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      糖皮質(zhì)激素聯(lián)合丙種球蛋白治療丙種球蛋白無(wú)反應(yīng)型川崎病的臨床療效

      2021-11-30 15:01:47張慎榮周芳邵啟民
      中國(guó)現(xiàn)代醫(yī)生 2021年18期
      關(guān)鍵詞:川崎病糖皮質(zhì)激素

      張慎榮 周芳 邵啟民

      [關(guān)鍵詞] 川崎病;靜脈丙種球蛋白無(wú)反應(yīng);糖皮質(zhì)激素;冠狀動(dòng)脈損害

      [中圖分類(lèi)號(hào)] R5? ? ? ? ? [文獻(xiàn)標(biāo)識(shí)碼] B? ? ? ? ? [文章編號(hào)] 1673-9701(2021)18-0057-04

      Clinical study of combination treatment of glucocorticoid and intravenous immunoglobulin (IVIG) in IVIG unresponsive Kawasaki disease

      ZHANG Shenrong? ?ZHOU Fang? ?SHAO Qimin

      Department of Rheumatology & Immunology, Nephrology, Hangzhou Children′s Hospital, Hangzhou? ?310014, China

      [Abstract] Objective To investigate the combination treatment of glucocorticoid and intravenous immunoglobulin (IVIG) in IVIG unresponsive Kawasaki disease(KD). Methods Date of 68 cases with initial IVIG unresponsive KD in Hangzhou Children's Hospital were collected from June 2016 to June 2020 and were divided into group A (IVIG) and group B (glucocorticoid combined with IVIG) according to re-treatment methods. 42 cases were in group A and 26 cases were in group B. The whole fever time,duration of fever after re-treatment,coronary arteries lesion,laboratory examination results of WBC, PLT, hsCRP,ESR, IL-6 before and one week after re-treatment were analyzed in the two groups. Results The whole fever time,duration of fever after re-treatment of group B were shorter than that of group A(P<0.05).The incidence of coronary artery dilatation and coronary artery aneurysm in group B were slightly higher than those in group A, but there were no significant differenc (P>0.05). The WBC of group B after re-treatment was higher than that of group A, and the difference of group B before and re-treatment was lower than that of group A.The difference of hsCRP before and after re-treatment in group B was higher than that in group A. After re-treatment, IL-6 in group B was lower than that in group A, and the? difference of IL-6 in group B before and after re-treatment was higher than that in group A, with statistical significance (P<0.05). Conclusion? Both schemes were effective in the treatment of IVIG unresponsive KD.There was no significant difference in the incidence of coronary artery lesion between the two groups. Glucocorticoid combined with IVIG did not increase the risk of coronary artery lesion. Different treatment regimens had effects on the levels of WBC, hsCRP and IL-6 in the two groups before and after re-treatment. Compared with IVIG alone, glucocorticoid combined with IVIG in the acute stage of KD could better control the inflammatory indexes of IVIG unresponsive KD children and shorten the time of fever.

      [Key words] Kawasaki disease; No response to intravenous gamma globulin; Glucocorticoids; Coronary arteries lesion

      川崎?。↘awasaki disease,KD)是一種以全身血管炎為主要病變的急性發(fā)熱性疾病,好發(fā)于5歲以下嬰幼兒[1],冠狀動(dòng)脈損害(coronary arteries lesion,CAL)是其嚴(yán)重并發(fā)癥。靜脈注射丙種球蛋白(intravenous immunoglobulin,IVIG)的應(yīng)用大大降低了KD 患兒冠脈損害的發(fā)生率,但仍有10%~20%的川崎病患兒接受首劑IVIG治療后失敗,這部分患兒稱(chēng)之為IVIG無(wú)反應(yīng)型KD,其發(fā)生CAL的風(fēng)險(xiǎn)增高[2,3]。本文通過(guò)對(duì)IVIG無(wú)反應(yīng)型KD患兒進(jìn)行病例回顧性分析,比較糖皮質(zhì)激素聯(lián)合IVIG與僅應(yīng)用IVIG治療IVIG無(wú)反應(yīng)型KD的臨床效果,尋找更有利于IVIG無(wú)反應(yīng)型KD患兒的治療方案。

      1 資料與方法

      1.1 一般資料

      選取2016年6月至2020年6月于我院住院治療的確診為IVIG無(wú)反應(yīng)型KD患兒68例作為研究對(duì)象,入選標(biāo)準(zhǔn):診斷符合2004年及2017年美國(guó)心臟協(xié)會(huì)發(fā)布的《川崎病的診斷、治療及遠(yuǎn)期管理》聲明中IVIG無(wú)反應(yīng)型KD定義:在首劑IVIG治療36 h后仍持續(xù)發(fā)熱或再次出現(xiàn)發(fā)熱[2];在首劑IVIG治療完成后至少36 h仍持續(xù)發(fā)熱或再次出現(xiàn)發(fā)熱[3]。排除合并嚴(yán)重心肝腎疾病及精神疾病者,兩組患者均對(duì)本研究知情同意且簽署知情同意書(shū),并經(jīng)倫理委員會(huì)審批通過(guò)檢查。根據(jù)再次治療方案不同分為A組和B組,兩組患者的性別、年齡、病程等一般資料比較,差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05),具有可比性。

      1.2 治療方法

      根據(jù)再次治療方案不同分為A組和B組,A組為僅應(yīng)用第2劑IVIG(2 g/kg)治療,共42例;B組為激素聯(lián)合第2劑IVIG治療(起始靜脈滴注甲潑尼龍2 mg/(kg·d),后根據(jù)退熱情況改潑尼松(華中藥業(yè)股份有限公司,國(guó)藥準(zhǔn)字H42021394)1~2 mg/(kg·d)分次口服,2~3周逐漸減停),共26例,兩組均口服阿司匹林。

      1.3 觀察指標(biāo)

      ①總熱程(發(fā)熱開(kāi)始至治療后體溫穩(wěn)定48 h的總天數(shù));②熱退時(shí)間(再次治療當(dāng)天至體溫穩(wěn)定48 h所需時(shí)間);③實(shí)驗(yàn)室檢測(cè)結(jié)果:治療前(再次治療前最近1次檢查結(jié)果)、治療后(再次治療后最接近1周時(shí))白細(xì)胞(WBC)、血小板(PLT)、超敏C反應(yīng)蛋白(hs-CRP)、血沉、IL-6,并計(jì)算治療前后差值;④治療后1周以?xún)?nèi)超聲心動(dòng)圖評(píng)價(jià)CAL情況。

      1.4 CAL診斷及分類(lèi)標(biāo)準(zhǔn)[8]

      根據(jù)超聲心動(dòng)圖檢查結(jié)果分類(lèi)。①超聲心動(dòng)圖正常指冠狀動(dòng)脈壁光滑,回聲細(xì)薄,無(wú)任何部位擴(kuò)張。冠狀動(dòng)脈內(nèi)徑:0~3歲<2.5 mm,~9歲<3.0 mm,~14 歲<3.5 mm。②冠狀動(dòng)脈擴(kuò)張(CAD)指冠狀動(dòng)脈內(nèi)徑超過(guò)上述標(biāo)準(zhǔn)但<4.0 mm,冠狀動(dòng)脈內(nèi)徑/主動(dòng)脈根部?jī)?nèi)徑(CA/AO)<0.3。③冠狀動(dòng)脈瘤(CAA)指不同形狀的冠狀動(dòng)脈擴(kuò)張,冠狀動(dòng)脈內(nèi)徑為4~7 mm,CA/AO>0.3,或冠狀動(dòng)脈呈瘤狀擴(kuò)張。④巨大冠狀動(dòng)脈瘤:冠狀動(dòng)脈內(nèi)徑≥8.0 mm,CA/AO≥0.6。

      1.5 統(tǒng)計(jì)學(xué)處理

      采用SPSS 22.0軟件對(duì)數(shù)據(jù)進(jìn)行分析和處理,正態(tài)分布計(jì)量資料采用均數(shù)±標(biāo)準(zhǔn)差表示,組間比較采用t檢驗(yàn)。非正態(tài)分布計(jì)量資料以中位數(shù)(P25~P75)表示,采用Mann-whitney U檢驗(yàn)。計(jì)數(shù)資料用[n(%)]表示,組間比較分別應(yīng)用Pearson χ2檢驗(yàn)和Fishers確切概率法。P<0.05表示差異有統(tǒng)計(jì)學(xué)意義。

      2 結(jié)果

      2.1 兩組患兒的臨床時(shí)間比較

      IVIG無(wú)反應(yīng)型KD患兒68例,其中男54例,女14例,男女性別比為3.86∶1;月齡最小3個(gè)月,最大10歲11個(gè)月,中位數(shù)24.7個(gè)月。兩組患兒在性別、年齡方面比較,差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)。B組患兒總熱程、熱退時(shí)間均短于A組患兒,差異有統(tǒng)計(jì)學(xué)意義(P均<0.05)。見(jiàn)表1。

      2.2 兩組患兒冠狀動(dòng)脈損害情況

      兩種方案治療IVIG耐藥型KD均有效,B組冠狀動(dòng)脈擴(kuò)張及冠脈瘤發(fā)生率均略高于A組,但差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05);兩組冠狀動(dòng)脈損害發(fā)生率差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)。見(jiàn)表2。

      2.3 兩組患兒治療前后實(shí)驗(yàn)室指標(biāo)比較

      不同治療方案對(duì)兩組患兒治療前后WBC、hs-CRP、IL-6水平存在影響,B組治療后WBC高于A組,B組WBC治療前后差值低于A組;B組治療前hs-CRP及治療前后hs-CRP差值均高于A組;B組治療后IL-6低于A組,B組IL-6治療前后差值高于A組,差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)。見(jiàn)表3。

      3 討論

      KD患兒發(fā)病率和患病數(shù)持續(xù)上升,現(xiàn)已成為發(fā)達(dá)國(guó)家兒童獲得性心臟病最常見(jiàn)的病因[1,4]。IVIG的應(yīng)用大大降低了KD 患兒CAL發(fā)生率,但仍有10%~20%的患兒對(duì)IVIG耐藥,且這部分患兒發(fā)生冠狀動(dòng)脈擴(kuò)張(coronary artery dilatation,CAD)及冠狀動(dòng)脈瘤(coronary artery aneurysm,CAA)風(fēng)險(xiǎn)增高[5],遠(yuǎn)期出現(xiàn)缺血性心臟病、動(dòng)脈粥樣硬化等發(fā)生的風(fēng)險(xiǎn)增大[6,7],是成年后發(fā)生嚴(yán)重心血管事件的危險(xiǎn)因素之一[8,9]。因此為這部分患兒尋找更有利的治療方案非常重要。目前治療包括第二劑IVIG、第二劑IVIG+糖皮質(zhì)激素、英夫利昔單抗單次靜脈注射、環(huán)孢霉素靜脈注射或口服、阿那白滯素皮下注射及環(huán)磷酰胺靜脈注射和血漿置換等[3,10-12],但選擇上尚存在爭(zhēng)議。

      糖皮質(zhì)激素可抑制免疫反應(yīng),具有強(qiáng)大的抗議效果,是臨床治療多種血管炎的一線(xiàn)藥物[13-15]。隨著對(duì)其在KD臨床療效及冠脈病變的長(zhǎng)期及深入研究,發(fā)現(xiàn)糖皮質(zhì)激素不但不會(huì)誘發(fā)CAL,還能迅速改善炎性反應(yīng)[2,3,16,17]。2017年美國(guó)心臟病協(xié)會(huì)修訂了KD診斷、治療和長(zhǎng)期隨訪指南中明確提出對(duì)于IVIG無(wú)反應(yīng)型KD患兒可使用IVIG+糖皮質(zhì)激素,并推薦2種激素使用劑量;對(duì)于首次治療直接使用糖皮質(zhì)激素存在爭(zhēng)議,但如預(yù)測(cè)KD患兒有IVIG耐藥高風(fēng)險(xiǎn),及時(shí)加用糖皮質(zhì)激素治療安全有效[3]。

      Zhu等[18]及 Yang等[19]均通過(guò)Mate分析發(fā)現(xiàn)糖皮質(zhì)激素不增加KD冠脈擴(kuò)張發(fā)生率,且可明顯縮短熱程。本研究中B組熱退時(shí)間及總熱程均短于A組,表明較之單純使用第2劑IVIG治療IVIG無(wú)反應(yīng)型KD,糖皮質(zhì)激素聯(lián)合IVIG的治療方案退熱快并可縮短總熱程。與上述學(xué)者的研究結(jié)論一致。

      本研究中B組患兒出現(xiàn)冠狀動(dòng)脈擴(kuò)張及冠脈瘤發(fā)生率均略高于A組,但無(wú)統(tǒng)計(jì)學(xué)差異,提示應(yīng)用糖皮質(zhì)激素并沒(méi)有增加急性期IVIG無(wú)反應(yīng)型KD患兒冠狀動(dòng)脈損害的發(fā)生風(fēng)險(xiǎn)。國(guó)內(nèi)研究表明在IVIG無(wú)反應(yīng)型KD患兒的遠(yuǎn)期隨訪中等也未發(fā)現(xiàn)糖皮質(zhì)激素應(yīng)用后存在冠脈損害風(fēng)險(xiǎn)增加[20]。

      在炎癥控制方面,通過(guò)比較本研究?jī)煞N治療方案的實(shí)驗(yàn)室指標(biāo)發(fā)現(xiàn),B組治療前hsCRP及治療前后hsCRP差值均高于A組,B組治療后IL-6低于A組,B組IL-6治療前后差值高于A組,以上提示聯(lián)合應(yīng)用糖皮質(zhì)激素后急性期炎癥指標(biāo)hsCRP及IL-6的下降幅度更明顯,表明糖皮質(zhì)激素+IVIG急性期治療效果肯定,且降低炎癥指標(biāo)方面優(yōu)于IVIG,對(duì)于IVIG不敏感的KD患兒再次應(yīng)用IVIG時(shí)可立即加用糖皮質(zhì)激素以改善急性期炎癥。兩組患兒血沉、PLT治療前后及差值無(wú)統(tǒng)計(jì)學(xué)差異,表明對(duì)IVIG無(wú)反應(yīng)型KD患兒急性期應(yīng)用激素安全、有效,并不會(huì)增加冠脈病變發(fā)生的風(fēng)險(xiǎn)。至于初始IVIG治療無(wú)反應(yīng)后直接應(yīng)用糖皮質(zhì)激素是否也能緩解癥狀,因本研究未納入此方案病例,需臨床研究進(jìn)一步證實(shí)。

      糖皮質(zhì)激素抗炎效果肯定,醫(yī)療費(fèi)用低,較之價(jià)格昂貴且有輸血相關(guān)風(fēng)險(xiǎn)的IVIG,其成本效益占有明顯優(yōu)勢(shì),可預(yù)見(jiàn)糖皮質(zhì)激素對(duì)于IVIG無(wú)反應(yīng)型KD的治療有廣闊的前景。

      本研究樣本量尚小,結(jié)論存在局限性,未進(jìn)行冠脈病變的遠(yuǎn)期隨訪,尚需大樣本量及長(zhǎng)期隨訪進(jìn)一步研究。

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      (收稿日期:2021-01-09)

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