慢性阻塞性肺疾病急性加重風(fēng)險(xiǎn)預(yù)警因子研究進(jìn)展

李曉俊，王明航，李素云

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·新進(jìn)展·

慢性阻塞性肺疾病急性加重風(fēng)險(xiǎn)預(yù)警因子研究進(jìn)展

李曉俊，王明航，李素云

慢性阻塞性肺疾病急性加重(AECOPD)患者病情復(fù)雜，合并癥多，預(yù)后較差?？茖W(xué)的AECOPD風(fēng)險(xiǎn)預(yù)警因子及預(yù)警體系可為臨床治療提供便利，有助于優(yōu)化慢性阻塞性肺疾病(COPD)臨床治療方案，減少AECOPD的發(fā)生，降低不良預(yù)后風(fēng)險(xiǎn)。本文從單因子評(píng)估法、多因子評(píng)估法及綜合評(píng)估法角度，總結(jié)AECOPD風(fēng)險(xiǎn)預(yù)警因子的研究現(xiàn)狀。

肺疾病，慢性阻塞性；預(yù)后；預(yù)測(cè)；綜述

李曉俊，王明航，李素云.慢性阻塞性肺疾病急性加重風(fēng)險(xiǎn)預(yù)警因子研究進(jìn)展[J].中國(guó)全科醫(yī)學(xué)，2016，19(35)：4408-4412.[www.chinagp.net]

LI X J,WANG M H,LI S Y.Research progress of risk early-warning factors of acute exacerbation of chronic obstructive pulmonary disease[J].Chinese General Practice，2016，19(35)：4408-4412.

疾病風(fēng)險(xiǎn)預(yù)警能夠較好地評(píng)估患者的疾病狀況、未來疾病風(fēng)險(xiǎn)和發(fā)展趨勢(shì)，是疾病管理的核心環(huán)節(jié)。慢性阻塞性肺疾病(chronic obstructive pulmonary disease，COPD)是氣道氣流受限、不完全可逆并呈進(jìn)行性發(fā)展的疾病。COPD急性加重(acute exacerbation of chronic obstructive pulmonary disease,AECOPD)嚴(yán)重影響患者生活能力及預(yù)后，是COPD患者就診的主要原因[1]。導(dǎo)致AECOPD發(fā)生的影響因素較多，科學(xué)篩選風(fēng)險(xiǎn)預(yù)警因子，對(duì)優(yōu)化COPD治療方案、減少AECOPD的發(fā)生尤其重要。本文從單因子評(píng)估法、多因子評(píng)估法及綜合評(píng)估法3個(gè)角度，總結(jié)預(yù)測(cè)AECOPD發(fā)生的標(biāo)志物及量表，科學(xué)篩選AECOPD風(fēng)險(xiǎn)預(yù)警因子，為建立AECOPD預(yù)警系統(tǒng)提供參考。

1 單因子評(píng)估法

1.1 C反應(yīng)蛋白(CRP) CRP由肝細(xì)胞合成并釋放入血，與病情變化同步。SU等[2]研究表明,CRP作為重要的細(xì)菌感染標(biāo)志物，與白細(xì)胞聯(lián)合作用，在COPD的發(fā)生、發(fā)展中發(fā)揮重要作用。FATTOUH等[3]研究表明,CRP水平升高與COPD患者病情惡化的風(fēng)險(xiǎn)增加有關(guān)。血清CRP水平與肺功能密切相關(guān)。徐英等[4]報(bào)道，有長(zhǎng)期吸煙史的COPD患者血清CRP水平與肺功能變化呈線性相關(guān)關(guān)系，通過檢測(cè)COPD患者血清CRP水平可一定程度上預(yù)測(cè)AECOPD的發(fā)生。CRP作為認(rèn)可度較高的風(fēng)險(xiǎn)預(yù)警因子，已被證明與AECOPD發(fā)生密切相關(guān)[5]。

1.2 降鈣素原(PCT) PCT是細(xì)菌感染的敏感指標(biāo)[6]。生理狀態(tài)下由甲狀腺C細(xì)胞合成，血清中水平極低。PCT水平在細(xì)菌感染后2～3 h開始升高，12～48 h達(dá)到峰值，與AECOPD患者細(xì)菌感染的嚴(yán)重程度呈正相關(guān)[7]。COPD患者氣道長(zhǎng)期慢性感染，PCT達(dá)到0.26～0.50 μg/L時(shí)，推薦給予抗感染治療；PCT>0.50 μg/L時(shí)，強(qiáng)烈推薦使用抗菌藥物[8]。一項(xiàng)前瞻性隨機(jī)對(duì)照試驗(yàn)表明，當(dāng)PCT<0.1 μg/L時(shí)，AECOPD患者未在抗生素治療中明顯受益[9]。一項(xiàng)PCT在細(xì)菌感染所致的AECOPD住院患者診斷價(jià)值對(duì)比研究報(bào)道，PCT在預(yù)測(cè)AECOPD患者細(xì)菌感染方面更可靠，但靈敏度和特異度較低[10]。在診斷和治療AECOPD患者的細(xì)菌感染方面，PCT聯(lián)合CRP檢測(cè)可提高靈敏度，并在評(píng)估AECOPD患者預(yù)后方面也發(fā)揮著重要作用[11]。

1.3 肺泡巨噬細(xì)胞 組織中的巨噬細(xì)胞彌散分布于結(jié)締組織或器官中，肺泡巨噬細(xì)胞在氣道的炎性反應(yīng)過程中發(fā)揮重要作用。肺泡巨噬細(xì)胞被活化后，釋放出腫瘤壞死因子α(TNF-α)、巨噬細(xì)胞炎性蛋白2(MIP-2)等遞質(zhì)。KEATINGS等[12]在COPD患者肺泡灌洗液和痰中發(fā)現(xiàn)了高水平的促炎細(xì)胞因子和趨化因子。肺泡巨噬細(xì)胞在機(jī)體抵抗病原微生物方面首當(dāng)其沖，其釋放的TNF-α屬快反應(yīng)炎性因子，其生成主要受核因子(NF)-κB調(diào)控，若NF-κB信號(hào)傳導(dǎo)通路被激活，NF-κB p65亞基轉(zhuǎn)入核內(nèi)，與目標(biāo)基因啟動(dòng)子結(jié)合并調(diào)節(jié)其轉(zhuǎn)錄。研究發(fā)現(xiàn)p65水平與COPD病情嚴(yán)重程度呈正相關(guān)[13]。

1.4 TNF-α TNF-α在機(jī)體炎癥和免疫調(diào)節(jié)過程中發(fā)揮重要作用。梁衛(wèi)娟等[14]檢測(cè)AECOPD患者和健康志愿者TNF-α水平發(fā)現(xiàn)，AECOPD患者治療前TNF-α水平顯著高于健康志愿者，經(jīng)治療病情穩(wěn)定后TNF-α水平顯著下降，但仍處于高值，提示AECOPD患者經(jīng)過治療后病情穩(wěn)定，但是氣道及肺組織的慢性炎癥仍然存在，說明AECOPD患者血清TNF-α水平與病情嚴(yán)重程度相關(guān)。

1.5 體質(zhì)指數(shù)(BMI) BMI是衡量營(yíng)養(yǎng)狀況的良好指標(biāo)。LAINSCAK等[15]調(diào)查了968例COPD住院患者，并持續(xù)隨訪3年，期間死亡426例，其中BMI為25.09～26.55 kg/m2的患者病死率最低，分析表明，BMI每增加1.00 kg/m2，相應(yīng)的病死率下降5%。陸梅等[16]報(bào)道，隨著BMI的下降，AECOPD患者發(fā)生低氧血癥或二氧化碳潴留的情況加重，更易出現(xiàn)呼吸衰竭，并且BMI是再住院的獨(dú)立危險(xiǎn)因素。

1.6 貧血 COPD患者貧血患病率達(dá)10%～30%，并導(dǎo)致病死率升高[17]。COPD患者貧血的本質(zhì)是免疫驅(qū)動(dòng)的炎性反應(yīng)[18]，炎性因子使鐵元素出現(xiàn)代謝異常。MARTINEZ-RIVERA等[19]隨訪研究顯示，與肺功能和營(yíng)養(yǎng)狀態(tài)近似的存活患者比較，死亡患者血紅蛋白水平和紅細(xì)胞分布容積顯著降低，AECOPD發(fā)作次數(shù)明顯增多。一項(xiàng)回顧性研究表明，AECOPD患者的貧血程度與肺功能呈負(fù)相關(guān)，與住院時(shí)間、病死率呈正相關(guān)[20]。貧血可作為AECOPD住院患者死亡的獨(dú)立預(yù)測(cè)指標(biāo)[21]。

1.7 血清蛋白 血清蛋白水平可衡量機(jī)體的營(yíng)養(yǎng)狀況，營(yíng)養(yǎng)不良是COPD患者預(yù)后不良的獨(dú)立危險(xiǎn)因素[22-23]。AECOPD患者處于應(yīng)激狀態(tài)，肝臟合成和分泌功能受損，分解代謝大于合成代謝，導(dǎo)致血清蛋白水平降低，營(yíng)養(yǎng)和免疫受損，影響呼吸系統(tǒng)結(jié)構(gòu)和功能，降低患者抵御病原微生物侵襲的能力，從而導(dǎo)致患者第1秒用力呼氣末容積(FEV1)、用力肺活量(FVC)等肺功能指標(biāo)進(jìn)一步下降。程云等[24]報(bào)道，重度氣流受限患者營(yíng)養(yǎng)不良率為50%，中度氣流受限患者營(yíng)養(yǎng)不良率為25%。HERSELMAN等[25]報(bào)道血清蛋白水平與病死率呈負(fù)相關(guān)，COPD患者應(yīng)及早進(jìn)行營(yíng)養(yǎng)干預(yù)。

1.8 中性粒細(xì)胞與淋巴細(xì)胞比值(NLR) AECOPD患者受炎性刺激，中性粒細(xì)胞增多、活化,加重肺組織及血管的損傷[26]，增加肺循環(huán)阻力和肺間質(zhì)水腫的發(fā)生風(fēng)險(xiǎn)[27-28]?；颊哐h(huán)中糖皮質(zhì)激素及兒茶酚胺類物質(zhì)水平增高，導(dǎo)致淋巴細(xì)胞計(jì)數(shù)減少，加之COPD患者多伴有感染,故NLR常出現(xiàn)增高的趨勢(shì)。TAYLAN等[29]報(bào)道，NLR在預(yù)警AECOPD發(fā)生中的價(jià)值與傳統(tǒng)意義的標(biāo)志物無明顯差別。GüNAY等[30]一項(xiàng)回顧性研究表明，NLR作為具有成本效益的風(fēng)險(xiǎn)預(yù)警標(biāo)志物，其預(yù)測(cè)AECOPD發(fā)作的價(jià)值等同于CRP等標(biāo)志物。

1.9 血管內(nèi)皮生長(zhǎng)因子(VEGF) VEGF是參與體內(nèi)血管重構(gòu)的重要因子。COPD早期病變主要以血管病變?yōu)橹鳎憩F(xiàn)為肺組織血管收縮、釋放白介素等炎性遞質(zhì)等，導(dǎo)致肺血管重構(gòu)，影響血清VEGF的表達(dá)。VALIPOUR等[31]報(bào)道，VEGF和系統(tǒng)性炎癥標(biāo)志物水平的上調(diào)增加AECOPD患者不良預(yù)后風(fēng)險(xiǎn)。SALA等[32]報(bào)道，循環(huán)內(nèi)皮祖細(xì)胞百分比與AECOPD期間血漿VEGF水平呈正相關(guān)，AECOPD的發(fā)生與VEGF水平升高呈正相關(guān)。樊淑青[33]報(bào)道，VEGF可用于區(qū)別健康者與COPD患者，作為COPD的診斷指標(biāo)之一，同時(shí)還可區(qū)分AECOPD與穩(wěn)定期COPD，作為AECOPD的生物學(xué)診斷指標(biāo),并可作為AECOPD患者的預(yù)后指標(biāo)。

1.10 血栓彈力圖(TEG) TEG是依據(jù)凝血過程中凝血塊的黏彈性變化而繪制的圖像，反映了全血的凝血和纖溶能力。COPD患者因通氣/血流比例失調(diào)導(dǎo)致低氧血癥、高碳酸血癥、紅細(xì)胞繼發(fā)性增多，加上感染等因素，引起肺動(dòng)脈的炎癥和痙攣，管壁增厚和狹窄，肺泡受到破壞，而肺泡間隔組織中微血管、毛細(xì)血管前微動(dòng)脈也受到損害，可大量釋放炎性遞質(zhì)，激活凝血系統(tǒng)，導(dǎo)致其凝血功能亢進(jìn)，進(jìn)而使血液表現(xiàn)高凝狀態(tài)，造成病情加重及惡化。王垚等[34]報(bào)道，TEG較凝血酶原時(shí)間、活化部分凝血活酶時(shí)間、凝血酶時(shí)間、纖維蛋白原、D-二聚體及血小板計(jì)數(shù)能更快地反映AECOPD的血凝狀態(tài)。

1.11 腦鈉肽(BNP) BNP是心力衰竭的敏感指標(biāo)。COPD患者氣道慢性感染，小動(dòng)脈收縮，肺血管內(nèi)皮功能改變，肺血管重塑，缺氧逐漸加重，繼發(fā)性紅細(xì)胞增多，肺循環(huán)阻力增加，導(dǎo)致右心功能不全，心肌細(xì)胞分泌BNP增多。ABROUG等[35]研究表明，N末端B型腦鈉肽前體(NT-proBNP)與AECOPD的發(fā)生和左心衰竭相關(guān)。另一研究表明，NT-proBNP作為有效的風(fēng)險(xiǎn)預(yù)警因子，可以提高COPD患者診斷發(fā)生左心衰竭的準(zhǔn)確性[36]。張明等[37]報(bào)道，AECOPD患者血BNP水平明顯增高，可有效預(yù)測(cè)肺動(dòng)脈高壓，預(yù)警AECOPD的發(fā)生。

2 多因子評(píng)估法

2.1 合并癥及年急性加重次數(shù) 合并癥及年急性加重次數(shù)均嚴(yán)重影響COPD患者的生活質(zhì)量及預(yù)后。2015年慢性阻塞性肺疾病全球倡議(GOLD)指出，COPD患者合并癥主要集中于心血管疾病、骨質(zhì)疏松癥、焦慮和抑郁、肺癌、感染、代謝綜合征和糖尿病[38]。合并癥一旦明確診斷，應(yīng)評(píng)價(jià)其對(duì)COPD進(jìn)程的影響，制訂最佳治療方案和多學(xué)科診治措施，并隨訪治療效果[39]。

2.2 其他 2016年GOLD提出，咳嗽和咳痰的增加與輕至重度COPD患者病死率增加相關(guān)。抑郁是COPD患者未執(zhí)行康復(fù)計(jì)劃的危險(xiǎn)因素[40]。

3 綜合評(píng)估法

3.1 圣喬治呼吸問卷(St George′s Respiratory Questionnaire，SGRQ) SGRQ評(píng)價(jià)COPD患者預(yù)后運(yùn)用最為廣泛，具有較高的可靠性、真實(shí)性和靈敏性，SGRQ評(píng)分已被證實(shí)是影響COPD患者病死率及再入院風(fēng)險(xiǎn)的獨(dú)立危險(xiǎn)因子[41]。

3.2 生活質(zhì)量呼吸問卷 生活質(zhì)量呼吸問卷可真實(shí)、有效地反映COPD患者的生活質(zhì)量，與肺功能檢查互相補(bǔ)充，共同用于監(jiān)測(cè)患者日常病情的變化。杜曉秋等[42]報(bào)道，慢性阻塞性肺疾病評(píng)估測(cè)試(CAT)評(píng)分、改良呼吸困難指數(shù)(mMRC)評(píng)分和臨床慢性阻塞性肺疾病調(diào)查問卷(CCQ)評(píng)分均與SGRQ評(píng)分有良好的相關(guān)性；CAT、mMRC、CCQ更簡(jiǎn)潔，實(shí)用性和可行性更強(qiáng)；mMRC評(píng)價(jià)呼吸困難對(duì)患者的影響，CAT和CCQ反映患者活動(dòng)耐力，在患者生理、心理方面的評(píng)估更突出，有利于醫(yī)患雙方對(duì)病情的了解及監(jiān)控。mMRC主觀上反映了患者的呼吸困難嚴(yán)重程度及氣道阻塞程度，肺功能是客觀反映氣流受限的程度，mMRC與第1秒用力呼氣末容積占預(yù)計(jì)值百分比(FEV1%pred)呈負(fù)相關(guān)，二者聯(lián)合對(duì)COPD患者預(yù)后的評(píng)價(jià)更加準(zhǔn)確，對(duì)于判斷疾病進(jìn)展及預(yù)后有重要的作用[43]。

3.3 急性生理性與慢性健康狀況評(píng)分系統(tǒng)Ⅱ(APACHEⅡ) APACHEⅡ評(píng)分是由急性生理性評(píng)分、年齡指數(shù)及慢性健康指數(shù)等組合的復(fù)合評(píng)分標(biāo)準(zhǔn)，簡(jiǎn)單、全面，結(jié)果相對(duì)客觀可靠，廣泛用于重癥醫(yī)學(xué)科。王瓊婭等[44]探討了APACHEⅡ與C0PD合并呼吸衰竭患者生存質(zhì)量的相關(guān)性，表明APACHEⅡ同患者病死率呈正相關(guān)，APACHEⅡ在預(yù)測(cè)患者生存質(zhì)量方面優(yōu)于其他評(píng)分。

3.4 CURB65評(píng)分及BAP65評(píng)分 AECOPD患者常合并重癥感染，短期死亡風(fēng)險(xiǎn)高，常借助機(jī)械通氣治療。高效價(jià)的機(jī)械通氣測(cè)評(píng)工具對(duì)評(píng)估患者的實(shí)際狀態(tài)及合理指導(dǎo)使用機(jī)械通氣具有重要價(jià)值。CURB65評(píng)分及BAP65評(píng)分在預(yù)測(cè)AECOPD患者機(jī)械通氣及病死率方面有一定參考價(jià)值[45]。BAP65評(píng)分中的生命體征項(xiàng)目為脈搏≥109次/min,CURB65評(píng)分中的生命體征項(xiàng)目包括呼吸頻率≥30次/min、低收縮壓〔<90 mm Hg(1 mm Hg=0.133 kPa)〕或舒張壓(≤60 mm Hg)。而AECOPD患者易并發(fā)心動(dòng)過速,較少發(fā)生低血壓，采用BAP65評(píng)分預(yù)測(cè)AECOPD患者行機(jī)械通氣可能比CURB65評(píng)分更實(shí)用。

3.5 重癥肺炎指數(shù)(pneumonia severity index,PSI) PSI基于年齡、合并癥、生命體征(脈搏≥125次/min或收縮壓<90 mm Hg)和實(shí)驗(yàn)室指標(biāo)(血細(xì)胞比容<30%、動(dòng)脈血氧分壓<60 mm Hg或血糖≥14.0 mmol/L)。LOKE等[46]的PSI預(yù)測(cè)肺炎患者病死率的Meta分析表明，PSI在辨別具有低死亡風(fēng)險(xiǎn)的肺炎患者中顯示出較好的準(zhǔn)確性。一項(xiàng)系統(tǒng)評(píng)價(jià)顯示，PSI預(yù)測(cè)社區(qū)獲得性肺炎(CAP)患者30 d內(nèi)死亡的ROC曲線下面積為0.8[47]。AECOPD與肺炎的臨床表現(xiàn)有諸多重疊，PSI中的部分變量可視為AECOPD的預(yù)后因素[48]。有研究發(fā)現(xiàn)，PSI預(yù)測(cè)AECOPD患者死亡的ROC曲線下面積為0.847，靈敏度為82.2%，特異度為77.6%[49]，而CURB65、BAP65評(píng)分預(yù)測(cè)AECOPD患者死亡的ROC曲線下面積分別為0.744〔95%CI(0.680,0.809)〕、0.665〔95%CI(0.594,0.736)〕[50],提示PSI在預(yù)測(cè)AECOPD患者死亡方面更具優(yōu)越性。

4 建立AECOPD風(fēng)險(xiǎn)預(yù)警體系的思考

除較為明確的高齡、吸煙、呼吸系統(tǒng)感染、較差的肺功能、營(yíng)養(yǎng)不良、免疫力低下等因素外，單因子中CRP、PCT、BMI等是認(rèn)可度較高的AECOPD風(fēng)險(xiǎn)預(yù)警因子，多因子及綜合評(píng)估法中，合并癥及年急性加重次數(shù)，SGRQ預(yù)警AECOPD風(fēng)險(xiǎn)可靠性較好。當(dāng)前研究更多焦點(diǎn)在于COPD的治療方案，尚缺乏科學(xué)的AECOPD風(fēng)險(xiǎn)預(yù)警因子及預(yù)警體系的系統(tǒng)研究。

科學(xué)的AECOPD風(fēng)險(xiǎn)預(yù)警因子及預(yù)警體系可為臨床治療提供便利，防患于未然對(duì)COPD患者身心大有裨益?？茖W(xué)篩選AECOPD風(fēng)險(xiǎn)預(yù)警因子并建立AECOPD風(fēng)險(xiǎn)預(yù)警體系，有助于優(yōu)化COPD臨床治療方案，減少AECOPD的發(fā)生，降低不良預(yù)后風(fēng)險(xiǎn)，減輕患者生理、心理及經(jīng)濟(jì)負(fù)擔(dān)。

志謝：感謝陳學(xué)昂在文獻(xiàn)收集與整理方面給予的幫助！

作者貢獻(xiàn)：李曉俊負(fù)責(zé)資料收集整理、成文；王明航指導(dǎo)課題設(shè)計(jì)與實(shí)施；李素云負(fù)責(zé)質(zhì)量控制及文章審校。

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(本文編輯：吳立波)

Research Progress of Risk Early-warning Factors of Acute Exacerbation of Chronic Obstructive Pulmonary Disease

LIXiao-jun,WANGMing-hang,LISu-yun.

TheFirstClinicalMedicalCollegeofHenanUniversityofTraditionalChineseMedicine,Zhengzhou450000,China

Correspondingauthor:LISu-yun,DepartmentofRespiratory,theFirstAffiliatedHospitalofHenanUniversityofTCM,Zhengzhou450000,China；E-mail：lisuyun2000@126.com

Patients with acute exacerbation of chronic obstructive pulmonary disease(AECOPD) are always in complicated conditions with multiple diseases,and of poor prognosis.Scientific risk early-warning factors and early warning system of AECOPD can provide convenience for clinical treatment,help to optimize the clinical treatment of COPD,reduce the occurrence of AECOPD,and reduce the risk of poor prognosis.The paper summarizes the research status of the risk early-warning factors of AECOPD through the single factor assessment,multi-factor evaluation and comprehensive evaluation methods.

Pulmonary disease，chronic obstruction;Prognosis;Forecasting;Review

國(guó)家自然科學(xué)基金面上項(xiàng)目(81473649)

450000河南省鄭州市，河南中醫(yī)藥大學(xué)第一臨床醫(yī)學(xué)院(李曉俊)；河南中醫(yī)藥大學(xué)第一附屬醫(yī)院呼吸科(王明航，李素云)

李素云，450000河南省鄭州市，河南中醫(yī)藥大學(xué)第一附屬醫(yī)院呼吸科；E-mail：lisuyun2000@126.com

R 563.9

A

10.3969/j.issn.1007-9572.2016.35.024

2016-03-16；

2016-10-14)