姜楠楠，尹　佳

[中國醫(yī)學(xué)科學(xué)院 北京協(xié)和醫(yī)學(xué)院 北京協(xié)和醫(yī)院變態(tài)(過敏)反應(yīng)科， 北京 100730]

ChinJAllergyClinImmunol，2016，10(3)：269- 275

經(jīng)典的Ⅰ型變態(tài)反應(yīng)的發(fā)生是變應(yīng)原結(jié)合在肥大細(xì)胞表面IgE抗體并使其橋聯(lián)，通過信號傳導(dǎo)引起組胺等生物活性物質(zhì)的釋放，從而導(dǎo)致臨床癥狀的發(fā)生。嚴(yán)重過敏反應(yīng)是最嚴(yán)重的Ⅰ型變態(tài)反應(yīng)，其臨床診斷標(biāo)準(zhǔn)是累及兩個及兩個以上的系統(tǒng)，主要包括皮膚、胃腸道系統(tǒng)、呼吸系統(tǒng)、心血管系統(tǒng)等。癥狀輕重不同，可在幾分鐘之內(nèi)從最輕微的皮膚癥狀迅速發(fā)展至死亡[1]。

嚴(yán)重過敏反應(yīng)的臨床流行病學(xué)數(shù)據(jù)有很大差異，可能是嚴(yán)重過敏反應(yīng)的臨床診斷標(biāo)準(zhǔn)不一致所致。2006年美國變態(tài)反應(yīng)、哮喘與免疫學(xué)學(xué)會(The American Academy of Allergy, Asthma & Immunology，AAAAI)一項系統(tǒng)回顧研究顯示嚴(yán)重過敏反應(yīng)的終生患病率是0.05%～0.2%[2]，2013年歐洲變應(yīng)性反應(yīng)與臨床免疫學(xué)會(European Academy of Allergy and Clinical Immunology，EAACI)的一項系統(tǒng)回顧研究顯示歐洲國家嚴(yán)重過敏反應(yīng)發(fā)病率是(1.5～7.9)/10萬人年[3]。盡管嚴(yán)重過敏反應(yīng)的發(fā)生大多是由變應(yīng)原誘發(fā)，但伴發(fā)因素在其中的作用越來越受到重視。運(yùn)動是最早被人們認(rèn)識也是目前研究最多的伴發(fā)因素。食物依賴運(yùn)動誘發(fā)的嚴(yán)重過敏反應(yīng)(food-dependent exercise induced anaphylaxis，F(xiàn)DEIA)已被單獨(dú)列為一種疾病。1979年Maulitz 等[4]首次報道了貝類依賴運(yùn)動誘發(fā)的嚴(yán)重過敏反應(yīng)。其他研究較多的伴發(fā)因素為非甾體類抗炎藥如阿司匹林、酒精及感染性疾病[1,5- 9]。 歐洲國家嚴(yán)重過敏反應(yīng)的研究及登記數(shù)據(jù)顯示[7,10- 14]，30%成人嚴(yán)重過敏反應(yīng)有伴發(fā)因素存在，3%～23%嚴(yán)重過敏反應(yīng)發(fā)生在運(yùn)動過程中，1%～15.2%的嚴(yán)重過敏反應(yīng)有酒精因素參與，6.1%～9%的重度嚴(yán)重過敏反應(yīng)阿司匹林為伴發(fā)因素，2.5%～3%兒童嚴(yán)重過敏反應(yīng)有感染性因素的參與，而在成人嚴(yán)重過敏反應(yīng)中的比例為1.3%～11%。確定變應(yīng)原誘因及伴發(fā)因素是嚴(yán)重過敏反應(yīng)的診斷、危險因素評估以及患者教育的關(guān)鍵，可降低患者發(fā)生致命性嚴(yán)重過敏反應(yīng)的風(fēng)險。目前關(guān)于伴發(fā)因素在過敏休克發(fā)生中的作用機(jī)制主要是增加變應(yīng)原生物利用度和降低效應(yīng)細(xì)胞活化的閾值[15]。

運(yùn)動依賴的嚴(yán)重過敏反應(yīng)及其機(jī)制研究

Maulitz 等[4]首次提出了運(yùn)動是嚴(yán)重過敏反應(yīng)的伴發(fā)/加重因素。他報道了1例患者在進(jìn)食貝類后慢跑過程中出現(xiàn)嚴(yán)重過敏反應(yīng)，但運(yùn)動和貝類作為單獨(dú)激發(fā)不能導(dǎo)致嚴(yán)重過敏反應(yīng)的發(fā)生。隨后報道了一系列類似病例，F(xiàn)DEIA被定義為一類疾病。盡管運(yùn)動依賴的嚴(yán)重過敏反應(yīng)并不只發(fā)生于食物過敏的患者，F(xiàn)DEIA是最常見的類型。目前已有研究顯示多種食物可導(dǎo)致FDEIA的發(fā)生，比如開心果、肉類、蝦、小麥等[16]。FDEIA常發(fā)生在慢跑過程中，但癥狀可由輕度和中度運(yùn)動強(qiáng)度誘發(fā)[17]。對敏感患者來說，輕微日?；顒幼阋哉T發(fā)嚴(yán)重過敏反應(yīng)，比如1例肉類過敏老年女性在熨衣服過程中發(fā)生嚴(yán)重過敏反應(yīng)[18]。

目前，小麥依賴運(yùn)動誘發(fā)的嚴(yán)重過敏反應(yīng)(wheat-dependent exercise induced anaphylaxis,WDEIA)為FDEIA最常見的類型。Palosuo 等[19]首次提出了WDEIA。檢測血清小麥醇溶蛋白ω- 5-gliadin (Tri a 19)特異性IgE的水平是診斷WDEIA最有價值的工具[20]。運(yùn)動作為伴發(fā)因素在食物誘發(fā)嚴(yán)重過敏反應(yīng)中的作用機(jī)制主要集中于以下兩個方面：其一是運(yùn)動增加了食物變應(yīng)原的生物利用度，另一方面運(yùn)動降低肥大細(xì)胞和嗜堿粒細(xì)胞活化閾值。WDEIA的研究顯示，運(yùn)動可通過破壞腸道屏障，增加小腸對變應(yīng)原的吸收，Matsuo 等[21]研究顯示W(wǎng)DEIA患者進(jìn)食小麥制品后運(yùn)動可以顯著增加血清小麥醇溶蛋白的水平，可能的原因是運(yùn)動可導(dǎo)致小腸屏障的破壞，但有研究顯示只有高強(qiáng)度和長時間(>8 h)的運(yùn)動才可引起小腸屏障的破壞，而且誘發(fā)FDEIA的運(yùn)動強(qiáng)度有很大差異，即使是輕微活動也可誘發(fā)癥狀，所以除了運(yùn)動引起小腸屏障破壞機(jī)制外，可能還另有機(jī)制介導(dǎo)[22]。Yano等[23]的研究顯示蛋白溶菌酶致敏的小鼠給予口服溶菌酶激發(fā)后，運(yùn)動組和非運(yùn)動組小鼠小腸攝取溶菌酶均有增加，說明致敏本身即可導(dǎo)致小腸屏障的破壞。腸道對變應(yīng)原的吸收增加可能受個體致敏程度和運(yùn)動強(qiáng)度的雙重影響。

除了增加變應(yīng)原的生物利用度，運(yùn)動還可影響肥大細(xì)胞和嗜堿粒細(xì)胞活化閾值。對于肥大細(xì)胞來說，這種假設(shè)主要基于運(yùn)動后速發(fā)型皮膚反應(yīng)的改變。FDEIA患者運(yùn)動后皮膚對特定變應(yīng)原的反應(yīng)性增強(qiáng)[24]。有學(xué)者提出高強(qiáng)度的運(yùn)動可通過血漿滲透壓增加和pH值的改變影響效應(yīng)細(xì)胞的閾值[22,25- 26]，他們通過體外研究顯示滲透壓達(dá)到340 mOsm才可使肥大細(xì)胞活化閾值下降，即使在高強(qiáng)度運(yùn)動如跑半程馬拉松后，滲透壓僅能升高至293 mOsm[22]，所以通過血漿滲透壓改變效應(yīng)細(xì)胞活性的理論有待進(jìn)一步研究。另一個可能的原因是腸道黏膜谷氨酰胺轉(zhuǎn)胺酶活化使效應(yīng)細(xì)胞脫顆粒增加，有研究顯示長跑后白細(xì)胞介素- 6(interleukin- 6，IL- 6)的表達(dá)量增加50～100倍[27]，IL- 6誘導(dǎo)腸道黏膜谷氨酰胺轉(zhuǎn)胺酶活化從而導(dǎo)致ω- 5-醇溶蛋白肽段的聚合，使效應(yīng)細(xì)胞上的sIgE橋聯(lián)活化效應(yīng)細(xì)胞[28]。此外運(yùn)動誘發(fā)的內(nèi)啡肽釋放能夠使肥大細(xì)胞或者嗜堿粒細(xì)胞活化，一項體外研究顯示β內(nèi)啡肽可導(dǎo)致肥大細(xì)胞脫顆粒和組胺釋放。過敏性鼻炎患者的鼻腔給予β內(nèi)啡肽和變應(yīng)原激發(fā)后鼻腔分泌物中的組胺水平顯著增高[29]，而只給予內(nèi)啡肽的患者組胺水平?jīng)]有變化[30]。

盡管目前相關(guān)科研數(shù)據(jù)有限，但仍可得出以下結(jié)論：(1)運(yùn)動可增加腸道對變應(yīng)原的吸收；(2)誘發(fā)嚴(yán)重過敏反應(yīng)的運(yùn)動強(qiáng)度取決于多種因素，如患者致敏狀態(tài)。在某些患者，伴發(fā)因素可同時存在，如運(yùn)動+酒精或者運(yùn)動+阿司匹林。

藥物依賴的嚴(yán)重過敏反應(yīng)及機(jī)制研究

非甾體類抗炎藥

一些藥物可以參與食物誘發(fā)的嚴(yán)重過敏反應(yīng)，非甾體類抗炎藥是研究最多的藥物伴發(fā)因素。1984年Cant等[31]首次報道了1例14歲男孩服用阿司匹林后進(jìn)食花生誘發(fā)嚴(yán)重過敏反應(yīng)，既往單獨(dú)進(jìn)食花生僅有一過性輕度過敏反應(yīng)發(fā)生。Flemstrom 等[32]在右旋糖酐過敏的豚鼠模型中，單純給予右旋糖酐無反應(yīng)，而同時給予右旋糖酐和阿司匹林可誘發(fā)休克。與運(yùn)動效應(yīng)類似，阿司匹林可能增加變應(yīng)原的腸道吸收。Matsuo等[21]研究顯示，WDEIA患者同時攝入小麥制品和阿司匹林比單純攝入小麥的患者血清醇溶蛋白的濃度高5倍。另一可能的機(jī)制是，阿司匹林影響小腸屏障緊密連接的建立。體外模型實驗顯示給予豚鼠5 mmol/L的阿司匹林可以減少緊密連接蛋白- 7的產(chǎn)生，從而顯著增加右旋糖酐的通透性[32]。

除了增加變應(yīng)原的腸道吸收外，非甾體類抗炎藥或可直接調(diào)節(jié)效應(yīng)細(xì)胞活性。體外研究顯示肥大細(xì)胞提前用阿司匹林孵育能直接介導(dǎo)FcεRⅠ依賴的肥大細(xì)胞脫顆粒和白三烯C4(Leukotriene C4，LTC4)釋放[33- 34]。FDEIA患者[21,35]提前服用阿司匹林能增加食物變應(yīng)原的皮膚反應(yīng)性。

其他藥物

能導(dǎo)致肥大細(xì)胞和嗜堿粒細(xì)胞介質(zhì)釋放的藥物均為潛在的IgE介導(dǎo)的嚴(yán)重過敏反應(yīng)的伴發(fā)因素，如碘造影劑、抗生素及某些阿片類藥物[36- 37]。由于胃酸消化可降低食物變應(yīng)原的變應(yīng)原性，一些抑制胃酸分泌的藥物如H2受體拮抗劑、質(zhì)子泵抑制劑等可使胃酸的pH值升高，從而不能有效降低食物變應(yīng)原的變應(yīng)原性，導(dǎo)致大分子變應(yīng)原到達(dá)腸道誘發(fā)局部或系統(tǒng)性變態(tài)反應(yīng)的發(fā)生。Diesner等[38]對卵清蛋白致敏的小鼠應(yīng)用質(zhì)子泵抑制劑可增加激發(fā)試驗中嚴(yán)重過敏反應(yīng)發(fā)生風(fēng)險。Untersmayr等[39]一項前瞻性研究顯示10%患者服用質(zhì)子泵抑制劑治療3個月后血清原有食物特異性IgE水平顯著增高，而15%患者出現(xiàn)新的食物特異性IgE抗體。若特應(yīng)性個體對某種胃酸不耐受的食物變應(yīng)原過敏，臨床僅表現(xiàn)為口腔變態(tài)反應(yīng)綜合征，在服用質(zhì)子泵抑制劑期間大量食入該變應(yīng)原，有發(fā)生嚴(yán)重過敏反應(yīng)的風(fēng)險[39- 40]。

有研究顯示抗高血壓藥物能增加重度嚴(yán)重過敏反應(yīng)發(fā)生風(fēng)險。Lee等[41]對302例急診嚴(yán)重過敏反應(yīng)的患者研究顯示服用抗高血壓藥物的個體重度嚴(yán)重過敏反應(yīng)的風(fēng)險增加1.8倍，住院風(fēng)險增加3倍。Rueff等[8]的研究顯示重度蜂毒嚴(yán)重過敏反應(yīng)與血管緊張素轉(zhuǎn)化酶抑制劑類藥物應(yīng)用相關(guān)，而與腎上腺素β受體拮抗劑的應(yīng)用不相關(guān)。然而，Brown等[42]的研究顯示，腎上腺素β受體拮抗劑和血管緊張素轉(zhuǎn)化酶抑制劑類藥物應(yīng)用不增加重度嚴(yán)重過敏反應(yīng)發(fā)作風(fēng)險，這說明抗高血壓藥物與嚴(yán)重過敏反應(yīng)的相關(guān)性還不明確，可能的機(jī)制為腎上腺素β受體拮抗劑(普萘洛爾、美托洛爾等)通過β腎上腺素受體cAMP系統(tǒng)效應(yīng)細(xì)胞(肥大細(xì)胞、嗜堿粒細(xì)胞)使信號傳導(dǎo)通路受到抑制，導(dǎo)致效應(yīng)細(xì)胞不穩(wěn)定[43]。另外，腎上腺素β受體拮抗劑加重嚴(yán)重過敏反應(yīng)的機(jī)制可能與心臟收縮力下降，干擾了腎上腺素的治療作用有關(guān)[41]。血管緊張素轉(zhuǎn)化酶可以使緩激肽失活，血管緊張素轉(zhuǎn)化酶抑制劑類藥物的應(yīng)用可使緩激肽水平升高[44]。緩激肽能促進(jìn)一氧化氮的合成，使血管擴(kuò)張。緩激肽和其他炎性介質(zhì)的累積可誘發(fā)血管痙攣[45]。此外，緩激肽水平的急速升高可導(dǎo)致嚴(yán)重的咽喉部水腫[46]。因此，血管緊張素轉(zhuǎn)化酶抑制劑類的藥物可導(dǎo)致血管神經(jīng)性水腫、低血壓以及氣管痙攣。Summers等[47]研究花生堅果過敏的患者，血清血管緊張素轉(zhuǎn)化酶水平降低與喉頭水腫相關(guān)，而與氣管痙攣、意識喪失不相關(guān)。血清血管緊張素轉(zhuǎn)化酶水平<37.0 mmol/L的患者發(fā)生嚴(yán)重喉頭水腫的風(fēng)險增加8.6倍。Lee等[41]的研究未顯示這種相關(guān)性，而在該項研究中應(yīng)用血管緊張素轉(zhuǎn)化酶抑制劑類藥物嚴(yán)重過敏反應(yīng)的患者3個以上系統(tǒng)累及的風(fēng)險增加1.3倍，住院治療的風(fēng)險增加2.2倍。然而，這些機(jī)制仍然有爭議并有待進(jìn)一步研究。

越來越多的證據(jù)提示多種藥物可作為嚴(yán)重過敏反應(yīng)的伴發(fā)因素，尤其是非甾體類抗炎藥類的藥物。因此嚴(yán)重過敏反應(yīng)的診斷應(yīng)該考慮藥物相關(guān)因素，并告知患者其為嚴(yán)重過敏反應(yīng)尤其是重度嚴(yán)重過敏反應(yīng)發(fā)生的危險因素。肌松劑或造影劑可能誘發(fā)嚴(yán)重過敏反應(yīng)，醫(yī)師應(yīng)該避免開處方或者事先給予糖皮質(zhì)激素或者抗組胺藥預(yù)防。如果有口腔變態(tài)反應(yīng)綜合征的患者需要使用質(zhì)子泵抑制劑類藥物，醫(yī)師應(yīng)告知患者質(zhì)子泵抑制劑類藥物可導(dǎo)致變應(yīng)原不被胃酸完全降解，有誘發(fā)嚴(yán)重過敏反應(yīng)的風(fēng)險。心肌梗死、心律失?；蛘邍?yán)重心力衰竭的患者使用腎上腺素β受體拮抗劑，避免應(yīng)用造成的風(fēng)險會高于嚴(yán)重過敏反應(yīng)發(fā)生的風(fēng)險，是否應(yīng)用腎上腺素β受體拮抗劑取決于個體的利益風(fēng)險比。

酒精在嚴(yán)重過敏反應(yīng)發(fā)生中的作用

Gonzalez-Quintela等[48]的一項成人過敏性疾病流行病學(xué)顯示，酒精攝入與總IgE水平升高和氣傳花粉致敏相關(guān)。10%食物過敏[49]或運(yùn)動誘發(fā)的嚴(yán)重過敏反應(yīng)[50]的患者在飲酒后癥狀更容易發(fā)生。Uguz等[14]的研究顯示15.2%成人嚴(yán)重過敏反應(yīng)中有酒精因素的參與，而法國食物過敏在線登記數(shù)據(jù)顯示8.9%的嚴(yán)重過敏反應(yīng)有酒精因素的參與。與阿司匹林的作用類似，酒精使小腸上皮緊密連接松弛，從而使小腸對變應(yīng)原尤其是小分子蛋白吸收率增加[22, 51]。但相關(guān)實驗數(shù)據(jù)少見。

感染在嚴(yán)重過敏反應(yīng)發(fā)生中的作用

多項研究顯示在感染性疾病的早期階段或者輕度感染能夠加重嚴(yán)重過敏反應(yīng)的發(fā)生[7,9- 14,52]。2.5%～3%兒童嚴(yán)重過敏反應(yīng)有感染性因素存在，而1.3%～11%成人嚴(yán)重過敏反應(yīng)有感染因素的存在。感染因素通常與花粉或蜂毒特異性免疫治療(allergen specific immunology，SIT)后出現(xiàn)嚴(yán)重過敏性反應(yīng)相關(guān)[1, 52]。由于感染因素在SIT后有出現(xiàn)嚴(yán)重過敏反應(yīng)的風(fēng)險，SIT的指南已建議在感染情況下暫停SIT的治療。Staden等[53]報道在25例雞蛋和牛奶口服脫敏的兒童中，12例發(fā)生了嚴(yán)重過敏反應(yīng)，最常見伴發(fā)因素為運(yùn)動和感染。

感染作為嚴(yán)重過敏反應(yīng)的伴發(fā)因素機(jī)制還不明確。病原體本身可作為變應(yīng)原致敏機(jī)體和產(chǎn)生IgE或使已存在的IgE分子產(chǎn)生橋聯(lián)[54- 56]。另外，IgE、IgM及IgG抗體與抗原能夠形成可溶性的抗原抗體復(fù)合物。在病理情況下，免疫復(fù)合物可通過補(bǔ)體激活系統(tǒng)導(dǎo)致過敏毒素C3a和C5a以及促炎因子和趨化因子的產(chǎn)生[57]。除了FcεRⅠ，嗜堿粒細(xì)胞和肥大細(xì)胞也表達(dá)FcγR，其能夠促進(jìn)效應(yīng)細(xì)胞脫顆粒[58]。FcγRⅠ導(dǎo)致的肥大細(xì)胞脫顆粒是由于IgG1亞群介導(dǎo)的[59- 60]。因此，感染過程中IgG的產(chǎn)生或可影響嚴(yán)重過敏反應(yīng)的發(fā)生。固有免疫系統(tǒng)可能也可參與Ⅰ型變態(tài)反應(yīng)的發(fā)生。細(xì)菌、真菌以及病毒是通常所說的病原體相關(guān)分子模式，能直接連接在病原體識別受體上從而導(dǎo)致細(xì)胞活化和免疫應(yīng)答而無需提前致敏[61- 62]。肥大細(xì)胞和嗜堿粒細(xì)胞表達(dá)病原體識別受體能被不同的病原體相關(guān)分子模式激活[63- 64]，因此能夠調(diào)節(jié)效應(yīng)細(xì)胞的反應(yīng)狀態(tài)[65]。病原體相關(guān)分子模式的肽聚糖能夠誘發(fā)人[66]和大鼠肥大細(xì)胞[67]的脫顆粒。有些病原體相關(guān)分子模式也能調(diào)節(jié)和抑制肥大細(xì)胞的脫顆粒使固有的肥大細(xì)胞的激活處于平衡狀態(tài)[68]。病原體也能夠激活不同系統(tǒng)導(dǎo)致過敏毒素C3a和C5a的產(chǎn)生。有研究顯示C3a和C5a能觸發(fā)肥大細(xì)胞組胺釋放，C5a的作用強(qiáng)于C3a[69]。然而，C3a和C5a的激活作用僅限于一部分肥大細(xì)胞亞群，因為黏膜肥大細(xì)胞不表達(dá)過敏毒素的受體[70]，而且其作用于嚴(yán)重過敏反應(yīng)的機(jī)制還不明確[71]。但細(xì)菌或者病毒產(chǎn)物能夠被肥大細(xì)胞和嗜堿粒細(xì)胞的受體感知，在某些特定的情況下，觸發(fā)或者增強(qiáng)肥大細(xì)胞脫顆粒。但微生物因素作為嚴(yán)重過敏反應(yīng)的伴發(fā)因素的證據(jù)尚不足，應(yīng)進(jìn)一步研究。了解感染因素是嚴(yán)重過敏反應(yīng)相關(guān)危險因素對SIT治療和管理非常重要，在感染情況下SIT必須暫?；蛘邷p少劑量。

小　　結(jié)

嚴(yán)重過敏反應(yīng)的發(fā)生及其嚴(yán)重程度取決于多種因素，包括變應(yīng)原本身的性質(zhì)、變應(yīng)原的劑量、患者本身的致敏狀態(tài)及變應(yīng)原IgE的結(jié)合力。近年來，嚴(yán)重過敏反應(yīng)的伴發(fā)因素在其發(fā)生中的作用受到重視，伴發(fā)因素包括運(yùn)動、酒精攝入、藥物以及感染性疾病，其作用機(jī)制仍需要更深入的研究。

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