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成人重度和难治性哮喘
Severe and Difficult-to-Treat Asthma in Adults


Elliot Israel ... 呼吸系统疾病 • 2017.09.07
相关阅读
• 未控制哮喘的治疗选项 • 增加吸入性糖皮质激素以预防哮喘发作 • 哮喘药物治疗的真实世界疗效比较试验 • 重度哮喘治疗的新靶点 • 噻托溴铵治疗标准联合疗法控制不佳的哮喘 • 伊马替尼在重度难治性哮喘患者中的KIT抑制作用研究 • 空气质量改善与儿童肺发育的关系 • 长期大环内酯疗法治疗未控制的哮喘 • 白三烯拮抗剂作为哮喘控制的一线或添加疗法研究

重度哮喘患者只占成人哮喘患者的3%1~10%2,但是其医疗成本估计占哮喘相关成本的60%以上,且主要是药物治疗3。每例重度哮喘患者的医疗成本要高于2型糖尿病、卒中或慢性阻塞性肺疾病(COPD)患者的成本4。重度哮喘的症状、加重和药物副作用可对心理和情绪健康、人际关系和职业生涯带来重大影响,因此带来重大的疾病负担5

对重度哮喘的理解和治疗在过去的5年中取得了重大的进展。这些进展包括形成了一个标准化的定义2和循证治疗指南2、汇总了表型模式和生物标志物的实质性证据,以及已有的或者即将获批的新型靶向治疗。

在本综述中,我们重点关注成人的重度和难治性哮喘。我们首先概述综合性评估和治疗方法,以确保患者存在重度哮喘,如果存在的话,再进一步确定其治疗是否充分利用了现有的不是基于单克隆抗体技术的治疗。我们也概述了重度哮喘气道的基础病理生理学特征,以及已经研发用于靶向该病的新型治疗药物。





作者信息

Elliot Israel, M.D., and Helen K. Reddel, M.B., B.S., Ph.D.
From the Pulmonary and Critical Care Medicine Division–Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston (E.I.); and the Clinical Management Group and Centre for Research Excellence in Severe Asthma, Woolcock Institute of Medical Research, University of Sydney, Sydney (H.K.R.). Address reprint requests to Dr. Israel at Pulmonary and Critical Care Medicine Division, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115, or at eisrael@partners.org.

 

参考文献

1. Hekking PP, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel EH. The prevalence of severe refractory asthma. J Allergy Clin Immunol 2015;135:896-902

2. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014;43:343-373

3. Sadatsafavi M, Lynd L, Marra C, et al. Direct health care costs associated with asthma in British Columbia. Can Respir J 2010;17:74-80

4. O’Neill S, Sweeney J, Patterson CC, et al. The cost of treating severe refractory asthma in the UK: an economic analysis from the British Thoracic Society Difficult Asthma Registry. Thorax 2015;70:376-378

5. Hyland ME, Whalley B, Jones RC, Masoli M. A qualitative study of the impact of severe asthma and its treatment showing that treatment burden is neglected in existing asthma assessment scales. Qual Life Res 2015;24:631-639

6. Heaney LG, Conway E, Kelly C, et al. Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol. Thorax 2003;58:561-566

7. McNicholl DM, Stevenson M, McGarvey LP, Heaney LG. The utility of fractional exhaled nitric oxide suppression in the identification of nonadherence in difficult asthma. Am J Respir Crit Care Med 2012;186:1102-1108

8. Gerald JK, Carr TF, Wei CY, Holbrook JT, Gerald LB. Albuterol overuse: a marker of psychological distress? J Allergy Clin Immunol Pract 2015;3:957-962

9. Fokkens WJ, Lund VJ, Mullol J, et al. European Position Paper on Rhinosinusitis and Nasal Polyps 2012. Rhinol Suppl 2012;50:Suppl 23:1-298

10. Postma DS, Rabe KF. The asthma–COPD overlap syndrome. N Engl J Med 2015;373:1241-1249

11. ten Brinke A, Ouwerkerk ME, Zwinderman AH, Spinhoven P, Bel EH. Psychopathology in patients with severe asthma is associated with increased health care utilization. Am J Respir Crit Care Med 2001;163:1093-1096

12. Kerstjens HAM, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012;367:1198-1207

13. Gibeon D, Heaney LG, Brightling CE, et al. Dedicated severe asthma services improve health-care use and quality of life. Chest 2015;148:870-876

14. Radhakrishna N, Tay TR, Hore-Lacy F, et al. Validated questionnaires heighten detection of difficult asthma comorbidities. J Asthma 2017;54:294-299

15. van der Meer AN, Pasma H, Kempenaar-Okkema W, et al. A 1-day visit in a severe asthma centre: effect on asthma control, quality of life and healthcare use. Eur Respir J 2016;48:726-733

16. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012;18:716-725

17. Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol 2015;16:45-56

18. Woodruff PG, Modrek B, Choy DF, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 2009;180:388-395

19. Brusselle GG, Maes T, Bracke KR. Eosinophils in the spotlight: eosinophilic airway inflammation in nonallergic asthma. Nat Med 2013;19:977-979

20. Wu W, Bleecker E, Moore W, et al. Unsupervised phenotyping of Severe Asthma Research Program participants using expanded lung data. J Allergy Clin Immunol 2014;133:1280-1288

21. Amelink M, de Nijs SB, de Groot JC, et al. Three phenotypes of adult-onset asthma. Allergy 2013;68:674-680

22. Newby C, Heaney LG, Menzies-Gow A, et al. Statistical cluster analysis of the British Thoracic Society Severe refractory Asthma Registry: clinical outcomes and phenotype stability. PLoS One 2014;9:e102987-e102987

23. Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008;178:218-224

24. Desai D, Newby C, Symon FA, et al. Elevated sputum interleukin-5 and submucosal eosinophilia in obese individuals with severe asthma. Am J Respir Crit Care Med 2013;188:657-663

25. Kuo CS, Pavlidis S, Loza M, et al. A transcriptome-driven analysis of epithelial brushings and bronchial biopsies to define asthma phenotypes in U-BIOPRED. Am J Respir Crit Care Med 2017;195:443-455

26. Moore WC, Hastie AT, Li X, et al. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol 2014;133:1557-63.e5

27. Loza MJ, Djukanovic R, Chung KF, et al. Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study. Respir Res 2016;17:165-165

28. Haldar P, Pavord ID. Noneosinophilic asthma: a distinct clinical and pathologic phenotype. J Allergy Clin Immunol 2007;119:1043-1052

29. Fahy JV. Type 2 inflammation in asthma — present in most, absent in many. Nat Rev Immunol 2015;15:57-65

30. Gibson PG, Yang IA, Upham JW, 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 July 4 (Epub ahead of print)

31. Busse WW, Holgate S, Kerwin E, et al. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med 2013;188:1294-1302

32. Grainge CL, Lau LCK, Ward JA, et al. Effect of bronchoconstriction on airway remodeling in asthma. N Engl J Med 2011;364:2006-2015

33. An SS, Bai TR, Bates JH, et al. Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma. Eur Respir J 2007;29:834-860

34. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 1998;339:1194-1200

35. Castro M, Fain SB, Hoffman EA, Gierada DS, Erzurum SC, Wenzel S. Lung imaging in asthmatic patients: the picture is clearer. J Allergy Clin Immunol 2011;128:467-478

36. Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 2016;388:31-44

37. Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev 2014:CD003559-CD003559

38. 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;187:804-811

39. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012;380:651-659

40. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014;371:1189-1197

41. 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;4:549-556

42. Hanania NA, Noonan M, Corren J, et al. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax 2015;70:748-756

43. Canonica GW, Senna G, Mitchell PD, O’Byrne PM, Passalacqua G, Varricchi G. Therapeutic interventions in severe asthma. World Allergy Organ J 2016;9:40-40

44. Trevor JL, Deshane JS. Refractory asthma: mechanisms, targets, and therapy. Allergy 2014;69:817-827

45. Molfino NA, Kuna P, Leff JA, et al. Phase 2, randomised placebo-controlled trial to evaluate the efficacy and safety of an anti-GM-CSF antibody (KB003) in patients with inadequately controlled asthma. BMJ Open 2016;6:e007709-e007709

46. Nair P, Gaga M, Zervas E, et al. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. Clin Exp Allergy 2012;42:1097-1103

47. O’Byrne PM, Metev H, Puu M, et al. Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2016;4:797-806

48. Cahill KN, Katz HR, Cui J, et al. KIT inhibition by imatinib in patients with severe refractory asthma. N Engl J Med 2017;376:1911-1920

49. 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

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