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Treatment of severe asthma in adolescents and adults

Author
Sally Wenzel, MD
Section Editor
Bruce S Bochner, MD
Deputy Editor
Helen Hollingsworth, MD

INTRODUCTION

The classification of "severe asthma" refers to patients who require high dose inhaled glucocorticoid (GC), or continuous or near continuous oral GC treatment to maintain asthma control or who never achieve control despite that treatment (table 1) [1].

The National Asthma Education and Prevention Program (NAEPP) and Global Initiative for Asthma (GINA) guidelines have a slightly different category of "severe persistent asthma" that describes patients who have frequent and severe asthma symptoms and evidence of airflow limitation, but are not on asthma controller medication (table 2) [2,3]. Patients with severe asthma (by European Respiratory Society [ERS]/American Thoracic Society [ATS] criteria) generally require high doses of controller medications to achieve control [1]; without these medications their asthma is either "not well controlled" or "very poorly controlled" by NAEPP/GINA criteria (table 3).

The evaluation of patients with severe asthma symptoms, a general overview of asthma management, and a review of nonpharmacologic management are presented separately. (See "Evaluation of severe asthma in adolescents and adults" and "An overview of asthma management" and "Trigger control to enhance asthma management".)

Treatment issues that pertain to patients with severe asthma are reviewed here. Treatment approaches to mild and moderate persistent asthma are reviewed separately. (See "An overview of asthma management" and "Treatment of intermittent and mild persistent asthma in adolescents and adults" and "Treatment of moderate persistent asthma in adolescents and adults".)

GENERAL TREATMENT PRINCIPLES

Treatment of severe asthma frequently requires a multidisciplinary approach to address patient education needs, remediate irritant and allergic triggers, treat comorbidities, and design an optimal medication regimen.

                              

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Literature review current through: Nov 2016. | This topic last updated: Mon Jul 11 00:00:00 GMT+00:00 2016.
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References
Top
  1. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014; 43:343.
  2. National Asthma Education and Prevention Program: Expert panel report III: Guidelines for the diagnosis and management of asthma. Bethesda, MD: National Heart, Lung, and Blood Institute, 2007. (NIH publication no. 08-4051) www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm (Accessed on December 04, 2014).
  3. GINA report. Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA). www.ginasthma.org (Accessed on November 02, 2015).
  4. Bender BG. Overcoming barriers to nonadherence in asthma treatment. J Allergy Clin Immunol 2002; 109:S554.
  5. Bateman ED, Boushey HA, Bousquet J, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004; 170:836.
  6. Schatz M, Sorkness CA, Li JT, et al. Asthma Control Test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists. J Allergy Clin Immunol 2006; 117:549.
  7. Juniper EF. Assessing asthma control. Curr Allergy Asthma Rep 2007; 7:390.
  8. Pauwels RA, Löfdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997; 337:1405.
  9. Nelson HS, Busse WW, deBoisblanc BP, et al. Fluticasone propionate powder: oral corticosteroid-sparing effect and improved lung function and quality of life in patients with severe chronic asthma. J Allergy Clin Immunol 1999; 103:267.
  10. 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.
  11. Lefebvre P, Duh MS, Lafeuille MH, et al. Acute and chronic systemic corticosteroid-related complications in patients with severe asthma. J Allergy Clin Immunol 2015; 136:1488.
  12. Ogirala RG, Aldrich TK, Prezant DJ, et al. High-dose intramuscular triamcinolone in severe, chronic, life-threatening asthma. N Engl J Med 1991; 324:585.
  13. ten Brinke A, Zwinderman AH, Sterk PJ, et al. "Refractory" eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids. Am J Respir Crit Care Med 2004; 170:601.
  14. Masoli M, Weatherall M, Holt S, Beasley R. Moderate dose inhaled corticosteroids plus salmeterol versus higher doses of inhaled corticosteroids in symptomatic asthma. Thorax 2005; 60:730.
  15. Noonan M, Chervinsky P, Busse WW, et al. Fluticasone propionate reduces oral prednisone use while it improves asthma control and quality of life. Am J Respir Crit Care Med 1995; 152:1467.
  16. Ayres JG, Bateman ED, Lundbäck B, Harris TA. High dose fluticasone propionate, 1 mg daily, versus fluticasone propionate, 2 mg daily, or budesonide, 1.6 mg daily, in patients with chronic severe asthma. International Study Group. Eur Respir J 1995; 8:579.
  17. Leach CL, Davidson PJ, Boudreau RJ. Improved airway targeting with the CFC-free HFA-beclomethasone metered-dose inhaler compared with CFC-beclomethasone. Eur Respir J 1998; 12:1346.
  18. 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.
  19. Corren J, Nelson H, Greos LS, et al. Effective control of asthma with hydrofluoroalkane flunisolide delivered as an extrafine aerosol in asthma patients. Ann Allergy Asthma Immunol 2001; 87:405.
  20. Faurschou P, Steffensen I, Jacques L. Effect of addition of inhaled salmeterol to the treatment of moderate-to-severe asthmatics uncontrolled on high-dose inhaled steroids. European Respiratory Study Group. Eur Respir J 1996; 9:1885.
  21. O'Byrne PM. Acute asthma intervention: insights from the STAY study. J Allergy Clin Immunol 2007; 119:1332.
  22. Wells KE, Peterson EL, Ahmedani BK, et al. The relationship between combination inhaled corticosteroid and long-acting β-agonist use and severe asthma exacerbations in a diverse population. J Allergy Clin Immunol 2012; 129:1274.
  23. Nightingale JA, Rogers DF, Barnes PJ. Comparison of the effects of salmeterol and formoterol in patients with severe asthma. Chest 2002; 121:1401.
  24. Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 1993; 306:1034.
  25. Nelson HS, Weiss ST, Bleecker ER, et al. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006; 129:15.
  26. Walters EH, Gibson PG, Lasserson TJ, Walters JA. Long-acting beta2-agonists for chronic asthma in adults and children where background therapy contains varied or no inhaled corticosteroid. Cochrane Database Syst Rev 2007; :CD001385.
  27. Price DB, Hernandez D, Magyar P, et al. Randomised controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma. Thorax 2003; 58:211.
  28. Robinson DS, Campbell D, Barnes PJ. Addition of leukotriene antagonists to therapy in chronic persistent asthma: a randomised double-blind placebo-controlled trial. Lancet 2001; 357:2007.
  29. Rabinovitch N, Zhang L, Gelfand EW. Urine leukotriene E4 levels are associated with decreased pulmonary function in children with persistent airway obstruction. J Allergy Clin Immunol 2006; 118:635.
  30. Virchow JC Jr, Prasse A, Naya I, et al. Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. Am J Respir Crit Care Med 2000; 162:578.
  31. Dahlén B, Nizankowska E, Szczeklik A, et al. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. Am J Respir Crit Care Med 1998; 157:1187.
  32. The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. European Network for Understanding Mechanisms of Severe Asthma. Eur Respir J 2003; 22:470.
  33. Berger W, De Chandt MT, Cairns CB. Zileuton: clinical implications of 5-Lipoxygenase inhibition in severe airway disease. Int J Clin Pract 2007; 61:663.
  34. Nathan, RA, Prenner, BM, Bernstein, JA, Walton-Bowen, K. Zileuton Provides Significant Improvement in Asthma Symptoms and beta-agonist and Rescue Medication Use Compared to Placebo in Asthma Patients with Reduced or Low Lung Function. J Allergy Clin Immunol 2006; 117 Suppl 2:S156.
  35. 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.
  36. Davies B, Brooks G, Devoy M. The efficacy and safety of salmeterol compared to theophylline: meta-analysis of nine controlled studies. Respir Med 1998; 92:256.
  37. Inoue H, Komori M, Matsumoto T, et al. Effects of salmeterol in patients with persistent asthma receiving inhaled corticosteroid plus theophylline. Respiration 2007; 74:611.
  38. 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.
  39. Chin SJ, Durmowicz AG, Chowdhury BA. Tiotropium Respimat Is Effective for the Treatment of Asthma at a Dose Lower Than That for Chronic Obstructive Pulmonary Disease. Ann Am Thorac Soc 2016; 13:173.
  40. Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012; 367:1198.
  41. Kerstjens HA, Disse B, Schröder-Babo W, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol 2011; 128:308.
  42. Bateman ED, Kornmann O, Schmidt P, et al. Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma. J Allergy Clin Immunol 2011; 128:315.
  43. Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs Long-Acting β-Agonist in Combination With Inhaled Corticosteroids in Black Adults With Asthma: The BELT Randomized Clinical Trial. JAMA 2015; 314:1720.
  44. Rodrigo GJ, Castro-Rodríguez JA. Tiotropium for the treatment of adolescents with moderate to severe symptomatic asthma: a systematic review with meta-analysis. Ann Allergy Asthma Immunol 2015; 115:211.
  45. Bousquet J, Wenzel S, Holgate S, et al. Predicting response to omalizumab, an anti-IgE antibody, in patients with allergic asthma. Chest 2004; 125:1378.
  46. Humbert M, Beasley R, Ayres J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005; 60:309.
  47. Brown R, Turk F, Dale P, Bousquet J. Cost-effectiveness of omalizumab in patients with severe persistent allergic asthma. Allergy 2007; 62:149.
  48. Omalizumab package insert. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/103976s5225lbl.pd (Accessed on July 11, 2016).
  49. Hanania NA, Alpan O, Hamilos DL, et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med 2011; 154:573.
  50. Hanania NA, Wenzel S, Rosén K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med 2013; 187:804.
  51. Vestbo J, Agusti A, Wouters EF, et al. Should we view chronic obstructive pulmonary disease differently after ECLIPSE? A clinical perspective from the study team. Am J Respir Crit Care Med 2014; 189:1022.
  52. Holgate ST, Chuchalin AG, Hébert J, et al. Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma. Clin Exp Allergy 2004; 34:632.
  53. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014; 371:1189.
  54. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012; 380:651.
  55. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009; 360:973.
  56. Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009; 360:985.
  57. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014; 371:1198.
  58. US Food and Drug Administration. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm471031.htm (Accessed on November 05, 2015).
  59. Ortega HG, Yancey SW, Mayer B, et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med 2016; 4:549.
  60. Mepolizumab prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125526Orig1s000Lbl.pdf (Accessed on November 05, 2015).
  61. Castro M, Mathur S, Hargreave F, et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med 2011; 184:1125.
  62. Powell C, Milan SJ, Dwan K, et al. Mepolizumab versus placebo for asthma. Cochrane Database Syst Rev 2015; :CD010834.
  63. Pavord ID, Haldar P, Bradding P, Wardlaw AJ. Mepolizumab in refractory eosinophilic asthma. Thorax 2010; 65:370.
  64. 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; 356:2144.
  65. 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; 167:1655.
  66. Flood-Page P, Swenson C, Faiferman I, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med 2007; 176:1062.
  67. US Food and Drug Administration. Reslizumab (Cinqair) prescribing information. http://www.cinqair.com/pdf/PrescribingInformation.pdf (Accessed on March 28, 2016).
  68. Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med 2015; 3:355.
  69. Solway J, Irvin CG. Airway smooth muscle as a target for asthma therapy. N Engl J Med 2007; 356:1367.
  70. Cox PG, Miller J, Mitzner W, Leff AR. Radiofrequency ablation of airway smooth muscle for sustained treatment of asthma: preliminary investigations. Eur Respir J 2004; 24:659.
  71. Cox G, Miller JD, McWilliams A, et al. Bronchial thermoplasty for asthma. Am J Respir Crit Care Med 2006; 173:965.
  72. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med 2007; 356:1327.
  73. Wahidi MM, Kraft M. Bronchial thermoplasty for severe asthma. Am J Respir Crit Care Med 2012; 185:709.
  74. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med 2011; 11:8.
  75. Torrego A, Solà I, Munoz AM, et al. Bronchial thermoplasty for moderate or severe persistent asthma in adults. Cochrane Database Syst Rev 2014; :CD009910.
  76. 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.
  77. Wechsler ME, Laviolette M, Rubin AS, et al. Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol 2013; 132:1295.
  78. Pavord ID, Cox G, Thomson NC, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med 2007; 176:1185.
  79. Pavord ID, Thomson NC, Niven RM, et al. Safety of bronchial thermoplasty in patients with severe refractory asthma. Ann Allergy Asthma Immunol 2013; 111:402.
  80. Bronchial thermoplasty for asthma. Med Lett Drugs Ther 2010; 52:65.
  81. Hawkins G, McMahon AD, Twaddle S, et al. Stepping down inhaled corticosteroids in asthma: randomised controlled trial. BMJ 2003; 326:1115.
  82. FitzGerald JM, Boulet LP, Follows RM. The CONCEPT trial: a 1-year, multicenter, randomized,double-blind, double-dummy comparison of a stable dosing regimen of salmeterol/fluticasone propionate with an adjustable maintenance dosing regimen of formoterol/budesonide in adults with persistent asthma. Clin Ther 2005; 27:393.
  83. Wenzel SE, Barnes PJ, Bleecker ER, et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med 2009; 179:549.
  84. 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.
  85. Kraft M, Cassell GH, Pak J, Martin RJ. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin. Chest 2002; 121:1782.
  86. Sutherland ER, Martin RJ. Asthma and atypical bacterial infection. Chest 2007; 132:1962.
  87. Corren J, Adinoff AD, Buchmeier AD, Irvin CG. Nasal beclomethasone prevents the seasonal increase in bronchial responsiveness in patients with allergic rhinitis and asthma. J Allergy Clin Immunol 1992; 90:250.
  88. Adams RJ, Fuhlbrigge AL, Finkelstein JA, Weiss ST. Intranasal steroids and the risk of emergency department visits for asthma. J Allergy Clin Immunol 2002; 109:636.
  89. Thomson NC, Chaudhuri R, Livingston E. Asthma and cigarette smoking. Eur Respir J 2004; 24:822.
  90. Teodorescu M, Consens FB, Bria WF, et al. Correlates of daytime sleepiness in patients with asthma. Sleep Med 2006; 7:607.
  91. Yigla M, Tov N, Solomonov A, et al. Difficult-to-control asthma and obstructive sleep apnea. J Asthma 2003; 40:865.
  92. Bonekat HW, Hardin KA. Severe upper airway obstruction during sleep. Clin Rev Allergy Immunol 2003; 25:191.
  93. Laforest L, Van Ganse E, Devouassoux G, et al. Influence of patients' characteristics and disease management on asthma control. J Allergy Clin Immunol 2006; 117:1404.
  94. Moreira A, Bonini M, Garcia-Larsen V, et al. Weight loss interventions in asthma: EAACI evidence-based clinical practice guideline (part I). Allergy 2013; 68:425.
  95. Dias-Júnior SA, Reis M, de Carvalho-Pinto RM, et al. Effects of weight loss on asthma control in obese patients with severe asthma. Eur Respir J 2014; 43:1368.
  96. Dixon AE, Pratley RE, Forgione PM, et al. Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation. J Allergy Clin Immunol 2011; 128:508.
  97. Hasegawa K, Tsugawa Y, Chang Y, Camargo CA Jr. Risk of an asthma exacerbation after bariatric surgery in adults. J Allergy Clin Immunol 2015; 136:288.
  98. ten Brinke A, Ouwerkerk ME, Bel EH, Spinhoven P. Similar psychological characteristics in mild and severe asthma. J Psychosom Res 2001; 50:7.
  99. Miranda C, Busacker A, Balzar S, et al. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol 2004; 113:101.
  100. 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.
  101. Green RH, Brightling CE, Bradding P. The reclassification of asthma based on subphenotypes. Curr Opin Allergy Clin Immunol 2007; 7:43.
  102. Green RH, Brightling CE, Woltmann G, et al. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 2002; 57:875.