• 1
    Braman SS. The Global Burden of asthma. Chest. 2006; 130 (1 Suppl.):4S12S.
  • 2
    British Thoracic Society/Scottish Intercollegiate Guidelines Network. British Guideline on Management of Asthma. 05/08. Available at: (accessed 30 April 2009).
  • 3
    Global Initiative for Asthma Guidelines 11/06. Available at: (accessed 30 April 2009).
  • 4
    Chanez P, Wenzel SE, Anderson GP et al. Severe asthma: what are the important questions? J Allergy Clin Immunol 2008; 119:133748.
  • 5
    Proceedings of the ATS Workshop on Refractory Asthma. Current understanding, recommendations, and unanswered questions. Am J Respir Crit Care Med 2000; 162:234151.
  • 6
    Haldar P, Pavord ID, Shaw DE et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008; 178:21824.
  • 7
    Green RH, Brightling CE, McKenna S et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002; 360:171521.
  • 8
    Jayaram L, Pizzichini MM, Cook RJ et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J 2006; 27:48394.
  • 9
    Brightling CE, Berry M, Amrani Y. Anti-TNF-α in asthma. J Allergy Clin Immunol 2008; 121:510.
  • 10
    Tarantini F, Baiardini I, Passalacqua G, Braido F, Canonica GW. Asthma treatment: ‘magic bullets which seek their own targets’. Allergy 2007; 62:60510.
  • 11
    Walker S, Monteil M, Phelan K, Lasserson TJ, Walters EH. Anti-IgE for chronic asthma in adults and children. Cochrane Database of Systematic Reviews, 2006, Issue 2. Art. no.: CD003559. DOI: 10.1002/14651858.CD003559.pub3.
  • 12
    Wardlaw AJ, Brightling C, Green R, Woltmann G, Pavord I. Eosinophils in asthma and other allergic diseases. Br Med Bull 2000; 56:9851003.
  • 13
    Humbles AA, Lloyd CM, McMillan SJ et al. A critical role for eosinophils in allergic airways remodelling. Science 2004; 305:17769.
  • 14
    Wardlaw AJ, Brightling CE, Green R, Woltmann G, Bradding P, Pavord ID. New insights into the relationship between airway inflammation and asthma. Clin Sci (Lond) 2002; 103:20111.
  • 15
    Brightling CE, Bradding P, Pavord ID, Wardlaw AJ. New insights into the role of the mast cell in asthma. Clin Exp Allergy 2003; 33:5506.
  • 16
    Haldar P, Pavord ID. Noneosinophilic asthma: a distinct clinical and pathologic phenotype. J Allergy Clin Immunol 2007; 119:104352.
  • 17
    Holgate ST. Novel targets of therapy in asthma. Curr Opin Pulm Med 2009; 15:6371.
  • 18
    Pepe C, Foley S, Shannon J et al. Differences in airway remodelling between subjects with severe and moderate asthma. J Allergy Clin Immunol 2005; 166:5449.
  • 19
    Hammad H, Lambrecht BN. Recent progress in the biology of airway dendritic cells and implications for understanding the regulation of asthmatic inflammation. J Allergy Clin Immunol 2006; 118:3316.
  • 20
    Medoff BD, Thomas SY, Luster AD. T cell trafficking in allergic asthma: the ins and outs. Annu Rev Immunol 2008; 26:20532.
  • 21
    Larché M, Robinson DS, Kay AB. The role of T lymphocytes in the pathogenesis of asthma. J Allergy Clin Immunol 2003; 111:45063.
  • 22
    Robinson DS, Hamid Q, Ying S et al. Predominant TH-2 like bronchoalveolar T-lymphocyte populations in atopic asthma. N Engl J Med 1992; 326:298304.
  • 23
    Brightling CE, Symon FA, Birring SS, Bradding P, Pavord ID, Wardlaw AJ. Th2 cytokine expression in bronchoalveolar lavage fluid T-lymphocytes and bronchial submucosa is a feature of asthma and eosinophilic bronchitis. J Allergy Clin Immunol 2002; 110:899905.
  • 24
    Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, Pavord ID. Interleukin-4 and -13 expression is co-localized to mast cells within the airway smooth muscle in asthma. Clin Exp Allergy 2003; 33:17116.
  • 25
    Saha SK, Berry MA, Parker D et al. Increased sputum and bronchial biopsy IL-13 expression in severe asthma. J Allergy Clin Immunol 2008; 121:68591.
  • 26
    Humbert M, Corrigan CJ, Durham SR, Kimmit P, Till SJ, Kay AB. Relationship between bronchial mucosal IL-4 and IL-5 mRNA expression and disease severity in atopic asthma. Am J Respir Crit Care Med 1997; 156:7048.
  • 27
    Humbert M, Durham SR, Kimmitt P et al. Elevated expression of messenger ribonucleic acid encoding IL-13 in the bronchial mucosa of atopic and nonatopic subjects with asthma. J Allergy Clin Immunol 1997; 99:65765.
  • 28
    Broide DH, Firestein GS. Endobronchial allergen challenge in asthma. Demonstration of cellular source of granulocyte macrophage colony-stimulating factor by in situ hybridization. J Clin Invest 1991; 88:104853.
  • 29
    Saha SK, Doe C, Mistry V et al. Granulocyte macrophage colony stimulating factor expression in induced sputum and bronchial mucosa in asthma and COPD. Thorax. 2009 Thorax Online First, published 12 February 2009 as 10.1136/thx.2008.108290
  • 30
    Grunig G, Warnock M, Wakil AE et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 1998; 282:22613.
  • 31
    Zhu Z, Homer RJ, Wang Z et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 1999; 103:77988.
  • 32
    Su YC, Rolph MS, Hansbro NG, Mackay CR, Sewell WA. Granulocyte–macrophage colony stimulating factor is required for bronchial eosinophilia in a murine model of allergic airway inflammation. J Immunol 2008; 180:26007.
  • 33
    Ying S, Robinson DS, Varney V et al. TNF alpha mRNA expression in allergic inflammation. Clin Exp Allergy 1991; 21:74550.
  • 34
    Bradding P, Roberts JA, Britten KM et al. Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines. Am J Respir Cell Mol Biol 1994; 10:47180.
  • 35
    Howarth PH, Babu KS, Arshad HS et al. Tumour necrosis factor (TNFα) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 2005; 60:10128.
  • 36
    Berry MA, Hargadon B, Shelley M et al. Evidence of a role of tumour necrosis factor alpha in refractory asthma. N Engl J Med 2006; 354:697708.
  • 37
    Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, Pavord ID. Mast cell infiltration of airway smooth muscle in asthma. N Engl J Med 2002; 346:1699705.
  • 38
    Carroll NG, Mutavdzic S, James AL. Distribution and degranulation of airway mast cells in normal and asthmatic subjects. Eur Respir J 2002; 19:87985.
  • 39
    Berger P, Girodet PO, Begueret H et al. Tryptase-stimulated human airway smooth muscle cells induce cytokine synthesis and mast cell chemotaxis. FASEB J 2003; 17:213941.
  • 40
    Slats AM, Janssen K, Van Schadewijk A et al. Bronchial inflammation and airway responses to deep inspiration in asthma and COPD. Am J Respir Crit Care Med 2007; 176:1218.
  • 41
    Siddiqui S, Mistry V, Doe C et al. Airway hyperresponsiveness is dissociated from airway wall structural remodeling. J Allergy Clin Immunol 2008; 122:33541.
  • 42
    Amin K, Janson C, Boman G, Venge P. The extracellular deposition of mast cell products is increased in hypertrophic airways smooth muscles in allergic asthma but not in nonallergic asthma. Allergy 2005; 60:12417.
  • 43
    Siddiqui S, Brightling CE. Microlocalisation of inflammatory cells and structural cells: functional consequences in airways disease. Eur Respir J 2007; 30:104356.
  • 44
    Tliba O, Deshpande D, Chen H et al. IL-13 enhances agonist-evoked calcium signals and contractile responses in airway smooth muscle. Br J Pharmacol 2003; 140:115962.
  • 45
    Laporte JC, Moore PE, Baraldo S et al. Direct effects of interleukin-13 on signalling pathways for physiological responses in cultured human airway smooth muscle cells. Am J Respir Crit Care Med 2001; 164:1418.
  • 46
    Grunstein MM, Hakonarson H, Leiter J et al. IL-13 dependent autocrine signalling mediates altered responsiveness of IgE-sensitized airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 2002; 282:5208.
  • 47
    Woodman L, Siddiqui S, Cruse G et al. Mast cells promote airway smooth muscle cell differentiation via autocrine upregulation of TGF-β1. J Immunol 2008; 181:50017.
  • 48
    Wenzel S. Severe asthma in adults. Am J Resp Crit Care Med 2005; 172:14960.
  • 49
    Kamath AV, Pavord AV, Ruparelia PR, Chilvers ER. Is the neutrophil the key effector cell in severe asthma? Thorax 2005; 60:52930.
  • 50
    Idris SF, Chilvers ER, Haworth C, McKeon D, Condliffe AM. Azithromycin therapy for neutrophilic airways disease: myth or magic? Thorax 2009; 64:1869.
  • 51
    Benayoun L, Druilhe A, Dombret M-C, Aubier M, Pretolani M. Airway structural alterations selectively associated with severe asthma. Am J Resp Crit Care Med 2003; 167:13608.
  • 52
    Leckie MJ, Ten Brinke A, Khan J et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000; 356:21448.
  • 53
    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; 167:199204.
  • 54
    Kips J, O'Connor BJ, Langley SJ et al. Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study [abstract. Am J Respir Crit Care Med 2003; 167:16559.
  • 55
    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; 176:106271.
  • 56
    Haldar P, Brightling CE, Hargadon B et al. Meoplizumab and exacerbations of eosinophilic refractory asthma. N Engl J Med 2009; 360:97384.
  • 57
    Nair P, Pizzichini MM, Kjarsgaard M et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009; 360:98593.
  • 58
    Flood-Page P, Menzies-Gow A, Phipps S et al. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J Clin Invest 2003; 112:102936.
  • 59
    Borish LC, Nelson HS, Lanz MJ et al. Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am J Respir Crit Care Med 1999; 160:181623.
  • 60
    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; 107:96370.
  • 61
    Hart TK, Blackburn MN, Brigham-Burke M et al. Preclinical efficacy and safety of pascolizumab (SB240683): a humanised anti-interleukin-4 antibody with therapeutic potential in asthma. Clin Exp Immunol 2002; 130:93100.
  • 62
    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; 370:142231.
  • 63
    Getz EB, Wilbraham D, Lalor C, Longphre M, Fuller R. Pharmacokinetics and local tolerance of an IL-4/IL-13 antagonist inhalation powder in humans. ERS Conference 2008:545S (abstract). Available at:
  • 64
    Gauvreau GM, Boulet LP, Fitzgerald JM et al. The effects of IMA-638 on allergen induced airway responses in subjects with mild atopic asthma. ERS Conference 2008:827S (abstract). Available at:
  • 65
    Bhowmick B, Singh D, Molfino N et al. A double-blind, placebo-controlled, study to assess the pharmacokinetics, safety and tolerability of multiple ascending intravenous doses of CAT 354, a recombinant human anti-IL13 antibody, in subjects with moderate asthma. ERS Conference 2008:515S (abstract). Available at:
  • 66
    Banfield C, Vincent M, Kakkar T et al. Multiple-dose study of AMG317 in adults with asthma: pharmacokinetics and safety. Am J Respir Crit Care Med 2008; 177:A568.
  • 67
    O'Byrne P, Boulet L-P, Gauvreau G, Leon F, Sari S, White B. A single dose of MEDI-528, a monoclonal antibody against interleukin-9, is well tolerated in mild and moderate asthmatics in the phase II trial MI-CP-138. Chest 2007; 132:478.
  • 68
    Boguniewicz M, Martin RJ, Martin D et al. The effects of nebulised recombinant interferon-γ in asthmatic airways. J Allergy Clin Immunol 1995; 95:1335.
  • 69
    Simon HU, Seelbach H, Ehmann R, Schmitz M. Clinical and immunological effects of low-dose IFNα treatment in patients with corticosteroid-resistant asthma. Allergy 2003; 58:12505.
  • 70
    Kroegel C, Bergmann N, Foerster M et al. Interferon-alphacon-1 treatment of three patients with severe glucocorticoid-dependent asthma. Effect on disease control and systemic glucocorticoid dose. Respiration 2006; 73:56670.
  • 71
    Bryan SA, O'Connor BJ, Matti S et al. Effects of recombinant human interleukin-12 on eosinophils, airway hyperresponsiveness, and the late asthmatic response. Lancet 2000; 356:214953.
  • 72
    Chernoff AE, Granowitz EV, Shapiro L et al. A randomised, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses. J Immunol 1995; 154:54929.
  • 73
    Erin EM, Leaker BR, Nicholson GC et al. The effects of a monoclonal antibody directed against tumor necrosis factor-alpha in asthma. Am J Respir Crit Care Med 2006; 174:75362.
  • 74
    Morjaria JB, Chauhan AJ, Babu KS, Polosa R, Davies DE, Holgate ST. The role of a soluble TNFα receptor fusion protein (Etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax 2008; 63:58491.
  • 75
    Wenzel SE, Barnes PJ, Bleecker ER et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-α blockade in severe persistent asthma. Am J Respir Crit Care Med 2009; 179:54958.
  • 76
    Rennard SI, Fogarty C, Kelsen S et al. The safety and efficacy of infliximab in moderate to severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 175:92634.
  • 77
    Louten J, Boniface K, De Waal Malefyt R. Development and function of Th17 cells in health and disease. J Allergy Clin Immunol 2009; 123:100411.
  • 78
    Al-Ramli W, Préfontaine D, Chouiali F et al. Th-17 associated cytokines (IL-17A and IL-17F) in severe asthma. J Allergy Clin Immunol 2009; 123:11857.
  • 79
    Ballantyne SJ, Barlow JL, Jolin HE et al. Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma. J Allergy Clin Immunol 2007; 120:12341.
  • 80
    Hayakawa H, Hayakawa M, Kume A, Tominaga S. Soluble ST blocks interleukin-33 signalling in allergic airway inflammation. J Biol Chem 2007; 282:2636980.