柯薩奇病毒A組6型與腸道病毒71型感染所致的手足口病臨床特點(diǎn)比較

顏 湘 劉泉波

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·論著·

柯薩奇病毒A組6型與腸道病毒71型感染所致的手足口病臨床特點(diǎn)比較

顏 湘 劉泉波

手足口病； 柯薩奇病毒A組6型； 腸道病毒71型； 脫甲； 脫屑

手足口病(HFMD)是以發(fā)熱伴手、足、臀等多部位皮疹為特征的傳染性疾病，其主要病原為腸道病毒71型(EV71)和柯薩奇病毒A組16型(CA16)[1,2]。但自2008年以來(lái)CA6感染所致的HFMD在世界各地報(bào)道逐漸增多[3,4]，2008年在芬蘭[3]首次出現(xiàn)了以后期脫甲為主要特征的HFMD，顯示CA6為其主要的病原，之后在美國(guó)和中國(guó)[4,5]相繼報(bào)道的HFMD病例中，CA6感染比例逐漸增加，成為HFMD重要的致病源。CA6感染所致的HFMD皮疹分布廣泛，形態(tài)多樣，難以與水痘、麻疹等疾病鑒別，臨床容易漏診和誤診，造成疾病擴(kuò)散流行，帶來(lái)了嚴(yán)重的經(jīng)濟(jì)和社會(huì)負(fù)擔(dān)，嚴(yán)重危害兒童健康[5]，但中國(guó)大陸尚未見(jiàn)關(guān)于CA6感染所致HFMD臨床特點(diǎn)的相關(guān)報(bào)道。本研究回顧性分析重慶醫(yī)科大學(xué)附屬兒童醫(yī)院(我院)HFMD住院患兒EV71及CA6感染病例的臨床資料，比較兩者臨床特點(diǎn)和流行特征，為臨床準(zhǔn)確診斷并治療提供依據(jù)。

1 方法

1.1 HFMD診斷標(biāo)準(zhǔn) 我院HFMD診斷參照中國(guó)衛(wèi)生部制定的2010年版《手足口病診療指南》[6]。

1.2 研究對(duì)象的納入標(biāo)準(zhǔn) ①2013年9月至2014年8月在我院確診為HFMD的住院患兒；②病原學(xué)確診為EV71和CA6感染。

1.3 EV71和CA6檢測(cè) 我院EV71和CA6檢測(cè)采用廣州中山達(dá)安基因試劑公司HFMD實(shí)時(shí)聚合酶鏈反應(yīng)(RT-PCR)試劑盒，臨床常規(guī)要求采集HFMD患兒的糞便、咽拭子或(和)腦脊液標(biāo)本。

1.4 出院結(jié)局的判斷標(biāo)準(zhǔn) 痊愈：急性感染期后所有臨床癥狀完全消失；好轉(zhuǎn)：急性感染期后臨床癥狀逐漸消失，但未完全消失；死亡。

1.6 分組 本研究根據(jù)RT-PCR檢測(cè)結(jié)果，將研究對(duì)象分為EV71組和CA6組。

1.7 資料采集 回顧性查閱病史，截取以下資料用于本文分析：①一般資料：性別、年齡；②臨床資料：發(fā)病月份，臨床表現(xiàn)(發(fā)熱、神經(jīng)系統(tǒng)受累癥狀)，皮疹(大小、形態(tài)、部位)，實(shí)驗(yàn)室檢查(血常規(guī)、CRP、血糖和病原學(xué)結(jié)果)；③出院時(shí)結(jié)局：痊愈、好轉(zhuǎn)和死亡；④隨訪結(jié)局：并發(fā)癥和后遺癥。

2 結(jié)果

2.1 一般情況 研究期間共確診HFMD住院患兒887例，其中438例(49.4%)確診為EV71感染，包括糞便檢出425例次，咽拭子檢出18例次，腦脊液檢出36例次，糞便及咽拭子同時(shí)檢出15例次，糞便及腦脊液同時(shí)檢出26例次，無(wú)3種樣本同時(shí)檢出病例。43例(4.8%)確診為CA6感染，所有病例均為糞便檢出。余406例中腸道病毒通用型陽(yáng)性387例，CA16陽(yáng)性19例。CA6組年齡6月齡至4歲，平均(17.6±8.7)月齡，<3歲42/43例(97.7%)；男29例，女14例。EV71組年齡1月齡至14歲，平均(27.2±18.2)月齡，<3歲338/438例(77.2%)；男275例，女163例。兩組年齡差異有統(tǒng)計(jì)學(xué)意義(P<0.001)，性別構(gòu)成差異無(wú)統(tǒng)計(jì)學(xué)意義(P=0.546)。

2.2 發(fā)病月份 如圖1所示，CA6組以1～3月冬春交季所占比例最大，分別占我院當(dāng)月總HFMD的26.1%(6/23)、17.6%(3/17)和12.5%(4/32)；8～10月夏秋交季分別占我院當(dāng)月總HFMD的3.0%(1/33)、6.5%(5/77)和5.3%(6/114)。而EV71組以4～7月春夏交季為最高峰，分別占我院當(dāng)月總HFMD的54.6%(59/108)、72.5%(100/138)和67.5%(77/114)、51.4%(53/103)；10～12月秋冬交季次之，分別占我院當(dāng)月總HFMD的26.3%(30/114)、40.9%(36/88)和37.5%(15/40)。

2.3 臨床特點(diǎn) 如表1所示，發(fā)熱和神經(jīng)系統(tǒng)受累癥狀(嘔吐、 驚跳及肢體抖動(dòng))發(fā)生率CA6組明顯低于EV71組(P均<0.05)，且意識(shí)障礙僅見(jiàn)于EV71組。CA6組重癥病例1/43例(2.3%)，為重型；EV71組中重癥病例201/438例(45.9%),其中重型188例，危重型13例。兩組重癥病例所占比例差異有統(tǒng)計(jì)學(xué)意義(P<0.001)。CA6組住院時(shí)間明顯短于EV71組(P=0.002)。

圖1 2013年9月至2014年8月確診為EV71及CA6感染所致的HFMD比例

Fig 1 Proportion of HFMD caused by CA6 and EV71 in each month from September 2013 to August 2014

Notes EV71: enterovirus 71; ca6: coxsackievirus A6; CA16: coxsackievirus A16; EV-U: universal enterovirus

ClinicalfeaturesCA6(n=43)EV71(n=438)t/χ2PHospitalization/d5.1±2.06.3±2.53.150.002SymptomsFever34(79.1)422(96.3)23.72<0.001Cough16(37.2)147(33.6)0.230.630Rhinorrhea8(18.6)101(23.1)0.440.506Salivation27(62.8)280(63.9)0.020.882Diarrhea6(14.0)56(12.8)0.050.827Poororalintake34(79.1)292(66.7)2.760.097Vomiting7(16.3)174(39.7)9.170.002Startleresponse2(4.7)258(58.9)46.40<0.001Febrileseizure3(7.0)16(3.7)1.140.236Alteredconscious-ness012(2.7)1.210.613Limbtrembling1(2.3)66(15.1)5.300.021Unsteadygait2(4.7)68(15.5)3.720.054RashesdistributionPalm/soles41(95.3)420(95.9)0.030.697Perioralareal14(32.6)0146.88<0.001Oralulcer27(62.8)315(71.9)1.590.208Trunks30(69.8)11(2.5)227.15<0.001Buttocks23(53.5)292(66.7)3.010.083Limbs30(69.8)36(8.2)125.29<0.001Externalia4(9.3)5(1.1)14.200.005RashesmorphologyMaculopapule28(65.1)410(93.6)39.04<0.001Vesicle23(53.5)49(11.2)55.05<0.001Bulla3(7.0)030.750.001LaboratorydataWBC/×109·L-111.7±5.111.1±4.10.810.419WBC>10×109 ·L-123(53.5)238(54.3)0.010.915CRP>8mg·L-116(37.2)317(72.4)26.26<0.001GLU/mmol·L-16.8±3.85.6±2.01.950.057GLU>6.11mmol ·L-114(32.6)101(23.1)0.420.515

2.4 皮疹 兩組患兒均出現(xiàn)皮疹，CA6組皮疹除分布于手足(95.3%)、口腔(62.8%)、臀部(53.5%)等部位，也見(jiàn)于軀干(69.8%)(圖2A)、四肢(69.8%) (圖2A～C) 、 口周(32.6%)(圖2D)和外生殖器(9.3%)；而EV71組皮疹主要局限于手和(或)足(95.9%)、口腔(71.9%)、臀(66.7%)等部位。就形態(tài)而言，CA6組斑丘疹28例(65.1%)，皰疹23例(53.5%)，大皰疹3例(7.0%)，腐蝕樣皮疹1例(2.3%)，斑丘疹及皰疹同時(shí)出現(xiàn)11例(25.6%)；而EV71組皮疹較CA6組細(xì)小，斑丘疹410例(93.6%)，大多呈針帽大小，皰疹49例(11.2%)，斑丘疹及皰疹同時(shí)出現(xiàn)35例(8.0%)。兩組皮疹形態(tài)為斑丘疹和皰疹的比例差異均有統(tǒng)計(jì)學(xué)意義(P均<0.001)(表1)。

圖2 CA6相關(guān)性HFMD的皮疹表現(xiàn)
Fig 2Characteristics of rashes in children with HFMD caused by CA6

NotesA:maculopapule and bulla were mainly distributed in upper limbs and trunks;B:erosions were noted in foot;C:bullae were found on the hand;D:maculopapule were mainly distributed in the perioral area

2.5 實(shí)驗(yàn)室檢查 CA6組中WBC增多23例(53.5%)；CRP增高16例(37.2%)，最高達(dá)51 mg·L-1；血糖升高14例(32.6%)，與EV71組相比，WBC和血糖均值兩組相近，且WBC增多與血糖升高的發(fā)生率兩組差異亦無(wú)統(tǒng)計(jì)學(xué)意義(P均>0.05)，而CA6組CRP增高的發(fā)生率低于EV71組(P<0.001)(表1)。

2.6 隨訪 CA6組43例患兒均痊愈，均完成來(lái)院隨訪；EV71組428例(97.7%)出院時(shí)痊愈，1例(0.2%)死亡，347/437例(79.4%)完成來(lái)院隨訪。

2.6.1 并發(fā)癥 隨訪至HFMD急性感染期后8周，脫甲發(fā)生率在CA6組(10/43，23.3%)明顯高于EV71組(5/347，1.4%)，差異有統(tǒng)計(jì)學(xué)意義(P<0.001)。兩組脫甲發(fā)生于急性感染期后2～8周，CA6組脫甲時(shí)間主要集中于急性感染期后第5周(3/10,30.0%)，EV71組主要發(fā)生于急性感染期后第4周(2/5,40.0%)。脫屑發(fā)生率CA6組(12/43,27.9%)明顯高于EV71組(15/347,4.3%)，差異有統(tǒng)計(jì)學(xué)意義(P<0.001)。兩組脫屑發(fā)生于急性感染期后1～8周，在CA6組和EV71組均集中發(fā)生于急性感染期后第4周，分別占33.3%(4/12)和46.7%(7/15)。

3 討論

本研究比較EV71和CA6感染所致HFMD的臨床特點(diǎn)和流行特征，結(jié)果顯示CA6組感染所致的HFMD發(fā)病高峰較EV71組有所提前，發(fā)病高峰主要為冬春交季和夏秋交季，與中國(guó)長(zhǎng)春地區(qū)[7]CA6病原引起的HFMD主要集中在夏季并不一致。本研究EV71組發(fā)病高峰以春夏交季和秋冬交季多見(jiàn)，這與中國(guó)香港及新加坡等地[8,9]報(bào)道EV71流行季節(jié)類(lèi)似。CA6和EV71感染發(fā)病高峰時(shí)間的差異是源于生物學(xué)特性不同，還是由遺傳表型所致，值得進(jìn)一步研究。這也提示在重慶地區(qū)除了在EV71好發(fā)季節(jié)重點(diǎn)防控HFMD外，同時(shí)也應(yīng)該對(duì)CA6發(fā)病高峰時(shí)間段提高警惕，防止引起局部或大規(guī)模流行。

本研究EV71和CA6組患兒年齡均集中在3歲以內(nèi)，但CA6組患兒年齡明顯小于EV71組，這與泰國(guó)地區(qū)[10]報(bào)道的CA6感染患兒1歲內(nèi)多見(jiàn)一致，然而CA6組患兒年齡較EV71組小的原因是否與CA6病原毒力的特殊屬性或變異有關(guān)尚未得知，但提示CA6感染所致的HFMD與小年齡患兒密切相關(guān)，應(yīng)提醒臨床醫(yī)生應(yīng)對(duì)小年齡兒童進(jìn)行重點(diǎn)預(yù)防和監(jiān)控。

本研究CA6組患兒較EV71組皮疹廣泛、皮損嚴(yán)重、形態(tài)多樣，皮疹累及口周、軀干和四肢等部位，且皰疹多見(jiàn)甚至出現(xiàn)大皰疹、腐蝕性皮疹等特殊皮疹表現(xiàn)，這與芬蘭[3]、美國(guó)[4]等地報(bào)道類(lèi)似，CA6感染所致的HFMD皮疹難以與水痘、膿皰病、麻疹等相鑒別。而EV71組患兒的皮疹主要局限于手足等肢體末端位置，皮疹細(xì)小，以斑丘疹為主。且有報(bào)道[11]CA6感染所致的HFMD與口周皮疹存在密切關(guān)系，本研究也支持這一觀點(diǎn)，本文口周皮疹僅見(jiàn)于CA6感染。提示對(duì)于疑診HFMD并存在口周皮疹的患兒，可能是由CA6病原感染引起，必要時(shí)可完善糞便等分子病原學(xué)檢測(cè)進(jìn)一步明確。

本研究隨訪發(fā)現(xiàn)EV71和CA6組均出現(xiàn)了后期并發(fā)癥(脫甲及脫屑)，但CA6組脫甲和脫屑的發(fā)生率明顯高于EV71組，這與中國(guó)臺(tái)灣地區(qū)報(bào)道[13]類(lèi)似，說(shuō)明HFMD中多種病原可引起脫甲和脫屑，但仍以CA6感染為主。本研究脫甲、脫屑主要發(fā)生于HFMD急性感染期后4～5周，這與?sterback等[3]報(bào)道的脫甲、脫屑發(fā)生在HFMD急性感染后1～2個(gè)月和Guimbao等[14]報(bào)道脫甲、脫屑平均發(fā)生在HFMD急性感染期后40 d基本一致，然而目前對(duì)于脫甲的機(jī)制尚不明確，有研究者提出與大量病毒復(fù)制導(dǎo)致甲基質(zhì)的破壞有關(guān)[3]，但仍需要更多實(shí)驗(yàn)進(jìn)一步探討。

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(本文編輯：張萍)

Comparison of clinical features of hand, foot, and mouth disease caused by coxsackievirus A6 and enterovirus 71

YANXiang,LIUQuan-bo

(DepartmentofInfectiousDisease,Children′sHospitalofChongqingMedicalUniversity,MinistryofEducationKeyLaboratoryofChildDevelopmentandDisorders,ChongqingKeyLaboratoryofPediatrics,Chongqing410014,China)

LIU Quan-bo，E-mail:liuqb1223@sina.com

ObjectiveTo investigate the difference of clinical features of hand, foot, and mouth disease (HFMD) caused by coxsackievirus A6 (CA6) and enterovirus 71 (EV71).MethodsInpatients with HFMD admitted to Children′s Hospital of Chongqing Medical University from September 2013 to August 2014 were collected. Complications and sequelae were investigated by follow-up interviews.ResultsA total of 887 inpatients with HFMD including 438 cases in EV71 group and 43 cases in CA6 group were recruited. There were different peaks in two groups: the largest proportion from January to March in CA6 group and the significant peak from April to July in EV71 group. The age of patients in the CA6 group was younger than that of EV71 group，(17.6±8.7) monthsvs(27.2±18.2) months,P<0.05. The rate of fever and manifestations of neurologic involvement including vomiting (16.3%), startle response (4.7%) and limb trembling (2.3%) were significantly lower in CA6 group than in EV71 group (allP<0.05). The distribution of rashes involving trunks (69.8%), limbs (69.8%), perioral area (32.6%) and externalia (9.3%) and the morphology of rashes as vesicle (53.5%) were significantly associated with that in CA6 group (allP<0.05). All the children in CA6 group recovered smoothly and received follow-up interviews after therapy successfully . While 428 children(97.7%) were recovered and 1 child(0.2%) was dead in EV71 group. And only 347 cases (79.4%) completed the interviews in EV71 group. The rate of onychomadesis and desquamation was significantly higher in CA6 group (allP<0.05). All the children in CA6 group showed total recovery without any sequela, however 8 children suffered from paralysis and 1 child had epilepsy with EV71 infection. ConclusionThe occurrence of HFMD had different seasonal distribution between two groups. Compared with those infected by EV71, the children with CA6 infection were younger. And the patients in CA6 group presented with widespread distribution and various morphology of rashes, had fewer manifestations of neurologic involvement and a relatively better prognosis. Moreover, it had higher rate of onychomadesis and desquamation .

Hand-foot-mouth disease; Coxsackievirus A6; Enterovirus 71; Onychomadesis； Desquamation

渝科發(fā)計(jì)字[2012]27號(hào)-cstc2012jjA10084

重慶醫(yī)科大學(xué)附屬兒童醫(yī)院感染科，兒童發(fā)育疾病研究教育部重點(diǎn)實(shí)驗(yàn)室,兒科學(xué)重慶市重點(diǎn)實(shí)驗(yàn)室 重慶，410014

劉泉波，E-mail:liuqb1223@sina.com

10.3969/j.issn.1673-5501.2015.03.010

2015-01-22

2015-05-20)