Mechanisms of respiratory virus-induced asthma exacerbations

Clinical and Experimental Allergy

Volumn 35, Issue 2, 2005, Pages 137-145

  Contoli, Marco ^a,b   Caramori, G ^a   Mallia, P ^b   Johnston, S ^b   Papi, A ^a  

^a UNIVERSITY OF FERRARA   (Italy)

^b NATIONAL HEART AND LUNG INSTITUTE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA 2 MACROGLOBULIN; CELL ADHESION MOLECULE; CHEMOKINE; CYTOKINE; DNK 333; EOSINOPHIL CATIONIC PROTEIN; GLUCOCORTICOID; HISTAMINE H1 RECEPTOR ANTAGONIST; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERCELLULAR ADHESION MOLECULE 1; INTERLEUKIN 1; INTERLEUKIN 4; INTERLEUKIN 5; INTERLEUKIN 6; INTERLEUKIN 8; MITOGEN ACTIVATED PROTEIN KINASE P38; NEUROKININ 1 RECEPTOR ANTAGONIST; NEUROKININ 2 RECEPTOR ANTAGONIST; NITRIC OXIDE; TACHYKININ; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR AP 1; UNCLASSIFIED DRUG; VASCULAR CELL ADHESION MOLECULE 1;

AIR POLLUTANT; AIR POLLUTION; ALLERGIC RHINITIS; ANIMAL MODEL; ANTIINFLAMMATORY ACTIVITY; ASTHMA; ATOPY; BRONCHUS MUCOSA; COMMON COLD; CYTOKINE PRODUCTION; DISEASE ASSOCIATION; DISEASE EXACERBATION; DISEASE SEVERITY; EFFECTOR CELL; EOSINOPHILIA; EPITHELIUM CELL; FORCED EXPIRATORY VOLUME; GENE ACTIVATION; HOSPITAL ADMISSION; HUMAN; IMMUNE RESPONSE; IN VITRO STUDY; IN VIVO STUDY; INFLAMMATION; MEDIATOR RELEASE; MORBIDITY; MORTALITY; NEUROGENIC INFLAMMATION; NONHUMAN; PATHOGENESIS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; PROTEIN SYNTHESIS; RESPIRATORY SYNCYTIAL PNEUMOVIRUS; RESPIRATORY TRACT INFECTION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; REVIEW; RHINOVIRUS; SENSITIZATION; SPUTUM ANALYSIS; TH2 CELL; UPPER RESPIRATORY TRACT INFECTION; VIRUS IDENTIFICATION; VIRUS INFECTION; VIRUS PATHOGENESIS; WINTER;

ACUTE DISEASE; ANIMALS; ASTHMA; BRONCHI; COMMON COLD; EPITHELIAL CELLS; GLUCOCORTICOIDS; HISTAMINE H1 ANTAGONISTS; HUMANS; MODELS, ANIMAL; RESPIRATORY SYSTEM; RESPIRATORY TRACT INFECTIONS;

EID: 14844362554     PISSN: 09547894     EISSN: None     Source Type: Journal    
DOI: 10.1111/j.1365-2222.2005.02163.x     Document Type: Review

References (97)

1. Pattemore PK. Epidemiology and diagnosis of virus-induced asthma exacerbations. In: Johnston SL, Papadopoulos NG, eds. Respiratory infections in allergy and asthma, Vol. 178. New York: Lung Biology in Health and Disease, 2003; 43-89.
2. Rodrigo GJ, Rodrigo C, Hall JB. Acute asthma in adults: a review. Chest 2004; 125:1081-102.
3. Reddel H, Ware S, Marks G, Salome C, Jenkins C, Woolcock A. Differences between asthma exacerbations and poor asthma control. Lancet 1999; 353:364-9.
4. Johnston SL, Pattemore PK, Sanderson G et al. Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. BMJ 1995; 310:1225-9.
5. Wark PA, Johnston SL, Moric I, Simpson JL, Hensley MJ, Gibson PG. Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma. Eur Respir J 2002; 19: 68-75.
6. Tan WC, Xiang X, Qiu D, Ng TP, Lam SF, Hegele RG. Epidemiology of respiratory viruses in patients hospitalized with near-fatal asthma, acute exacerbations of asthma, or chronic obstructive pulmonary disease. Am J Med 2003; 115:272-7.
7. Johnston SL, Xie P, Johnson W. Comparison of standard virology and PCR in diagnosis of rhinovirus and respiratory syncytial virus infections in nasal aspirates from children hospitalised with wheezing illness and bronchiolitis. Am J Respir Crit Care Med 1996; 153:A503.
8. Johnston SL, Pattemore PK, Sanderson G et al. The relationship between upper respiratory infections and hospital admissions for asthma: a time-trend analysis. Am J Respir Crit Care Med 1996; 154:654-60.
9. Nichols T, Hansell A, Strachan D. The contribution of 'holiday deaths' to seasonal variations in asthma mortality in England and Wales. Clin Exp Allergy 1999; 29:1415-7.
10. Campbell MJ, Cogman GR, Holgate ST, Johnston SL. Age specific trends in asthma mortality in England and Wales, 1983-95: results of an observational study. BMJ 1997; 314:1439-41.
11. Campbell MJ, Holgate ST, Johnston SL. Trends in asthma mortality. Data on seasonality of deaths due to asthma. BMJ 1997; 315:1012.
12. O'Sullivan S, Cormican L, Faul JL et al. Activated, cytotoxic CD8+T lymphocytes contribute to the pathology of asthma death. Am J Respir Crit Care Med 2001; 164:560-4.
13. Rakes GP, Arruda E, Ingram JM et al. Rhinovirus and respiratory syncytial virus in wheezing children requiring emergency care. Ige and eosinophil analyses. Am J Respir Crit Care Med 1999; 159:785-90.
14. Green RM, Custovic A, Sanderson G, Hunter J, Johnston SL, Woodcock A. Synergism between allergens and viruses and risk of hospital admission with asthma: case-control study. BMJ 2002; 324:763.
15. Lemanske RF Jr, Dick EC, Swenson CA, Vrtis RF, Busse WW. Rhinovirus upper respiratory infection increases airway hyperreactivity and late asthmatic reactions. J Clin Invest 1989; 83:1-10.
16. Calhoun WJ, Dick EC, Schwartz LB, Busse WW. A common cold virus, rhinovirus 16, potentiates airway inflammation after segmental antigen bronchoprovocation in allergic subjects. J Clin Invest 1994; 94:2200-8.
17. Greiff L, Venge P, Andersson M et al. Effects of rhinovirus-induced common colds on granulocyte activity in allergic rhinitis. J Infect Dis 2002; 45:227-32.
18. Greiff L, Andersson M, Svensson C, Linden M, Myint S, Persson CG. Allergen challenge-induced acute exudation of IL-8, ECP and alpha2-macroglobulin in human rhinovirus-induced common colds. Eur Respir J 1999; 13:41-7.
19. Zambrano JC, Carper HT, Rakes GP et al. Experimental rhinovirus challenges in adults with mild asthma: response to infection in relation to IgE. J Allergy Clin Immunol 2003; 111:1008-16.
20. Makela MJ, Tripp R, Dakhama A et al. Prior airway exposure to allergen increases virus-induced airway hyperresponsiveness. J Allergy Clin Immunol 2003; 112:861-9.
21. de Kluijver J, Evertse CE, Sont JK et al. Are rhinovirus-induced airway responses in asthma aggravated by chronic allergen exposure? Am J Respir Crit Care Med 2003; 168:1174-80.
22. Avila PC, Abisheganaden JA, Wong H et al. Effects of allergic inflammation of the nasal mucosa on the severity of rhinovirus 16 cold. J Allergy Clin Immunol 2000; 105:923-32.
23. Massaro AF, Gaston B, Kita D, Fanta C, Stamler JS, Drazen JM. Expired nitric oxide levels during treatment of acute asthma. Am J Respir Crit Care Med 1995; 152:800-3.
24. Johnston SL. Experimental models of rhinovirus-induced exacerbations of asthma: where to now? Am J Respir Crit Care Med 2003; 168:1145-6.
25. Schwarze J, Johnston SL. Unravelling synergistic immune interactions between respiratory virus infections and allergic airway inflammation. Clin Exp Allergy 2004; 34:1153-5.
26. Chauhan AJ, Johnston SL. Air pollution and infection in respiratory illness. Br Med Bull 2003; 68:95-112.
27. 2) and the severity of virus-induced asthma in children. Lancet 2003; 361:1939-44.
28. Frampton MW, Boscia J, Roberts NJ Jr et al. Nitrogen dioxide exposure: effects on airway and blood cells. Am J Physiol Lung Cell Mol Physiol 2002; 282:L155-65.
29. Spannhake EW, Reddy SP, Jacoby DB, Yu XY, Saatian B, Tian J. Synergism between rhinovirus infection and oxidant pollutant exposure enhances airway epithelial cell cytokine production. Environ Health Perspect 2002; 110:665-70.
30. Ando M, Shima M, Adachi M. Tsunetoshi Y. The role of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and regulated on activation, normal T-cell expressed and secreted (RANTES) in the relationship between air pollution and asthma among children. Arch Environ Health 2001; 56:227-33.
31. Fraenkel DJ, Bardin PG, Sanderson G, Lampe F, Johnston SL, Holgate ST. Lower airways inflammation during rhinovirus colds in normal and in asthmatic subjects. Am J Respir Crit Care Med 1995; 151:879-86.
32. Grunberg K, Timmers MC, de Klerk EP, Dick EC, Sterk PJ. Experimental rhinovirus 16 infection causes variable airway obstruction in subjects with atopic asthma. Am J Respir Crit Care Med 1999; 160:1375-80.
33. Sterk PJ. Virus-induced airway hyperresponsiveness in man. Eur Respir J 1993; 6:894-902.
34. Bardin PG, Sanderson G, Robinson BS, Holgate ST, Tyrrell DA. Experimental rhinovirus infection in volunteers. Eur Respir J 1996; 9:2250-5.
35. Gern JE, Calhoun W, Swenson C, Shen G, Busse WW. Rhinovirus infection preferentially increases lower airway responsiveness in allergic subjects. Am J Respir Crit Care Med 1997; 155:1872-6.
36. Bardin PG, Fraenkel DJ, Sanderson G, van Schalkwyk EM, Holgate ST, Johnston SL. Peak expiratory flow changes during experimental rhinovirus infection. Eur Respir J 2000; 16:980-5.
37. Fleming HE, Little FF, Schnurr D et al. Rhinovirus-16 colds in healthy and in asthmatic subjects: similar changes in upper and lower airways. Am J Respir Crit Care Med 1999; 160:100-8.
38. Grunberg K, Sharon RF, Sont JK et al. Rhinovirus-induced airway inflammation in asthma: effect of treatment with inhaled corticosteroids before and during experimental infection. Am J Respir Crit Care Med 2001; 164:1816-22.
39. Papadopoulos NG, Stanciu LA, Papi A, Holgate ST, Johnston SL. A defective type 1 response to rhinovirus in atopic asthma. Thorax 2002; 57:328-32.
40. Brooks GD, Buchta KA, Swenson CA, Gern JE, Busse WW. Rhinovirus-induced interferon-gamma and airway responsiveness in asthma. Am J Respir Crit Care Med 2003; 168:1091-4.
41. Wimalasundera SS, Katz DR, Chain BM. Characterization of the T cell response to human rhinovirus in children: implications for understanding the immunopathology of the common cold. J Infect Dis 1997; 176:755-9.
42. Gern JE, Vrtis R, Grindle KA, Swenson C, Busse WW. Relationship of upper and lower airway cytokines to outcome of experimental rhinovirus infection. Am J Respir Crit Care Med 2000; 162:2226-31.
43. Grunberg K, Smits HH, Timmers MC, de Klerk EP, Dolhain RJ, Sterk PJ. Experimental rhinovirus 16 infection effects on cell differentials and soluble markers in sputum in asthmatic subjects. Am J Respir Crit Care Med 1997; 156:609-16.
44. Trigg CJ, Nicholson KG, Wang JH et al. Bronchial inflammation and the common cold: a comparison of atopic and non-atopic individuals. Clin Exp Allergy 1996; 26:665-76.
45. Hers JF. Disturbances of the ciliated epithelium due to influenza virus. Am Rev Respir Dis 1966; 93 (Suppl.):162-77.
46. Papi A, Stanciu LA, Papadopoulos NG, Teran LM, Holgate ST, Johnston SL. Rhinovirus infection induces major histocompatibility complex class 1 and costimulatory molecule upregulation on respiratory epithelial cells. J Infect Dis 2000; 181:1780-4.
47. Chung KF, Barnes PJ. Cytokines in asthma. Thorax 1999; 54: 825-57.
48. Johnston SL. Bronchial hyperresponsiveness and cytokines in virus-induced asthma exacerbations. Clin Exp Allergy 1997; 27: 7-9.
49. Jarjour NN, Gern JE, Kelly EA, Swenson CA, Dick CR, Busse WW. The effect of an experimental rhinovirus 16 infection on bronchial lavage neutrophils. J Allergy Clin Immunol 2000; 105:1169-77.
50. Zhu Z, Tang W, Ray A et al. Rhinovirus stimulation of interleukin-6 in vivo and in vitro. Evidence for nuclear factor kappa B-dependent transcriptional activation. J Clin Invest 1996; 97: 421-30.
51. Tang W, Geba GP, Zheng T et al. Targeted expression of IL-11 in the murine airway causes lymphocytic inflammation, bronchial remodeling, and airways obstruction. J Clin Invest 1996; 98: 2845-53.
52. Einarsson O, Geba GP, Zhu Z, Landry M, Elias JA. Interleukin-II: Stimulation in vivo and in vitro by respiratory viruses and induction of airways hyperresponsiveness. J Clin Invest 1996; 97:915-24.
53. Teran LM. CCL chemokines and asthma. Immunol Today 2000; 21:235-42.
54. Folkerts G, Busse WW, Nijkamp FP, Sorkness R, Gern JE. Virus-induced airway hyperresponsiveness and asthma. Am J Respir Crit Care Med 1998; 157:1708-20.
55. Hu C, Wedde-Beer K, Auais A, Rodriguez MM, Piedimonte G. Nerve growth factor and nerve growth factor receptors in respiratory syncytial virus-infected lungs. Am J Physiol Lung Cell Mol Physiol 2002; 283:L494-502.
56. Joos GF, De Swert KO, Schelfhout V, Pauwels RA. The role of neural inflammation in asthma and chronic obstructive pulmonary disease. Ann NY Acad Sci 2003; 992:218-30.
57. Piedimonte G, Rodriguez MM, King KA, McLean S, Jiang X. Respiratory syncytial virus upregulates expression of the substance P receptor in rat lungs. Am J Physiol Lung Cell Mol Physiol 1999; 277:L831-40.
58. Auais A, Adkins B, Napchan G, Piedimonte G. Immunomodulatory effects of sensory nerves during respiratory syncytial virus infection in rats. Am J Physiol Lung Cell Mol Physiol 2003; 285:L105-13.
59. Joos GF, Vincken W, Louis R et al. Dual tachykinin NK1/NK2 antagonist DNK333 inhibits neurokinin A-induced bronchoconstriction in asthma patients. Eur Respir J 2004; 23:76-81.
60. Springer TA. Adhesion receptors of the immune system. Nature 1990; 346:425-34.
61. Grunberg K, Sharon RF, Hiltermann TJ et al. Experimental rhinovirus 16 infection increases intercellular adhesion molecule-1 expression in bronchial epithelium of asthmatics regardless of inhaled steroid treatment. Clin Exp Allergy 2000; 30:1015-23.
62. Papi A, Johnston SL. Rhinovirus infection induces expression of its own receptor intercellular adhesion molecule 1 (ICAM-1) via increased NF-kappab-mediated transcription. J Biol Chem 1999; 274:9707-20.
63. Whiteman SC, Bianco A, Knight RA, Spiteri MA. Human rhinovirus selectively modulates membranous and soluble forms of its intercellular adhesion molecule-1 (ICAM-1) receptor to promote epithelial cell infectivity. J Biol Chem 2003; 278:11954-61.
64. Canonica GW, Ciprandi G, Pesce GP, Buscaglia S, Paolieri F, Bagnasco M. ICAM-1 on epithelial cells in allergic subjects: a hallmark of allergic inflammation. Int Arch Allergy Immunol 1995; 107:99-102.
65. Bianco A, Whiteman SC, Sethi SK, Allen JT, Knight RA, Spiteri MA. Expression of intercellular adhesion molecule-1 (ICAM-1) in nasal epithelial cells of atopic subjects: a mechanism for increased rhinovirus infection? Clin Exp Immunol 2000; 121:339-45.
66. Bloemen PG, Henricks PA, Nijkamp FP. Cell adhesion molecules and asthma. Clin Exp Allergy 1997; 27:128-41.
67. Pesce G, Ciprandi G, Buscaglia S et al. Preliminary evidence for 'aberrant' expression of the leukocyte integrin LFA-1 (CD11a/CD18) on conjunctival epithelial cells of patients with mite allergy. Int Arch Allergy Immunol 2001; 125:160-3.
68. Hirata N, Kohrogi H, Iwagoe H et al. Allergen exposure induces the expression of endothelial adhesion molecules in passively sensitized human bronchus: time course and the role of cytokines. Am J Respir Cell Mol Biol 1998; 18:12-20.
69. Braunstahl GJ, Overbeek SE, Kleinjan A, Prins JB, Hoogsteden HC, Fokkens WJ. Nasal allergen provocation induces adhesion molecule expression and tissue eosinophilia in upper and lower airways. J Allergy Clin Immunol 2001; 107:469-76.
70. Bentley AM, Durham SR, Robinson DS et al. Expression of endothelial and leukocyte adhesion molecules interacellular adhesion molecule-1, E-selectin, and vascular cell adhesion molecule-1 in the bronchial mucosa in steady-state and allergen-induced asthma. J Allergy Clin Immunol 1993; 92:857-68.
71. Bianco A, Sethi SK, Allen JT, Knight RA, Spiteri MA. Th2 cytokines exert a dominant influence on epithelial cell expression of the major group human rhinovirus receptor, ICAM-1. Eur Respir J 1998; 12:619-26.
72. Corne JM, Marshall C, Smith S et al. Frequency, severity, and duration of rhinovirus infections in asthmatic and non-asthmatic individuals: a longitudinal cohort study. Lancet 2002; 359:831-4.
73. Grunstein MM, Hakonarson H, Hodinka RL, Masked N, Kim C, Chuang S. Mechanism of cooperative effects of rhinovirus and atopic sensitization on airway responsiveness. Am J Physiol Lung Cell Mol Physiol 2001; 280:L229-38.
74. Papi A, Johnston SL. Respiratory epithelial cell expression of vascular cell adhesion molecule-1 and its up-regulation by rhinovirus infection via NF-kappaB and GATA transcription factors. J Biol Chem 1999; 274:30041-51.
75. Kharitonov SA, Yates D, Barnes PJ. Increased nitric oxide in exhaled air of normal human subjects with upper respiratory tract infections. Eur Respir J 1995; 8:295-7.
76. de Gouw HW, Grunberg K, Schot R, Kroes AC, Dick EC, Sterk PJ. Relationship between exhaled nitric oxide and airway hyperresponsiveness following experimental rhinovirus infection in asthmatic subjects. Eur Respir J 1998; 11:126-32.
77. Sanders SP, Siekierski ES, Richards SM, Porter JD, Imani F, Proud D. Rhinovirus infection induces expression of type 2 nitric oxide synthase in human respiratory epithelial cells in vitro and in vivo. J Allergy Clin Immunol 2001; 107:235-43.
78. Sanders SP, Proud D, Permutt S, Siekierski ES, Yachechko R, Liu M. Role of nasal nitric oxide in the resolution of experimental rhinovirus infection. J Allergy Clin Immunol 2004; 113:697-702.
79. Sanders SP, Siekierski ES, Porter JD, Richards SM, Proud D. Nitric oxide inhibits rhinovirus-induced cytokine production and viral replication in a human respiratory epithelial cell line. J Virol 1998; 72:934-42.
80. Muijsers RBR, Nijkamp FP, Folkerts G. Nitric oxide and other inflammatory mediators. In: Johnston SL, Papadopoulos NG, eds. Respiratory infections in allergy and asthma, Vol. 178. New York: Lung Biology in Health and Disease, 2003; 43-89.
81. Barnes PJ, Adcock IM. Transcription factors and asthma. Eur Respir J 1998; 12:221-34.
82. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001; 413:732-8.
83. Kim J, Sanders SP, Siekierski ES, Casolaro V, Proud D. Role of NF-kappa B in cytokine production induced from human airway epithelial cells by rhinovirus infection. J Immunol 2000; 165: 3384-92.
84. Griego SD, Weston CB, Adams JL, Tal-Singer R, Dillon SB. Role of p38 mitogen-activated protein kinase in rhinovirus-induced cytokine production by bronchial epithelial cells. J Immunol 2000; 165:5211-20.
85. Mastronarde JG, Monick MM, Mukaida N, Matsushima K, Hunninghake GW. Activator protein-1 is the preferred transcription factor for cooperative interaction with nuclear factor-kappaB in respiratory syncytial virus-induced interleukin-8 gene expression in airway epithelium. J Infect Dis 1998; 177:1275-81.
86. Casola A, Burger N, Liu T, Jamaluddin M, Brasier AR, Garofalo RP. Oxidant tone regulates RANTES gene expression in airway epithelial cells infected with respiratory syncytial virus. Role in viral-induced interferon regulatory factor activation. J Biol Chem 2001; 276:19715-22.
87. Caramori G, Papi A. Oxidants and asthma. Thorax 2004; 59: 170-3.
88. Papi A, Papadopoulos NG, Stanciu LA et al. Reducing agents inhibit rhinovirus-induced up-regulation of the rhinovirus receptor intercellular adhesion molecule-1 (ICAM-1) in respiratory epithelial cells. FASEB J 2002; 16:1934-6.
89. Suzuki T, Yamaya M, Sekizawa K et al. Effects of dexamethasone on rhinovirus infection in cultured human tracheal epithelial cells. Am J Physiol Lung Cell Mol Physiol 2000; 278:L560-71.
90. Mincarini M, Cagnoni F, Canonica GW et al. Quantitative flow cytometric analysis of the effects of cetirizine on the expression of ICAM1/CD54 on primary cultured nasal cells. Allergy 2000; 55:226-31.
91. Papi A, Papadopoulos NG, Degitz K, Holgate ST, Johnston SL. Corticosteroids inhibit rhinovirus-induced intercellular adhesion molecule-1 up-regulation and promoter activation on respiratory epithelial cells. J Allergy Clin Immunol 2000; 105:318-26.
92. Ciprandi G, Tosca MA, Cosentino C, Riccio AM, Passalacqua G, Canonica GW. Effects of fexofenadine and other antihistamines on components of the allergic response: adhesion molecules. J Allergy Clin Immunol 2003; 112:578-82.
93. Ciprandi G, Ricca V, Passalacqua G, Fasolo A, Canonica GW. Intranasal fluticasone propionate reduces ICAM-1 on nasal epithelial cells both during early and late phase after allergen challenge. Clin Exp Allergy 1998; 28:293-9.
94. Doull IJ, Lampe FC, Smith S, Schreiber J, Freezer NJ, Holgate ST. Effect of inhaled Corticosteroids on episodes of wheezing associated with viral infection in school age children: randomised double blind placebo controlled trial. BMJ 1997; 315:858-62.
95. Oommen A, Lambert PC, Grigg J. Efficacy of a short course of parent-initiated oral prednisolone for viral wheeze in children aged 1-5 years: randomised controlled trial. The Lancet 2003; 362: 1433-8.
96. Ciprandi G, Tosca M, Passalacqua G, Canonica G, Ricca V, Landi M. Continuous antihistamine treatment controls allergic inflammation and reduces respiratory morbidity in children with mite allergy. Allergy 1999; 54:358-65.
97. FitzGerald JM, Becker A, Sears MR, Mink S, Chung K, Lee J. Canadian Asthma Exacerbation Study Group. Doubling the dose of budesonide vs. maintenance treatment in asthma exacerbations. Thorax 2004; 59:550-6.