過敏性鼻炎及其對哮喘的影響(修改)

1、Asthma and rhinitis are commonco-morbidities, suggesting the concept of “one airway, one disease”癥狀= 流鼻涕 鼻塞 鼻癢 打噴嚏 變態(tài)反應(yīng) 感染性因素 其他原因-藥物相關(guān)的原因，PCD，囊性纖維化，免疫缺陷性因素，GORD,血管運動性，激素性，肉芽腫性由IgE介導(dǎo)的鼻黏膜變應(yīng)性炎癥在ARIA發(fā)表之前分為- 季節(jié)性過敏性鼻炎(枯草熱)戶外空氣中的變應(yīng)原引起特別是花粉 常年性過敏性鼻炎由室內(nèi)變應(yīng)原(主要是塵螨、真菌和動物皮屑、職業(yè)性變應(yīng)原)IL-10Basic proteinsEnzymesLipi

2、d mediatorsCytokinesChemokinesTh0Th2EosinophilMast cellHistamineLipid mediatorsEnzymesCytokinesChemokinesRecruitment,activationAPCSelectionExpansion+AllergenIgEAllergen Nasal blockage Loss of smell Nasalhyperreactivity Itch, sneezing Watery discharge Nasal congestionSymptomsof allergicinflammationAc

3、uteChronicHolt PG et al. Nature 1999B-cell6257General health perception5055Change in health (1 yr)7774Pain5559Energy / fatigue6566Mental health6470Role limitation (emotional)6166Role limitation (physical)7384Social functioning8980Physical functioningRhinitis (n=111)Asthma (n=252)Health concept肺肺鼻鼻中耳

4、中耳氣道氣道平滑肌平滑肌鼻旁竇鼻旁竇 過敏性鼻炎患者對組胺和乙酰膽堿具有支氣管高反應(yīng)性 (Townley,1975; Ramsdale 1984) 季節(jié)性過敏性鼻炎患者在花粉季節(jié)發(fā)展為無癥狀的支氣管收縮(Gerblich,1986) 鼻內(nèi)使用糖皮質(zhì)激素或色苷酸鈉能夠逆轉(zhuǎn)支氣管高反應(yīng)性，提示支氣管反應(yīng)性受鼻部炎癥的影響 Lowhagen O, Rak S.JACI 1985 Dorward AJ et al Clin. Allergy 1986 Sotomayer H et al ARRD 1984 Prieto L et al Eur. Respir. J. 1994 Boulet LP et

5、 al JACI 1993鼻炎和氣道高反應(yīng)性流行病學(xué)過敏性鼻炎過敏性鼻炎在在463463，801801個個13-1413-14歲的兒童中進行遺傳過敏癥世界范圍的發(fā)病率研究。超過歲的兒童中進行遺傳過敏癥世界范圍的發(fā)病率研究。超過1212個月的兒童個月的兒童自述癥狀的問卷調(diào)查自述癥狀的問卷調(diào)查Adapted from the International Study of Asthma and Allergies Adapted from the International Study of Asthma and Allergies in Childhood (ISAAC) Steering Com

6、mittee. in Childhood (ISAAC) Steering Committee. LancetLancet 1998;351:1225-1232. 1998;351:1225-1232. 英國英國澳大利亞澳大利亞加拿大加拿大巴西巴西美國美國南非南非德國德國法國法國阿根廷阿根廷阿爾及利亞阿爾及利亞中國中國俄國俄國0510152025303540% 發(fā)病率發(fā)病率英國英國澳大利亞澳大利亞加拿大加拿大巴西巴西美國美國南非南非德國德國法國法國阿根廷阿根廷阿爾及利亞阿爾及利亞中國中國俄國俄國0510152025303540%發(fā)病率發(fā)病率哮喘哮喘Adapted from The Worksh

7、op 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 C

8、rit Care Med 2000;162:1391-1396.僅有哮喘僅有哮喘僅有過敏性鼻炎僅有過敏性鼻炎過敏性鼻炎過敏性鼻炎+ 哮喘哮喘 過敏性鼻炎使哮喘的風(fēng)險增加了過敏性鼻炎使哮喘的風(fēng)險增加了3 3倍倍接受過敏試驗的大學(xué)新生的接受過敏試驗的大學(xué)新生的2323年的跟蹤研究年的跟蹤研究；數(shù)據(jù)亦來源于；數(shù)據(jù)亦來源于738738名（名（69%69%為男性）平為男性）平均年齡為均年齡為4040歲的研究對象。歲的研究對象。Adapted from Settipane RJ et al Adapted from Settipane RJ et al Allergy ProcAllergy Proc 1

9、994;15:21-25.1994;15:21-25.121086420發(fā)展為哮喘發(fā)展為哮喘的病人數(shù)的病人數(shù)%10.5研究開始有過敏性研究開始有過敏性鼻炎鼻炎 (n=162)3.6研究開始無過敏性鼻炎研究開始無過敏性鼻炎 (n=528)p0.002對照組對照組(n=448)過敏性鼻炎組過敏性鼻炎組 (n=297)哮喘哮喘+過敏性鼻炎過敏性鼻炎組組 (n=76) 對性別，年齡，抽煙狀況等因素進行偏倚調(diào)節(jié)的對性別，年齡，抽煙狀況等因素進行偏倚調(diào)節(jié)的20-4420-44歲的患者的多中心研究。歲的患者的多中心研究。Adapted from Leynaert B et al Adapted from L

10、eynaert B et al Am J Respir Crit Care MedAm J Respir Crit Care Med 2000;162:1391-1396. 2000;162:1391-1396.p0.0016050403020100 評分均值評分均值 身體損害身體損害 精神損害精神損害p0.001p0.001p0.001對低于對低于6565歲的目標(biāo)人群的流行病學(xué)及過敏性鼻炎合并哮喘所需費用增長的普查。歲的目標(biāo)人群的流行病學(xué)及過敏性鼻炎合并哮喘所需費用增長的普查。數(shù)據(jù)提供從數(shù)據(jù)提供從 19871996. 19871996. * *除去藥費除去藥費 n= n=人人- -年年Ada

11、pted from Yawn BP et al Adapted from Yawn BP et al J Allergy Clin ImmunolJ Allergy Clin Immunol 1999;103:54-59. 1999;103:54-59. 350300250200150100500哮喘哮喘 (n=3821) 哮喘哮喘+過敏性鼻炎過敏性鼻炎 (n=4743)$249.89$335.82p0.00010.9該群病人（該群病人（12-6012-60歲過敏性鼻炎合并哮喘）一年內(nèi)醫(yī)療費用的回顧。歲過敏性鼻炎合并哮喘）一年內(nèi)醫(yī)療費用的回顧。Adapted from Crystal-Pete

12、rs J et al Adapted from Crystal-Peters J et al J Allergy Clin ImmunolJ Allergy Clin Immunol 2002;109(1):57-62. 2002;109(1):57-62. 2.52.01.51.00.50病人數(shù)病人數(shù)%未被治療過敏性鼻炎的病人未被治療過敏性鼻炎的病人 (n=1357)被治療過敏性鼻炎的病人被治療過敏性鼻炎的病人 (n=3587)2.3p0.01IL-10Basic proteinsEnzymesLipid mediatorsCytokinesChemokinesTh0Th2Eosinophi

13、lMast cellHistamineLipid mediatorsEnzymesCytokinesChemokinesRecruitment,activationAPCSelectionExpansion+allergenB-cell Bronchialhyper-responsiveness(BHR) Cough Chest tightness Wheeze DyspneaSymptomsof allergicinflammationAcuteChronicIgEAllergenHolt PG et al. Nature 1999 非類固醇類消炎藥（如阿司匹林） 室內(nèi)的過敏原/刺激因子屋塵

14、螨動物皮屑昆蟲（如蟑螂）煙草的煙 室外的過敏原花粉霉菌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 Manag

15、ement of Allergic Rhinitis and its Impact on Asthma (ARIA) Pocket Guide. A Pocket Guide for Physicians and Nurses. 2001.CysLTs=CysLTs=半胱酰胺白三烯半胱酰胺白三烯; PGs=; PGs=前列腺素前列腺素; PAF=; PAF=血小板活化因子血小板活化因子Based on and modified from Casale TB, Amin BV Based on and modified from Casale TB, Amin BV Clin Rev Aller

16、gy ImmunolClin Rev Allergy Immunol 2001;21(1):27-49; Kay AB 2001;21(1):27-49; Kay AB N Engl J N Engl J MedMed 2001;344:30-37. 2001;344:30-37.膜上的膜上的IgE 急性過敏反應(yīng)急性過敏反應(yīng)包括早發(fā)相應(yīng)答包括早發(fā)相應(yīng)答慢性過敏反應(yīng)慢性過敏反應(yīng)包括遲發(fā)相應(yīng)答包括遲發(fā)相應(yīng)答肥大細(xì)胞肥大細(xì)胞 T 細(xì)胞細(xì)胞 過敏原過敏原 細(xì)胞因子細(xì)胞因子 組胺前體組胺前體 新形成的介質(zhì)新形成的介質(zhì)CysLTs、PGs，PAFEosinophilsAdapted from Varner

17、 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. 哮喘哮喘過敏性鼻炎過敏性鼻炎癥狀評分癥狀評分刺激后時間（小時）刺激后時間（小時）1過敏原刺激過敏原刺激 3481224早發(fā)相早發(fā)相 晚發(fā)相晚發(fā)相FEV1（變（變化率化率%）時間（小時）時間（小時） 11024023456789050100100500Eos=嗜酸性細(xì)胞嗜酸性細(xì)胞 neu

18、t=嗜中性白細(xì)胞嗜中性白細(xì)胞 MC=肥大細(xì)胞肥大細(xì)胞 Ly=淋巴細(xì)胞淋巴細(xì)胞 MP=巨噬細(xì)胞巨噬細(xì)胞Adapted from Bousquet J et al J Allergy Clin Immunol Suppl 2001;108(5):S148-S149.嗜酸性細(xì)胞浸潤嗜酸性細(xì)胞浸潤Adapted from Togias A Allergy 1999;54(suppl 57):94-105. 炎性分泌物的吸入從炎性分泌物的吸入從上呼吸道到下呼吸道上呼吸道到下呼吸道 鼻到嘴的交替呼吸鼻到嘴的交替呼吸鼻支氣管反射鼻支氣管反射 鼻和下呼吸道系統(tǒng)炎鼻和下呼吸道系統(tǒng)炎癥對整個系統(tǒng)的影響癥對整個系統(tǒng)

19、的影響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 Rhinit

20、is and its Impact on Asthma (ARIA) Pocket Guide. A Pocket Guide for Physicians and Nurses. 2001; Kay AB N Engl J Med 2001;344:30-37; Varner AE, Lemanske RF Jr. In: Asthma and Rhinitis. 2nd ed. Oxford, UK: Blackwell Science, 2000:1172-1185; Togias A J Allergy Clin Immunol 2000;105(6 pt 2):S599-S604;

21、Togias A Allergy 1999;54(suppl 57):94-105. 有關(guān)枯草熱的病人（平均年齡有關(guān)枯草熱的病人（平均年齡2020歲）的支氣管高反應(yīng)性的研究；在每年秋季和約歲）的支氣管高反應(yīng)性的研究；在每年秋季和約6 6個月后進行刺激。個月后進行刺激。* *刺激物劑量刺激物劑量1mg1mg導(dǎo)致導(dǎo)致FEV1FEV1下降下降20% 20% Adapted from Madonini E et al Adapted from Madonini E et al J Allergy Clin ImmunolJ Allergy Clin Immunol 1987;79:358-363 19

22、87;79:358-363 6050403020100病人數(shù)病人數(shù)%季節(jié)外季節(jié)外 季節(jié)內(nèi)季節(jié)內(nèi)(n=27)1148p0.02ChemoattractantsEosinophil activationMediatorreleaseChemotaxisAdhesionBlood vesselAirway epitheliumBone marrowIL-5generationPluripotentstem cellsEosinophils對無論是否合并過敏性鼻炎的哮喘病人是否存在鼻黏膜炎癥的研究，研究對象年齡對無論是否合并過敏性鼻炎的哮喘病人是否存在鼻黏膜炎癥的研究，研究對象年齡20-6620-66

23、歲。歲。Adapted from Gaga M et al Adapted from Gaga M et al Clin Exp AllergyClin Exp Allergy 2000;20:663-669. 2000;20:663-669.4035302520151050哮喘者鼻黏膜哮喘者鼻黏膜的嗜酸性細(xì)胞的嗜酸性細(xì)胞0r=0.851, p1515歲的哮喘病人，孟魯司特和安慰劑對比，多中心，隨機，歲的哮喘病人，孟魯司特和安慰劑對比，多中心，隨機，1212周雙盲試驗。周雙盲試驗。* *p0.001p0.001孟魯司特與安慰劑比較孟魯司特與安慰劑比較 Adapted from Reiss TF

24、 et al Adapted from Reiss TF et al Arch Intern MedArch Intern Med 1998;158:1213-1220; Malmstrom K et al. Poster presentation 1998;158:1213-1220; Malmstrom K et al. Poster presentation at at the 57th AAAAI Annual Meeting, March 1621, 2001.the 57th AAAAI Annual Meeting, March 1621, 2001.31510500691215

25、安慰劑安慰劑(n=273)哮喘哮喘 均值均值SE FEV1* 00.10.20.30.40.5每晚臨睡前每晚臨睡前 10mg孟魯司特孟魯司特 (n=348)過敏性鼻炎過敏性鼻炎 白天鼻癥狀評分白天鼻癥狀評分* 安慰劑安慰劑 (n=352)每天每天10mg孟魯司特孟魯司特 (n=408)基礎(chǔ)評分的基礎(chǔ)評分的改變（改變（LS均均值）值） 晨晨FEV1均值均值%改變改變周周 證實過敏性鼻炎病人增加了證實過敏性鼻炎病人增加了BHRBHR。 鼻過敏原刺激增加了哮喘合并過敏性鼻炎病人的鼻過敏原刺激增加了哮喘合并過敏性鼻炎病人的BHRBHR 哮喘病人的鼻嗜酸性細(xì)胞明顯增加哮喘病人的鼻嗜酸性細(xì)胞明顯增加 鼻嗜

26、酸性細(xì)胞增加與支氣管嗜酸性細(xì)胞增加相關(guān)鼻嗜酸性細(xì)胞增加與支氣管嗜酸性細(xì)胞增加相關(guān) 支氣管過敏原刺激增加了鼻、肺及全身組織的炎癥支氣管過敏原刺激增加了鼻、肺及全身組織的炎癥 相同的藥物治療對兩種疾病均有療效相同的藥物治療對兩種疾病均有療效 過敏性鼻炎的治療可更好控制哮喘過敏性鼻炎的治療可更好控制哮喘 抗白三烯治療已證明對抗白三烯治療已證明對2 2種疾病均有療效種疾病均有療效Adapted from Madonini E et al J Allergy Clin Immunol 1987;79:358-363; Corren J et al J Allergy Clin Immunol 1992;

27、89:611-618; Gaga M et al Clin Exp Allergy 2000;20:663-669; Braunstahl G-J et al Am J Respir Crit Care Med 2000;161:2051-2057; Welsh PW et al Mayo Clin Proc 1987;62(2):125-134; Reiss TF et al Arch Intern Med 1998;158:1213-1220; Malstrom K et al. Poster presentation at the 57th AAAAI Annual Meeting, M

28、arch 1621, 2001.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 Institutesof Health, 1998; Bousquet J et al J Allergy Clin Immunol

29、 Suppl 2001;108(5):S148-S149; Casale TB, Amin BV Clin Rev Allergy Immunol 2001;21(1):27-49. Adapted from Dale HH Bull Johns Hopkins Hosp 1933;53(6):297-347.Ref 20,p 1628,Fig 1, C1, L1* *與基礎(chǔ)值對比與基礎(chǔ)值對比 ; ; * * *與之前的花粉量及基礎(chǔ)值的對比與之前的花粉量及基礎(chǔ)值的對比 Adapted from Creticos PS et al Adapted from Creticos PS et al N

30、 Engl J Med N Engl J Med 1984;31:1626-1630.1984;31:1626-1630.p=0.01*6543210 刺激前刺激前 10(n=17)稀釋液刺激稀釋液刺激10010005000p=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.節(jié)前節(jié)前節(jié)中節(jié)中 節(jié)后節(jié)后 121086420節(jié)前節(jié)前節(jié)中節(jié)中 節(jié)后節(jié)后121086420p0.001p0.051.87 0.435.52 0.74.45 1.046.8 1.6

31、10.61 1.57.8 2.1YESNAR的改變的改變%刺激刺激*小時小時1501251001/2 1 3 57 9 11 (n=7)Adapted from Okuda M et al Ann Allergy 1988;60:537-540.鼻分泌物鼻分泌物(10-2g/min)05101520時間時間 (分鐘分鐘)1.000.750.500.250(n=8)YESYES最小面積均值*與安慰劑相比Adapted from Malmstrom K et al. Poster presentation at the American Academy of Allergy, Asthma, an

32、d Immunology 57th Annual Meeting, March 2001, New Orleans, Louisiana, USA; Philip G et al. Poster presentation at the European Academy of Allergy and Clinical Immunology, May 2001, Berlin, Germany; Data on file, MSD.0.2400.10.20.30.40.50.37p 0.001*0.47p 0.001*0.140.27p 0.001*0.23p 0.01*00.050.100.15

33、0.200.250.300.010.0100.0050.0150.025 0.0350.03p 0.001Adapted from Creticos PS et al N Engl J Med 1984;31:1626-1630; Okuda M et al Ann Allergy 1988;60:537-540; Knapp HR N Engl J Med 1990;323(25):1745-1748; Donnelly AL et al Am J Respir Crit Care Med 1995;151(6):1734-1739; Drazen JM. In: Asthma and Rh

34、initis, vol. 2, 2nd ed. London: Blackwell Science, 2000:1014-1026; Volovitz B et al J Allergy Clin Immunol 1988;82(3 pt 1):414-418.YESYESYES*與世界衛(wèi)生組織（與世界衛(wèi)生組織（WHO）合作發(fā)展）合作發(fā)展Adapted from the Workshop Expert Panel Management of Allergic Rhinitis and its Impact on Asthma (ARIA) Pocket Guide. A Pocket Guid

35、e for Physicians and Nurses. 2001. Adapted from Bousquet J et al J Allergy Clin Immunol Suppl 2001;108(5):S148-S149. 同時有哮喘和鼻炎的治療 哮喘的治療應(yīng)遵循全球哮喘防治小組GINA指南Bousquet J, Van Cauwenberge P, Khaltaev N, ARIA Workshop Group, World Health Organization. Allergic rhinitis and its impact on asthma. J Allergy Clin

36、 Immunol 2001;108:S147-S334.哮喘鼻炎YesYesYesYesNoYesYesNoNoYes 同時有哮喘和鼻炎的治療 經(jīng)由口服給予藥物，將同時影響鼻腔及支氣管的癥狀 糖皮質(zhì)激素鼻噴劑安全性已被建立。然而，糖皮質(zhì)激素鼻噴劑安全性已被建立。然而，大劑量吸入性（支氣管內(nèi)）皮質(zhì)激素使用，大劑量吸入性（支氣管內(nèi)）皮質(zhì)激素使用，可能引發(fā)副作用。同時經(jīng)由這二重途徑給予可能引發(fā)副作用。同時經(jīng)由這二重途徑給予藥物，副作用可能疊加藥物，副作用可能疊加 過敏性鼻炎的預(yù)防及早期治療，將有助于避免哮喘及嚴(yán)重支氣管癥狀的發(fā)生，此假說已被提出，但仍需要更多的資料來證實1 Bousquet J, V

37、an Cauwenberge P, Khaltaev N, ARIA Workshop Group, World Health Organization. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001;108:S147-S334.分類: 白三烯受體拮抗劑 非糖皮質(zhì)激素類抗炎藥花生四烯酸（花生四烯酸（AA）5-HPETE膜磷脂膜磷脂LTB4 LTC4 LTD4 LTE4 CysLTsLTA4 CysLTR5-脂氧化酶抑制劑脂氧化酶抑制劑PLA2水解酶雙肽酶GGTGGTGGLGGL孟魯司特鈉孟魯司特鈉

38、1. Bousquet J and the ARIA Workshop Group J Allergy Clin Immunol 2001;108(5):S147-S334孟魯司特鈉孟魯司特鈉 10 mg qd +布地奈德布地奈德 400 g bid布地奈德布地奈德 800 g bid 布地奈德布地奈德400g bid第一階段第一階段篩選期篩選期(4周周) 單盲單盲第二階段第二階段治療期治療期 (12周周)雙盲雙盲 04161812 確定并比較分析 吸入布地奈德(800g/日)和孟魯司特鈉（10 mg/日）合用 與 吸入雙倍劑量布地奈德(由800g/日增加至1600g/日) 對哮喘合并過敏性鼻

39、炎的病人帶來的額外益處p=0.360.010.020.030.040.050.04812Change from Baseline(L/Min, LS Mean SEM)Montelukast* (N=433)Budesonide* (N=425)周周 * Montelukast 10 mg once-daily along with budesonide 400 g twice-daily.* Budesonide 800 g twice-dailyAM PEF 值值Montelukast*N=433Budesonide*N=425基線值基線值 (L/min)391.0388.5增長的絕對值

40、(L/min)33.530.1增長的百分比 (%) 8.6% 7.7%MontelukastBudesonide組組的差異的差異(L/min)最小面積均值 (95% CI)4.2 (-4.7, 13.0) P=0.357 * Montelukast 10 mg once-daily along with budesonide 400 g twice-daily.* Budesonide 800 g twice-dailyp0.030.010.020.030.040.050.004812Changes from Baseline(L/Min, LS Mean + SEM) * Monteluka

41、st 10 mg once-daily with budesonide 400 g twice-daily.* Budesonide 800 g twice-daily周周Montelukast* (N=433)Budesonide* (N=425)AM PEF 值值Montelukast*N=216Budesonide*N=184基線值基線值 (L/min)394.7403.4增長的絕對值 (L/min)36.424.1增長的百分比 (%)9.2%6.0%MontelukastBudesonide組組的差異的差異(L/min)最小面積均值(95% CI)14.2 (1.58, 26.84)P

42、=0.028 * Montelukast 10 mg once-daily along with budesonide 400 g twice-daily.* Budesonide 800 g twice-daily-20.0-10.00.010.020.030.040.050.060.070.04812Changes from Baseline(L/Min, LS Mean + SEM) Intranasal steroids or antihistamines or other treatments for rhinitisp0.02周周 * Montelukast 10 mg once-daily along with budesonide 400 g twice-daily.* Budesonide 800 g twice-dailyMontelukast* (N=433)Budesonide* (N=425)AM PEF 值值Montel