陸愛珍 楊皓偉 王傳凱 錢莉玲 張曉波 王立波
·論著·
上海地區(qū)單中心住院兒童難治性肺炎支原體肺炎相關因素分析
陸愛珍1楊皓偉1王傳凱 錢莉玲 張曉波 王立波
目的 分析普通肺炎支原體肺炎(MPP)進展為難治性MPP的相關因素,為早期識別難治性MPP提供參考。方法 采集2012年9月至2013年8月復旦大學附屬兒科醫(yī)院住院的MPP且排除了其他常見病毒和細菌感染的病例,分為難治性MPP組和普通MPP組。復習文獻收集與難治性MPP相關的指標,采集入院次日相關實驗室檢查指標、入院3 d內采集胸部X線和CT資料;以單因素和多因素分析進展為難治性MPP的相關因素。結果 653例MPP患兒進入分析,占同期收治肺炎患兒的51.9%(653/1 257例)。難治性MPP組300例,男171例;普通MPP組353例,男221例。①單因素分析顯示,難治性MPP組年齡顯著高于普通MPP組,(66.8 ± 37.5)vs(51.4 ± 34.4)月齡,>3歲的比例也顯著高于普通MPP組(234/300vs224/353,P<0.01)。難治性MPP組發(fā)熱時間和住院天數(shù)均顯著高于普通MPP組(P均<0.01);CK、LDH、HBDH、ALT、AST、CRP、PCT和IL-6水平難治性MPP組均顯著高于普通MPP組;難治性MPP組肺滲出面積評分顯著高于普通MPP組,(1.95±1.12)vs(1.55±0.97),P<0.01。②選擇單因素分析后有統(tǒng)計學意義的臨床、實驗室和影像學指標行逐步Logistic回歸分析,發(fā)熱天數(shù)(OR=1.954,95%CI:1.403~2.722)、血清LDH水平(OR=1.009,95%CI:1.001~1.018)和肺滲出面積評分(OR=2.422,95%CI:1.111~5.279)是難治性MPP的獨立相關因素。結論 肺炎支原體已成為社區(qū)獲得性肺炎住院患兒的主要病原體,難治性MPP病例常發(fā)生于3歲以上兒童。疾病早期存在持續(xù)高熱、肺部滲出面積大、血清LDH水平增高是進展為難治性MPP的獨立相關因素。
肺炎支原體; 難治性肺炎支原體肺炎; 相關因素; 兒童
肺炎支原體(Mp)是引起人類非典型性肺炎和許多呼吸道疾病的病原體之一。Mp呈全球性分布,肺炎支原體肺炎(MPP)每2~6年可引起一次全球暴發(fā)流行[1],人群普遍易感。在社區(qū)獲得性肺炎(CAP)中10%~30%由Mp引起[2]。一項CAP的流行病學調查結果顯示Mp的感染率已超過肺炎鏈球菌,成為成人CAP首要致病菌[3]。盡管Mp感染大部分是自限性疾病,僅有部分感染患兒需要住院治療[1],但近年來Mp感染的危重病例不斷增多,危重病例造成的后遺癥如肺不張、支氣管擴張、閉塞性細支氣管炎、肺間質纖維化、肺蛋白沉積癥、腦炎并發(fā)癥和慢性腎病等嚴重損害了患兒的生活質量。在臨床上如能早期識別Mp感染難治性病例,并給予早期干預可顯著降低Mp感染的后遺癥,提高危重患兒生活質量。目前國內相關難治性MPP危險因素的分析多為回顧性研究,相關因素報告差異較大和觀察時間不統(tǒng)一,特別是影像學測量偏倚較大,結果偏倚的可能性較大。
1.1 研究設計 復習文獻盡可能收集難治性MPP潛在的相關因素,采集在復旦大學附屬兒科醫(yī)院(我院)住院且次日Mp檢測陽性,并排除其他常見病原感染的肺炎患兒,統(tǒng)一截取入院次日采集的相關實驗室和入院3 d內影像學指標,分為難治性MPP組和普通MPP組,以單因素和多因素分析進展為難治性MPP的相關因素。
1.2 診斷標準 難治性MPP診斷標準[4]:①符合MPP的診斷;②經(jīng)大環(huán)內酯類抗菌藥物正規(guī)治療7 d及以上,臨床癥狀加重、仍持續(xù)發(fā)熱、肺部影像學所見加重者。
1.3 納入標準 2012年9月至2013年8月在我院住院的MPP患兒,并符合以下條件:①入院次日Mp檢測陽性,血清Mp-IgM陽性(滴度>1∶320)或鼻咽分泌物Mp-DNA陽性;②入院次日鼻咽分泌物細菌培養(yǎng)和其他病原學檢查(呼吸道合胞病毒、腺病毒、副流感病毒、流感病毒、偏肺病毒、沙眼衣原體DNA、肺炎支原體DNA)陰性;③入院次日外周血EB病毒和血培養(yǎng)陰性。
1.4 排除標準 ①合并慢性基礎性疾病,如先天性心臟病、慢性腎炎、腎病綜合征、自身免疫性疾病和免疫缺陷?。虎诮谑褂妹庖咭种苿┱?如糖皮質激素、雷公藤多苷等)。
1.5 Mp檢測方法 Mp-IgM 采用SeroMPTMIgM 檢測試劑盒(酶聯(lián)免疫法),按照說明書操作進行檢測;Mp-DNA檢測采用肺炎支原體核酸擴增熒光檢測試劑盒(上海申友生物有限公司)進行檢測, >2 500 copies·mL-1為陽性結果。
1.6 相關因素的采集和定義 復習文獻[5~11]共總結20余項與難治性MPP相關因素,編制病例登記表,逐項截取上述相關因素,20項相關因素包括①性別、年齡、入我院前發(fā)熱天數(shù)、住院天數(shù);②入院3 d內的胸部X線和(或)CT影像學資料,根據(jù)MPP的影像學特點分為:滲出、間質病變、肺門淋巴結改變、大葉性肺實變和肺不張、胸腔積液和肺壞死,對于滲出病變部位采用右上肺、右中肺、右下肺、左上肺,左中肺和左下肺進行描述,滲出面積采用評分法[12]進行描述,每個部位面積評分為1分;③肺外發(fā)現(xiàn):住院過程中觀察到的Mp感染相關的皮疹(除外藥疹),淺表淋巴結腫大(查體檢出的既往未被發(fā)現(xiàn)的淋巴結腫大),肝功能損害(病程中B超證實伴肝功能指標異常),腦病(住院期間精神狀態(tài)改變,譫妄或意識模糊);④病原負荷量:入院次日清晨鼻咽分泌物標本Mp-DNA和血清Mp-IgM;⑤入院次日清晨實驗室指標:血常規(guī),CRP,ALT,AST,心肌酶譜(CK, CK-MB, LDH, HBDH),PCT,IL-6和ESR。
1.7 質量控制 ①我院呼吸科病房入院患兒臨床常規(guī)為入院次日完成相關實驗室檢查(鼻咽分泌物、血清Mp-IgM等),入院3 d內完成影像學檢查;②在本文病例收集結束后,統(tǒng)一調閱相關病例影像學資料,由我院放射科1名影像學主治醫(yī)生在不知曉患兒臨床信息的情況下閱片和評估。
2.1 一般情況 653例MPP患兒進入分析(圖1),占同期收治的肺炎患兒的51.9%(653/1 257)。難治性MPP組300例,男171例;普通MPP組353例,男221例。兩組性別構成比差異無統(tǒng)計學意義(P=0.15)。
2.2 難治性MPP組相關因素的單因素分析 表1顯示,難治性MPP組年齡顯著高于普通MPP組,(66.8 ± 37.5)vs (51.4 ± 34.4)月齡,>3歲的比例也顯著高于普通MPP組(234/300vs224/353,P<0.01)。難治性MPP組發(fā)熱時間和住院天數(shù)均顯著高于普通MPP組(P均<0.01)。肺外發(fā)現(xiàn),兩組肝功能損害發(fā)生率差異有統(tǒng)計學意義(8/353vs33/300,P<0.01),皮疹、淋巴結腫大的發(fā)生率差異無統(tǒng)計學意義。難治性MPP組IgM≥1∶1 280比例和Mp-DNA也顯著高于普通MPP組(P均<0.01) 。 難治性MPP組的CK、LDH、HBDH、ALT、AST、PLT、CRP、PCT和IL-6水平均顯著高于普通MPP組。
圖1 病例納入和排除流程圖
Fig 1 Flow chart of inclusion and exclusion of patients
VariablesUMPP(n=353)RMPP(n=300)χ2/t/ZPSex(M/F)221/132171/1292.120.15Age/months51.4±34.466.8±37.56.350.00<1year43(12.2)24(8.0)16.540.00-3years86(24.4)42(14.0)≥3years224(63.4)234(78.0)ClinicalfindingsDurationoffever/d4.7±3.512.±8.613.820.00Hospitalization/d7.1±3.59.6±5.44.540.00Extra?pulmonaryfindingRash8(2.3)5(1.7)0.300.78Lymphadenopathy3(0.8)2(0.7)2.560.25Liverimpairment8(2.3)33(11.0)21.020.00Encephalopathy04(1.3)1.040.42MploadingIgM≥1∶320195(55.2)91(30.3)47.380.00-1∶64073(20.7)69(23.0)≥1∶128085(24.1)140(46.7)Log(copies)6.15±1.336.44±1.192.650.01LaboratoryfindingsCK/U·L-172(52-105)74(44-129)-1.180.85CK?MB/U·L-125(19.8-33.0)24(18.8-33.2)-0.840.40LDH/U·L-1304±78449±2589.320.00HBDH/U·L-1249±69357±2337.680.00ALT/U·L-112.4±18.223.2±42.83.950.00AST/U·L-121.9±20.730.1±28.74.020.00WBC/×109·L-18.2±4.08.6±3.80.640.11CRP/mg·L-17(7-11)13(7-38)-6.860.00ESR/mm·h-128.2±20.040.8±23.46.360.00PCT/ng·L-10.05(0.03-0.09)0.09(0.05-0.21)-7.210.00IL?6/pg·mL-17.3(3.0-13.6)14.4(5.0-34.1)-4.380.00
Notes RMPP:refractorymycoplasmapneumoniaepneumonia; UMPP: usualmycoplasmapneumoniaepneumonia; M/F: male/female
483例MPP患兒入我院3 d內行胸部X線和(或)CT檢查,其中普通MPP組242例,難治性MPP組241例。兩組均以滲出性病變?yōu)橹?,均為右下肺滲出最多(分別為56.8%和44.2%),其次是左下肺(分別為49.0%和41.3%)。難治性MPP組肺滲出面積評分顯著高于普通MPP組(1.95±1.12)vs(1.55±0.97),P<0.01。兩組肺間質病變的發(fā)生率分別為34.4%和47.9%,難治性MPP組觀察到大葉性肺實變不張38例,中等量以上的胸腔積液 56例,壞死性肺炎3例(表2)。
表2 難治性MPP組和普通MPP組影像學特征比較[n(%)]
Tab 2 Comparison of characteristics of chest images of subjects with RMPP and UMPP[n(%)]
VariablesUMPP(n=242)RMPP(n=241)χ2PLocationofinfiltrationRight?up73(30.2)79(32.8)0.380.54Right?mid37(15.3)60(24.9)6.940.01Right?down107(44.2)137(56.8)7.710.01Left?up45(18.6)47(19.5)0.060.81Left?mid15(6.2)30(12.4)5.580.02Left?down100(41.3)118(49.0)2.840.09Infiltrationarea1.55±0.971.95±1.124.010.00Interstitialchanges116(47.9)83(34.4)9.070.00Pulmonaryhilarlymph?nodesenlargement9(3.7)16(6.6)2.010.15Lobarlungconsolidationandatelectasis038(15.8)41.30.00Pleuraleffusion056(23.2)63.50.00Pulmonarygangrene03(1.2)3.020.08
Notes RMPP:refractorymycoplasmapneumoniaepneumonia; UMPP: usualmycoplasmapneumoniaepneumonia
2.3 難治性MPP相關因素的Logistic回歸 選擇單因素分析后有統(tǒng)計學意義的指標(臨床、實驗室和影像學)行逐步Logistic回歸分析,發(fā)現(xiàn)發(fā)熱天數(shù)(OR=1.954,95%CI:1.403~2.722,P=0.000)、血清LDH水平(OR=1.009,95%CI:1.001~1.018,P=0.029)和肺滲出面積評分(OR=2.422,95%CI:1.111~5.279,P=0.026)是難治性MPP的獨立相關因素。
本研究采集MPP病例行難治性MPP的相關因素分析,在設計和實施時充分考慮了研究中可能的偏倚和混雜因素,主要體現(xiàn)在:①我院呼吸科臨床常規(guī)為入院次日行鼻咽分泌物細菌培養(yǎng)和其他病原學檢查,并行血培養(yǎng),較好的保證了納入的病例為單一Mp感染的患兒;②本文觀察的實驗室檢查指標均在入院次日采集,對早期判斷MPP病情的嚴重程度有重要意義;③僅采集入院3 d內的影像學檢查資料,且在研究結束后由放射科專人盲法讀片,降低了可能的測量偏倚。因此本文結果可以較好的描述難治性MPP的相關因素。
本研究發(fā)現(xiàn),因單一MPP住院的患兒占全年肺炎住院患兒的51.9%,是我院住院肺炎患兒的首要病原。近年來,Mp的感染率全球范圍內呈增高趨勢,尤其是亞洲地區(qū)Mp感染發(fā)生率和重癥肺炎發(fā)生率遠高于歐美[13~19]。一項亞洲范圍內的流行病學調查顯示,Mp感染引起的CAP占12.2%[16]。一項兒童呼吸道感染的調查顯示Mp在呼吸道感染中占19.1%[15]。本研究顯示,單一MPP患兒,男童構成比高于女童,與中國杭州地區(qū)的調查結果相似[20],但也有研究顯示MPP無性別差異[21]。同時,本研究發(fā)現(xiàn)難治性MPP組>3歲患兒占78%,與既往的研究結果相似[20,22]??赡茉蚺c3歲以上兒童入托后容易感染Mp,且大年齡兒童由于免疫系統(tǒng)發(fā)育相對完善,Mp感染后易于激發(fā)過強的免疫反應,造成免疫損傷。
本文難治性MPP組發(fā)熱時間和住院天數(shù)顯著高于普通MPP組,皮疹、淋巴結腫大兩組分布差異無統(tǒng)計學意義,難治性MPP組肝功能損害情況較普通MPP組嚴重。值得一提的是本文難治性MPP組有4例合并腦病。Mp感染的肺外表現(xiàn)可累及全身任何一個器官[23~28],引起急性期損傷甚至死亡,部分患兒可能會留下后遺癥[29,30]。Mp感染肺外表現(xiàn)的機制與支原體觸發(fā)過強的免疫反應有關,另外,近年來提出的血管炎性/閉塞性損傷可能是Mp感染肺外表現(xiàn)的重要機制[31]。其他實驗室指標的單因素分析顯示,Mp-IgM、Mp-DNA與難治性MPP有一定關聯(lián),提示MPP嚴重程度與病原載量呈明顯的量效關系;此外,LDH、HBDH水平與難治性MPP組有一定的相關性,LDH是糖酵解途徑中一種重要的酶,被認為是肺間質性疾病中的重要血清學指標[32,33],HBDH是LDH活性的間接反映,兩者水平的增高提示有發(fā)展為難治性Mp肺炎的趨向,炎癥相關指標在難治性MPP組均呈顯著高于普通MPP組的趨勢,提示在難治性MPP的早期,強烈的炎癥反應可能參與了MPP病情進展。Logistic 回歸分析僅篩選出LDH為相關因素,考慮可能由于上述炎癥因子之間存在一定的生物學相關性,因此未進入最終的回歸模型。
普通MPP組和難治性MPP組肺滲出部分均以右下葉最多,其次是左下葉,與文獻報道較為一致[34];難治性MPP組的肺滲出面積評分顯著高于普通MPP組,兩組累及間質的病例均較多(34.4%vs47.9%)。有研究顯示[35],MPP的影像學表現(xiàn)早期為支氣管壁的增厚、肺門淋巴結增大、片狀模糊影和節(jié)段實變,難治性MPP可出現(xiàn)大葉實變不張、胸腔積液和肺壞死。本文病例資料顯示,難治性MPP組中大葉性肺實變不張、胸腔積液、肺壞死和肺門淋巴結增大的比例較普通MPP組顯著增多,與文獻[35]報道一致。另外,該研究提示早期的胸部CT形態(tài)學特征如氣管壁的增厚和小葉結節(jié)樣改變對是否進展為難治性MPP無預測作用[35]。而關于早期炎癥滲出面積與難治性MPP的相關性研究甚少,本文單因素分析發(fā)現(xiàn)肺滲出面積評分與進展為難治性MPP相關,進一步Logistic 回歸顯示肺滲出面積評分是難治性MPP的獨立相關因素。
本研究的不足與局限性:兒童無法完全配合,僅取鼻咽部分泌物,其檢測結果不能完全取代肺內分泌物的病原情況。
綜上所述,Mp已成為CAP住院患兒的主要病原體,重癥病例常發(fā)生于3歲以上兒童。疾病早期存在持續(xù)高熱、肺部滲出面積大、血清LDH增高是進展為難治性MPP的獨立相關因素,應早期積極干預,預防并發(fā)癥的發(fā)生。
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(本文編輯:丁俊杰)
The associated factors of refractory Mycoplasma pneumoniae pneumonia in hospitalized children in a mono-center in Shanghai
LUAi-zhen1,YANGHao-wei1,WANGChuan-kai,QIANLi-ling,ZHANGXiao-bo,WANGLi-bo
(DepartmentofRespiratory,Children′sHospitalofFudanUniversity,Shanghai, 201102,China; 1hasequalcontributiontothisstudy)
Corresponding Author:ZHANG Xiao-bo,E-mail: zhangxiaobo0307@163.com; WANG Li-bo,E-mail:wanglbc@163.com
ObjectiveTo analyze the associated factors of refractoryMycoplasmapneumoniae(Mp) pneumonia.MethodsThe cases of Mono-Mp pneumonia admitted in Children′s Hospital of Fudan University from September 2012 to August 2013 were collected, and divided into two groups, refractory Mp pneumonia(RMPP) and usual Mp pneumonia(UMPP) . Laboratory outcomes collected by literature review were performed on the next day of admission. Chest X-ray and/or CT data were also collected in the first 3 days after admission. The laboratory outcomes and chest images were analyzed for the associated factors of refractory Mp pneumonia by univariate and multivariate logistic regression analysis.Results653 cases of Mono-Mp pneumonia were collected, covered 51.7% (653/1257) of the total number of pneumonia. There were 300 cases in refractory pneumonia group, 171 boys and 129 girls. And there were 353 cases in normal pneumonia group, 221 boys and 132 girls. ①Univariate analysis showed the age in RMPP group was significantly higher than that of UMPP group, (66.8 ± 37.5)vs(51.4 ± 34.4) months,P<0.01; the proportion of cases over 3 years old in RMPP group was also significantly higher than that in UMPP group (234/300vs224/353,P<0.01); the hospitalized days and febrile days in RMPP group were significantly higher than those in UMPP group (P<0.01, respectively); laboratory outcomes in RMPP group, CK, LDH, HBDH, ALT, AST, CRP, PCT, IL-6, were significantly higher than those in UMPP group (P<0.01, respectively); infiltration area of chest images in RMPP was significantly greater than that in UMPP, (1.95 ± 1.12)vs(1.55 ± 0.97),P<0.01. ② Those significant outcomes in univariate analysis were chosen to perform stepwise logistic regression, and the analysis showed that febrile days (OR=1.954,95%CI:1.403-2.722), serum LDH level (OR=1.009,95%CI:1.001-1.018), and infiltration area of chest images (OR=2.422,95%CI:1.111-5.279) were the independent associated factors of RMPP. ConclusionMp became a major pathogen of hospitalized children with CAP. Severe cases often occurred in children over 3 years old. The persistent fever, the large area of infiltration in chest images, high level of serum LDH in the early stage suggested that it may progress into severe pneumonia.
Mycoplasmapneumoniae; Refractory Mycoplasma pneumoniae pneumonia; Associated factors; Children
復旦大學附屬兒科醫(yī)院呼吸科 上海,201102;1 共同第一作者
張曉波,E-mail: zhangxiaobo0307@163.com;王立波,E-mail:wanglbc@163.com
10.3969/j.issn.1673-5501.2014.06.003
2014-07-03
2014-11-27)