崔新國,郭曉芳,2,周紅寧,2
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我國登革熱病例臨床特征研究進(jìn)展
崔新國1,郭曉芳1,2,周紅寧1,2
登革熱是由登革病毒感染引起經(jīng)蚊蟲叮咬傳播的一種蟲媒病毒性疾病。廣泛流行于全球熱帶和亞熱帶地區(qū),人對登革病毒普遍易感,登革熱臨床癥狀、體征主要包括高熱、全身肌肉關(guān)節(jié)痛、皮疹等,實(shí)驗(yàn)室生化檢查指標(biāo)主要有白細(xì)胞和血小板減少等。登革熱重癥病例救治不及時(shí),死亡率較高,早期臨床診斷登革熱病例對于降低患者死亡率和防止登革熱疫情暴發(fā)或擴(kuò)散具有重要價(jià)值。登革熱臨床病例特征主要包括癥狀、體征和實(shí)驗(yàn)室生化檢查,本文就登革熱上述臨床特征研究進(jìn)展進(jìn)行綜述。
登革熱;臨床病例;實(shí)驗(yàn)室生化檢測;綜述
登革熱(Dengue fever, DF)是由登革病毒(Dengue virus, DENV)感染引起經(jīng)伊蚊叮咬傳播的一種蟲媒病毒性疾病,該病廣泛流行于全球熱帶和亞熱帶100多個(gè)國家和地區(qū),每年約有39.7億人感染,其中在東南亞和加勒比海地區(qū)最為嚴(yán)重[1]。DENV共有4個(gè)血清型,分別為登革Ⅰ型、Ⅱ型、Ⅲ型和Ⅳ型,可引起不同的臨床類型,2009年WHO根據(jù)DF病例臨床特征,把DF臨床病例分為非重癥DF病例和重癥DF病例兩類。其中,前者非重癥DF病例臨床表現(xiàn)主要包括急起高熱、頭痛、肌肉和關(guān)節(jié)痛,可伴有皮疹,白細(xì)胞和血小板減少等,病死率低;重癥DF病例癥狀和體征主要有嚴(yán)重出血、血漿滲漏、臟器嚴(yán)重?fù)p傷等,病死率高[2]。盡管目前還未有證據(jù)證實(shí)DF在我國呈本地性流行,但近幾年在我國廣東、云南、福建、浙江、廣西、臺灣等省先后出現(xiàn)了以輸入性和以輸入性導(dǎo)致的局部DF暴發(fā)疫情,其臨床特征與東南亞國家DF流行地區(qū)相比存在差別,極易漏診、誤診。為此,醫(yī)務(wù)工作者如何根據(jù)癥狀、體征和實(shí)驗(yàn)室生化指標(biāo)正確判別DF病例及時(shí)隔離治療,對于有效降低患者死亡率和防止DF疫情暴發(fā)或擴(kuò)散具有重要價(jià)值,本文就我國DF臨床特征研究進(jìn)展進(jìn)行綜述。
一般來說,DENV感染人群的潛伏期為3~15 d,多數(shù)5~8 d;DENV感染患者臨床癥狀可表現(xiàn)為無癥狀隱性感染、非重癥感染和重癥感染3種類型[3]。由于我國DF疫情主要屬于輸入性登革熱病毒引發(fā),二次感染幾率相對少見,臨床癥狀多以非重癥感染為主,程度較輕[4]。
1.1 無癥狀隱性感染 病人可表現(xiàn)為無癥狀或無體征,或在DF流行季節(jié)和流行區(qū)域內(nèi),因病毒血癥水平較低,僅出現(xiàn)短暫的流行性感冒癥狀如全身酸困和乏力等,隨即迅速恢復(fù)正常人群狀態(tài),采用DENV特異性抗體(IgM/G)或核酸檢測亦可呈陽性[5-6]。該類患者占DENV感染人群的3/4,較難被一般臨床醫(yī)生識別,屬DF流行的最大傳染源[7]。
1.2 非重癥感染癥狀 在我國其典型癥狀主要為發(fā)熱、頭痛、肌肉酸痛等,但不同DENV血清型有不同的癥狀,見表1。其中,DENV-1型患者的臨床表現(xiàn)多以非重癥DF為主,DENV-2型患者的器官損害程度較高,出現(xiàn)重癥比率高,DENV-3型病例也多表現(xiàn)為非重癥,但癥狀多樣,在早期較容易誤診,DENV-4型患者的臨床表現(xiàn)以輕型DF為主,器官損害少見[8-9]。
表1 我國登革熱臨床主要癥狀[8-14]
Tab.1 The main clinical symptoms of dengue fever in China[8-14]
DENVType作者Authors年份Decade地點(diǎn)Location病例(例)Cases臨床癥狀ClinicalsymptomsⅠ型Ⅰtype梁偉波等2013廣東省257高熱100.0%,頭痛84.1%,肌肉骨關(guān)節(jié)疼痛75 9%,未發(fā)現(xiàn)重癥DF病例應(yīng)巖素等2004-2006廣州市1342高熱70.4%,頭痛85.9%,肌肉酸痛64.5%和骨痛46.6%,重癥癥狀2例(0.15%).張復(fù)春等2002-2003廣州市1032高熱100.0%,頭痛90.9%,肌肉酸痛68.4%和骨痛48.8%,乏力79.3%,登革出血熱2例(0.2%)Ⅱ型Ⅱtype柳美華等1999福州市1649高熱100.0%,全身骨關(guān)節(jié)疼痛87.0%和出血2 0%Ⅲ型Ⅲtype吳 霜等2009義烏市52高熱100.0%,畏寒65.38%,頭痛78.85%和肌痛75 00%,誤診為血液系統(tǒng)疾病4例、上呼吸道感染3例、傷寒1例、淋巴結(jié)炎1例Ⅳ型Ⅳtype王 建等1986-2003廣州市62發(fā)熱100.0%,頭痛83.9%,肌痛72.6%,惡心、嘔吐21.0%,出血0張霞意等2010廣州市16頭痛44.7%,肌肉痛55.3%和骨關(guān)節(jié)痛19.1%,出血0
1.3 重癥感染癥狀 該類患者癥狀主要表現(xiàn)為熱退后病情加重、并發(fā)出血、腹瀉、腹痛和昏睡、煩躁不安等癥狀,見表2。我國學(xué)者還發(fā)現(xiàn),單一血清型感染的患者多數(shù)為非重癥型,病程短,癥狀輕,僅少數(shù)會發(fā)展為重癥DF,但DENV-2型和DENV-3型感染發(fā)生重癥DF比例較高,與國外Nunes PC等(2016年)在巴西和Solomon T等(2000年)在越南南部地區(qū)報(bào)道的DENV-2型較容易引起重癥DF的結(jié)論,與Danilo Bretas de Oliverira等(2016年)和Soares CN等(2010年)在巴西報(bào)道DENV-3型較容易引起中樞神經(jīng)系統(tǒng)感染的重癥結(jié)果相似[17-20]。
值得關(guān)注的是,重癥DF常可并發(fā)中毒性肝炎、心肌炎、電解質(zhì)及酸堿失衡、二重感染、急性血管內(nèi)溶血,也可合并周圍神經(jīng)系統(tǒng)改變等[21-22]。張國明等(2015年)對2014 年在廣州市的2 例DF合并吉蘭-巴雷綜合征的病例進(jìn)行臨床分析,發(fā)現(xiàn)DF并發(fā)神經(jīng)性損害較常見,但出現(xiàn)吉蘭-巴雷綜合征的報(bào)告卻極罕見,提示DENV感染除了病毒的直接損傷外,免疫損傷也參與其致病進(jìn)程[23]。李劍萍等(2008年)在廣州市對2006年收治的398例DF分析也顯示,231例(58.04%)出現(xiàn)多器官損害,其中以血液系統(tǒng)損害最常見,其次是肝臟、腎臟、胃腸道及心臟,其它器官受損較少[24]。
表2 我國重癥登革熱主要癥狀[15-16]
Tab.2 The main clinical symptoms of severe dengue fever in China[15,16]
作者Authors年份Decade結(jié) 果Conclusion應(yīng)若素等2014廣州市1942例DF中重癥6.2%;重癥病例中發(fā)生嚴(yán)重出血52.1%,休克54 5%,嚴(yán)重器官功能損害者71.9%,并發(fā)心肌炎者46.3%;兩次感染者163例中,非重癥DF和重癥DF比例分別為47.6%和55.0%。ZhangH等20142012年8月之前的Meta分析顯示惡心/嘔吐、腹痛、皮疹、出血(嘔血/黑便)和肝腫大常為重癥信號,性別、嗜睡、眼眶痛、腹瀉和束臀試驗(yàn)陽性與重癥DF相關(guān)性小。
部分病人在病程第4~6 d全身出現(xiàn)充血性皮疹或點(diǎn)狀出血疹,而典型皮疹常見于四肢的針尖樣出血點(diǎn)或“皮島”樣表現(xiàn)等,可合并不同程度的出血現(xiàn)象和束臂試驗(yàn)陽性,少數(shù)病人有肝腫大和淋巴結(jié)腫,見表3[21]。Ehelepola ND(2016年)在斯里蘭卡的研究也證實(shí)出疹多處于DF極期的恢復(fù)階段[27]。該綜述研究結(jié)果表明皮疹作為DF病例體征差異較大,同樣在印度,Deshwal R等(2015年)和Pothapregada S等(2016年)也分別報(bào)告了DF出疹率為37.86%和62.8%,提示臨床醫(yī)生不應(yīng)僅把皮疹作為DF病例的唯一體征診斷,應(yīng)綜合患者癥狀和實(shí)驗(yàn)室生化指標(biāo)進(jìn)行考慮[28-29]。
3.1 血、尿常規(guī) 常見DF患者白細(xì)胞總數(shù)和血小板減少,其中白細(xì)胞減少可降至10×109/L 以下,當(dāng)體溫下降或發(fā)生休克時(shí)白細(xì)胞可迅速升高,血小板升高也晚于白細(xì)胞[30]。尿常規(guī)可見少量蛋白和紅細(xì)胞,也可有管型細(xì)胞出現(xiàn)[21]。鄧勤勤等(2016年)在我國廣州市對200例DF病人的實(shí)驗(yàn)室檢查發(fā)現(xiàn),白細(xì)胞減少的患者占76.5%(153/200),PLT減少的占58.0%(116/200),說明DF病人白細(xì)胞和血小板計(jì)數(shù)減少較明顯,但尿常規(guī)異常較少,僅為6.0%(12/200)[31]。陳燕清等(2008年)在廣州市對DENV-1型484例DF病人血常規(guī)和生化檢查的回顧性分析,結(jié)果也顯示這些病例中白細(xì)胞減少為76.0%,血小板減少為62.6%[32]。這些研究結(jié)果提示DF的白細(xì)胞和血小板減少可作為DF患者常規(guī)診斷較好的指標(biāo)[33]。
3.2 血生化指標(biāo) DF患者肝臟丙氨酸氨基轉(zhuǎn)氨酶(Alanine aminotransferase, ALT)、乳酸脫氫酶(Lactate dehydrogenase, LDH)升高較常見,部分患者心肌酶譜、尿素氮和血肌酐升高,但少數(shù)患者總膽紅素升高,血清白蛋白降低,電解質(zhì)紊亂多見于低鉀血癥,凝血功能檢查可見纖維蛋白原(Fibrinogen, FIB)減少、凝血酶原時(shí)間(Prothrombin time, PT)和部分凝血活酶時(shí)間(Activated partial thromboplastin time, APTT)延長,重癥病例可呈彌漫性血管內(nèi)凝血(Disseminated Intravascular coagulation, DIC)的改變,見表4[2]。
表3 我國登革熱主要體征[12,25-26]
Tab.3 The main clinical sign of dengue fever in China[12,25,26]
作者Authors年 份Decade地點(diǎn)Location病例(例)Cases體 征Clinicalsign張復(fù)春等2002-2003廣州市1032皮疹60.1%,束臂試驗(yàn)陽性45.3%鄒 林等2014佛山市106皮疹38.7%,淋巴結(jié)腫大12.3%王慧敏等2014廣州市643皮疹6.7%
表4 我國登革熱血生化主要指標(biāo)[34-38]
Tab.4 The main laboratory biochemical indicator of dengue fever in China[34-38]
作者Authors年 份Decade地點(diǎn)Location病例(例)Cases血生化指標(biāo)Laboratorybiochemicalindicator羅 純等2014廣州293ALT升高76.03%,AST升高88.4%陳群玲等2014廣州60APTT、TT延長,F(xiàn)IB減少,白蛋白和球蛋白均降低冼中任等2014廣州253心肌酶升高68.4%,以LDH和a?羥丁酸脫氨酶升高為主張全會等2007廣州125ALT升高46.4%,AST升高80.0%,y?谷氨酰轉(zhuǎn)肽酶升高22.4%張堅(jiān)生等2006廣州390導(dǎo)致13例心肌炎,其中6例出現(xiàn)胸悶和(或)心悸癥狀,心肌酶譜早期均有升高
綜合分析說明,我國大多數(shù)DF病例中存在肝功能異常,主要表現(xiàn)在AST升高較ALT明顯,且多出現(xiàn)于病程中后期,這與急性病毒性肝炎引起的以ALT升高為主不同。DF患者在急性發(fā)熱期凝血功能及血清蛋白均出現(xiàn)不同程度的異常,易在早期發(fā)生心肌損害。同時(shí),Cavailler P等(2016年)在柬埔寨的研究也認(rèn)為白細(xì)胞減少,血小板減少和ALT升高可作為實(shí)驗(yàn)室確診DF的重要參考因素[39]。但以上結(jié)論與Kuna A等(2016年)在波蘭報(bào)告的ALT升高率35.3%,白細(xì)胞減少24.6%和血小板減少20.0%差異較大[40]。
除了以上我國學(xué)者對DF的研究外,新近DF的罕見臨床特征也不斷被報(bào)告,其中,譚麗梅等(2015年)對廣州市12例新生兒DF并結(jié)合國外相同的報(bào)告進(jìn)行研究,進(jìn)一步證實(shí)了DENV可母嬰垂直傳播,新生兒DF臨床特征以發(fā)熱和凝血功能障礙為主,病情較輕[41]。盧鴻基等(2016年)對廣州市4例DF腦病的病例進(jìn)行研究發(fā)現(xiàn),患者均有較嚴(yán)重的意識障礙,顱腦影像學(xué)檢查均無明顯異常[42]。潘越峻等(2016年)對廣州市120例重癥DF病例的肺部影像學(xué)改變進(jìn)行研究,結(jié)果表明患有高血壓、糖尿病、心臟病和肺部基礎(chǔ)疾病的高齡重癥DF患者更容易合并肺部異常[43]。
雖然DF臨床表現(xiàn)復(fù)雜,但其癥狀、體征和生化指標(biāo)仍有明顯特征性改變,臨床醫(yī)生只要綜合考慮這些指征的變化規(guī)律,同時(shí)配合必要的DF流行病學(xué)知識,仍可較好的對DF病例進(jìn)行正確診斷。為此,相關(guān)衛(wèi)生部門應(yīng)進(jìn)一步加強(qiáng)臨床醫(yī)生對DF的知識培訓(xùn),才能做到DF患者的早期診斷、治療和采取相應(yīng)的控制措施,防止DF輸入引起的暴發(fā)或流行。
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Zhou Hong-ning, Email: zhouhn66@163.com
Advances in clinical features of dengue fever
CUI Xin-guo1, GUO Xiao-fang1,2, ZHOU Hong-ning1,2
(1.InstitutionofPathogensandVectors,Pu'erDivision,DaliUniversity,Pu'er665000,China; 2.YunnanKeyLaboratoryofArborInfectiousDiseasesPreventionandControlResearch/YunnanPublicHealthCoordinationandInnovationCenterandYunnanArbor-virusResearchCenterofYunnanInstitutionofParasiticDiseases,Pu'er665000,China)
Dengue fever is an arbovirus disease caused by dengue virus and transmitted by mosquitoes. Dengue fever is widely distributed to tropical and subtropical regions in the world. Human are generally susceptible to dengue virus, its clinical sign and symptom mainly include high fever, muscle and joints pain, and rash etc, and its main laboratory biochemical indicator is associated with leucopenia and thrombocytopenia. Severe dengue fever has a high mortality incidence without timely diagnosis and treatment. Therefore, it is important for early clinical diagnosis dengue virus infectious case and treatment to reduce mortality incidence and prevent from its epidemic outbreak and spread. Normally, the clinical features of dengue patient mainly include symptom, sign and laboratory test. In this paper, commonly clinical feature of dengue patient was reviewed.
dengue fever; clinical cases; laboratory biochemical test; review
10.3969/j.issn.1002-2694.2017.04.015
國家自然科學(xué)基金項(xiàng)目(Nos.81160357,30960327,30660160),中英學(xué)者基金資助項(xiàng)目(Sino-British fellowship trust in UK,No.313669)和云南公共衛(wèi)生與疾病防控協(xié)同創(chuàng)新中心項(xiàng)目(No.2014YNPHXT03)聯(lián)合資助
周紅寧,Email: zhouhn66@163.com
1.大理大學(xué)病原與媒介生物研究所(普洱分部),普洱 665000; 2.云南省蟲媒傳染病防控研究重點(diǎn)實(shí)驗(yàn)室,云南省公共衛(wèi)生協(xié)同創(chuàng)新中心,普洱 665000
Supported by the Incubate projects of Yunnan Public Health and Disease Control-Prevention Collaborative Innovation Center (No.2014YNPHXT03), the National Natural Science Foundation of China (Nos.81160357, 30960327, 30660160) and the Program of Sino-British Fellowship Trust in UK (No.313669)
R373
A
1002-2694(2017)04-0366-06
2016-07-21 編輯:李友松