课件：鼻炎.ppt

过敏性鼻炎/哮喘 同一气道的疾病 白三烯在过敏性鼻炎/哮喘中的作用,This presentation includes preliminary results of an ongoing clinical program.,Adapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention: A Pocket Guide for Physicians and Nurses. Publication No. 95-3659B. Bethesda, MD: National Institutes of Health, 1998; Bousquet J et al J Allergy Clin Immunol Suppl 2001;108(5):S148-S149.,Slide 1,SGA 2001-W-6472-SS,哮喘及过敏性鼻炎 两者均是炎症性疾病,哮喘 A chronic inflammatory disorder in which exposure to various stimuli results in airway obstruction and airflow limitation 过敏性鼻炎 An IgE-mediated inflammatory disorder in which exposure of the nasal membranes to allergens leads to nasal symptoms,过敏性鼻炎,Epidemiologic Links Between Allergic Rhinitis and Asthma 过敏性鼻炎同哮喘有相似的发病情况,Study of worldwide prevalence of atopic diseases in 463,801 children 1314 years of age. Children self-reported symptoms over 12 months using questionnaires. Adapted from the International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet 1998;351:1225-1232.,Slide 2,SGA 2001-W-6472-SS,哮喘,Epidemiologic Links Between Allergic Rhinitis and Asthma 过敏性鼻炎是哮喘的危险因素,过敏性鼻炎能增加哮喘的危险约 3倍,Slide 3,SGA 2001-W-6472-SS,23-year follow-up of college freshmen undergoing allergy testing; data based on 738 individuals (69% male) with average age of 40 years. Adapted from Settipane RJ et al Allergy Proc 1994;15:21-25.,12 10 8 6 4 2 0,% of patients who developed asthma,10.5,Allergic rhinitis at baseline (n=162),3.6,No allergic rhinitis at baseline (n=528),p0.002,Epidemiologic Links Between Allergic Rhinitis and Asthma 大部分的哮喘患者同时患有鼻炎,近80%的哮喘病人有过敏性鼻炎,Slide 4,SGA 2001-W-6472-SS,Adapted from The Workshop Expert Panel. Management of Allergic Rhinitis and its Impact on Asthma (ARIA) Pocket Guide. A Pocket Guide for Physicians and Nurses. 2001; Bousquet J and the ARIA Workshop Group J Allergy Clin Immunol 2001;108(5):S147-S334; Sibbald B, Rink E Thorax 1991;46:895-901; Leynaert B et al Am J Respir Crit Care Med 2000;162:1391-1396.,Asthma alone,Allergic rhinitis alone,Allergic rhinitis + asthma,0.9,Epidemiologic Links Between Allergic Rhinitis and Asthma 治疗过敏性鼻炎能相对减轻治疗哮喘的资源利用,Slide 7,SGA 2001-W-6472-SS,Retrospective cohort study of costs over a period of up to one year incurred by patients 12 to 60 years of age with both allergic rhinitis and asthma. Adapted from Crystal-Peters J et al J Allergy Clin Immunol 2002;109(1):57-62.,2.5 2.0 1.5 1.0 0.5 0,% of patients,未接受过敏性鼻炎治疗的病人 (n=1357),接受过敏性鼻炎治疗的病人 (n=3587),2.3,p0.01,住院率降低61%,Shared Pathophysiology of Allergic Rhinitis and Asthma 过敏性鼻炎同哮喘有共同的促发因子,非甾体类解热镇痛药 (e.g., aspirin) 室内过敏源 House-dust mite Animal dander Insects (e.g., cockroach allergen) Tobacco smoke 室外过敏源 Pollens Molds,Slide 9,SGA 2001-W-6472-SS,Adapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention: A Pocket Guide for Physicians and Nurses. Publication No. 95-3659B. Bethesda, MD: National Institutes of Health, 1998; Workshop Expert Panel Management of Allergic Rhinitis and its Impact on Asthma (ARIA) Pocket Guide. A Pocket Guide for Physicians and Nurses. 2001.,Shared Pathophysiology of Allergic Rhinitis and Asthma 过敏性鼻炎同哮喘有共同的免疫病理途径,CysLTs=cysteinyl leukotrienes; PGs=prostaglandins; PAF=platelet activating factor Based on and modified from Casale TB, Amin BV Clin Rev Allergy Immunol 2001;21(1):27-49; Kay AB N Engl J Med 2001;344:30-37.,Slide 10,SGA 2001-W-6472-SS,Membrane-bound,IgE,Acute allergic reaction including early-phase response,Chronic allergic reaction including late-phase response,Mast cell,T cells,Allergen,Cytokines,Preformed mediators Histamine,Newly formed mediators CysLTs, PGs, PAF,Eosinophils,Shared Pathophysiology of Allergic Rhinitis and Asthma 过敏性鼻炎和哮喘有相似的速发相/迟发相反应,Adapted from Varner AE, Lemanske RF Jr. In: Asthma and Rhinitis. 2nd ed. Oxford: Blackwell Science, 2000:1172-1185; Togias A J Allergy Clin Immunol 2000;105(6 pt 2):S599-S604.,Slide 11,SGA 2001-W-6472-SS,Asthma Allergic rhinitis,Symptom score,Time postchallenge (hr),1,Antigen challenge,34,812,24,Immediate (early) phase,Late phase,FEV1 (% change),Time (hr),1,10,24,0,2,3,4,5,6,7,8,9,0,50,100,Shared Pathophysiology of Allergic Rhinitis and Asthma 以嗜酸性细胞为主的炎症是过敏性鼻炎和哮喘的共同特点,Eos=eosinophils; neut=neutrophils; MC=mast cells; Ly=lymphocytes; MP=macrophages Adapted from Bousquet J et al J Allergy Clin Immunol Suppl 2001;108(5):S148-S149.,Slide 12,SGA 2001-W-6472-SS,嗜酸性细胞侵润,Allergic Rhinitis,Asthma,Adapted from Togias A Allergy 1999;54(suppl 57):94-105.,Slide 13,SGA 2001-W-6472-SS,Aspiration of inflammatory secretions from the upper airway into the lower airway,Shift from nasal to mouth breathing,Nasobronchial reflex,Systemic mediation of nasal and lower-airway inflammation,Shared Pathophysiology of Allergic Rhinitis and Asthma 过敏性鼻炎/哮喘: 内在的相互作用机制,气道高反应的发生率*,Clinical Links Between Allergic Rhinitis and Asthma 过敏性鼻炎的患者在花粉季节 会有更多的气道高反应,Slide 15,SGA 2001-W-6472-SS,Study of bronchial hyperreactivity in patients (mean age 20 years) with hay fever; challenges were performed in the fall of one year and approximately six months later. *Provocative dose 1 mg causes a 20% fall in FEV1 Adapted from Madonini E et al J Allergy Clin Immunol 1987;79:358-363.,60 50 40 30 20 10 0,% of patients,非花粉季节,花粉季节,(n=27),11,48,p0.02,Clinical Links Between Allergic Rhinitis and Asthma 鼻腔的抗原激发会增加气道高反应,Change from baseline in PC20 after nasal provocation*,Slide 16,SGA 2001-W-6472-SS,Randomized crossover two-day investigation of the relationship between allergic rhinitis and lower airway dysfunction in patients with allergic rhinitis and asthma (mean age 31.4 years). *Lower PC20 values (provocative dose of methacholine causing 20% fall in FEV1) indicate greater hyperresponsiveness; *p=0.011; *p=0.0009 Adapted from Corren J et al J Allergy Clin Immunol 1992;89:611-618.,0800 Baseline,3 2 0,Geometric mean PC20 (methacholine, mg/ml),Placebo (n=10) Allergen (n=10),1200 Postchallenge,1600 Postchallenge,*,*,Time,Clinical Links Between Allergic Rhinitis and Asthma 哮喘病人有鼻腔炎症,鼻粘膜中的嗜酸性细胞计数,Slide 17,SGA 2001-W-6472-SS,Study of whether nasal mucosal inflammation exists in asthma regardless of the presence of allergic rhinitis in atopic subjects 20 to 66 years of age. Bars represent median values Adapted from Gaga M et al Clin Exp Allergy 2000;20:663-669.,18 16 14 12 10 8 6 4 2 0,Eosinophils/ field of nasal biopsy,Rhinitis,No rhinitis,Control,(n=9),(n=8),(n=10),p0.001,p0.001,Asthmatic,Clinical Links Between Allergic Rhinitis and Asthma 鼻腔及支气管粘膜的炎症变化互相关联,Slide 18,SGA 2001-W-6472-SS,Study of whether nasal mucosal inflammation exists in asthma regardless of the presence of allergic rhinitis in atopic subjects 20 to 66 years of age. Adapted from Gaga M et al Clin Exp Allergy 2000;20:663-669.,40 35 30 25 20 15 10 5 0,Asthmatic nasal mucosa eosinophils,0,r=0.851, p0.001,Asthmatic bronchial mucosa eosinophils,5,10,15,20,25,30,(n=17),Clinical Links Between Allergic Rhinitis and Asthma 支气管的抗原激发能增加气道及鼻腔的炎症指标,Slide 19,SGA 2001-W-6472-SS,Evaluation of allergic inflammation in the upper and lower airways after bronchial challenge in nonasthmatic allergic rhinitis patients vs. controls (age range 1831 years) T0= before challenge; T24=24 hours postchallenge; *p0.05; *p0.01; *p=0.001 Adapted from Braunstahl G-J et al Am J Respir Crit Care Med 2000;161:2051-2057.,T0,100 80 60 40 20 0,Eosinophils (no. cells/ mm2),Control patients (n=8) Allergic patients (n=8),T24,T24,T0,1600 1200 800 400 0,Unchallenged left lung,Allergen- challenged right middle lobe,*,Nasal tissue (lamina propria),Bronchial tissue (subepithelial layer),*,*,*,*,The Allergic Rhinitis and its Impact on Asthma (ARIA) Initiative ARIA 建议共同治疗同时兼顾上/下气道,过敏性鼻炎的患者需被评估是否有哮喘 哮喘的患者需被评估是否有过敏性鼻炎 共同治疗的策略是在安全有效的基础上同时兼顾上/下气道,Slide 25,SGA 2001-W-6472-SS,Adapted from Bousquet J et al J Allergy Clin Immunol Suppl 2001;108(5):S148-S149.,Clinical Links Between Allergic Rhinitis and Asthma 抗白三烯的治疗能改善哮喘及过敏性鼻炎的终点指标,Slide 22,SGA 2001-W-6472-SS,Multicenter, 12-week double-blind, randomized trial in patients 15 to 81 years with seasonal allergic rhinitis. Multicenter, randomized, 12-week double-blind trial of montelukast vs. placebo in patients 15 years and older with asthma *p0.001 montelukast vs. placebo Adapted from Reiss TF et al Arch Intern Med 1998;158:1213-1220; Malmstrom K et al. Poster presentation at the 57th AAAAI Annual Meeting, March 1621, 2001.,3,15 10 5 0,0,6,9,12,15,Placebo (n=273),Asthma,Mean SE FEV1*,0 0.1 0.2 0.3 0.4 0.5,Montelukast 10 mg once daily at bedtime (n=348),Allergic Rhinitis,Daytime Nasal Symptom Score*,Montelukast 10 mg once daily (n=408),Change from baseline score (LS mean),Morning FEV1 mean % change from baseline,Weeks,白三烯的合成途径,5-LO = 5 lipoxygenase; FLAP = 5-lipoxygenase-activating protein; 5-HPETE = 5-hydroperoxyeicosatetraenoic acid; CysLT1 = cysteinyl leukotriene antagonists Adapted from Holgate ST et al J Allergy Clin Immunol 1996;98(1):1-13; Smith LJ Arch Intern Med 1996;156:2181-2189.,Arachidonic Acid,CysLT1 receptor antagonists,5-HPETE,LTB4,LTC4 LTD4 LTE4,LTA4,FLAP,5-LO,5-LO and FLAP inhibitors,半胱胺酰白三烯在鼻腔及呼吸道组织中的作用,Adapted from Hay DWP Chest 1997;111(Suppl 2):35S-45S; Lemanske RF JAMA 1997; 278(22):1855-1873; Hay DWP et al Trends Pharmacol Sci 1995;16:304-309.,Airway epithelium,Increased mucus secretion,Decreased mucus transport,Cationic proteins (epithelial cell damage),Sensory C fibers,Smooth muscle (lungs only),Contraction and proliferation,Inflammatory cells (e.g., mast cells, eosinophils),Blood vessel,Edema,Cysteinyl leukotrienes,Eosinophil recruitment,Increased release of tachykinins,半胱胺酰白三烯在速发相/迟发相的反应阶段,PAF = platelet-activating factor Adapted from Togias A J Allergy Clin Immunol 2000;105(6 pt 2):S599-S604; Rachelevsky G J Pediatr 1997;131:348-355; Rouadi P, Naclerio R. SRS-A to Leukotrienes: The Dawning of a New Treatment. S Holgaate, S Dahlen, eds. Oxford, England: Blackwell Science, 1997; Creticos PS et al N Engl J Med 1984;31:1626-1630.,Symptom score,Antigen challenge,1,34,812,Time Postchallenge (hours),Early phase Cysteinyl leukotrienes, prostaglandins, thromboxanes, histamine, heparin, proteases, PAF,Late phase Cysteinyl leukotrienes, cytokines,24,半胱胺酰白三烯鼻腔的抗原刺激中被发现,*vs. baseline; *vs. previous pollen dose and baseline Adapted from Creticos PS et al N Engl J Med 1984;31:1626-1630.,p=0.01*,6 5 4 3 2 1 0,Total Cys-LT (ng/ml),Pre,10,(n=17),Ragweed pollen grains/challenge dose,Diluent challenge,100,1000,5000,p=0.03*,p=0.004*,p=0.02*,Adapted from Volovitz B et al J Allergy Clin Immunol 1988;82(3 pt 1):414-418.,LTC4 concentrations (n=16),Mean LTC4 (ng/ml),Before,During,After,12 10 8 6 4 2 0,Ragweed season,Mean symptom score,Before,During,After,12 10 8 6 4 2 0,Ragweed season,Symptoms (n=16),半胱胺酰白三烯的浓度随症状的严重程度而增加,p0.001,p0.05,1.87 0.43,5.52 0.7,4.45 1.04,6.8 1.6,10.61 1.5,7.8 2.1,半胱胺酰白三烯刺激增加鼻腔气道的阻力,*p0.05 vs. baseline NAR = nasal airway resistance Adapted from Okuda M et al Ann Allergy 1988;60:537-540.,% change in NAR,Challenge,*,*,*,*,*,Hour,150 125 100,1/2 1 3 5 7 9 11,LTD4 was approximately 5000 times more potent than histamine in mediating nasal responses,(n=