Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline

This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including metaanalyses, were performed to summarise all available evidence relevant to the European Respiratory Society/American Thoracic Society Task Force’s questions. The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of asthma experts, who made specific recommendations on six specific questions. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made the following recommendations:

• suggest using anti-interleukin (IL)-5 and anti-IL-5 receptor α for severe uncontrolled adult eosinophilic asthma phenotypes;
• suggest using a blood eosinophil cut-point ≥150 μL⁻¹ to guide anti-IL-5 initiation in adult patients with severe asthma;
• suggest considering specific eosinophil (≥260 μL⁻¹) and exhaled nitric oxide fraction (≥19.5 ppb) cut-offs to identify adolescents or adults with the greatest likelihood of response to anti-IgE therapy;
• suggest using inhaled tiotropium for adolescents and adults with severe uncontrolled asthma despite Global Initiative for Asthma (GINA) step 4 – 5 or National Asthma Education and Prevention Program (NAEPP) step 5 therapies;
• suggest a trial of chronic macrolide therapy to reduce asthma exacerbations in persistently symptomatic or uncontrolled patients on GINA step 5 or NAEPP step 5 therapies, irrespective of asthma phenotype;
• suggest using anti-IL-4/13 for adult patients with severe eosinophilic asthma and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels.

These recommendations should be reconsidered as new evidence becomes available.

1. Chung K.F., Wenzel S.E., Brozek J.L. et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur. Respir. J. 2014; 43 (2): 343–373. DOI: 10.1183/09031936.00202013.

2. Guyatt G.H., Oxman A.D., Vist G.E. et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008; 336: 924–926. DOI: 10.1136/bmj.39489.470347.AD.

3. Wedzicha J., Miravitlles M., Hurst J.R. et al. Management of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur. Respir. J. 2017; 49 (3): 1600791. DOI: 10.1183/13993003.00791-2016.

4. Wedzicha J.A., Calverley P.M.A., Albert R.K. et al. Prevention of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur. Respir. J. 2017; 50 (3): 1602265. DOI: 10.1183/13993003.02265-2016.

5. Santanello N.C., Zhang J., Seidenberg B. et al. What are minimal important changes for asthma measures in a clinical trial? Eur. Respir. J. 1999; 14 (1): 23–27. DOI: 10.1034/j.1399-3003.1999.14a06.x.

6. Juniper E.F., Svensson K., Mork A.C. et al. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir. Med. 2005; 99 (5): 553–558. DOI: 10.1016/j.rmed.2004.10.008.

7. Juniper E.F., Guyatt G.H., Willan A., Griffith L.E. Determining a minimal important change in a disease-specific quality of life questionnaire. J. Clin. Epidemiol. 1994; 47 (1): 81–87. DOI: 10.1016/0895-4356(94)90036-1.

8. Bel E.H., Wenzel S.E., Thompson P.J. et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N. Engl. J. Med. 2014; 371 (13): 1189–1197. DOI: 10.1056/NEJMoa1403291.

9. Ortega H.G., Liu M.C., Pavord I.D. et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N. Engl. J. Med. 2014; 371 (13): 1198–1207. DOI: 10.1056/NEJMoa1403290.

10. Chupp G.L., Bradford E.S., Albers F.C. et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir. Med. 2017; 5 (5): 390–400. DOI: 10.1016/S2213-2600(17)30125-X.

11. Bjermer L., Lemiere C., Maspero J. et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels: a randomized phase 3 study. Chest. 2016; 150 (4): 789–798. DOI: 10.1016/j.chest.2016.03.032.

12. 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 (10): 1125–1132. DOI: 10.1164/rccm.201103-0396OC.

13. Castro M., Zangrilli J., Wechsler M.E. 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 (5): 355–366. DOI: 10.1016/S2213-2600(15)00042-9.

14. Corren J., Weinstein S., Janka L. et al. Phase 3 study of reslizumab in patients with poorly controlled asthma: effects across a broad range of eosinophil counts. Chest. 2016; 150 (4): 799–810. DOI: 10.1016/j.chest.2016.03.018.

15. Bleecker E.R., FitzGerald J.M., Chanez P. et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016; 388 (10056): 2115–2127. DOI: 10.1016/S0140-6736(16)31324-1.

16. Castro M., Wenzel S.E., Bleecker E.R. et al. Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir. Med. 2014; 2 (11): 879–890. DOI: 10.1016/S2213-2600(14)70201-2.

17. FitzGerald J.M., Bleecker E.R., Nair P. et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016; 388 (10056): 2128–2141. DOI: 10.1016/S0140-6736(16)31322-8.

18. Nair P., Wenzel S., Rabe K.F. et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N. Engl. J. Med. 2017; 376 (25): 2448–2458. DOI: 10.1056/NEJMoa1703501.

19. Park H.S., Kim M.K., Imai N. et al. A phase 2a study of benralizumab for patients with eosinophilic asthma in South Korea and Japan. Int. Arch. Allergy Immunol. 2016; 169: 135–145. DOI: 10.1159/000444799.

20. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. 2019. Available at: http://ginasthma.org/2019-gina-report-global-strategy-for-asthma-management-and-prevention [Accessed: October 28, 2019].

21. National Institute for Health and Care Excellence. Mepolizumab for treating severe refractory eosinophilic asthma. TA431. 2017. Available at: www.nice.org.uk/guidance/ta431 [Accessed: October 1, 2019].

22. National Institute for Health and Care Excellence. Reslizumab for treating severe eosinophilic asthma. TA479. 2017. Available at: www.nice.org.uk/guidance/ta479 [Accessed: October 01, 2019].

23. National Institute for Health and Care Excellence. Benralizumab for treating severe eosinophilic asthma. TA565. 2019. Available at: www.nice.org.uk/guidance/ta565 [Accessed: October 01, 2019].

24. Institute for Clinical and Economic Review. Biologic therapies for treatment of asthma associated with type 2 inflammation: effectiveness, value, and value-based price benchmarks. 2018. Available at: https://icer-review.org/wp-content/uploads/2018/04/ICER_Asthma_Draft_Report_092418v1.pdf [Accessed: October 01, 2019].

25. Nair P., Pizzichini M.M., Kjarsgaard M. et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N. Engl. J. Med. 2009; 360 (10): 985–993. DOI: 10.1056/NEJMoa0805435.

26. Ortega H.G., Yancey S.W., 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 (7): 549–556. DOI: 10.1016/S2213-2600(16)30031-5.

27. Mukherjee M., Aleman Paramo F., Kjarsgaard M. et al. Weight-adjusted intravenous reslizumab in severe asthma with inadequate response to fixed-dose subcutaneous mepolizumab. Am. J. Respir. Crit. Care Med. 2018; 197 (1): 38–46. DOI: 10.1164/rccm.201707-1323OC.

28. Khatri S., Moore W., Gibson P.G. et al. Assessment of the long-term safety of mepolizumab and durability of clinical response in patients with severe eosinophilic asthma. J. Allergy Clin. Immunol. 2019; 143 (5): 1742–1751. DOI: 10.1016/j.jaci.2018.09.033.

29. Busse W.W., Bleecker E.R., FitzGerald J.M. et al. Long-term safety and efficacy of benralizumab in patients with severe, uncontrolled asthma: 1-year results from the BORA phase 3 extension trial. Lancet Respir. Med. 2019; 7 (1): 46–59. DOI: 10.1016/S2213-2600(18)30406-5.

30. National Institute for Health and Care Excellence. Asthma: diagnosis, monitoring and chronic asthma management. 2017. Available at: www.nice.org.uk/guidance/ng80 [Accessed: October 28, 2019].

31. Ledford D., Busse W., Trzaskoma B. et al. A randomized multicenter study evaluating Xolair persistence of response after long-term therapy. J. Allergy Clin. Immunol. 2017; 140 (1): 162–169. DOI: 10.1016/j.jaci.2016.08.054.

32. Hanania N.A., Wenzel S., Rosen 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 (8): 804–811. DOI: 10.1164/rccm.201208-1414OC.

33. Busse W., Spector S., Rosen K. et al. High eosinophil count: a potential biomarker for assessing successful omalizumab treatment effects. J. Allergy Clin. Immunol. 2013; 132 (2): 485–486. DOI: 10.1016/j.jaci.2013.02.032.

34. Izuhara K., Ohta S., Ono J. Using periostin as a biomarker in the treatment of asthma. Allergy Asthma Immunol. Res. 2016; 8 (6): 491–498. DOI: 10.4168/aair.2016.8.6.491.

35. Casale T.B., Chipps B.E., Rosen K. et al. Response to omalizumab using patient enrichment criteria from trials of novel biologics in asthma. Allergy. 2018; 73 (2): 490–497. DOI: 10.1111/all.13302.

36. Busse W., Corren J., Lanier B.Q. et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J. Allergy Clin. Immunol. 2001; 108 (2): 184–190. DOI: 10.1067/mai.2001.117880.

37. Soler M., Matz J., Townley R. et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur. Respir. J. 2001; 18 (2): 254–261. DOI: 10.1183/09031936.01.00092101.

38. Humbert M., Taille C., Mala L. et al. Omalizumab effectiveness in patients with severe allergic asthma according to blood eosinophil count: the STELLAIR study. Eur. Respir. J. 2018; 51 (5): 1702523. DOI: 10.1183/13993003.02523-2017.

39. British Thoracic Society, Scottish Intercollegiate Guidelines Network. British Guideline on the Management of Asthma. SIGN 158. 2019. Available at: www.sign.ac.uk [Accessed: October 28, 2019].

40. Kerstjens H.A.M., Disse B., Schroder-Babo W. et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J. Allergy Clin. Immunol. 2011; 128 (2): 308–314. DOI: 10.1016/j.jaci.2011.04.039.

41. Kerstjens H.A.M., Engel M., Dahl R. et al. Tiotropium in asthma poorly controlled with standard combination therapy. N. Engl. J. Med. 2012; 367 (13): 1198–1207. DOI: 10.1056/NEJMoa1208606.

42. Hamelmann E., Bernstein J.A., Vandewalker M. et al. A randomised controlled trial of tiotropium in adolescents with severe symptomatic asthma. Eur. Respir. J. 2017; 49 (1): 1601100. DOI: 10.1183/13993003.01100-2016.

43. Kerwin E., Wachtel A., Sher L. et al. Efficacy, safety, and dose response of glycopyrronium administered by metered dose inhaler using co-suspension delivery technology in subjects with intermittent or mild-to-moderate persistent asthma: a randomized controlled trial. Respir. Med. 2018; 139: 39–47. DOI: 10.1016/j.rmed.2018.04.013.

44. Lee L.A., Briggs A., Edwards L.D. et al. A randomized, three-period crossover study of umeclidinium as monotherapy in adult patients with asthma. Respir. Med. 2015; 109 (1): 63–73. DOI: 10.1016/j.rmed.2014.10.009.

45. Lee L.A., Yang S., Kerwin E. et al. The effect of fluticasone furoate/umeclidinium in adult patients with asthma: a randomized, dose-ranging study. Respir. Med. 2015; 109 (1): 54–62. DOI: 10.1016/j.rmed.2014.09.012.

46. Peters S.P., Bleecker E.R., Kunselman S.J. et al. Predictors of response to tiotropium versus salmeterol in asthmatic adults. J. Allergy Clin. Immunol. 2013; 132 (5): 1068–1074. DOI: 10.1016/j.jaci.2013.08.003.

47. Kerstjens H.A., Moroni-Zentgraf P., Tashkin D.P. et al. Tiotropium improves lung function, exacerbation rate, and asthma control, independent of baseline characteristics including age, degree of airway obstruction, and allergic status. Respir. Med. 2016; 117: 198–206. DOI: 10.1016/j.rmed.2016.06.013.

48. Szefler S.J., Murphy K., Harper T. 3 rd et al. A phase III randomized controlled trial of tiotropium add-on therapy in children with severe symptomatic asthma. J. Allergy Clin. Immunol. 2017; 140 (5): 1277–1287. DOI: 10.1016/j.jaci.2017.01.014.

49. National asthma education and prevention program. Guidelines for the diagnosis and management of asthma 2007 (EPR-3). Available at: www.nhlbi.nih.gov/health-topics/guidelines-for-diagnosis-management-of-asthma [Accessed: October 28, 2019].

50. Brusselle G.G., VanderStichele C., Jordens P. et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013; 68 (4): 322–329. DOI: 10.1136/thoraxjnl-2012-202698.

51. Gibson P.G., Yang I.A., Upham J.W. et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017; 390 (10095): 659–668. DOI: 10.1016/S0140-6736(17)31281-3.

52. Strunk R.C., Bacharier L.B., Phillips B.R. et al. Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderate-to-severe childhood asthma study. J. Allergy Clin. Immunol. 2008; 122 (6): 1138–1144. DOI: 10.1016/j.jaci.2008.09.028.

53. Hahn D.L., Grasmick M., Hetzel S., Yale S. Azithromycin for bronchial asthma in adults: an effectiveness trial. J. Am. Board Fam. Med. 2012; 25 (4): 442–459. DOI: 10.3122/jabfm.2012.04.110309.

54. Sutherland E.R., King T.S., Icitovic N. et al. A trial of clarithromycin for the treatment of suboptimally controlled asthma. J. Allergy Clin. Immunol. 2010; 126 (4): 747–753. DOI: 10.1016/j.jaci.2010.07.024.

55. Simpson J.L., Powell H., Boyle M.J. et al. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am. J. Respir. Crit. Care Med. 2008; 177 (2): 148–155. DOI: 10.1164/rccm.200707-1134OC.

56. Taylor S.L., Leong L.E.X., Mobegi F.M. et al. Long-term azithromycin reduces Haemophilus influenzae and increases antibiotic resistance in severe asthma. Am. J. Respir. Crit. Care Med. 2019; 200 (3): 309–317. DOI: 10.1164/rccm.201809-1739OC.

57. British Thoracic Society, Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. 2016. SIGN 153. Available at: www.brit-thoracic.org.uk/quality-improvement/guidelines/asthma [Accessed: October 28, 2019].

58. Wenzel S., Castro M., Corren J. et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of mediumto-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomized double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016; 388 (10039): 31–44. DOI: 10.1016/S0140-6736(16)30307-5.

59. Castro M., Corren J., Pavord I.D. et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N. Engl. J. Med. 2018; 378 (26): 2486–2496. DOI: 10.1056/NEJMoa1804092.

60. Rabe K.F., Nair P., Brusselle G. et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N. Engl. J. Med. 2018; 378 (26): 2475–2485. DOI: 10.1056/NEJMoa1804093.

61. B rown T., Jones T., Gove K. et al. Randomised controlled trials in severe asthma: selection by phenotype or stereotype. Eur. Respir. J. 2018; 52 (6): 1801444. DOI: 10.1183/13993003.01444-2018.

62. Agusti A., Bel E., Thomas M. et al. Treatable traits: toward precision medicine of chronic airway diseases. Eur. Respir. J. 2016; 47 (2): 410–419. DOI: 10.1183/13993003.01359-2015.

63. Pavord I.D., Beasley R., Agusti A. et al. After asthma: redefining airways diseases. Lancet. 2018; 391 (10118): 350–400. DOI: 10.1016/S0140-6736(17)30879-6.

64. Shrimanker R., Beasley R., Kearns C. Letting the right one in: evaluating the generalisability of clinical trials. Eur. Respir. J. 2018; 52 (6): 1802218. DOI: 10.1183/13993003.02218-2018.

65. Pavord I.D., Chanez P., Criner G.J. et al. Mepolizumab for eosinophilic chronic obstructive pulmonary disease. N. Engl. J. Med. 2017; 377 (17): 1613–1629. DOI: 10.1056/NEJMoa1708208.

66. Kerkhof M., Sonnappa S., Postma D.S. et al. Blood eosinophil count and exacerbation risk in patients with COPD. Eur. Respir. J. 2017; 50 (1): 1700761. DOI: 10.1183/13993003.00761-2017.

67. Levy M.L., Winter R. Asthma deaths: what now? Thorax. 2015; 70 (3): 209–210. DOI: 10.1136/thoraxjnl-2015-206800.

68. Royal College of Physicians. National Review of Asthma Deaths 2012–2013. 2015. Available at: www.rcplondon.ac.uk/projects/national-review-asthma-deaths [Accessed: October 01, 2019].

69. Bush A., Saglani S., Fleming L. Severe asthma: looking beyond the amount of medication. Lancet Respir. Med. 2017; 5 (11): 844–846. DOI: 10.1016/S2213-2600(17)30379-X.

70. Green R.H., Shaw D. Strict adherence rules to obtain monoclonal therapy might cost lives. Lancet Respir. Med. 2017; 5 (9): 678–679. DOI: 10.1016/S2213-2600(17)30238-2.

71. Andersson C.K., Adams A., Nagakumar P. et al. Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function. J. Allergy Clin. Immunol. 2017; 139 (6): 1819–1829. DOI: 10.1016/j.jaci.2016.09.022.

72. Bossley C.J., Fleming L., Gupta A. et al. Pediatric severe asthma is characterized by eosinophilia and remodeling without TH 2 cytokines. J. Allergy Clin. Immunol. 2012; 129 (4): 974–982. DOI: 10.1016/j.jaci.2012.01.059.

73. Kuo C.S., Pavlidis S., Loza M. et al. T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED. Eur. Respir. J. 2017; 49 (2): 1602135. DOI: 10.1183/13993003.02135-2016.

74. Travers J., Rothenberg M.E. Eosinophils in mucosal immune responses. Mucosal. Immunol. 2015; 8 (3): 464–475. DOI: 10.1038/mi.2015.2.

75. Normansell R., Walker S., Milan S.J. et al. Omalizumab for asthma in adults and children. Cochrane Database Syst. Rev. 2014; (1): CD003559. DOI: 10.1002/14651858.CD003559.pub4.

76. Corren J., Kavati A., Ortiz B. et al. Efficacy and safety of omalizumab in children and adolescents with moderate-to-severe asthma: a systematic literature review. Allergy Asthma Proc. 2017; 38 (4): 250–263. DOI: 10.2500/aap.2017.38.4067.

77. Odajima H., Ebisawa M., Nagakura T. et al. Long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with severe uncontrolled asthma. Allergol. Int. 2017; 66 (1): 106–115. DOI: 10.1016/j.alit.2016.06.004.

78. Saglani S., Bush A., Carroll W. et al. Biologics for paediatric severe asthma: trick or TREAT? Lancet Respir. Med. 2019; 7 (4): 294–296. DOI: 10.1016/S2213-2600(19)30045-1.

79. Nair P., O’Byrne P.M. The interleukin-13 paradox in asthma: effective biology, ineffective biologicals. Eur. Respir. J. 2019; 53 (2): 1802250. DOI: 10.1183/13993003.02250-2018.

80. Chung K.F. Tralokinumab unsuccessful for management of severe, uncontrolled asthma. Lancet Respir. Med. 2018; 6 (7): 480–481. DOI: 10.1016/S2213-2600(18)30194-2.

81. Busse W.W., Brusselle G.G., Korn S. et al. Tralokinumab did not demonstrate oral corticosteroid-sparing effects in severe asthma. Eur. Respir. J. 2019; 53 (2): 1800948. DOI: 10.1183/13993003.00948-2018.

82. Russell R.J., Chachi L., FitzGerald J.M. et al. Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial. Lancet Respir. Med. 2018; 6 (7): 499–510. DOI: 10.1016/S2213-2600(18)30201-7.

83. Panettieri R.A. Jr, Sjobring U., Peterffy A. et al. Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials. Lancet Respir. Med. 2018; 6 (7): 511–525. DOI: 10.1016/S2213-2600(18)30184-X.

84. Pilette C., Brightling C., Lacombe D., Brusselle G. Urgent need for pragmatic trial platforms in severe asthma. Lancet Respir. Med. 2018; 6 (8): 581–583. DOI: 10.1016/S2213-2600(18)30291-1.

85. Bousquet J., Mantzouranis E., Cruz A.A. et al. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J. Allergy Clin. Immunol. 2010; 126 (5): 926–938. DOI: 10.1016/j.jaci.2010.07.019.