張娟娟 汪東海 代繼宏

大氣可吸入性顆粒物暴露與兒童哮喘顯著關(guān)聯(lián)：基于22篇觀察性研究的Meta分析

張娟娟1汪東海1代繼宏2

目的 定量分析大氣可吸入性顆粒物(PM2.5，PM10)暴露對兒童哮喘發(fā)病風(fēng)險的影響。方法 計算機檢索PubMed、EMBASE、Cochrane圖書館、Ovid、中國生物醫(yī)學(xué)文獻(xiàn)數(shù)據(jù)庫、中國知網(wǎng)和萬方數(shù)據(jù)庫，檢索時間均為建庫至2014年11月，同時手工檢索相關(guān)雜志,納入可吸入性顆粒物暴露與兒童哮喘關(guān)聯(lián)的觀察性研究文獻(xiàn)。采用NOS和AHRQ量表進(jìn)行文獻(xiàn)偏倚評價。以可吸入性顆粒物濃度每升高10 μg·m-3與兒童哮喘發(fā)病風(fēng)險關(guān)聯(lián)強度的OR及其95%CI作為效應(yīng)量，按急性效應(yīng)和慢性效應(yīng)分別行Meta分析，進(jìn)一步按PM2.5和PM10行亞組分析。采用RevMan 5.3和Stata 12.0軟件分別行異質(zhì)性分析及發(fā)表偏倚檢驗，根據(jù)異質(zhì)性分析結(jié)果采用相應(yīng)的效應(yīng)模型合并效應(yīng)值。結(jié)果 31篇文獻(xiàn)進(jìn)入Meta分析，隊列研究10篇，橫斷面研究12篇，病例交叉研究8篇，時間序列研究2篇。①22篇文獻(xiàn)報道了可吸入性顆粒物對兒童哮喘發(fā)病風(fēng)險的慢性效應(yīng)，文獻(xiàn)間具異質(zhì)性，隨機效應(yīng)模型的Meta分析結(jié)果顯示，合并OR=1.10(95%CI：1.03～1.17)，即大氣PM2.5或PM10濃度每上升10 μg·m-3，兒童哮喘的發(fā)病風(fēng)險升高10%，亞組分析顯示，PM2.5和PM10的合并OR值分別為1.08(95%CI：1.02～1.15)和1.10(95%CI：1.01～1.20)。②9篇文獻(xiàn)報道了可吸入性顆粒物對兒童哮喘發(fā)病風(fēng)險的急性效應(yīng)，文獻(xiàn)間具異質(zhì)性，隨機效應(yīng)模型的Meta分析結(jié)果顯示，合并OR=1.05(95%CI：1.02～1.08)，即大氣PM2.5或PM10濃度每上升10 μg·m-3，兒童哮喘的發(fā)病風(fēng)險升高5%；亞組分析顯示，PM2.5和PM10的合并OR值分別為1.06(95%CI：1.02～1.10)和1.05(95%CI：1.02～1.08)。③Egger直線回歸法發(fā)表偏倚檢驗顯示，急性效應(yīng)不存在發(fā)表偏倚，慢性效應(yīng)存在發(fā)表偏倚。結(jié)論 PM2.5和PM10水平與兒童哮喘發(fā)病風(fēng)險的急性和慢性效應(yīng)存在顯著關(guān)聯(lián)。

可吸入性顆粒物； 兒童； 哮喘； 系統(tǒng)評價； Meta分析

近幾十年內(nèi)兒童哮喘的患病率呈明顯的上升趨勢[1]。有研究表明[2]，哮喘是在遺傳易感性的基礎(chǔ)上與環(huán)境因素相互作用而發(fā)生的疾病，主要歸納為感染因素、理化因素及致敏因素。與此同時，隨著人們對環(huán)境污染與自身健康關(guān)系的日益關(guān)注，大氣污染特別是大氣顆粒物污染已成為近年來的熱點問題。國內(nèi)外流行病學(xué)研究和毒理學(xué)研究顯示[3]，大氣可吸入顆粒物暴露與人群健康效應(yīng)相關(guān)，主要包括呼吸系統(tǒng)和心腦血管疾病發(fā)病率和死亡率升高等。兒童處于不斷生長中，單位體重呼吸量高于成人，且呼吸系統(tǒng)和免疫系統(tǒng)發(fā)育尚不完善，使其更易遭受空氣污染侵害[4]。目前關(guān)于大氣可吸入顆粒物對兒童哮喘發(fā)病風(fēng)險的影響已有較多的研究，如采用隊列和橫斷面設(shè)計分析可吸入顆粒物對兒童哮喘發(fā)病風(fēng)險的慢性效應(yīng)[5]，即長期可吸入顆粒物暴露對兒童哮喘發(fā)病的影響；以時間序列(time-series)和病例交叉(case-crossover)設(shè)計觀察大氣顆粒物短期波動對兒童哮喘發(fā)病風(fēng)險的影響；但已發(fā)表的研究結(jié)論不一致。Gasana等[6]在2012年發(fā)表的Meta分析探討了可吸入顆粒物暴露與兒童哮喘的關(guān)聯(lián)性，但僅從慢性效應(yīng)角度分析，且未納入中文發(fā)表的文獻(xiàn)，因此有必要對該Meta進(jìn)行更新和進(jìn)一步分析，明確可吸入顆粒物暴露對兒童哮喘患病風(fēng)險的影響。

1 方法

1.1 文獻(xiàn)納入標(biāo)準(zhǔn) ①觀察性研究(隊列、病例交叉、橫斷面和時間序列研究)；②報道了大氣可吸入顆粒物PM2.5和PM10水平；③研究對象為兒童，且文獻(xiàn)中描述了哮喘的診斷標(biāo)準(zhǔn)；④文獻(xiàn)中報道了本文結(jié)局指標(biāo)數(shù)據(jù)，且提供了OR值及其95%CI；⑤重復(fù)發(fā)表的文獻(xiàn)，取樣本量較大的研究，同一研究不同觀察時間發(fā)表的文獻(xiàn)，取觀察時間最長的文獻(xiàn)；⑥語種限定為中文和英文。

1.2 文獻(xiàn)排除標(biāo)準(zhǔn) 研究人群包括成人和兒童，但無法單獨提取兒童數(shù)據(jù)的文獻(xiàn)。

1.3 結(jié)局指標(biāo) 報道的兒童哮喘患病率、發(fā)病率和就診率，可直接表示或間接轉(zhuǎn)化為可吸入性顆粒物濃度每升高10 μg·m-3，與兒童哮喘發(fā)病風(fēng)險關(guān)聯(lián)強度的OR值及其95%CI。

1.4 文獻(xiàn)檢索策略 計算機檢索PubMed、EMBASE、Cochrane圖書館、Ovid、中國生物醫(yī)學(xué)文獻(xiàn)數(shù)據(jù)庫(CBM)、中國知網(wǎng)和萬方數(shù)據(jù)庫,檢索時間均為建庫至2014年11月27日。回溯納入文獻(xiàn)的參考文獻(xiàn)。以PubMed數(shù)據(jù)庫為例的檢索式為((Child* OR Pediatrics [MeSH] OR Child [MeSH]) AND (Asthma [MeSH])) AND (Air Pollut* OR Air quality OR PM2.5 OR PM10 OR ultrafine particles OR fine particulate matter OR particles OR "Air pollutants" [MeSH]) AND Risk；以CBM為例的檢索式為(兒童哮喘 OR 兒童喘息) AND (空氣污染 OR 顆粒物 OR PM10 OR PM2.5)。

1.5 文獻(xiàn)篩選、資料提取和偏倚風(fēng)險評估 由本文作者張娟娟和汪東海分別獨立完成，如遇分歧討論決定。

1.5.1 文獻(xiàn)篩選 剔除重復(fù)發(fā)表、與研究目的不符和明顯不滿足納入標(biāo)準(zhǔn)的文獻(xiàn)，初篩后的文獻(xiàn)獲取全文再評估是否符合納入標(biāo)準(zhǔn)。

1.5.2 資料提取 采用資料登記表提取納入文獻(xiàn)的數(shù)據(jù)，包括文獻(xiàn)題目、發(fā)表年份、研究設(shè)計、受試對象、人口學(xué)特征、樣本量和結(jié)局指標(biāo)等。

1.5.3 偏倚風(fēng)險評價 納入的隊列和病例交叉研究采用NOS量表(the Newcastle Ottawa Scale)行偏倚風(fēng)險評價，包括入組標(biāo)準(zhǔn)符合性(4項內(nèi)容)、研究方法可比性(2項內(nèi)容)和資料完整性(3項內(nèi)容)，滿足1項內(nèi)容記1分，總分為9分。橫斷面研究采用AHRQ量表行偏倚風(fēng)險評估,推薦的標(biāo)準(zhǔn)包括11個條目，分別用“是”、“否”、“不清楚”及“不適用”作答。目前無時間序列研究的質(zhì)量評估工具。

1.6 統(tǒng)計學(xué)方法 采用RevMan 5.3和Stata 12.0軟件進(jìn)行Meta分析,效應(yīng)量以O(shè)R及其95%CI表示。采用χ2檢驗行統(tǒng)計學(xué)異質(zhì)性分析，P≤0.1為研究間存在顯著異質(zhì)性；采用I2對異質(zhì)性進(jìn)行定量，I2≤50%為低中度異質(zhì)性，采用固定效應(yīng)模型分析；I2>50%為高度異質(zhì)性，采用隨機效應(yīng)模型分析。對無法合并效應(yīng)量的文獻(xiàn)采用描述性分析,P<0.05為差異有統(tǒng)計學(xué)意義。

2 結(jié)果

2.1 納入文獻(xiàn)基本情況 共檢索到7 105篇文獻(xiàn)(PubMed 805篇、EMBASE 950篇、Cochrane圖書館63篇、Ovid 5 159篇、CBM 20篇、中國知網(wǎng)53篇、萬方數(shù)據(jù)庫53篇及參考文獻(xiàn)回溯7篇)。31篇文獻(xiàn)符合本文納入標(biāo)準(zhǔn)進(jìn)入Meta分析(圖1)，其中隊列研究10篇[7～16]，橫斷面研究12篇[17～28]，病例交叉研究8篇[29～36]，時間序列研究2篇[34,37]。納入文獻(xiàn)的基本特征如表1所示。

圖1 文獻(xiàn)篩選流程圖

Fig 1 Flow chart of article inclusion and exclusion process

2.2 文獻(xiàn)偏倚評價結(jié)果 偏倚評價結(jié)果顯示，10篇隊列研究[7～16]暴露隊列的代表性均充分，9篇文獻(xiàn)[7～14,16]非暴露組與暴露組不是來自同一人群，10篇文獻(xiàn)暴露因素的確定方法均可靠，確定研究起始時均無需觀察的結(jié)局指標(biāo)，暴露組和非暴露組間均具可比性，結(jié)局的測量方法均可靠，3篇文獻(xiàn)[13,14,16]未設(shè)計恰當(dāng)?shù)碾S訪時間，10篇文獻(xiàn)均完成隨訪且失訪率較低。3篇文獻(xiàn)[13,14,16]評為7分，6篇文獻(xiàn)[7～12]評為8分，文獻(xiàn)[15]評為9分。

8篇病例交叉研究[29～36]病例的確定、病例的代表性和對照的選擇均恰當(dāng)，對照的確定均不恰當(dāng)，5篇文獻(xiàn)[30～32，35，36]組間可比性較好，8篇文獻(xiàn)暴露因素的確定方法可靠、且采用相同的方法測量病例組和對照組的暴露因素，均描述了無應(yīng)答率的數(shù)據(jù)。3篇文獻(xiàn)[29，33，34]評為7分，5篇文獻(xiàn)[30～32,35,36]評為8分。

12篇橫斷面研究[17～28]偏倚評價的11個條目中，條目4(如不是人群來源，研究對象是否連續(xù))和條目11(如有隨訪，報告失訪數(shù)據(jù))不適用，故行9個條目的評價。12篇文獻(xiàn)均明確數(shù)據(jù)的來源，文獻(xiàn)[17]明確了納入和排除標(biāo)準(zhǔn)，余11篇文獻(xiàn)未提及；8篇文獻(xiàn)[17,19,21～26]給出了鑒別患兒的時間階段，均描述了研究的質(zhì)量控制；3篇文獻(xiàn)[17,20,25]描述了排除分析患兒的理由；10篇[17～25,28]文獻(xiàn)描述了控制混雜因素的措施；均未報道缺失數(shù)據(jù)的處理；8篇文獻(xiàn)[17,19,21～26]描述了應(yīng)答率。

2.3 Meta分析結(jié)果

2.3.1 可吸入性顆粒物對兒童哮喘發(fā)病風(fēng)險的慢性效應(yīng) 22篇文獻(xiàn)報道了可吸入性顆粒物對兒童哮喘的慢性效應(yīng)。文獻(xiàn)間具異質(zhì)性(P<0.001，I2=72%)，采用隨機效應(yīng)模型合并結(jié)果。Meta分析結(jié)果顯示(圖2)，合并OR=1.10(95%CI：1.03～1.17，P=0.03)，即大氣PM2.5或PM10濃度每上升10 μg·m-3兒童哮喘的發(fā)病風(fēng)險升高10%。

根據(jù)顆粒物的大小行亞組分析，報道PM2.5和哮喘關(guān)聯(lián)性的文獻(xiàn)間具同質(zhì)性，采用固定效應(yīng)模型分析，Meta分析結(jié)果顯示，合并OR=1.08(95%CI：1.02～1.15，P=0.01)；報道PM10和哮喘關(guān)聯(lián)性的文獻(xiàn)間具異質(zhì)性(I2=82%)，采用隨機效應(yīng)模型分析，合并OR=1.10(95%CI：1.01～1.20，P=0.02)。

圖2 可吸入顆粒物對兒童哮喘慢性效應(yīng)的Meta分析

Fig 2 Meta-analysis of chronic effects of inhaled particulate matter on asthma in children

2.3.2 可吸入性顆粒物對兒童哮喘發(fā)病風(fēng)險的急性效應(yīng) 9篇文獻(xiàn)報道了可吸入性顆粒物暴露對兒童哮喘的急性效應(yīng)，文獻(xiàn)間具顯著統(tǒng)計學(xué)異質(zhì)性(P<0.1，I2=63%)，采用隨機效應(yīng)模型合并，Meta分析結(jié)果顯示(圖3)，合并OR=1.05(95%CI：1.02～1.08，P=0.003)，即大氣PM2.5或PM10濃度每上升10 μg·m-3兒童哮喘的發(fā)病風(fēng)險升高5%。

根據(jù)顆粒物的大小行亞組分析，報道PM2.5和哮喘關(guān)聯(lián)性的文獻(xiàn)間具異質(zhì)性(I2=70%)，采用隨機效應(yīng)模型合并結(jié)果，合并OR=1.06(95%CI：1.02～1.10，P=0.004)；報道PM10和哮喘關(guān)聯(lián)性的文獻(xiàn)間具同質(zhì)性(I2=20%)，采用固定效應(yīng)模型分析，Meta分析結(jié)果顯示，合并OR=1.05(95%CI:1.02～1.08,P=0.001)。

2.4 發(fā)表偏倚 分別采用Begg 秩相關(guān)法和Egger直線回歸法行發(fā)表偏倚檢驗。用Begg秩相關(guān)法結(jié)果顯示(表3)， 納入文獻(xiàn)連續(xù)性校正，各文獻(xiàn)P值>0.05；采用Egger直線回歸法結(jié)果顯示(表3)，慢性效應(yīng)中存在發(fā)表偏倚(P=0.013)，與Begg 秩相關(guān)法結(jié)果不一致。通常Egger檢驗效能較Begg稍高[38]，故認(rèn)為報告慢性效應(yīng)文獻(xiàn)存在發(fā)表偏倚，報告急性效應(yīng)文獻(xiàn)不存在發(fā)表偏倚。

圖3 可吸入性顆粒物對兒童哮喘急性效應(yīng)的Meta分析

表3 發(fā)表偏倚的Egger和Begg直線回歸法檢驗結(jié)果

Notes 1) continuity corrected

3 討論

本文Meta分析納入的31篇文獻(xiàn)均為觀察性研究，其中隊列研究10項，是探討病因?qū)W較好的研究設(shè)計類型，納入文獻(xiàn)的總體樣本量較大。本文納入的隊列研究和病例交叉研究采用NOS評分評估偏倚風(fēng)險，12/18篇文獻(xiàn)≥8分，納入的橫斷面研究采用AHQR量表評價，其中9個條目的符合率均較高，進(jìn)入本文分析的文獻(xiàn)質(zhì)量為高。急性和慢性效應(yīng)均存在劑量效應(yīng)關(guān)系。本文納入的文獻(xiàn)間存在一定的臨床異質(zhì)性，如可吸入性顆粒物大小，不同地區(qū)及不同年齡段等均存在差異，故進(jìn)一步對顆粒物大小進(jìn)行亞組分析，但仍不能完全消除文獻(xiàn)間的異質(zhì)性，同時慢性效應(yīng)文獻(xiàn)存在發(fā)表偏倚，結(jié)合GRADE證據(jù)質(zhì)量評價工具，可吸入顆粒物對兒童哮喘發(fā)病風(fēng)險急性和慢性效應(yīng)的證據(jù)質(zhì)量均為低。

多項研究結(jié)果表明，可吸入性顆粒物是引起和加重支氣管哮喘尤其是過敏性哮喘的重要危險因素，其作用主要是免疫-炎癥機制，主要為兩方面[39]：①可吸入性顆粒物本身可通過引起Th1/Th2和細(xì)胞因子的失衡而誘發(fā)哮喘；②可吸入性顆粒物表面吸附一定的過敏原，可以強化和放大此炎癥反應(yīng)。本文Meta分析結(jié)果顯示，可吸入性顆粒物(PM2.5、PM10)不論從急性抑或慢性效應(yīng)均會增加兒童哮喘患病風(fēng)險，其中慢性效應(yīng)的關(guān)聯(lián)強度更高。關(guān)于顆粒物大小對兒童哮喘患病風(fēng)險的影響，急性效應(yīng)時PM2.5更為明顯，在慢性效應(yīng)時PM10更為明顯。Gasana等[6]在2012年從隊列和橫斷面研究角度分析室外空氣污染物與兒童哮喘關(guān)聯(lián)性的Meta分析顯示，PM2.5和PM10從慢性效應(yīng)可增加哮喘患病風(fēng)險。中國2015年發(fā)表的基于病例交叉和時間序列研究的Meta分析顯示，可吸入顆粒物從急性效應(yīng)可增加兒童哮喘的風(fēng)險[40]。與本文Meta分析結(jié)果一致。

結(jié)論：本文Meta分析結(jié)果提示，PM2.5和PM10水平與兒童哮喘發(fā)病風(fēng)險的急性效應(yīng)和慢性效應(yīng)存在顯著關(guān)聯(lián)。

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(本文編輯：丁俊杰)

Association between inhalable particulate matter and asthma in children: a meta-analysis based on 22 observational studies

ZHANGJuan-juan1,WANGDong-hai1,DAIJi-hong2

(1KeyLaboratoryofDevelopmentalDiseasesinChildhoodofMinistryofEducation,Chongqing400014; 2CenterofRespiratoryDisordersofChildren'sHospital,ChongqingMedicalUniversity,Chongqing400014,China)

DAI Ji-hong，E-mail:danieljh@163.com

ObjectiveTo quantitatively estimate the association between particulate matter with asthma in children.MethodsPubMed, EMBASE, Ovid, Cochrane Library, CBM, CNKI and Wanfang database were searched up to November 2014, and additional studies were manual screened. Observational studies assessing the association between inhalable particulate matter(PM2.5，PM10) and risk of childhood asthma were included. The quality of the literatures was evaluated by the Newcastle Ottawa Scale and AHRQ. The adjusted effect sizes and corresponding 95% CI for asthma attack corresponding to a 10 μg·m-3increment in exposure to inhalable particulate matter were investigated and conducted to identify the acute and chronic effects. Furthermore, subgroup analysis was conducted by the sizes of inhalable particulate matter. RevMan 5.3 and Stata 12.0 software were used to perform heterogeneity analysis and the test of publication bias. The pooled effect was conducted on the basis of effect model.Results Thirty-one studies were identified, including 10 cohort studies, 12 cross-sectional studies, 8 case-crossover studies and 2 time-series studies. ①Twenty-two literatures reported the chronic effects of exposure to inhalable particles on childhood asthma, which exhibited heterogeneity (P<0.001,I2=72%). The pooled effect sizes of odds ratio based on random effect model were 1.10 (95%CI: 1.03-1.17), which indicated that the incidence of pediatric asthma increased 10% by a weighted average of adjusted OR for a 10 μg·m-3increase in inhalable particles. In subgroup analysis, the combined odds ratios of PM2.5 and PM10 were 1.08 (95%CI: 1.02-1.15) and 1.0 (95%CI: 1.01-1.20) respectively. ② Nine literatures reported the acute effects of exposure to inhalable particles on childhood asthma. The pooled effect sizes were 1.05 (95%CI: 1.02-1.08), which indicated that the incidence of pediatric asthma increased 5% by a weighted average of for a 10 μg·m-3increment of adjusted OR in inhalable particles. In subgroup analysis, the combined OR of PM2.5 and PM10 corresponded to 1.06 (95%CI: 1.02-1.10) and 1.05 (95%CI: 1.02-1.08) respectively. ③The test of publication bias using Egger's regression method showed the absence of publication bias in reports of acute effects, and the presence in reports of chronic effects.ConclusionThere is significant association between the level of PM 2.5, PM 10 and the risks of acute and chronic childhood asthma.

Inhalable particulate matter; Children; Asthma; Systematic review; Meta-analysis

10.3969/j.issn.1673-5501.2015.05.004

1 重慶醫(yī)科大學(xué)附屬兒童醫(yī)院兒童發(fā)育與疾病教育部重點實驗室 重慶，400014；2 重慶醫(yī)科大學(xué)附屬兒童醫(yī)院呼吸中心 重慶，400014

代繼宏，E-mail:danieljh@163.com

2015-07-30

2015-09-15)