Pharmacological treatment of severe, therapy-resistant asthma in children: What can we learn from where?

European Respiratory Journal

Volumn 38, Issue 4, 2011, Pages 947-958

  Bush, A ^a,b   Pedersen, S ^c   Hedlin, G ^d   Baraldi, E ^e   Barbato, A ^e   De Benedictis, F ^f   Lodrup Carlsen K C ^h,i   De Jongste, J ^j   Piacentini, G ^g  

^a IMPERIAL COLLEGE SCHOOL OF MEDICINE   (United Kingdom)

^b ROYAL BROMPTON HOSPITAL   (United Kingdom)

^c UNIVERSITY OF SOUTHERN DENMARK   (Denmark)

^d KAROLINSKA INSTITUTE   (Sweden)

^e UNIVERSITY OF PADOVA   (Italy)

^f Salesi Children's Hospital   (Italy)

^g UNIVERSITY OF VERONA   (Italy)

^h OSLO UNIVERSITY HOSPITAL   (Norway)

ⁱ UNIVERSITY OF OSLO   (Norway)

^j SOPHIA CHILDREN S HOSPITAL   (Netherlands)

more..

Author keywords

Cyclosporin; Long acting agonist; Methotrexate; Omalizumab; Prednisolone; Steroid sparing

Indexed keywords

AZATHIOPRINE; BECLOMETASONE; BETA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; BUDESONIDE PLUS FORMOTEROL; CLARITHROMYCIN; CORTICOSTEROID; CYCLOSPORIN; ERYTHROMYCIN; FLUTICASONE PROPIONATE; GOLD SALT; IMMUNOGLOBULIN; ITRACONAZOLE; LEUKOTRIENE RECEPTOR BLOCKING AGENT; MACROLIDE; METHOTREXATE; METHYLPREDNISOLONE; MONTELUKAST; OMALIZUMAB; PLACEBO; PREDNISOLONE; ROXITHROMYCIN; TELITHROMYCIN; TERBUTALINE; THEOPHYLLINE; TRIAMCINOLONE; TROLEANDOMYCIN; VORICONAZOLE;

ALLERGIC ASTHMA; ASEPTIC MENINGITIS; ASTHMA; BRONCHIECTASIS; BRONCHIOLITIS; CHILD; CHLAMYDOPHILA PNEUMONIAE; CYSTIC FIBROSIS; DIFFUSE PANBRONCHIOLITIS; DISEASE EXACERBATION; DISEASE SEVERITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DOSE INCREASE; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG HALF LIFE; DRUG INTERMITTENT THERAPY; DRUG MEGADOSE; DRUG SAFETY; EOSINOPHILIA; FORCED EXPIRATORY VOLUME; HUMAN; HYPOGLYCEMIA; HYPOKALEMIA; LIVER FUNCTION; LOW DRUG DOSE; MYCOPLASMA PNEUMONIAE; MYOSITIS; PRIORITY JOURNAL; RESPIRATORY TRACT INFLAMMATION; REVIEW; SIDE EFFECT; UNSPECIFIED SIDE EFFECT;

ADRENERGIC BETA-2 RECEPTOR ANTAGONISTS; ANTI-ASTHMATIC AGENTS; ANTIFUNGAL AGENTS; ASTHMA; CHILD; DRUG RESISTANCE; EVIDENCE-BASED MEDICINE; HUMANS; IMMUNOSUPPRESSIVE AGENTS; SEVERITY OF ILLNESS INDEX;

EID: 80053498278     PISSN: 09031936     EISSN: 13993003     Source Type: Journal    
DOI: 10.1183/09031936.00030711     Document Type: Review

References (182)

1. 2LEN initiative. Eur Respir J 2010; 36: 196-201.
2. Lødrup Carlsen K, Hedlin G, Bush A, et al. Assessment of problematic severe asthma in children. Eur Respir J 2011; 37: 432-440.
3. Haselkorn T, Fish JE, Zeiger RS, et al. Consistently very poorly controlled asthma, as defined by the impairment domain of the Expert Panel Report 3 guidelines, increases risk for future severe asthma exacerbations in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. J Allergy Clin Immunol 2009; 124: 895-902.
4. Lemanske RF Jr, Mauger DT, Sorkness CA, et al. Childhood Asthma Research and Education (CARE) Network of the National Heart, Lung, and Blood Institute. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med 2010; 362: 975-985.
5. Drake AJ, Howells RJ, Shield JP, et al. Symptomatic adrenal insufficiency presenting with hypoglycaemia in children with asthma receiving high dose inhaled fluticasone propionate. BMJ 2002; 324: 1081-1082. (Pubitemid 34492819)
6. Todd GR, Acerini CL, Ross-Russell R, et al. Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Arch Dis Child 2002; 87: 457-461. (Pubitemid 35440691)
7. Kam JC, Szefler SJ, Surs W, et al. Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. J Immunol 1993; 151: 3460-3466. (Pubitemid 23282658)
8. Nimmagadda SR, Szefler SJ, Spahn JD, et al. Allergen exposure decreases glucocorticoid receptor binding affinity and steroid responsiveness in atopic asthmatics. Am Rev Respir Crit Care Med 1997; 155: 87-93. (Pubitemid 27053146)
9. Brutsche MH, Brutsche IC, Munawar M, et al. Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study. Lancet 2000; 356: 556-561. (Pubitemid 30611861)
10. Mortimer KJ, Harrison TW, Tang Y, et al. Plasma concentrations of inhaled corticosteroids in relation to airflow obstruction in asthma. Br J Clin Pharmacol 2006; 62: 412-419. (Pubitemid 44401524)
11. Adams NP, Bestall JC, Jones P, et al. Fluticasone at different doses for chronic asthma in adults and children. Cochrane Database Syst Rev 2008; 4: CD003534.
12. van Staa TP, Cooper C, Leufkens HG, et al. Children and the risk of fractures caused by oral corticosteroids. J Bone Miner Res 2003; 18: 913-918. (Pubitemid 37294976)
13. Allen DB. Effects of inhaled steroids on growth, bone metabolism, and adrenal function. Adv Pediatr 2006; 53: 101-110. (Pubitemid 44415932)
14. Pedersen S. Do inhaled corticosteroids inhibit growth in children? Am J Respir Crit Care Med 2001; 164: 521-535. (Pubitemid 32807684)
15. Bracken MB, Fleming L, Hall P, et al. The importance of nurse led home visits in the assessment of children with problematic asthma. Arch Dis Child 2009; 94: 780-784.
16. Massanari M, Kianifard F, Zeldin RK, et al. Efficacy of omalizumab in cat-allergic patients with moderate-to-severe persistent asthma. Allergy Asthma Proc 2009; 30: 534-539.
17. Bossley CJ, Saglani S, Kavanagh C, et al. Corticosteroid responsiveness and clinical characteristics in childhood difficult asthma. Eur Respir J 2009; 34: 1052-1059.
18. Milgrom H, Berger W, Nayak A, et al. Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Paediatrics 2001; 108: 6-45.
19. Lemanske R, Nayak A, McAlary M, et al. Oamlizumab improves asthma-related quality of life in children with allergic asthma. Paediatrics 2002; 110: e55-e59.
20. Berger W, Gupta N, McAlary M, et al. Evaluation of long term safety of the anti-IgE antibody, omalizumab, in children with allergic asthma. Annals Allergy, Asthma Immunol 2003; 91: 182-188. (Pubitemid 36999479)
21. Lanier B, Bridges T, Kulus M, et al. Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. J Allergy Clinical Immunol 2009; 124: 1210-1216.
22. Bousquet J, Cabrera P, Berkman N, et al. The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma. Allergy 2005; 60: 302-308. (Pubitemid 40293345)
23. D'Amato G, Salzillo A, Piccolo A, et al. A review of anti-IgE monoclonal antibody (omalizumab) as add on therapy for severe allergic (IgE-mediated) asthma. Ther Clin Risk Manag 2007; 3: 613-619. (Pubitemid 47496966)
24. Rodrigo GJ, Neffen H, Castro-Rodriguez JA. Efficacy and safety of subcutaneous omalizumab vs placebo as add-on therapy to corticosteroids for children and adults with asthma: a systematic review. Chest 2011; 139: 28-35.
25. Bush A, Lenney W, Spencer D, et al. Not NICE: a better way forward? Arch Dis Child 2011; [Epub ahead of print DOI: 10.1136/adc.2010.194647].
26. Silkoff PE, Romero FA, Gupta N, et al. Exhaled nitric oxide in children with asthma receiving xolair (omalizumab), a monoclonal anti-immunoglobulin E antibody. Paediatrics 2004; 113: e308-e312.
27. Djukanović R, Wilson SJ, Kraft M, et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med 2004; 170: 583-593.
28. Wahn U, Martin C, Freeman P, et al. Relationship between pretreatment specific IgE and the response to omalizumab therapy. Allergy 2009; 64: 1780-1787.
29. Oba Y, Salzman GA. Cost-effectiveness analysis of omalizumab in adults and adolescents with moderate-to-severe allergic asthma. J Allergy Clin Immiunol 2004; 114: 265-269. (Pubitemid 39119022)
30. Kraft M, Djukanovic R, Wilson S, et al. Alveolar tissue inflammation in asthma. Am J Respir Crit Care Med 1996; 154: 1505-1510. (Pubitemid 26391205)
31. Sutherland ER, Martin RJ, Bowler RP, et al. Physiologic correlates of distal lung inflammation in asthma. J Allergy Clin Immunol 2004; 113: 1046-1050. (Pubitemid 38857984)
32. Kraft M, Martin RJ, Wilson S, et al. Lymphocyte and eosinophil influx into alveolar tissue in nocturnal asthma. Am J Respir Crit Care Med 1999; 159: 228-234. (Pubitemid 29036528)
33. Carroll NE, Carello S, Cooke C, et al. Airway structure and inflammatory cells in fatal attacks of asthma. Eur Respir J 1996; 9: 709-715. (Pubitemid 26167875)
34. Whitehead B, Scott JP, Helms P, et al. Technique and use of transbronchial biopsy in children and adolescents. Pediatr Pulmonol 1992; 12: 240-246.
35. Tsoukias NM, George SC. A two-compartment model of pulmonary nitric oxide exchange dynamics. J Appl Physiol 1998; 85: 653-666. (Pubitemid 28365835)
36. Tsoukias NM, Shin HW, Wilson AF, et al. A single-breath technique with variable flow rate to characterize nitric oxide exchange dynamics in the lungs. J Appl Physiol 2001; 91: 477-487. (Pubitemid 32574759)
37. Piacentini GL, Bodini A, Costella S, et al. Exhaled nitric oxide and sputum eosinophil markers of inflammation in asthmatic children. Eur Respir J 1999; 13: 1386-1390. (Pubitemid 29357157)
38. Nair P, Kjarsgaard M, Armstrong S, et al. Nitric oxide in exhaled breath is poorly correlated to sputum eosinophils in patients with prednisone-dependent asthma. J Allergy Clin Immunol 2010; 126: 404-406.
39. Cohen J, Douma WR, ten Hacken NH, et al. Ciclesonide improves measures of small airway involvement in asthma. Eur Respir J 2008; 31: 1213-1220.
40. Cohen J, Postma DS, Douma WR, et al. Particle size matters: diagnostics and treatment of small airways involvement in asthma. Eur Respir J 2011; 37: 532-540.
41. Berry M, Hargadon B, Morgan A, et al. Alveolar nitric oxide in adults with asthma: evidence of distal lung inflammation in refractory asthma. Eur Respir J 2005; 25: 986-991. (Pubitemid 40823772)
42. Paraskakis E, Brindicci C, Fleming L, et al. Measurement of bronchial and alveolar nitric oxide production in normal children and children with asthma. Am J Respir Crit Care Med 2006; 174: 260-267. (Pubitemid 44156604)
43. Cates CJ, Lasserson TJ. Combination formoterol and budesonide as maintenance and reliever therapy versus inhaled steroid maintenance for chronic asthma in adults and children. Cochrane Database Syst Rev 2009; 2: CD007313.
44. Bisgaard H, Le Roux P, Bjåmer D, et al. Budesonide/formoterol maintenance plus reliever therapy: a new strategy in Paediatrics asthma. Chest 2006; 130: 1733-1743. (Pubitemid 46033427)
45. Chapman KR, Barnes NC, Greening AP, et al. Single maintenance and reliever therapy (SMART) of asthma: a critical appraisal. Thorax 2010; 65: 747-752.
46. Peters MJ, Jenkins CR. Correspondence in relation to critical appraisal by Chapman et al. Thorax 2011; 66: 86.
47. Reddel HK, Yan KW. Single maintenance and reliever therapy (SMART) of asthma. Thorax 2011; 66: 86-87.
48. Bowler S, Serisier D. Single maintenance and reliever therapy. Thorax 2011; 66: 87.
49. Chapman KR, Barnes NC, Greening AP, et al. Authors' response. Thorax 2011; 66: 87-88.
50. Bush A, Pavord I. Editors' response. Thorax 2011; 66: 88.
51. Drazen JM, O'Byrne PM. Risks of long-acting β-agonists in achieving asthma control. N Engl J Med 2009; 360: 1671-1672.
52. Weatherall M, Wijesinghe M, Perrin K, et al. Meta-analysis of the risk of mortality with salmeterol and the effect of concomitant inhaled corticosteroid therapy. Thorax. 2010; 65: 39-43.
53. 2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol. Thorax 2006; 61: 940-944.
54. 2-receptor polymorphisms in patients receiving salmeterol with or without fluticasone propionate. Am J Respir Crit Care Med 2010; 181: 676-681.
55. Sullivan PJ, Bekir S, Jaffar Z, et al. The effects of low-dose theophylline on the bronchial wall infiltrate after allergen challenge. Lancet 1993; 343: 1006-1008.
56. Yasui K, Hu B, Nakazawa T, et al. Theophylline accelerates human granulocyte apoptosis not via phosphodiesterase inhibition. J Clin Invest 1997; 100: 1677-1684. (Pubitemid 27431323)
57. Yasui K, Agematsu K, Shinozaki K, et al. Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism. J Leukoc Biol 2000; 67: 529-535.
58. Kidney J, Dominguez M, Taylor PM, et al. Immunomodulation by theophylline in asthma. Demonstration by withdrawal of therapy. Am J Respir Crit Care Med 1995; 151: 1907-1914.
59. Cosío BG, Mann B, Ito K, et al. Histone acetylase and deacetylase activity in alveolar macrophages and blood mononocytes in asthma. Am J Respir Crit Care Med 2004; 170: 141-147. (Pubitemid 38925159)
60. Derks MG, Koopmans RP, Oosterhoff E, et al. Prevention by theophylline of beta-2-receptor down regulation in healthy subjects. Eur J Drug Metab Pharmacokinet 2000; 25: 179-188. (Pubitemid 32531239)
61. Seddon P, Bara A, Ducharme FM, et al. Oral xanthines as maintenance treatment for asthma in children. Cochrane Database Syst Rev 2006; 1: CD002885.
62. American Lung Association Asthma Clinical Research Centers. Clinical trial of low-dose theophylline and montelukast in patients with poorly controlled asthma. Am J Respir Crit Care Med 2007; 175: 235-242.
63. Payne D, Bush A. Phenotype-specific treatment of difficult asthma in children. Paediatr Respir Rev 2004; 5: 116-123. (Pubitemid 38701810)
64. Payne DN, Hubbard M, McKenzie SA. Corticosteroid unresponsiveness in asthma: primary or acquired? Pediatr Pulmonol 1998; 25: 59-61. (Pubitemid 28079933)
65. Willey RF, Fergusson RJ, Godden DJ, et al. Comparison of oral prednisolone and intramuscular depot triamcinolone in patients with severe chronic asthma. Thorax 1984; 39: 340-344. (Pubitemid 14140402)
66. Jacobs MB. Local subcutaneous atrophy after corticosteroid injection. Postgrad Med 1986; 80: 159-160. (Pubitemid 16008587)
67. Panickar JR, Kenia P, Silverman M, et al. Intramuscular triamcinolone for difficult asthma. Pediatr Pulmonol 2005; 39: 421-425. (Pubitemid 40548283)
68. Panickar JR, Bhatnagar N, Grigg J. Exhaled nitric oxide after a single dose of intramuscular triamcinolone in children with difficult to control asthma. Pediatr Pulmonol 2007; 42: 573-578. (Pubitemid 47021049)
69. Jaffe A, Bush A. Anti-inflammatory effects of macrolides in lung disease. Pediatr Pulmonol 2001; 31: 464-473. (Pubitemid 32523640)
70. Bush A, Rubin BK. Macrolides as biologic response modifiers in cystic fibrosis and bronchiectasis. Sem Respir Crit Care Med 2003; 24: 737-747. (Pubitemid 38036768)
71. Jaffe A, Bush A. Macrolides in cystic fibrosis. In: Rubin BK, Tamaoki J, eds. Progress in Inflammation Research. Antibiotics as Anti-inflammatory and Immunomodulatory Agents. Basel, Birkhauser Verlag Basel, 2005; pp 167-191.
72. Kudoh S, Azuma A, Yamamoto M, et al. Improvement in survival of patients with diffuse panbronchiolitis treated with low dose erythromycin. Am J Respir Crit Care Med 1998; 157: 1829-1832.
73. Nagai H, Shishido H, Yoneda R, et al. Long-term, low-dose administration of erythromycin to patients with diffuse panbronchiolitis. Respiration 1991; 58: 145-149.
74. Kadota J, Mukae H, Ishii H, et al. Long-term efficacy and safety of clarithromycin treatment in patients with diffuse panbronchiolitis. Respir Med 2003; 97: 844-850. (Pubitemid 36763898)
75. Wolter J, Seeney S, Bell S, et al. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised controlled trial. Thorax 2002; 57: 212-216. (Pubitemid 34214405)
76. Equi A, Balfour-Lynn I, Bush A, et al. Long term azithromycin in children with cystic fibrosis: a randomized, placebo-controlled crossover trial. Lancet 2002; 360: 978-984. (Pubitemid 35284109)
77. Saiman L, Marshall BC, Meyer-Hamblett N, et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2003; 290: 1749-1756. (Pubitemid 37430625)
78. Clement A, Tamalet A, Leroux E, et al. Long term effects of azithromycin in patients with cystic fibrosis: a double blind, placebo controlled trial. Thorax 2006; 61: 895-902. (Pubitemid 44570311)
79. Yalçin E, Kiper N, Ozçelik U, et al. Effects of claritromycin on inflammatory parameters and clinical conditions in children with bronchiectasis. J Clin Pharm Ther 2006; 31: 49-55.
80. Koh YY, Lee MH, Sun YH, et al. Effect of roxithromycin on airway responsiveness in children with bronchiectasis: a double-blind, placebo-controlled study. Eur Respir J 1997; 10: 994-999. (Pubitemid 27201800)
81. Cymbala AA, Edmonds LC, Bauer MA, et al. The disease-modifying effects of twice-weekly oral azithromycin in patients with bronchiectasis. Treat Respir Med 2005; 4: 117-122. (Pubitemid 40613959)
82. Zeiger RS, Schatz M, Sperling W, et al. Efficacy of troleandomycin in outpatients with severe, corticosteroid-dependent asthma. J Allergy Clin Immunol 1980; 66: 438-446. (Pubitemid 11207450)
83. Eitches RW, Rachelefsky GS, Katz RM, et al. Methylprednisolone and troleandomycin in treatment of steroid-dependent asthmatic children. Am J Dis Child 1985; 139: 264-268. (Pubitemid 15133707)
84. Kamada AK, Hill MR, Iklé DN, et al. Efficacy and safety of low-dose troleandomycin therapy in children with severe, steroid-requiring asthma. J Allergy Clin Immunol 1993; 91: 873-882. (Pubitemid 23118504)
85. Siracusa A, Brugnami G, Fiordi T, et al. Troleandomycin in the treatment of difficult asthma. J Allergy Clin Immunol 1993; 92: 677-682. (Pubitemid 23343775)
86. Nelson HS, Hamilos DL, Corsello PR, et al. A double-blind study of troleandomycin and methylprednisolone in asthmatic subjects who require daily corticosteroids. Am Rev Respir Dis 1993; 147: 398-404. (Pubitemid 23044914)
87. Harris R, German D. The incidence of corticosteroid side effects in chronic steroid-dependent asthmatics on TAO (troleandomycin) and methylprednisolone. Ann Allergy 1989; 63: 110-111. (Pubitemid 19203481)
88. Flotte TR, Loughlin GM. Benefits and complications of troleandomycin (TAO) in young children with steroid-dependent asthma. Pediatr Pulmonol 1991; 10: 178-182.
89. Ball BD, Hill MR, Brenner M, et al. Effect of low-dose troleandomycin on glucocorticoid pharmacokinetics and airway hyperresponsiveness in severely asthmatic children. Ann Allergy 1990; 65: 37-45. (Pubitemid 20233090)
90. Evans DJ, Cullinan P, Geddes DM. Troleandomycin as an oral corticosteroid steroid sparing agent in stable asthma. Cochrane Database Syst Rev 2001; 2: CD002987.
91. Fost DA, Leung DY, Martin RJ, et al. Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy. J Allergy Clin Immunol 1999; 103: 1031-1035. (Pubitemid 29343066)
92. Kraft M, Cassell GH, Pak J, et al. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin. Chest 2002; 121: 1782-1788. (Pubitemid 34634396)
93. Black PN, Blasi F, Jenkins CR, et al. Trial of roxithromycin in subjects with asthma and serological evidence of infection with Chlamydia pneumoniae. Am J Respir Crit Care Med 2001; 164: 536-541. (Pubitemid 32801652)
94. Johnston SL, Blasi F, Black PN, et al. TELICAST Investigators. The effect of telithromycin in acute exacerbations of asthma. N Engl J Med 2006; 354: 1589-1600.
95. Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999; 160: 1001-1008. (Pubitemid 29442043)
96. Simpson JL, Powell H, Boyle MJ, et al. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med 2008; 177: 148-155.
97. 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. (Pubitemid 38618141)
98. Ekici A, Ekici M, Erdemoǧlu AK. Effect of azithromycin on the severity of bronchial hyperresponsiveness in patients with mild asthma. J Asthma 2002; 39: 181-185. (Pubitemid 34464576)
99. Amayasu H, Yoshida S, Ebana S, et al. Clarithromycin suppresses bronchial hyperresponsiveness associated with eosinophilic inflammation in patients with asthma. Ann Allergy Asthma Immunol 2000; 84: 594-598. (Pubitemid 30418859)
100. Chu HW, Kraft M, Rex MD, et al. Evaluation of blood vessels and oedema in the airways of asthma patients: regulation with clarithromycin treatment. Chest 2001; 120: 416-422. (Pubitemid 32881256)
101. Spahn JD, Fost DA, Covar R, et al. Clarithromycin potentiates glucocorticoid responsiveness in patients with asthma: results of a pilot study. Ann Allergy Asthma Immunol 2001; 87: 501-505. (Pubitemid 34001039)
102. Piacentini GL, Peroni DG, Bodini A, et al. Azithromycin reduces bronchial hyperresponsiveness and neutrophilic airway inflammation in asthmatic children: a preliminary report. Allergy Asthma Proc 2007; 28: 194-198.
103. Fonseca-Aten M, Okada PJ, Bowlware KL, et al. Effect of clarithromycin on cytokines and chemokines in children with an acute exacerbation of recurrent wheezing: a double-blind, randomized, placebo-controlled trial. Ann Allergy Asthma Immunol 2006; 97: 457-463. (Pubitemid 44595092)
104. Shimizu T, Kato M, Mochizuki H, et al. Roxithromycin reduces the degree of bronchial hyperresponsiveness in children with asthma. Chest 1994; 106: 458-461. (Pubitemid 24252043)
105. Strunk RC, Bacharier LB, Phillips BR, et al. CARE Network. Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderate-to-severe childhood asthma study. J Allergy Clin Immunol 2008; 122: 1138-1144.
106. Hilty M, Burke C, Pedro H, et al. Disordered microbial communities in asthmatic airways. PLoS One 2010; 5: e8578.
107. Evans DJ, Cullinan P, Geddes DM. Cyclosporin as an oral corticosteroid sparing agent in stable asthma. Cochrane Database Syst Rev 2001; 2: CD002993.
108. Coren ME, Rosenthal M, Bush A. The use of cyclosporin in corticosteroid dependent asthma. Arch Dis Child 1997; 77: 522-523. (Pubitemid 28016374)
109. Corcoran TE, Smaldone GC, Dauber JH, et al. Preservation of post-transplant lung function with aerosol cyclosporin. Eur Respir J 2004; 23: 378-383. (Pubitemid 38344372)
110. Iacono AT, Johnson BA, Grgurich WF, et al. A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med 2006; 354: 141-150. (Pubitemid 43076711)
111. Davies H, Olson L, Gibson P. Methotrexate as a steroid sparing agent for asthma in adults. Cochrane Database Syst Rev 2000; 2: CD000391.
112. Stempel DA, Lammert J, Mullarkey MF. Use of methotrexate in the treatment of steroid-dependent adolescent asthmatics. Ann Allergy 1991; 67: 346-348.
113. Guss S, Portnoy J. Methotrexate treatment of severe asthma in children. Paediatrics 1992; 89: 635-639.
114. Solé D, Costa-Carvalho BT, Soares FJ, et al. Methotrexate in the treatment of corticodependent asthmatic children. J Investig Allergol Clin Immunol 1996; 6: 126-130. (Pubitemid 26148460)
115. Dean T, Dewey A, Bara A, et al. Azathioprine as an oral corticosteroid sparing agent for asthma. Cochrane Database Syst Rev 2004; 1: CD003270.
116. Bernstein IL, Bernstein DI, Dubb JW, et al. 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. (Pubitemid 26326126)
117. Evans DJ, Cullinan P, Geddes DM. Gold as an oral corticosteroid sparing agent in stable asthma. Cochrane Database Syst Rev 2001; 2: CD002985.
118. Muranaka M, Miyamoto T, Shida T, et al. Gold salt in the treatment of bronchial asthma - a double-blind study. Ann Allergy 1978; 40: 132-137. (Pubitemid 8285358)
119. Nierop G, Gijzel WP, Bel EH, et al. Auranofin in the treatment of steroid dependent asthma: a double blind study. Thorax 1992; 47: 349-354.
120. Salmun LM, Barlan I, Wolf HM, et al. Effect of intravenous immunoglobulin on steroid consumption in patients with severe asthma: a double-blind, placebo-controlled, randomized trial. J Allergy Clin Immunol 1999; 103: 810-815. (Pubitemid 29297583)
121. Kishiyama JL, Valacer D, Cunningham-Rundles C, et al. A multicenter, randomized, double-blind, placebo-controlled trial of high-dose intravenous immunoglobulin for oral corticosteroid-dependent asthma. Clin Immunol 1999; 91: 126-133. (Pubitemid 29203411)
122. Jakobsson T, Croner S, Kjellman NI, et al. Slight steroid-sparing effect of intravenous immunoglobulin in children and adolescents with moderately severe bronchial asthma. Allergy 1994; 49: 413-420. (Pubitemid 24180107)
123. Mazer BD, Gelfand EW. An open-label study of high-dose intravenous immunoglobulin in severe childhood asthma. J Allergy Clin Immunol 1991; 87: 976-983.
124. Niggemann B, Leupold W, Schuster A, et al. Prospective, double-blind, placebo-controlled, multicentre study on the effect of high-dose, intravenous immunoglobulin in children and adolescents with severe bronchial asthma. Clin Exp Allergy 1998; 28: 205-210. (Pubitemid 28137336)
125. Vrugt B, Wilson S, van Velzen E, et al. Effects of high dose intravenous immunoglobulin in two severe corticosteroid insensitive asthmatic patients. Thorax 1997; 52: 662-664. (Pubitemid 27342220)
126. O'Hallaren MT, Yunginger JW, Offord KP, et al. Exposure to aeroallergen as a possible precipitating factor in respiratory arrest in young patients with asthma. N Engl J Med 1991; 324: 359-363.
127. Neukirch C, Henry C, Leynaert B, et al. Is sensitization to Alternaria alternata a risk factor for severe asthma? A population based study. J Allergy Clin Immunol 1999; 103: 709-711. (Pubitemid 29295582)
128. Black PN, Udy AA, Brodie SM. Sensitivity to fungal allergens is a risk factor for life-threatening asthma. Allergy 2000; 55: 501-504. (Pubitemid 30230362)
129. O'Driscoll BR, Powell G, Chew F, et al. Comparison of skin prick tests with specific immunoglobulin E in the diagnosis of fungal sensitization in patients with severe asthma. Clin Exp Allergy 2009; 39: 1677-1683.
130. Denning DW, O'Driscoll BR, Powell G, et al. Randomized controlled trial of oral antifungal sensitization. The fungal asthma sensitization trial (FAST) study. Am J Respir Crit Care Med 2009; 179: 11-18.
131. Frith J, Fleming L, Bossley C, et al. The complexities of defining atopy in severe childhood asthma. Clin Exp Allergy 2011; 41: 948-953.
132. Vicencio AG, Muzumdar H, Tsirilakis K, et al. Severe asthma with fungal sensitization in a child: response to itraconazole therapy. Paediatrics 2010; 125: e1255-e1258.
133. De Wachter E, Vanbesien J, De Schutter I, et al. Rapidly developing Cushing syndrome in a 4-year-old patient during combined treatment with itraconazole and inhaled budesonide. Eur J Pediatr 2003; 162: 488-489. (Pubitemid 36904271)
134. Lewis LD, O'Driscoll BR, Hartley RB, et al. An unusual local reaction to continuous subcutaneous infused terbutaline in unstable asthmatics. Br J Dis Chest 1987; 81: 189-193. (Pubitemid 17054291)
135. O'Driscoll BR, Ruffles SP, Ayres JG, et al. Long term treatment of severe asthma with subcutaneous terbutaline. Br J Dis Chest 1988; 82: 360-367. (Pubitemid 19020647)
136. Cluzel M, Bousquet J, Daures JP, et al. Ambulatory long-term subcutaneous salbutamol infusion in chronic severe asthma. J Allergy Clin Immunol 1990; 85: 599-606. (Pubitemid 20099003)
137. Payne DNR, Balfour-Lynn IM, Biggart EA, et al. Subcutaneous terbutaline in children with chronic severe asthma. Pediatr Pulmonol 2002; 33: 356-361. (Pubitemid 34407751)
138. 2-agonists in infantile asthma. Pediatr Pulmonol 1992; 12: 81-83.
139. Vitez T. Potassium and the anaesthetist. Can J Anaesth 1987; 34: s30-s31.
140. Smith SR, Kendall MJ. Potentiation of the adverse effects of intravenous terbutaline by oral theophylline. Br J Clin Pharmacol 1986; 21: 451-453. (Pubitemid 17173265)
141. Sykes AP, Lawson N, Finnegan JA, et al. Creatine kinase activity in patients with brittle asthma treated with long term subcutaneous terbutaline. Thorax 1991; 46: 580-583.
142. Covar RA, Szefler SJ, Zeiger RS, et al. Factors associated with asthma exacerbations during a long-term clinical trial of controller medications in children. J Allergy Clin Immunol 2008; 122: 741-747.
143. Haselkorn T, Zeiger RS, Chipps BE, et al. Recent asthma exacerbations predict future exacerbations in children with severe or difficult-to-treat asthma. J Allergy Clin Immunol 2009; 124: 921-927.
144. Pedersen S. From asthma severity to control: a shift in clinical practice. Prim Care Respir J 2010; 19: 3-9.
145. Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003; 361: 1071-1076. (Pubitemid 36369558)
146. CAMP Study. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med 2000; 343: 1054-1063.
147. Reddel H, Ware S, Marks G, et al. Differences between asthma exacerbations and poor asthma control. Lancet 1999; 353: 364-369. (Pubitemid 29088164)
148. 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: 1225-1229.
149. Ballester F, Soriano JB, Otero I, et al. Asthma visits to emergency rooms and soybean unloading in the harbors of Valencia and A Coruña, Spain. Am J Epidemiol 1999; 149: 315-322. (Pubitemid 29302103)
150. Marks GB, Colquhoun JR, Girgis ST, et al. Thunderstorm outflows preceding epidemics of asthma during spring and summer. Thorax 2001; 56: 468-471. (Pubitemid 32521365)
151. Brand PLP, Baraldi E, Bisgaard H, et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J 2008; 32: 1096-1110.
152. Murray CS, Poletti G, Kebadze T, et al. Study of modifiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children. Thorax 2006; 61: 376-382. (Pubitemid 43723318)
153. Robertson CF, Price D, Henry R, et al. Short-course montelukast for intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med 2007; 175: 323-329.
154. Ducharme FM, Lemire C, Noya FJ, et al. Preemptive use of high-dose fluticasone for virus-induced wheezing in young children. N Engl J Med 2009; 360: 339-353.
155. McKean M, Ducharme F. Inhaled steroids for episodic viral wheeze of childhood. Cochrane Database Syst Rev 2000; 2: CD001107.
156. Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008; 178: 218-224.
157. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009; 360: 973-984.
158. Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009; 360: 985-993.
159. Roberts G, Patel N, Levi-Schaffer F, et al. Food allergy as a risk factor for life-threatening asthma in childhood: a case-controlled study. J Allergy Clin Immunol 2003; 112: 168-174. (Pubitemid 36819822)
160. Simpson AB, Glutting J, Yousef E. Food allergy and asthma morbidity in children. Pediatr Pulm 2007; 42: 489-495. (Pubitemid 46870379)
161. Pedersen S, O'Byrne PM. Exhaled nitric oxide in guideline-based asthma management. Lancet 2008; 372: 1015-1017.
162. Szefler SJ, Mitchell H, Sorkness CA, et al. Management of asthma based on
163. Stirling RG, Kharitonov SA, Campbell D, et al. Increase in exhaled nitric oxide levels in patients with difficult asthma and correlation with symptoms and disease severity despite treatment with oral and inhaled corticosteroids. Asthma and Allergy Group. Thorax 1998; 53: 1030-1034. (Pubitemid 28567003)
164. Smith AD, Cowan JO, Brassett KP, et al. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 2005; 352: 2163-2173.
165. Fritsch M, Uxa S, Horak F Jr, et al. Exhaled nitric oxide in the management of childhood asthma: a prospective 6-months study. Pediatr Pulmonol 2006; 41: 855-862. (Pubitemid 44300181)
166. Pijnenburg MW, Bakker EM, Hop WC, et al. Titrating steroids on exhaled nitric oxide in children with asthma: a randomized controlled trial. Am J Respir Crit Care Med 2005; 172: 831-836. (Pubitemid 41369065)
167. Shaw DE, Berry MA, Thomas M, et al. The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial. Am J Respir Crit Care Med 2007; 176: 231-237. (Pubitemid 47195872)
168. Sont JK, Willems LN, Bel EH, et al. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group. Am J Respir Crit Care Med 1999; 159: 1043-1051. (Pubitemid 29202534)
169. Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002; 360: 1715-1721. (Pubitemid 35447900)
170. Jayaram L, Pizzichini MM, Cook RJ, et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J 2006; 27: 483-494. (Pubitemid 43372521)
171. Zacharasiewicz A, Wilson N, Lex C, et al. Clinical use of non-invasive measurements of airway inflammation in steroid reduction in children. Am J Respir Crit Care Med 2005; 177: 1077-1082. (Pubitemid 40663717)
172. Pijnenburg MW, Hofhuis W, Hop WC, et al. Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission. Thorax 2005; 60: 215-218. (Pubitemid 40380280)
173. Fleming L, Wilson N, Regamey N, et al. The use of non-invasive markers of inflammation to guide management in children with severe asthma. Am J Respir Crit Care Med 2009; 179: A1305.
174. Fleming L, Tsartsali L, Wilson N, et al. Discordance between sputum eosinophils and exhaled nitric oxide in children with asthma. Thorax 2008; 63: Suppl. V11, A34.
175. Fleming L, Wilson N, Regamey N, et al. Are inflammatory phenotypes in children with severe asthma stable? Eur Respir J 2007; 30: Suppl. 51, 483S.
176. Bush A. Evidence-based medicines for children: important implications for new therapies at all ages. Eur Respir J 2006; 28: 1069-1072. (Pubitemid 44883836)
177. Berry MA, Hargadon B, Shelley M, et al. Evidence of a role of tumour necrosis factor a in refractory asthma. N Engl J Med 2006; 354: 697-708. (Pubitemid 43247140)
178. Wenzel SE, Barnes PJ, Bleecker ER, et al. A randomized, double-blind, placebo-controlled study of tumour necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med 2009; 179: 549-558.
179. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med 2007; 356: 1327-1337. (Pubitemid 46513298)
180. 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.
181. Bush A, Hedlin G, Calsen K-H, et al. Severe childhood asthma: a common international approach? Lancet 2008; 372: 1019-1021.
182. Bush A, Saglani S. Management of severe asthma in children. Lancet. 2010; 376: 814-825.