哮喘变应原免疫治疗现状与思考-苏州九龙医院倪殿涛

1、 哮喘变应原免疫治疗现状与思考哮喘变应原免疫治疗现状与思考上海交通大学医学院上海交通大学医学院苏州九龙医院苏州九龙医院倪殿涛倪殿涛过敏性疾病作为一个全球性问题过敏性疾病作为一个全球性问题WAO White Book on Allergy 2011-2012 A steady increase in the prevalence of allergic diseases globally has occurred with about 30-40% of the world population now being affected by one or more allergic conditi

2、onsTypes of allergiesAllergen Any substance often a protein that induces an allergy Common allergens过敏原种类很多“除了水、葡萄糖和盐之外都可以成为过敏原”Common cold or allergy Asthma Derived from the Greek root Originally did not define a disease, but was employed to describe respiratory symptoms of a variety of pulmonary c

3、onditions By the beginning of the 20th century, asthma was seen to be a unique illness characterized by spasmodic afflictions of the bronchial tubes. Today, asthma is seen as a chronic inflammatory disease which is not yet fully understood in its pathophysiology Therapy is still on the path to becom

4、ing optimal.Bergmann KC.Asthma.Chem Immunol Allergy. 2014;100:69-80.盲人摸象2014 GINA哮喘表型Allergic asthma: usually respond well to inhaled corticosteroid(ICS) treatment Non-allergic asthma: often respond less well to ICS.Late-allergic asthma: some adults, particularly women, patient with asthma for the f

5、irst time in a dult life. These patients tend to be non-allergic, and often require higher doses of ICS or are relatively refractory to corticosteroid treatment Asthma with fixed airflow limitation: some patients with long-standing asthma develop fixed airflow limitation that is thought to be due to

6、 airway wall remodeling.Asthma with obesity: some obese patients with asthma have prominent respiratory symptoms and little eosinophilic airway inflammation.GINA Guidelines for Asthma 2014Terminology of allergic phenomena idiosyncrasy - antipathy - Hypersensitivity -Anaphylaxis -allergy A.F. Coca an

7、d R.A. Cooke introduced the term atopy：hypersensitiveness occurred spontaneously atopy gained a new sense, since IgE is a characteristic - Clinically similar diseases such as asthma, rhinoconjunctivitis or eczema can be found in the absence of IgE, and are then called intrinsic variants of the same

8、diseaseChem Immunol Allergy. 2014;100:46-52. Coombs and Gells Classification of HypersensitivityDoes intrinsic asthma exist? Ten to forty percent of asthmatics are intrinsic Analysis of bronchial mucosal expression of pro-eosinophilic and pro-atopic markers IL-3, -4, -5, -13, GM-CSF, RANTES, MCP-3,

9、IgE and high affinity IgE receptor (Fc epsilon RI) There were more similarities than differences in immunopathology between atopic and nonatopicHumbert M.Does intrinsic asthma exist?Rev Mal Respir.2000 Feb;17(1 Pt 2):245-54.Allergic vs nonallergic asthma: what makes the difference? Nonallergic：Great

10、er age, female sex, sinusal polyposis, and FEV1 below 80% of the predicted value Allergic：history of hay fever, seasonal exacerbation of asthma, and asthma duration Allergy. 2002 Jul;57(7):607-13.Asthma phenotypes: nonallergic (intrinsic) asthma. The definition ：subjects with asthma and with whom al

11、lergic sensitization cannot be demonstrated negative skin prick test or in vitro specific-IgE test to a panel of seasonal and perennial allergens Nonallergic asthma occurs in 10% to 33% of individuals with asthma and has a later onset than allergic asthma, with a female predominance. Nonallergic ast

12、hma appears to be more severe than allergic asthma in many cases and may be less responsive to standard therapyPeters SP. Asthma phenotypes: nonallergic (intrinsic) asthma.J Allergy Clin Immunol Pract. 2014 Nov-Dec;2(6):650-2.Novel diagnostic approaches and biological therapeutics for intrinsic asth

13、ma. Controversies have emerged in relation to this concept Not finding specific allergen sensitization in an asthmatic patient neither excludes an allergic component nor the essential role that immunoglobulin E may play in asthma The atopic status is one among many other questions Omalizumab, the on

14、ly monoclonal anti-immunoglobulin E antibody commercialized for asthma, should be tried in patients with uncontrolled severe asthma independent of their atopic status Vennera Mdel C1, Picado C1.Novel diagnostic approaches and biological therapeutics for intrinsic asthma.Int J Gen Med. 2014 Jul 8;7:3

15、65-71.哪些哮喘患者需要行哪些哮喘患者需要行AIT？ 过敏的概念过敏的概念 总总tIgESenti et al Allergy 2011;66(6):798 1911 Noon 1th SCIT1950s 1th SCIT Control Study;1980s 1th DBPC SLIT;2000s 1th sublingual Tablet2011s Innovating for patient benefit100 yeas of antigen specific immunotherpy Allergen specific immunotherapySelf-amplificati

16、on mechanisms of mast cell activation: a new look in allergy. The current definition of allergy, a group of IgE mediated diseases appears difficult to cover all allergic reactions Since even IgE dependent allergic reactions are carried out through activation of mast cells and basophils, and all alle

17、rgens mentioned above can activate these cells we hypothesize that allergic reactions are mast cell and basophil mediated inflammatory process as it is the activated mast cells and basophils that initiate the pathological process of the immediate allergic reactions whereas IgE only serves as one of

18、the activators of these cells.He S, Zhang H, Zeng X, Yang P.Curr Mol Med. 2012 Dec;12(10):1329-39.过敏性疾病实验室诊断的理想程序过敏性疾病实验室诊断的理想程序皮试、斑贴试验皮试、斑贴试验 （阳性）过敏原、半抗原或小分子物质过敏原、半抗原或小分子物质嗜碱性粒细胞嗜碱性粒细胞/肥大细胞激发试验肥大细胞激发试验 （阳性）（阴性基本排除急性过敏） 特异性特异性IgE 、IgG 检测检测 （阴性） （阳性） （阳性） 类过敏反应类过敏反应 IgE依赖性依赖性 IgG依赖性依赖性 （目前定义为过敏）（目前定义

19、为食物不耐受） 避免接触类过敏原 （IgG阳性） 脱敏疗法的适应症脱敏疗法的适应症 低敏食物、食物脱敏？低敏食物、食物脱敏？AIT适应症-中国专家共识AIT禁忌症-中国专家共识哮喘患者哮喘患者AIT现状现状结 论Sublingual immunotherapy Included 5,131 patients from 63 studies were analyzed that sublingual immunotherapy improves symptoms of asthma reduces the use of asthma medications improves the qualit

20、y of lifeLin et al.Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review. JAMA 2013;309:1278-88AIT的安全性哮喘哮喘AIT困惑与思考困惑与思考过敏原识别过敏原识别过敏原的特异性诊断过敏原的特异性诊断查找过敏原是与其他学科的基本区别查找过敏原是与其他学科的基本区别IgE介导变态反应的诊断介导变态反应的诊断Allergic rhinitis and its impact on asthma Alle

21、rgy, 2008,s1-153.体内试验体内试验- -皮肤试验皮肤试验 皮内试验皮内试验 I型速发性变态反应型速发性变态反应 点刺试验点刺试验 I型速发性变态反应型速发性变态反应 斑贴试验斑贴试验 IVIV型迟发型变态反应型迟发型变态反应常常用过敏原点刺液种类用过敏原点刺液种类 螨属：螨属：户尘螨、粉尘螨户尘螨、粉尘螨、热螨、仓储螨、热螨、仓储螨 宠物毛发皮屑：猫毛、狗毛宠物毛发皮屑：猫毛、狗毛 树木花粉：桤木、榛属、杨属、榆科、柳属、树木花粉：桤木、榛属、杨属、榆科、柳属、悬铃木悬铃木 杂草花粉：蒿草、豚草、葎草、鸡足草、酥油杂草花粉：蒿草、豚草、葎草、鸡足草、酥油草、毒麦、梯牧草、牧场草

22、草、毒麦、梯牧草、牧场草 作物花粉：向日葵、玉米作物花粉：向日葵、玉米 真菌：链格孢、毛壳菌、芽枝霉、镰刀菌、青真菌：链格孢、毛壳菌、芽枝霉、镰刀菌、青霉、扩展青霉、点青霉霉、扩展青霉、点青霉 蟑螂：德国小蠊、美洲大蠊蟑螂：德国小蠊、美洲大蠊体外试验体外试验-sIgE检测检测 严重皮炎不能作皮试者严重皮炎不能作皮试者 皮试假阳性的划痕症患者皮试假阳性的划痕症患者 皮肤反应差的老年人及皮肤反应差的老年人及3 3岁以下儿童岁以下儿童 用药的影响用药的影响 严重过敏状态发作者严重过敏状态发作者 对作皮试时产生的不适恐惧者对作皮试时产生的不适恐惧者 对过敏严重度评估对过敏严重度评估 拟行特异性免疫治疗

23、者拟行特异性免疫治疗者我国过敏原体外诊断种类我国过敏原体外诊断种类uRAST-RAST-放射过敏原吸附试验放射过敏原吸附试验uFEIA-FEIA-固相荧光酶免疫技术（固相荧光酶免疫技术（CAPCAP）u免疫印迹技术（免疫印迹技术（ASAS）uELISA-ELISA-酶联免疫吸附试验酶联免疫吸附试验u免疫捕获法（酶联免疫吸附试验中之一种）免疫捕获法（酶联免疫吸附试验中之一种）u过敏原芯片：固相液相过敏原芯片：固相液相u免疫化学发光法免疫化学发光法u过敏原诱发组胺释放试验：期望能解决过敏原诱发组胺释放试验：期望能解决IgEIgE不不能解决的问题能解决的问题血中血中IgEIgE含量甚微，仅为血中含量

24、甚微，仅为血中IgGIgG的四万分的四万分之一之一 特异性特异性IgEIgE含量则更甚微含量则更甚微一般的免疫学方法测不到一般的免疫学方法测不到sIgE 放射过敏原吸附试验放射过敏原吸附试验(RAST)(RAST) 荧光免疫标记分析法荧光免疫标记分析法 ELISAELISA（酶联免疫吸附测定）（酶联免疫吸附测定） 蛋白芯片检测蛋白芯片检测 荧光酶免法（荧光酶免法（ImmunoCAP SwedenImmunoCAP Sweden）是检）是检测的金标准测的金标准 影响总影响总IgEIgE水平其它因素水平其它因素 年龄年龄 性别性别 种族种族 寄生虫感染寄生虫感染 升高与皮肤试验及升高与皮肤试验及阳

25、性率存在阳性率存在相关性相关性可导致总可导致总IgE升高的疾病升高的疾病 过敏性疾病过敏性疾病 免疫性疾病：选择性免疫性疾病：选择性IgAIgA缺乏症缺乏症 感染：寄生虫、霉菌、病毒感染：寄生虫、霉菌、病毒 肿瘤：骨髓瘤、霍奇金病、支气管肿瘤肿瘤：骨髓瘤、霍奇金病、支气管肿瘤 其他：输血、川崎氏病、肾病综合症、其他：输血、川崎氏病、肾病综合症、肝脏疾病肝脏疾病问题 有过敏症状，未查到过敏原处方抗过敏有过敏症状，未查到过敏原处方抗过敏药合适吗？药合适吗？ sIgEsIgE升高明显，临床无症状要治疗吗？升高明显，临床无症状要治疗吗？ sIgEsIgEAllergy testing in the diagnosis of asthmaIncorvaia C, Riario-Sforza GG Lancet Respir Med. 2015 May;3(5):e16治疗药物 螨虫螨虫