 2010;376:750-751.
Google Scholar
 
 
43.
Kanniess F, Boulet LP, Pierzchala W et al. Efficacy and safety of indacaterol, a new 24-hour beta2-agonist, in patients with asthma: a dose-ranging study. J Asthma 2008;45:887-892.
Google Scholar
 
 
44.
LaForce C, Alexander M, Deckelmann R et al. Indacaterol provides sustained 24 h bronchodilation on once-daily dosing in asthma: a 7-day dose-ranging study. Allergy 2008;63:103-111.
Google Scholar
 
 
45.
Yang WH, Martinot JB, Pohunek P et al. Tolerability of indacaterol, a novel once-daily beta2-agonist, in patients with asthma: a randomized, placebo-controlled, 28-day safety study. Ann. Allergy Asthma Immunol 2007;99:555-561.
Google Scholar
 
 
46.
Sin DD, Man SF. Corticosteroids and adrenoceptor agonists: the compliments for combination therapy in chronic airways diseases. Eur J Pharmacol 2006;533:28-35.
Google Scholar
 
 
47.
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;171:129-136.
Google Scholar
 
 
48.
Cates CJ, Lasserson TJ. Combination formoterol and inhaled steroid versus beta2-agonist as relief medication for chronic asthma in adults and children. Cochrane Database Syst Rev 2009CD007085.
Google Scholar
 
 
49.
Chapman KR, Barnes NC, Greening AP, Jones PW, Pedersen S. Single maintenance and reliever therapy (SMART) of asthma: a critical appraisal. Thorax 2010;65:747-752.
Google Scholar
 
 
50.
Campbell JD, Borish L, Haselkorn T et al. The response to combination therapy treatment regimens in severe/difficultto-treat asthma. Eur Respir J 2008;32:1237-1242.
Google Scholar
 
 
51.
Rodger IW. Role of leukotrienes and leukotriene receptor antagonist in asthma: new advances. J Investig Allergol Clin Immunol 1997;7:279.
Google Scholar
 
 
52.
Kemp JP. Recent advances in the management of asthma using leukotriene modifiers. Am J Respir Med 2003;2:139-156.
Google Scholar
 
 
53.
Clinical trial of low-dose theophylline and montelukast in patients with poorly controlled asthma. Am J Respir Crit Care Med 2007;175:235-242.
Google Scholar
 
 
54.
Strunk RC, Bacharier LB, Phillips BR et al. Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderateto severe childhood asthma study. J Allergy Clin Immunol 2008;122:1138-1144.
Google Scholar
 
 
55.
Tonelli M, Zingoni M, Bacci E et al. Short-term effect of the addition of leukotriene receptor antagonists to the current therapy in severe asthmatics. Pulm Pharmacol Ther 2003;16:237-240.
Google Scholar
 
 
56.
Lee DK, Haggart K, Robb FM, Lipworth BJ. Montelukast protects against nasal lysine-aspirin challenge in patients with aspirininduced asthma. Eur Respir J 2004;24:226-230.
Google Scholar
 
 
57.
Tee AK, Koh MS, Gibson PG et al. Long-acting beta2-agonists versus theophylline for maintenance treatment of asthma. Cochrane Database Syst Rev 2007CD001281.
Google Scholar
 
 
58.
Patel YA, Patel P, Bavadia H, Dave J, Tripathi CB. A randomized, open labeled, comparative study to assess the efficacy and safety of controller medications as add on to inhaled corticosteroid and long-acting beta2 agonist in the treatment of moderate-to-severe persistent asthma. J Postgrad Med 2010;56:270-274.
Google Scholar
 
 
59.
Vatrella A, Ponticiello A, Pelaia G, Parrella R, Cazzola M. Bronchodilating effects of salmeterol, theophylline and their combination in patients with moderate to severe asthma. Pulm Pharmacol Ther 2005;18:89-92.
Google Scholar
 
 
60.
Barnes PJ, Adcock IM, Ito K. Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J 2005;25:552-563.
Google Scholar
 
 
61.
D’Amato G. Role of anti-IgE monoclonal antibody (omalizumab) in the treatment of bronchial asthma and allergic respiratory diseases. Eur J Pharmacol 2006;533:302-307.
Google Scholar
 
 
62.
Holgate ST, Chuchalin AG, Hebert J et al. Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma. Clin Exp Allergy 2004;34:632-638.
Google Scholar
 
 
63.
Humbert M, Beasley R, Ayres J et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005;60:309- 316.
Google Scholar
 
 
64.
Corren J, Casale TB, Lanier B et al. Safety and tolerability of omalizumab. Clin Exp Allergy 2009;39:788-797.
Google Scholar
 
 
65.
Bousquet J, Siergiejko Z, Swiebocka E et al. Persistency of response to omalizumab therapy in severe allergic (IgE-mediated) asthma. Allergy 2011;66:671-678.
Google Scholar
 
 
66.
Busse WW, Morgan WJ, Gergen PJ et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med 2011;364:1005-1015.
Google Scholar
 
 
67.
Domingo C, Moreno A, Jose AM et al. Omalizumab in the management of oral corticosteroid-dependent IGE-mediated asthma patients. Curr Med Res Opin 2011;27:45-53.
Google Scholar
 
 
68.
Molimard M, Buhl R, Niven R et al. Omalizumab reduces oral corticosteroid use in patients with severe allergic asthma: real-life data. Respir Med 2010;104:1381-1385.
Google Scholar
 
 
69.
Slavin RG, Ferioli C, Tannenbaum SJ et al. Asthma symptom re-emergence after omalizumab withdrawal correlates well with increasing IgE and decreasing pharmacokinetic concentrations. J Allergy Clin Immunol 2009;123:107-113.
Google Scholar
 
 
70.
Nopp A, Johansson SG, Adedoyin J et al. After 6 years with Xolair; a 3-year withdrawal follow-up. Allergy 2010;65:56-60.
Google Scholar
 
 
71.
ten BA, van Dissel JT, Sterk PJ et al. Persistent airflow limitation in adult-onset nonatopic asthma is associated with serologic evidence of Chlamydia pneumoniae infection. J Allergy Clin Immunol 2001;107:449-454.
Google Scholar
 
 
72.
Huang YJ, Nelson CE, Brodie EL et al. Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma. J Allergy Clin Immunol 2011;127:372-381.
Google Scholar
 
 
73.
Karabela E, Demopoulos G. Immunomodulatory actions of antibiotics. Pneumon 2008;21:33-44.
Google Scholar
 
 
74.
Beuther DA, Martin RJ. Antibiotics in asthma. Curr Allergy Asthma Rep 2004;4:132-138.
Google Scholar
 
 
75.
Kraft M, Cassell GH, Pak J, Martin RJ. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin. Chest 2002;121:1782-1788.
Google Scholar
 
 
76.
Kostadima E, Tsiodras S, Alexopoulos EI et al. Clarithromycin reduces the severity of bronchial hyperresponsiveness in patients with asthma. Eur Respir J 2004;23:714-717.
Google Scholar
 
 
77.
Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med 2008;177:148-155.
Google Scholar
 
 
78.
Garey KW, Rubinstein I, Gotfried MH et al. Long-term clarithromycin decreases prednisone requirements in elderly patients with prednisone-dependent asthma. Chest 2000;118:1826- 1827.
Google Scholar
 
 
79.
Sutherland ER, King TS, Icitovic N et al. A trial of clarithromycin for the treatment of suboptimally controlled asthma. J Allergy Clin Immunol 2010;126:747-753.
Google Scholar
 
 
80.
Rodrigo GJ, Rodrigo C. The role of anticholinergics in acute asthma treatment: an evidence-based evaluation. Chest 2002;121:1977-1987.
Google Scholar
 
 
81.
Westby M, Benson M, Gibson P. Anticholinergic agents for chronic asthma in adults. Cochrane Database Syst Rev 2004CD003269.
Google Scholar
 
 
82.
Iwamoto H, Yokoyama A, Shiota N et al. Tiotropium bromide is effective for severe asthma with noneosinophilic phenotype. Eur Respir J 2008;31:1379-1380.
Google Scholar
 
 
83.
Park HW, Yang MS, Park CS et al. Additive role of tiotropium in severe asthmatics and Arg16Gly in ADRB2 as a potential marker to predict response. Allergy 2009.
Google Scholar
 
 
84.
Peters SP, Kunselman SJ, Icitovic N et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 2010;363:1715-1726.
Google Scholar
 
 
85.
Lommatzsch M, Julius P, Virchow JC. Tiotropium step-up therapy in asthma. N Engl J Med 2011;364:578-579.
Google Scholar
 
 
86.
Miller DR, Chetty M, Currie GP. Tiotropium step-up therapy in asthma. N Engl J Med 2011;364:578-579.
Google Scholar
 
 
87.
Falah Y. A potential role for tiotropium bromide as an added therapy for adults with uncontrolled asthma. Thorax 2011.
Google Scholar
 
 
88.
Evaluation of Tiotropium 5 µg/Day Delivered Via the Respimat® Inhaler Over 48 Weeks in Patients With Severe Persistent Asthma on Top of Usual Care (Study I): ClinicalTrials.gov Identifier: NCT00772538.
Google Scholar
 
 
89.
Evaluation of Tiotropium 5 µg/Day Delivered Via the Respimat® Inhaler Over 48 Weeks in Patients With Severe Persistent Asthma on Top of Usual Care (Study II): ClinicalTrials.gov Identifier: NCT00776984.
Google Scholar
 
 
90.
Corrigan CJ, Shiner RJ, Shakur BH, Ind PW. Methotrexate therapy of oral corticosteroid-dependent asthmatics reduces serum immunoglobulins: correlation with clinical response to therapy. Clin Exp Allergy 2005;35:579-584.
Google Scholar
 
 
91.
Bernstein IL, Bernstein DI, Dubb JW, Faiferman I, Wallin B. A placebo-controlled multicenter study of auranofin in the treatment of patients with corticosteroid-dependent asthma. Auranofin Multicenter Drug Trial. J Allergy Clin Immunol 1996;98:317-324.
Google Scholar
 
 
92.
Lock SH, Kay AB, Barnes NC. Double-blind, placebo-controlled study of cyclosporin A as a corticosteroid-sparing agent in corticosteroid-dependent asthma. Am J Respir Crit Care Med 1996;153:509-514.
Google Scholar
 
 
93.
Davies H, Olson L, Gibson P. Methotrexate as a steroid sparing agent for asthma in adults. Cochrane Database Syst Rev 2000CD000391.
Google Scholar
 
 
94.
Busse WW, Banks-Schlegel S, Wenzel SE. Pathophysiology of severe asthma. J Allergy Clin Immunol 2000;106:1033-1042.
Google Scholar
 
 
95.
Brightling C, Berry M, Amrani Y. Targeting TNF-alpha: a novel therapeutic approach for asthma. J Allergy Clin Immunol 2008;121:5-10.
Google Scholar
 
 
96.
Berry MA, Hargadon B, Shelley M et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 2006;354:697-708.
Google Scholar
 
 
97.
Howarth PH, Babu KS, Arshad HS et al. Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 2005;60:1012-1018.
Google Scholar
 
 
98.
Morjaria JB, Chauhan AJ, Babu KS et al. The role of a soluble TNFalpha receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax 2008;63:584-591.
Google Scholar
 
 
99.
Wenzel SE, Barnes PJ, Bleecker ER et al. A Randomized, Doubleblind, Placebo-controlled Study of TNF-{alpha} Blockade in Severe Persistent Asthma. Am J Respir Crit Care Med 2009.
Google Scholar
 
 
100.
Holgate ST, Noonan M, Chanez P et al. Efficacy/safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial. Eur Respir J 2010.
Google Scholar
 
 
101.
Antoniu SA. Daclizumab: a potential asthma therapy? Recent Pat Inflamm Allergy Drug Discov. 2010;4:214-221.
Google Scholar
 
 
102.
Busse WW, Israel E, Nelson HS et al. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. Am J Respir Crit Care Med 2008;178:1002-1008.
Google Scholar
 
 
103.
Nakajima H, Takatsu K. Role of cytokines in allergic airway inflammation. Int.Arch.Allergy Immunol 2007;142:265-273.
Google Scholar
 
 
104.
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.
Google Scholar
 
 
105.
Chung KF, Barnes PJ. Cytokines in asthma. Thorax 1999;54:825- 857.
Google Scholar
 
 
106.
Leckie MJ, ten BA, Khan J et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness, and the late asthmatic response. Lancet 2000;356:2144-2148.
Google Scholar
 
 
107.
Flood-Page P, Swenson C, Faiferman I et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med 2007;176:1062- 1071.
Google Scholar
 
 
108.
Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS. Eosinophil’s role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med 2003;167:199-204.
Google Scholar
 
 
109.
Haldar P, Brightling CE, Hargadon B et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009;360:973-984.
Google Scholar
 
 
110.
Nair P, Pizzichini MM, Kjarsgaard M et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009;360:985-993.
Google Scholar
 
 
111.
Dose Ranging Efficacy And Safety With Mepolizumab in Severe Asthma (DREAM): ClinicalTrials.gov Identifier: NCT01000506.
Google Scholar
 
 
112.
Renauld JC, Houssiau F, Louahed J et al. Interleukin-9. Adv Immunol 1993;54:79-97.
Google Scholar
 
 
113.
Oh CK, Raible D, Geba GP, Molfino NA. Biology of the interleukin-9 pathway and its therapeutic potential for the treatment of asthma. Inflamm Allergy Drug Targets 2011;10:180-186.
Google Scholar
 
 
114.
Cheng G, Arima M, Honda K et al. Anti-interleukin-9 antibody treatment inhibits airway inflammation and hyperreactivity in mouse asthma model. Am J Respir Crit Care Med 2002;166:409- 416.
Google Scholar
 
 
115.
Parker JM, Oh CK, LaForce C et al. Safety profile and clinical activity of multiple subcutaneous doses of MEDI-528, a humanized anti-interleukin-9 monoclonal antibody, in two randomized phase 2a studies in subjects with asthma. BMC Pulm Med 2011;11:14.
Google Scholar
 
 
116.
Wills-Karp M, Chiaramonte M. Interleukin-13 in asthma. Curr. Opin.Pulm Med 2003;9:21-27.
Google Scholar
 
 
117.
Yang G, Li L, Volk A et al. Therapeutic dosing with anti-interleukin-13 monoclonal antibody inhibits asthma progression in mice. J Pharmacol Exp Ther 2005;313:8-15.
Google Scholar
 
 
118.
Gauvreau GM, Boulet LP, Cockcroft DW et al. Effects of Interleukin-13 Blockade on Allergen-induced Airway Responses in Mild Atopic Asthma. Am J Respir Crit Care Med 2011;183:1007- 1014.
Google Scholar
 
 
119.
Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 2007;370:1422-1431.
Google Scholar
 
 
120.
Study evaluating the effect of IMA-638 in subjects with persistent asthma: ClinicalTrials.gov Identifier: NCT 00425061. 1-1-2009.
Google Scholar
 
 
121.
Corren J, Busse W, Meltzer EO et al. A randomized, controlled, phase 2 study of AMG 317, an IL-4Ralpha antagonist, in patients with asthma. Am J Respir Crit Care Med 2010;181:788-796.
Google Scholar
 
 
122.
Spina D. Phosphodiesterase-4 inhibitors in the treatment of inflammatory lung disease. Drugs 2003;63:2575-2594.
Google Scholar
 
 
123.
Bateman ED, Izquierdo JL, Harnest U et al. Efficacy and safety of roflumilast in the treatment of asthma. Ann.Allergy Asthma Immunol 2006;96:679-686.
Google Scholar
 
 
124.
Bousquet J, Aubier M, Sastre J et al. Comparison of roflumilast, an oral anti-inflammatory, with beclomethasone dipropionate in the treatment of persistent asthma. Allergy 2006;61:72-78.
Google Scholar
 
 
125.
Nials AT, Tralau-Stewart CJ, Gascoigne MH et al. In vivo characterization of GSK256066, a high-affinity inhaled phosphodiesterase 4 inhibitor. J Pharmacol Exp Ther 2011;337:137-144.
Google Scholar
 
 
126.
Chapman RW, House A, Richard J et al. Pharmacology of a potent and selective inhibitor of PDE4 for inhaled administration. Eur J Pharmacol 2010;643:274-281.
Google Scholar
 
 
127.
Cox G, Thomson NC, Rubin AS et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med 2007;356:1327- 1337.
Google Scholar
 
 
128.
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. Am J Respir Crit Care Med 2010;181:116-124.
Google Scholar
 
 
129.
Pavord ID, Cox G, Thomson NC et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med 2007;176:1185-1191.
Google Scholar
 
 
130.
Cox G, Miller JD, McWilliams A, Fitzgerald JM, Lam S. Bronchial thermoplasty for asthma. Am J Respir Crit Care Med 2006;173:965-969.
Google Scholar
 
 
131.
Thomson NC, Rubin AS, Niven RM et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med 2011;11:8.
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