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A Rational Approach to the Management of Severe Refractory Asthma

  • Therapy in Practice
  • Published:
Treatments in Respiratory Medicine

Abstract

Severe refractory asthma is a heterogeneous condition with different patterns of severity and different reasons for loss of asthma control. The three main patterns include asthma with frequent exacerbations, asthma with irreversible airway obstruction, and asthma with reduced sensitivity or resistance to corticosteroids. Each of these patterns has distinct risk factors. The assessment of patients with severe asthma requires a systematic, diagnostic and management protocol. The majority of patients will benefit from thorough analysis and treatment of aggravating factors. In some patients with severe refractory asthma, in particular those with concomitant chronic rhinosinusitis, long-term administration of systemic corticosteroids may be necessary. In these patients all efforts should be directed towards reducing the dose of corticosteroids as much as possible. Although several corticosteroid-sparing agents and immunosuppressants have been proposed in the literature, none of these has gained complete acceptance in clinical practice, either because of limited efficacy or unacceptable adverse effects. Novel potent anti-inflammatory therapies aimed at reducing the need for systemic corticosteroids in patients with severe, refractory asthma are urgently needed.

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References

  1. Beasley R. The burden of asthma with specific reference to the United States. J Allergy Clin Immunol 2002; 109: S482–9

    PubMed  Google Scholar 

  2. Akinbami LJ, Schoendorf KC. Trends in childhood asthma: prevalence, health care utilization, and mortality. Pediatrics 2002; 110: 315–22

    PubMed  Google Scholar 

  3. Barnes PJ, Woolcock AJ. Difficult asthma. Eur Respir J 1998; 12: 1209–18

    PubMed  CAS  Google Scholar 

  4. Bavbek S, Celik G, Ediger D, et al. Severity and associated risk factors in adult asthma patients in Turkey. Ann Allergy Asthma Immunol 2000; 85: 134–9

    PubMed  CAS  Google Scholar 

  5. Lozano P, Sullivan SD, Smith DH, et al. The economic burden of asthma in US children: estimates from the National Medical Expenditure Survey. J Allergy Clin Immunol 1999; 104: 957–63

    PubMed  CAS  Google Scholar 

  6. Gendo K, Sullivan SD, Lozano P, et al. Resource costs for asthma-related care among pediatric patients in managed care. Ann Allergy Asthma Immunol 2003; 91: 251–7

    PubMed  Google Scholar 

  7. 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/Therapy-Resistant Asthma. European Respiratory Society. Eur Respir J 1999; 13: 1198–208

    CAS  Google Scholar 

  8. Proceedings of the ATS workshop on refractory asthma. Current understanding, recommendations, and unanswered questions. Am J Respir Crit Care Med 2000; 162 (6): 2341–51

    Google Scholar 

  9. Global strategy for asthma management and prevention. Bethesda (MD): NHLBI/ WHO Workshop report; 2002 Apr. NIH Publication No. 02-3659

  10. Cockcroft DW, Swystun VA. Asthma control versus asthma severity. J Allergy Clin Immunol 1996; 98: 1016–8

    PubMed  CAS  Google Scholar 

  11. Combescure C, Chanez P, Saint-Pierre P, et al. Assessment of variations in control of asthma over time. Eur Respir J 2003; 22: 298–304

    PubMed  CAS  Google Scholar 

  12. The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. Eur Respir J 2003; 22: 470–7

    Google Scholar 

  13. McFadden Jr ER. Acute severe asthma. Am J Respir Crit Care Med 2003; 168: 740–59

    PubMed  Google Scholar 

  14. Jones PW. Quality of life measurement in asthma. Eur Respir J 1995; 8: 885–7

    PubMed  CAS  Google Scholar 

  15. Hoskins G, McCowan C, Neville RG, et al. Risk factors and costs associated with an asthma attack. Thorax 2000; 55: 19–24

    PubMed  CAS  Google Scholar 

  16. Turner MO, Noertjojo K, Vedal S, et al. Risk factors for near-fatal asthma: a case-control study in hospitalized patients with asthma. Am J Respir Crit Care Med 1998; 157: 1804–9

    PubMed  CAS  Google Scholar 

  17. Mitchell I, Tough SC, Semple LK, et al. Near-fatal asthma: a population-based study of risk factors. Chest 2002; 121: 1407–13

    PubMed  Google Scholar 

  18. ten Brinke A, Sterk PJ, Masclee AAM, et al. Risk factors of frequent exacerbations in difficult-to-treat asthma. Eur Respir J. In press

  19. ten Brinke A, Ouwerkerk ME, Zwinderman AH, et al. Psychopathology in patients with severe asthma is associated with increased health care utilization. Am J Respir Crit Care Med 2001; 163: 1093–6

    PubMed  Google Scholar 

  20. Bosley CM, Fosbury JA, Cochrane GM. The psychosocial factors associated with poor compliance with treatment in asthma. Eur Respir Dis 1995; 8: 899–904

    CAS  Google Scholar 

  21. in’t Veen JC, Smits HH, Ravensberg AJ, et al. Impaired perception of dyspnea in patients with severe asthma: relation to sputum eosinophils. Am J Respir Crit Care Med 1998; 158: 1134–41

    Google Scholar 

  22. in’t Veen JC, Smits HH, Hiemstra PS, et al. Lung function and sputum characteristics of patients with severe asthma during an induced exacerbation by double-blind steroid withdrawal. Am J Respir Crit Care Med 1999; 160: 93–9

    PubMed  Google Scholar 

  23. in ’t Veen JC, Beekman AJ, Bel EH, et al. Recurrent exacerbations in severe asthma are associated with enhanced airway closure during stable episodes. Am J Respir Crit Care Med 2000; 161: 1902–6

    PubMed  Google Scholar 

  24. in ’t Veen JC, de Gouw HW, Smits HH, et al. Repeatability of cellular and soluble markers of inflammation in induced sputum from patients with asthma. Eur Respir J 1996; 9: 2441–7

    PubMed  Google Scholar 

  25. Fahy JV, Boushey HA, Lazarus SC, et al. Safety and reproducibility of sputum induction in asthmatic subjects in a multicenter study. Am J Respir Crit Care Med 2001; 163: 1470–5

    PubMed  CAS  Google Scholar 

  26. ten Brinke A, de Lange C, Zwinderman AH, et al. Sputum induction in severe asthma by a standardized protocol: predictors of excessive bronchoconstriction. Am J Respir Crit Care Med 2001; 164: 749–53

    PubMed  Google Scholar 

  27. Harrison BDW. Lessons to be learnt from confidential enquiries into asthma mortality in adults. In: Holgate ST, Boushey HA, Fabbri LM, editors. Difficult asthma. London: Martin Dunitz Ltd, 1999: 463–75

    Google Scholar 

  28. Molfino NA, Slutsky AS. Near-fatal asthma. Eur Respir J 1994; 7: 981–90

    PubMed  CAS  Google Scholar 

  29. Kuyper LM, Pare PD, Hogg JC, et al. Characterization of airway plugging in fatal asthma. Am J Med 2003; 115: 6–11

    PubMed  Google Scholar 

  30. Carroll N, Cooke C, James A. The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics. Eur Respir J 1997; 10: 292–300

    PubMed  CAS  Google Scholar 

  31. Groneberg DA, Eynott PR, Lim S, et al. Expression of respiratory mucins in fatal status asthmaticus and mild asthma. Histopathology 2002; 40: 367–73

    PubMed  CAS  Google Scholar 

  32. James AL, Maxwell PS, Pearce-Pinto G, et al. The relationship of reticular basement membrane thickness to airway wall remodeling in asthma. Am J Respir Crit Care Med 2002; 166: 1590–5

    PubMed  Google Scholar 

  33. Seow CY, Schellenberg RR, Pare PD. Structural and functional changes in the airway smooth muscle of asthmatic subjects. Am J Respir Crit Care Med 1998; 158: S179–86

    PubMed  CAS  Google Scholar 

  34. Saetta M, Di Stefano A, Rosina C, et al. Quantitative structural analysis of peripheral airways and arteries in sudden fatal asthma. Am Rev Respir Dis 1991; 143: 138–43

    PubMed  CAS  Google Scholar 

  35. Sur S, Crotty TB, Kephart GM, et al. Sudden-onset fatal asthma: a distinct entity with few eosinophils and relatively more neutrophils in the airway submucosa? Am Rev Respir Dis 1993; 148: 713–9

    PubMed  CAS  Google Scholar 

  36. 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: 1001–8

    PubMed  CAS  Google Scholar 

  37. Gibbons WJ, Sharma A, Lougheed D, et al. Detection of excessive bronchoconstriction in asthma. Am J Respir Crit Care Med 1996; 153: 582–9

    PubMed  CAS  Google Scholar 

  38. FitzGerald JM, Macklem P. Fatal asthma. Annu Rev Med 1996; 47: 161–8

    PubMed  CAS  Google Scholar 

  39. Turner-Warwick M. On observing patterns of airflow obstruction in chronic asthma. Br J Dis Chest 1977; 71: 73–86

    PubMed  CAS  Google Scholar 

  40. Ayres JG, Miles JF, Barnes PJ. Brittle asthma. Thorax 1998; 53: 315–21

    PubMed  CAS  Google Scholar 

  41. Wasserfallen JB, Schaller MD, Feihl F, et al. Sudden asphyxic asthma: a distinct entity? Am Rev Respir Dis 1990; 142: 108–11

    PubMed  CAS  Google Scholar 

  42. Picado C, Castillo JA, Montserrat JM, et al. Aspirin-intolerance as a precipitating factor of life-threatening attacks of asthma requiring mechanical ventilation. Eur Respir J 1989; 2: 127–9

    PubMed  CAS  Google Scholar 

  43. Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol 2001; 107: 191–3

    PubMed  CAS  Google Scholar 

  44. Fabbri LM, Danieli D, Crescioli S, et al. Fatal asthma in a subject sensitized to toluene diisocyanate. Am Rev Respir Dis 1988; 137: 1494–8

    PubMed  CAS  Google Scholar 

  45. Tan KS. Premenstrual asthma: epidemiology, pathogenesis and treatment. Drugs 2001; 61(14): 2079–86

    PubMed  CAS  Google Scholar 

  46. Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J Allergy Clin Immunol 2003 May; 111: 913–21

    PubMed  CAS  Google Scholar 

  47. Balzano G, Fuschillo S, Melillo G, et al. Asthma and sex hormones. Allergy 2001; 56: 13–20

    PubMed  CAS  Google Scholar 

  48. Tan KS, McFarlane LC, Coutie WJ, et al. Effects of exogenous female sex-steroid hormones on lymphocyte beta 2-adrenoceptors in normal females. Br J Clin Pharmacol 1996; 41: 414–6

    PubMed  CAS  Google Scholar 

  49. Beynon HL, Garbett ND, Barnes PJ. Severe premenstrual exacerbations of asthma: effect of intramuscular progesterone. Lancet 1988; II(8607): 370–2

    Google Scholar 

  50. Barnes PJ, Greening AP, Crompton GK. Glucocorticoid resistance in asthma. Am J Respir Crit Care Med 1995; 152: S125–42

    PubMed  CAS  Google Scholar 

  51. Tan KS, McFarlane LC, Lipworth BJ. Modulation of airway reactivity and peak flow variability in asthmatics receiving the oral contraceptive pill. Am J Respir Crit Care Med 1997; 155: 1273–7

    PubMed  CAS  Google Scholar 

  52. Murray RD, New JP, Barber PV, et al. Gonadotrophin-releasing hormone analogues: a novel treatment for premenstrual asthma. Eur Respir J 1999; 14: 966–7

    PubMed  CAS  Google Scholar 

  53. Bellomo R, McLaughlin P, Tai E, et al. Asthma requiring mechanical ventilation: a low morbidity approach. Chest 1994; 105: 891–6

    PubMed  CAS  Google Scholar 

  54. Reid LM. The presence or absence of bronchial mucus in fatal asthma. J Allergy Clin Immunol 1987; 80: 415–6

    PubMed  CAS  Google Scholar 

  55. Arm JP, Austen KF. Leukotriene receptors and aspirin sensitivity. N Engl J Med 2002; 347: 1524–6

    PubMed  Google Scholar 

  56. Ulrik CS, Backer V. Nonreversible airflow obstruction in life-long nonsmokers with moderate to severe asthma. Eur Respir J 1999; 14: 892–6

    PubMed  CAS  Google Scholar 

  57. Lange P, Parner J, Vestbo J, et al. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 1998; 339: 1194–2000

    PubMed  CAS  Google Scholar 

  58. Peat JK, Woolcock AJ, Cullen K. Rate of decline of lung function in subjects with asthma. Eur J Respir Dis 1987; 70: 171–9

    PubMed  CAS  Google Scholar 

  59. Fabbri LM, Romagnoli M, Corbetta L, et al. Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 167: 418–24

    PubMed  Google Scholar 

  60. Ulrik CS, Backer V, Dirksen A. A 10 year follow up of 180 adults with bronchial asthma: factors important for the decline in lung function. Thorax 1992; 47: 14–8

    PubMed  CAS  Google Scholar 

  61. ten Brinke A, Zwinderman AH, Sterk PJ, et al. Factors associated with persistent airflow limitation in severe asthma. Am J Respir Crit Care Med 2001; 164: 744–8

    PubMed  Google Scholar 

  62. Hansen EF, Phanareth K, Laursen LC, et al. Reversible and irreversible airflow obstruction as predictor of overall mortality in asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 159: 1267–71

    PubMed  CAS  Google Scholar 

  63. Grol MH, Gerritsen J, Vonk JM, et al. Risk factors for growth and decline of lung function in asthmatic individuals up to age 42 years: a 30-year follow-up study. Am J Respir Crit Care Med 1999; 160: 1830–7

    PubMed  CAS  Google Scholar 

  64. Gottlieb DJ, Sparrow D, O’Connor GT, et al. Skin test reactivity to common aeroallergens and decline of lung function. The Normative Aging Study. Am J Respir Crit Care Med 1996; 153: 561–6

    CAS  Google Scholar 

  65. Burrows B, Lebowitz MD, Barbee RA, et al. Findings before diagnoses of asthma among the elderly in a longitudinal study of a general population sample. J Allergy Clin Immunol 1991; 88: 870–7

    PubMed  CAS  Google Scholar 

  66. Ulrik CS, Lange P. Decline of lung function in adults with bronchial asthma. Am J Respir Crit Care Med 1994; 150: 629–34

    PubMed  CAS  Google Scholar 

  67. Frette C, Annesi I, Korobaeff M, et al. Blood eosinophilia and FEV1: cross-sectional and longitudinal analyses. Am Rev Respir Dis 1991; 143: 987–92

    PubMed  CAS  Google Scholar 

  68. Ulrik CS. Eosinophils and pulmonary function: an epidemiologic study of adolescents and young adults. Ann Allergy Asthma Immunol 1998; 80: 487–93

    PubMed  CAS  Google Scholar 

  69. Sears MR. Consequences of long-term inflammation: the natural history of asthma. Clin Chest Med 2000; 21: 315–29

    PubMed  CAS  Google Scholar 

  70. Gilliland FD, Berhane K, Li YF, et al. Effects of early onset asthma and in utero exposure to maternal smoking on childhood lung function. Am J Respir Crit Care Med 2003; 167: 917–24

    PubMed  Google Scholar 

  71. Ulrik CS. Outcome of asthma: longitudinal changes in lung function. Eur Respir J 1999; 13: 904–18

    PubMed  CAS  Google Scholar 

  72. Rackemann FM. A working classification of asthma. Am J Med 1947; 3: 601–6

    PubMed  CAS  Google Scholar 

  73. ten Brinke A, 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: 449–54

    PubMed  Google Scholar 

  74. McIntosh JC, Simecka JW, Ross SE, et al. Infection-induced airway fibrosis in two rat strains with differential susceptibility. Infect Immun 1992; 60: 2936–42

    PubMed  CAS  Google Scholar 

  75. Macek V, Sorli J, Kopriva S, et al. Persistent adenoviral infection and chronic airways obstruction in children. Am J Respir Crit Care Med 1994; 150: 7–10

    PubMed  CAS  Google Scholar 

  76. Lemanske Jr RF. Is asthma an infectious disease? Thomas A. Neff lecture. Chest 2003; 123(3 Suppl.): 385S–90S

    PubMed  Google Scholar 

  77. Vignola AM, Kips J, Bousquet J. Tissue remodelling as a feature of persistent asthma. J Allergy Clin Immunol 2000; 105: 1041–53

    PubMed  CAS  Google Scholar 

  78. Elias JA. Airway remodeling in asthma: unanswered questions. Am J Respir Crit Care Med 2000; 161: S168–71

    PubMed  CAS  Google Scholar 

  79. McDonald DM. Angiogenesis and remodeling of airway vasculature in chronic inflammation. Am J Respir Crit Care Med 2001; 164: S39–45

    PubMed  CAS  Google Scholar 

  80. Bai TR, Cooper J, Koelmeyer T, et al. The effect of age and duration of disease on airway structure in fatal asthma. Am J Respir Crit Care Med 2000; 162: 663–9

    PubMed  CAS  Google Scholar 

  81. Wenzel SE, Szefler SJ, Leung DY, et al. Bronchoscopic evaluation of severe asthma: persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 1997; 156: 737–43

    PubMed  CAS  Google Scholar 

  82. Martin RJ. Therapeutic significance of distal airway inflammation in asthma. J Allergy Clin Immunol 2002; 109(2 Suppl.): S447–60

    PubMed  Google Scholar 

  83. ten Brinke A, Grootendorst DC, Schmidt JT, et al. Chronic sinusitis in severe asthma is related to sputum eosinophilia. J Allergy Clin Immunol 2002; 109: 621–6

    PubMed  Google Scholar 

  84. Woolcock AJ. Steroid resistant asthma: what is the clinical definition? Eur Respir J 1993; 6: 743–7

    PubMed  CAS  Google Scholar 

  85. Rand CS, Wise RA. Measuring adherence to asthma medication regimens. Am J Respir Crit Care Med 1994; 149: S69–76

    PubMed  CAS  Google Scholar 

  86. Woolcock AJ. Corticosteroid-resistant asthma: definitions. Am J Respir Crit Care Med 1996; 154: S45–8

    PubMed  CAS  Google Scholar 

  87. Dong Y, Poellinger L, Gustafsson JA, et al. Regulation of glucocorticoid receptor expression: evidence for transcriptional and posttranslational mechanisms. Mol Endocrinol 1988; 2: 1256–64

    PubMed  CAS  Google Scholar 

  88. Adcock IM, Brown CR, Shirasaki H, et al. Effects of dexamethasone on cytokine and phorbol ester stimulated c-Fos and c-Jun DNA binding and gene expression in human lung. Eur Respir J 1994; 7: 2117–23

    PubMed  CAS  Google Scholar 

  89. Bamberger CM, Bamberger AM, de Castro M, et al. Glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans. J Clin Invest 1995; 95: 2435–41

    PubMed  CAS  Google Scholar 

  90. Barnes PJ. Molecular mechanisms of corticosteroids in allergic diseases. Allergy 2001; 56: 928–36

    PubMed  CAS  Google Scholar 

  91. Vlahakis NE, Patel AM, Maragos NE, et al. Diagnosis of vocal cord dysfunction: the utility of spirometry and plethysmography. Chest 2002; 122: 2246–9

    PubMed  Google Scholar 

  92. Dekker E, Groen J. Asthmatic wheezing; compression of the trachea and major bronchi as a cause. Lancet 1957 May 25; 272(6978): 1064–8

    PubMed  CAS  Google Scholar 

  93. Chipps BE, Chipps DR. Approach to the difficult pediatric asthmatic. Curr Opin Pulm Med 1999; 5: 52–7

    PubMed  CAS  Google Scholar 

  94. Greenberger PA. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 2002; 110: 685–92

    PubMed  Google Scholar 

  95. Noth I, Strek ME, Leff AR. Churg-Strauss syndrome. Lancet 2003 Feb 15; 361(9357): 587–94

    PubMed  Google Scholar 

  96. Adams R, Ruffin R, Campbell D. Psychosocial factors in severe asthma. In: Holgate ST, Boushey HA, Fabbri LM, editors. Difficult asthma. Maiden (MA): Blackwell Science Inc., 1999: 413–43

    Google Scholar 

  97. Hoover GE, Newman LJ, Platts-Mills TA, et al. Chronic sinusitis: risk factors for extensive disease. J Allergy Clin Immunol 1997; 100(2): 185–91

    PubMed  CAS  Google Scholar 

  98. Lamblin C, Gosset P, Salez F, et al. Eosinophilic airway inflammation in nasal polyposis. J Allergy Clin Immunol 1999; 104(1): 85–92

    PubMed  CAS  Google Scholar 

  99. Hoffman GS, Specks U. Antineutrophil cytoplasmic antibodies. Arthritis Rheum 1998; 41: 1521–37

    PubMed  CAS  Google Scholar 

  100. Eaton T, Garrett J, Milne D, et al. Allergic bronchopulmonary aspergillosis in the asthma clinic: a prospective evaluation of CT in the diagnostic algorithm. Chest 2000; 118: 66–72

    PubMed  CAS  Google Scholar 

  101. Bresciani M, Paradis L, Des Roches A, et al. Rhinosinusitis in severe asthma. J Allergy Clin Immunol 2001; 107: 73–80

    PubMed  CAS  Google Scholar 

  102. Mays EE. Intrinsic asthma in adults: association with gastroesophageal reflux. JAMA 1976; 236: 2626–8

    PubMed  CAS  Google Scholar 

  103. O’Connor JF, Singer ME, Richter JE. The cost-effectiveness of strategies to assess gastroesophageal reflux as an exacerbating factor in asthma. Am J Gastroenterol 1999; 94: 1472–80

    PubMed  Google Scholar 

  104. de Moraes Lui C, Oliveira LC, Diogo CL, et al. Immunoglobulin G subclass concentrations and infections in children and adolescents with severe asthma. Pediatr Allergy Immunol 2002; 13: 195–202

    PubMed  Google Scholar 

  105. Guilleminault C, Quera-Salva MA, Powell N, et al. Nocturnal asthma: snoring, small pharynx and nasal CPAP. Eur Respir J 1988; 1: 902–7

    PubMed  CAS  Google Scholar 

  106. Wenzel SE. Approach to severe asthma: experience of a national referral center. In: Holgate ST, Boushey HA, Fabbri LM, editors. Difficult asthma. Maiden (MA): Blackwell Science Inc., 1999: 535–44

    Google Scholar 

  107. Irwn RS, Curley FJ, French CL. Difficult-to-control asthma: contributing factors and outcome of a systematic management protocol. Chest 1993; 103: 1662–9

    Google Scholar 

  108. Heaney LG, Conway E, Kelly C, et al. Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol. Thorax 2003; 58: 561–6

    PubMed  CAS  Google Scholar 

  109. Platts-Mills TA, Tovey ER, Mitchell EB, et al. Reduction of bronchial hyperreactivity during prolonged allergen avoidance. Lancet 1982; II(8300): 675–8

    Google Scholar 

  110. Grootendorst DC, Dahlen SE, Van Den Bos JW, et al. Benefits of high altitude allergen avoidance in atopic adolescents with moderate to severe asthma, over and above treatment with high dose inhaled steroids. Clin Exp Allergy 2001; 31: 400–8

    PubMed  CAS  Google Scholar 

  111. Kolbe J, Vamos M, Fergusson W, et al. Differential influences on asthma self-management knowledge and self-management behavior in acute severe asthma. Chest 1996; 110: 1463–8

    PubMed  CAS  Google Scholar 

  112. Bone RC. The bottom line in asthma management is patient education. Am J Med 1993; 94: 561–3

    PubMed  CAS  Google Scholar 

  113. Campbell DA, MacLennan G, Coates JR, et al. Near fatal asthma attacks: the reliability of descriptive information collected from close acquaintances. Thorax 1993; 48: 1099–104

    PubMed  CAS  Google Scholar 

  114. Jones KP, Mullee MA, Middleton M, et al. Peak flow based asthma self management: a randomised controlled study in general practice. British Thoracic Society Research Committee. Thorax 1995; 50: 851–7

    CAS  Google Scholar 

  115. Ram FS, Robinson SM, Black PN. Physical training for asthma. Cochrane Database Syst Rev 2000; (2): CD001116

  116. Emtner M, Herala M, Stalenheim G. High-intensity physical training in adults with asthma: a 10-week rehabilitation program. Chest 1996; 109: 323–30

    PubMed  CAS  Google Scholar 

  117. Huang SW, Veiga R, Sila U, et al. The effect of swimming in asthmatic children: participants in a swimming program in the city of Baltimore. J Asthma 1989; 26: 117–21

    PubMed  CAS  Google Scholar 

  118. Nelson HS, Chapman KR, Pyke SD, et al. Enhanced synergy between fluticasone propionate and salmeterol inhaled from a single inhaler versus separate inhalers. J Allergy Clin Immunol 2003; 112: 29–36

    PubMed  CAS  Google Scholar 

  119. Barnes PJ. Scientific rationale for inhaled combination therapy with long-acting beta2-agonists and corticosteroids. Eur Respir J 2002; 19: 182–91

    PubMed  CAS  Google Scholar 

  120. Malo JL, Cartier A, Merland N, et al. Four-times-a-day dosing frequency is better than a twice-a-day regimen in subjects requiring a high-dose inhaled steroid, budesonide, to control moderate to severe asthma. Am Rev Respir Dis 1989; 140: 624–8

    PubMed  CAS  Google Scholar 

  121. Barnes PJ. Theophylline: new perspectives for an old drug. Am J Respir Crit Care Med 2003; 167: 813–8

    PubMed  Google Scholar 

  122. 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: 237–40

    PubMed  CAS  Google Scholar 

  123. Wallaert B, Brun P, Ostinelli J, et al. A comparison of two long-acting beta-agonists, oral bambuterol and inhaled salmeterol, in the treatment of moderate to severe asthmatic patients with nocturnal symptoms. The French Bambuterol Study Group. Respir Med 1999; 93: 33–8

    CAS  Google Scholar 

  124. Hauber HP, Gotfried M, Newman K, et al. Effect of HFA-flunisolide on peripheral lung inflammation in asthma. J Allergy Clin Immunol 2003; 112: 58–63

    PubMed  CAS  Google Scholar 

  125. Keenan GF. Management of complications of glucocorticoid therapy. Clin Chest Med 1997; 18: 507–20

    PubMed  CAS  Google Scholar 

  126. Davies H, Olson L, Gibson P. Methotrexate as a steroid-sparing agent for asthma in adults. Cochrane Database Syst Rev 2000; (2): CD000391

  127. Corrigan CJ, Shiner R, Shakur BH, et al. Methotrexate therapy in asthma increases T cell susceptibility to corticosteroid inhibition. Clin Exp Allergy 2003; 33: 1090–6

    PubMed  CAS  Google Scholar 

  128. Evans DJ, Cullinan P, Geddes DM. Cyclosporin as an oral corticosteroid sparing agent in stable asthma. Cochrane Database Syst Rev 2001; (2): CD002993

  129. 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: 509–14

    PubMed  CAS  Google Scholar 

  130. Nizankowska E, Soja J, Pinis G, et al. Treatment of steroid-dependent bronchial asthma with cyclosporin. Eur Respir J 1995; 8(7): 1091–9

    PubMed  CAS  Google Scholar 

  131. Eckstein JW, Fung J. A new class of cyclosporin analogues for the treatment of asthma. Expert Opin Investig Drugs 2003; 12: 647–53

    PubMed  CAS  Google Scholar 

  132. Evans DJ, Cullinan P, Geddes DM. Gold as an oral corticosteroid sparing agent in stable asthma. Cochrane Database Syst Rev 2001; (2): CD002985

  133. Nierop G, Gijzel WP, Bel EH, et al. Auranofin in the treatment of steroid-dependent asthma; a double blind study. Thorax 1992; 47: 349–54

    PubMed  CAS  Google Scholar 

  134. Evans DJ, Cullinan P, Geddes DM. Troleandomycin as an oral corticosteroid steroid sparing agent in stable asthma. Cochrane Database Syst Rev 2001; (2): CD002987

  135. Garey KW, Alwani A, Danziger LH, et al. Tissue reparative effects of macrolide antibiotics in chronic inflammatory sinopulmonary diseases. Chest 2003; 123: 261–5

    PubMed  Google Scholar 

  136. Garey KW, Rubinstein I, Gotfried MH, et al. Long-term clarithromycin decreases prednisone requirements in elderly patients with prednisone-dependent asthma. Chest 2000; 118: 1826–7

    PubMed  CAS  Google Scholar 

  137. 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: 126–33

    PubMed  CAS  Google Scholar 

  138. 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: 963–70

    PubMed  CAS  Google Scholar 

  139. 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(9248): 2144–8

    PubMed  CAS  Google Scholar 

  140. Kips JC, O’Connor BJ, Langley SJ, et al. Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am J Respir Crit Care Med 2003; 16: 1655–9

    Google Scholar 

  141. 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: 1029–36

    PubMed  CAS  Google Scholar 

  142. Baugh JA, Bucala R. Mechanisms for modulating TNF alpha in immune and inflammatory disease. Curr Opin Drug Discov Devel 2001; 4: 635–50

    PubMed  CAS  Google Scholar 

  143. Bryan SA, O’Connor BJ, Matti S, et al. Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000; 356: 2149–53

    PubMed  CAS  Google Scholar 

  144. Hanifin JM, Schneider LC, Leung DY, et al. Recombinant interferon gamma therapy for atopic dermatitis. J Am Acad Dermatol 1993; 28: 189–97

    PubMed  CAS  Google Scholar 

  145. Boguniewicz M, Schneider LC, Milgrom H, et al. Treatment of steroid-dependent asthma with recombinant interferon-gamma. Clin Exp Allergy 1993; 23: 785–90

    PubMed  CAS  Google Scholar 

  146. Walker S, Monteil M, Phelan K, et al. Anti-IgE for chronic asthma. Cochrane Database Syst Rev 2003; (3): CD003559

  147. Milgrom H, Fick Jr RB, Su JQ, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. rhuMAb-E25 Study Group. N Engl J Med 1999; 341: 1966–73

    CAS  Google Scholar 

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Acknowledgements

E. Bel and A. ten Brinke are paid by the Leiden University Medical Center and the Medical Center Leeuwarden. No additional funding was used to prepare this manuscript. E. Bel and A. ten Brinke do not have any conflicts of interest.

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Bel, E., ten Brinke, A. A Rational Approach to the Management of Severe Refractory Asthma. Treat Respir Med 4, 365–379 (2005). https://doi.org/10.2165/00151829-200504060-00002

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