重癥哮喘表型及內(nèi)型的研究進(jìn)展

韓國敬，胡 紅

(解放軍總醫(yī)院呼吸內(nèi)科，北京 100853)

哮喘近年被認(rèn)為是一種異質(zhì)性疾病[1]，而重癥哮喘是指在過去一年中≥50%的時(shí)間需要給予全球哮喘防治創(chuàng)議(global initiative for asthma，GINA)指南中4～5級(jí)哮喘藥物治療，即高劑量吸入激素聯(lián)合長效β2受體激動(dòng)劑和(或)白三烯調(diào)節(jié)劑/緩釋茶堿，或全身激素治療才能維持哮喘控制狀態(tài)或上述治療下仍不能控制哮喘[2]。研究表明，約5%～10%的哮喘患者為重癥哮喘患者[3]。重癥哮喘反復(fù)發(fā)作會(huì)導(dǎo)致患者生活質(zhì)量下降，不僅消耗大量醫(yī)療費(fèi)用，而且使用大劑量糖皮質(zhì)激素(簡稱激素)會(huì)導(dǎo)致激素相關(guān)并發(fā)癥風(fēng)險(xiǎn)升高[3-5]。

表型(phenotype)通常指生物體由基因型和環(huán)境相互作用后而被觀察到的特征[6,7]。內(nèi)型(endotype)指通過一個(gè)特殊的可以識(shí)別的生物途徑來解釋表型中觀察到的特性，即從發(fā)病機(jī)制層面反映哮喘的本質(zhì)[7-9]。哮喘表型指通過哮喘患者的病史、臨床特征、病理生理學(xué)等生物學(xué)特征以及對(duì)治療的反應(yīng)等鑒定出不同的哮喘亞型[10,11]。重癥哮喘患者具有不同的表型和內(nèi)型，其病理機(jī)制復(fù)雜多樣[9]。重癥哮喘不同表型的特征包括年齡、性別、發(fā)病年齡、特應(yīng)性狀態(tài)、肥胖、發(fā)作頻率、阿司匹林加重性呼吸系統(tǒng)疾病(aspirin aggravated respiratory disease，AERD)及激素抵抗等。然而，這些特征同時(shí)存在大量重疊[5]。重癥哮喘不同表型和內(nèi)型的診斷及個(gè)體化治療將有助于優(yōu)化重癥哮喘患者的管理，改善哮喘預(yù)后[12]。目前被廣泛認(rèn)可的重癥哮喘表型不是很多，本文對(duì)7種不同的重癥哮喘表型進(jìn)行了綜述。

1 與炎癥生物標(biāo)志物相關(guān)的重癥哮喘表型

1.1 高輔助性T淋巴細(xì)胞2(helper T cell 2，Th2)型哮喘/晚發(fā)型嗜酸性粒細(xì)胞型哮喘

高Th2型重癥哮喘的發(fā)病機(jī)制與Th2炎癥通路參與的氣道炎癥和氣道重構(gòu)有關(guān)。首先上皮細(xì)胞分泌白細(xì)胞介素-25(interleukin-25，IL-25)和白細(xì)胞介素-33(interleukin-33，IL-33)激活肺部樹突狀細(xì)胞，并誘導(dǎo)CD4+T淋巴細(xì)胞分化為Th2，其次激活的Th2細(xì)胞可產(chǎn)生特定的細(xì)胞因子白細(xì)胞介素-4(interleukin-4,IL-4)、IL-5I和L-13，參與Th2型炎癥并促進(jìn)B淋巴細(xì)胞合成免疫球蛋白E(immuno-globulin，IgE)。此外，Th17炎癥通路也參與重癥哮喘的發(fā)病過程[13]。重癥哮喘研究項(xiàng)目(Severe Asthma Research Program，SARP)結(jié)果表明，大約50%重癥哮喘與Th2型輔助性T淋巴細(xì)胞水平持續(xù)升高相關(guān)[14-17]。高Th2型重癥哮喘患者的表型特征為患者臨床癥狀更重、嗜酸性粒細(xì)胞增多、疾病多為早發(fā)型、患者存在過敏反應(yīng)和IgE水平升高，以及Th2型炎癥抑制劑有效[8,18,19]。高Th2型重癥哮喘的炎癥生物標(biāo)志物包括嗜酸性粒細(xì)胞、高水平呼出氣一氧化氮((fractional exhaled nitric oxide，F(xiàn)eNO)、骨膜蛋白、溴酪氨酸、嗜酸性粒細(xì)胞趨化因子。研究表明氣道或痰液中嗜酸性粒細(xì)胞增多的患者對(duì)激素治療可能更有效。

晚發(fā)型嗜酸性粒細(xì)胞型哮喘多見于成人，而兒童期哮喘發(fā)病常與過敏相關(guān)[5]。晚發(fā)型嗜酸性粒細(xì)胞型重癥哮喘約占重癥哮喘患者的25%，患者血液和肺部嗜酸性粒細(xì)胞持續(xù)可見，臨床癥狀更多，第一秒用力呼氣量(forced expiratory volume in 1 second,FEV1)水平更低，F(xiàn)eNO水平增高，過敏性因素較少，更易出現(xiàn)重癥急性加重以及治療困難等[5,20-23]。

1.2 中性粒細(xì)胞型哮喘

中性粒細(xì)胞型哮喘的致病原因目前尚不清楚，可能是吸煙、肥胖、空氣污染、職業(yè)刺激性接觸以及病毒、細(xì)菌感染等多因素導(dǎo)致中性粒細(xì)胞浸潤型氣道炎癥[7]。一般哮喘患者誘導(dǎo)痰中的中性粒細(xì)胞比例>(60%～63%)定義為中性粒細(xì)胞型哮喘[24-26]。研究表明中性粒細(xì)胞型氣道炎癥可能與哮喘的持續(xù)性氣流受限相關(guān)[23]。中性粒細(xì)胞型重癥哮喘表型特征為老年人、吸煙，常見于接近致死性哮喘或多次氣管插管病史、突發(fā)性致死性等重癥哮喘患者,伴有睡眠障礙和胃食管返流疾病患者的鼻竇炎發(fā)病率增高，同時(shí)對(duì)激素抵抗[27-29]。此類患者的支氣管活檢、支氣管肺泡灌洗液和誘導(dǎo)痰中，均可見到較多的中性粒細(xì)胞，并且大多數(shù)患者中性粒細(xì)胞增加數(shù)量與疾病嚴(yán)重程度相關(guān)，中性粒細(xì)胞型哮喘相關(guān)的炎癥介質(zhì)包括IL-8、 彈性蛋白酶、 基質(zhì)金屬蛋白酶-9(matrix metalloproteinase-9，MMP-9)、IL-17A、 白細(xì)胞三烯B4(leukotriene B4，LTB4)、粒細(xì)胞-巨噬細(xì)胞集落刺激因子(granulocyte-macrophage colony stimulating factor，GM-CSF)和腫瘤壞死因子-α(tumor necrosis factor alpha，TNF-α)[27]。

2 兒童期過敏性哮喘

研究表明，兒童期過敏性哮喘，即早發(fā)型過敏性哮喘，約占所有重癥哮喘患者的40%～50%[30]，發(fā)病機(jī)制可能與IgE介導(dǎo)的免疫反應(yīng)有關(guān)。其表型特征包括兒童期發(fā)病、具有嚴(yán)重過敏史和哮喘家族史、總IgE水平升高。特征性生物標(biāo)志物包括特異性IgE水平增高、高水平的FeNO、半乳糖凝集素-3、嗜酸性粒細(xì)胞增多。

3 成人期過敏性哮喘

成人期重度過敏性哮喘患者(34%)比成人期輕至中度持續(xù)性過敏性哮喘(52%)更少見[31]。重癥成人期過敏性哮喘患者，通常在兒童期即患有過敏性鼻炎，成年后出現(xiàn)過敏性哮喘。早期識(shí)別此型患者的特應(yīng)性及過敏原，對(duì)選擇治療及改善居住環(huán)境具有意義。研究表明對(duì)于IgE水平升高以及多種過敏原陽性的重癥成人期發(fā)作性過敏性哮喘患者，使用奧馬珠單抗治療可減少哮喘急性發(fā)作頻率及吸入激素的量[32，33]。

4 成人期非過敏性哮喘

成人期非過敏性哮喘患者在癥狀發(fā)作前多有病毒感染史、職業(yè)暴露史或服用阿司匹林，而兒童期哮喘患者較少有此類病史。相比早發(fā)型過敏型哮喘，12歲之后患哮喘患者的特異性過敏癥狀或過敏皮膚測試陽性較少。因此，成人期非過敏性哮喘混雜因素很多，過敏性因素可能更難明確。

5 阿司匹林加重性呼吸系統(tǒng)疾病

阿司匹林加重性呼吸系統(tǒng)疾病(aspirin-exacerbated respiratory disease,AERD) 包括哮喘、慢性鼻-鼻竇炎(chronic rhinosinusitis，CRS)、鼻息肉以及攝入阿司匹林和其他抑制環(huán)氧合酶-1的非甾體類抗炎藥(non steroidal anti-inflammatory drugs， NSAID)后出現(xiàn)的急性上、下呼吸道反應(yīng)。AERD是多種重癥哮喘表型復(fù)雜重疊的表現(xiàn)。約50%的AERD患者外周血嗜酸性粒細(xì)胞增多。研究表明，30%～70%的AERD患者是特應(yīng)性體質(zhì)患者[5]。

6 哮喘性肉芽腫

一些重癥哮喘患者進(jìn)行肺組織活檢時(shí)被發(fā)現(xiàn)存在肉芽腫性炎癥，例如，變應(yīng)性肉芽腫血管炎(churg-strauss syndrome，CSS)、過敏性支氣管肺曲霉病(allergic broncho-pulmonary aspergillosis，ABPA)等。大多數(shù)哮喘性肉芽腫患者的外周血嗜酸性粒細(xì)胞增多，F(xiàn)eNO水平升高，部分患者出現(xiàn)過敏癥狀[34]。

7 與臨床特征相關(guān)的重癥哮喘表型

7.1 激素抵抗型哮喘

部分哮喘患者長期或大量使用激素治療后療效仍不理想，這部分對(duì)激素治療不敏感的哮喘稱為激素抵抗型哮喘，約占哮喘總患病率的5%～10%，具有高齡、病史長、急診就診及住院率高、嚴(yán)重的氣道高反應(yīng)、易出現(xiàn)夜間喘息、誘導(dǎo)痰中中性粒細(xì)胞增多等特點(diǎn)。其發(fā)病機(jī)制較為復(fù)雜，可能與糖皮質(zhì)激素受體異常、遺傳基因以及免疫調(diào)節(jié)等機(jī)制有關(guān)。

7.2 頻繁發(fā)作型哮喘

頻繁發(fā)作型哮喘尚無一致的定義，一般指哮喘發(fā)作1年超過2或3次[2]，重癥哮喘患者約30%符合頻繁發(fā)作的定義[35]。頻繁發(fā)作型哮喘患者具有更高的外周氣道阻力、外周血和支氣管肺泡灌洗液中嗜酸性粒細(xì)胞持續(xù)增多。此外，共存疾病更多，如慢性鼻竇炎、反復(fù)發(fā)生的呼吸道感染、吸煙、肥胖、阻塞性睡眠呼吸暫停及心理社會(huì)問題等[36-38]。

7.3 肥胖型哮喘

2014年GINA指南中首次提出肥胖型哮喘[39]。肥胖型哮喘患者體質(zhì)量指數(shù)(body mass index，BMI)≥30 kg/m2、女性居多、中度氣道高反應(yīng)性(airway hyper-reactivity，AHR)及可逆性、哮喘癥狀重、氣道重塑發(fā)生早、哮喘晚期激素治療效果較差、誘導(dǎo)痰嗜酸性粒細(xì)胞數(shù)量低而中性粒細(xì)胞數(shù)量高、特應(yīng)性低(IgE水平不高)、對(duì)激素藥物反應(yīng)不佳等。一項(xiàng)荷蘭隊(duì)列研究表明，重癥哮喘隊(duì)列中肥胖型哮喘的發(fā)生率為21%[40]；英國一項(xiàng)隊(duì)列研究表明，肥胖型哮喘的發(fā)生率為48%[41]。肥胖型哮喘常難控制，并且對(duì)傳統(tǒng)哮喘治療藥物反應(yīng)差。研究表明，肥胖型哮喘患者血清中IL-6、TNF-α及瘦素水平升高，而脂聯(lián)素水平下降[42]。

7.4 圍絕經(jīng)期哮喘

圍絕經(jīng)期哮喘是指女性末次月經(jīng)后1年內(nèi)發(fā)生的哮喘[43,44]，發(fā)病機(jī)制可能是圍絕經(jīng)期女性激素水平降低，導(dǎo)致氣道免疫炎癥反應(yīng)增強(qiáng)[45]。研究表明絕經(jīng)期哮喘患者誘導(dǎo)痰中的中性粒細(xì)胞比例較高，而嗜酸性粒細(xì)胞比例輕度降低[44]。此外，絕經(jīng)期發(fā)病的哮喘患者特應(yīng)性低，相比單純哮喘患者，呼吸困難癥狀明顯，存在焦慮比例高，哮喘常規(guī)治療效果差[44,46]。

綜上所述，重癥哮喘存在明顯的異質(zhì)性，未來研究方向應(yīng)從重癥哮喘的臨床表型逐步轉(zhuǎn)向分子表型，開展對(duì)不同表型重癥哮喘的臨床特征、生物標(biāo)志物及個(gè)體治療的研究將有助于控制哮喘，使更多哮喘患者從中獲益。目前重癥哮喘表型及內(nèi)型更深層次的機(jī)制仍未闡明,具體表型的分型方法尚需進(jìn)一步研究。雖然對(duì)這些表型尚未達(dá)成共識(shí),但可以肯定的是,表型及內(nèi)型研究有助于重癥哮喘患者的精準(zhǔn)診斷、科學(xué)管理以及有效個(gè)體治療方案的制定。

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