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通讯作者:

杜军保(1960-),男,北京人,博士生导师,主要从事儿童心血管疾病的临床与基础研究。E-mail:junbaodu1@126.com

中图分类号:R447,R593.2

文献标识码:A

文章编号:2096-8965(2020)01-0061-05

DOI:10.12287/j.issn.2096-8965.20200110

参考文献 1
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参考文献 11
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参考文献 12
SHAO S,LUO C,ZHOU K,et al.The role of agespecific N-terminal pro-brain natriuretic peptide cutoff values in predicting intravenous immunoglobulin resistance in Kawasaki disease:a prospective cohort study[J].Pediatr Rheumatol Online J,2019,17(1):65.
参考文献 13
WU Y,LIU F F,XU Y,et al.Interleukin-6 is prone to be a candidate biomarker for predicting incomplete and IVIG nonresponsive Kawasaki disease rather than coronary artery aneurysm[J].Clin Exp Med,2019,19(2):173-181
参考文献 14
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参考文献 15
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参考文献 16
ANGKANANARD T,ANOTHAISINTAWEE T,MCEVOY M,et al.Neutrophil lymphocyte ratio and cardio-vascular disease risk:a systematic review and metaanalysis[J].Biomed Res Int,2018,2018:2703518.
参考文献 17
HA K S,LEE J,JANG G Y,et al.Value of neutrophillymphocyte ratio in predicting outcomes in Kawasaki disease[J].Am J Cardiol,2015,116(2):301-306.
参考文献 18
CHEN Y B,HUA Y,ZHANG C Y,et al.Neutrophilto-lymphocyte ratio predicts intravenous immunoglobulin-resistance in infants under 12-months old with Kawasaki disease[J].Front Pediatr,2019,7:81.
参考文献 19
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参考文献 20
KAWAMURA Y,TAKESHITA S,KANAI T,et al.The combined usefulness of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in predicting intravenous immunoglobulin resistance with Kawasaki disease[J].J Pediatr,2016,178:281-284.e1.
参考文献 21
CHANTASIRIWAN N,SILVILAIRAT S,MAKONKAE YOON K,et al.Predictors of intravenous immunoglobulin resistance and coronary artery aneurysm in patients with Kawasaki disease[J].Paediatr Int Child Health,2018,38(3):209-212.
参考文献 22
袁迎第,孙军,李鹏飞,等.中性粒细胞与淋巴细胞比值及血小板与淋巴细胞比值对于川崎病IVIG敏感性的预测价值[J].中国当代儿科杂志,2017,19(4):410-413.
参考文献 23
KOBAYASHI T,INOUE Y,TAKEUCHI K,et al.Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease[J].Circulation,2006,113(22):2606-2612.
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EGAMI K,MUTA H,ISHII M,et al.Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease[J].J Pediatr,2006,149(2):237-240.
参考文献 25
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参考文献 26
BAR-MEIR M,KALISKY I,SCHWARTZ A,et al.Prediction of Resistance to intravenous immunoglobulin in children with kawasaki disease[J].J Pediatric Infect Dis Soc,2018,7(1):25-29.
参考文献 27
SATO S,KAWASHIMA H,KASHIWAGI Y,et al.Inflammatory cytokines as predictors of resistance to intravenous immunoglobulin therapy in Kawasaki disease patients[J].Int J Rheum Dis,2013,16(2):168-172.
参考文献 28
LIN M T,CHANG C H,SUN L C,et al.Risk factors and derived formosa score for intravenous immunoglobulin unresponsiveness in Taiwanese children with Kawasaki disease[J].J Formo Med Assoc,2016,115(5):350-355.
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SONG R,YAO W,LI X.Efficacy of four scoring systems in predicting intravenous immunoglobulin resistance in children with Kawasaki disease in a children's hospital in Beijing,North China[J].J Pediatr,2017,184:120-124.
参考文献 30
QIAN W,TANG Y,YAN W,et al.A comparison of efficacy of six prediction models for intravenous immunoglobulin resistance in Kawasaki disease[J].Ital J Pediatr,2018,44(1):33.
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参考文献 36
WU S,LIAO Y,SUN Y,et al.Prediction of intravenous immunoglobulin resistance in Kawasaki disease in children[J].World J Pediatr,2020,16(6):607-613.
目录contents

    摘要

    川崎病多发病于 5岁以下的儿童,静脉免疫球蛋白 (Intravenous Immunoglobulin,IVIG) 无反应的川崎病患儿罹患心血管并发症风险明显增高,而早期识别IVIG无反应的川崎病患儿并予以积极治疗可有效改善其预后。本综述结合文献,对IVIG无反应川崎病的预测单项指标及预测模型进行总结,为川崎病患儿诊疗提供依据。

    Abstract

    Kawasaki disease (KD) mostly occurs in children under 5 years of age, and intravenous immunoglobulin (IVIG)-resistant children with KD are at higher risk of cardiovascular complications, and early identification and active treatment of KD children with IVIG resistance can effectively improve their prognosis. Combined with the latest literature, this review summarizes the single indexes and predictive models of IVIG-resistant KD and provides the evidence for the diagnosis and treatment of children with KD.

    关键词

    川崎病IVIG无反应预测综述

  • 1967 年日本医生Kobayashi首次以文献的形式描述川崎病(Kawasaki Disease,KD)[1],该病急性期主要表现为发热、眼结膜充血、皮疹、口腔黏膜发红、颈部淋巴结肿大(直径≥1.5 cm) 及四肢末端硬肿等[2]。KD是儿童期常见的自身免疫性血管炎, 其冠状动脉并发症是儿童期获得性心脏病常见的原因[3]。静脉免疫球蛋白(Intravenous Immunoglobulin,IVIG) 为KD的首选治疗,但其中一部分患儿在应用第一剂IVIG治疗后48 h仍有持续发热或者应用IVIG后2-7 天内再次出现发热且伴有至少一项KD的主要临床症状,称之为IVIG无反应[4]。因此早期识别IVIG无反应患儿并及时调整其治疗方案尤为重要。

  • 1 IVIG无反应KD的单项预测指标

  • 1.1 血清谷丙转氨酶(Alanine Aminotransferase, ALT)

  • Park等研究IVIG治疗前血清ALT预测IVIG无反应的受试者工作特征曲线(Receiver Operating Characteristic Curve,ROC),发现曲线下面积为0.751,其高于84 IU/L时预测IVIG无反应的敏感度和特异度分别为73%和75%[5]

  • 1.2 血清胆红素

  • Park等研究得出IVIG治疗前血清胆红素水平高于0.9 mg/dL预测IVIG无反应的ROC曲线下面积、 敏感度和特异度分别为0.739、70.0%和86.0%[5]

  • 1.3 血清白蛋白

  • Kuo等研究表明当IVIG治疗前1天内的血清白蛋白低于29 g/L时,预测KD患儿IVIG无反应的敏感度为96%,特异度为34%[6]。Xie等研究发现IVIG治疗前血清白蛋白低于32 g/L时,预测完全KD患儿IVIG无反应的敏感度和特异度分别为72.0%和83.2%,预测不完全KD患儿IVIG无反应的敏感度和特异度分别为42.9%和92.7%[7]

  • 1.4 血清铁蛋白

  • 血清铁蛋白为多种炎症反应的重要标记物。 Yamamoto等研究显示,满足KD诊断时的血清铁蛋白水平用来预测IVIG无反应的ROC曲线下面积为0.674,其高于165 ng/mL时,预测敏感度为70.4%, 特异度为63.2%[8]。Kong等研究发现当IVIG治疗前血清铁蛋白水平≥269.7 ng/mL时,预测IVIG无反应的ROC曲线下面积、敏感度和特异度分别为0.663、42.9%和88.8%[9]

  • 1.5 D-二聚体(D-dimer)

  • 血液D-dimer水平为反应血管内皮损伤的重要指标。Kong等研究显示,当IVIG治疗前血液D-dimer水平高于1.09 mg/L时,预测IVIG无反应的ROC曲线下面积为0.737,预测IVIG无反应的敏感度为87.0%,特异度为56.3%[9]

  • 1.6 氨基末端B型利钠肽前体(N-Terminal pro Bran Natriuretic Peptide, NT-proBNP)

  • 血清NT-proBNP的水平代表心脏功能,KD病情严重的儿童存在心功能不全甚至心力衰竭。最早Yoshimura等针对日本KD儿童的研究显示,以IVIG治疗前血清NT-proBNP预测IVIG无反应的ROC曲线下面积为0.724,其值高于800 pg/mL时预测敏感度为71%,特异度为62%[10]。Kim等针对韩国KD儿童的研究结果显示,IVIG治疗前血清NT-proBNP≥1 093 pg/mL预测IVIG无反应的敏感度和特异度分别为70.0%和76.5%[11]。不同年龄段KD患儿的血清NT-BNP水平存在差异,Shao等的研究针对不同年龄组KD儿童研究发现,在所有年龄儿童、2~6 岁儿童、1~2岁儿童及小于1岁儿童中,应用IVIG治疗时的血清NT-proBNP水平预测IVIG无反应的ROC曲线下面积分别为0.64、0.69、0.61 和0.77, 界值分别为3 755 pg/mL、3 710 pg/mL、2 800 pg/mL和2 480 pg/mL,预测IVIG无反应的敏感度分别为44.0%、52.2%、50.0%和75.0%,预测IVIG无反应的特异度分别为84.1%、86.3%、25.0%和71.8%[12]

  • 1.7 白细胞介素-6(Interleukin-6,IL-6)

  • 血IL-6水平反应KD患儿体内炎症反应严重程度。Wu等研究发现,当血IL-6>26.40 pg/mL时, 预测IVIG无反应的ROC曲线下面积为0.580,预测敏感度为60.0%,特异度为66.3%[13]

  • 1.8 硫化氢气体

  • 内源性硫化氢为心血管系统重要气体信号分子[14]。Lin等对50 名KD患儿进行研究,其中IVIG无反应者11 名,结果显示当淋巴细胞硫化氢产率高于15.285 nmol/min/108 时,预测IVIG无反应的敏感度为90.9%,特异度为76.9%[15]

  • 1.9 外周血中性粒细胞计数与淋巴细胞计数比值(Neutrophil-to-lymphocyte Ratio,NLR)

  • 严重炎症过程中存在外周血中性粒细胞计数增加及淋巴细胞计数减少,NLR升高可反应炎症反应严重程度[16]。Ha等首先系统研究了外周血NLR在KD中的预测价值,以IVIG治疗前NLR>5.49 预测IVIG无反应的ROC曲线下面积、敏感度和特异度分别为0.67、39%和69%,而以IVIG治疗后2天外周血NLR>1.26 预测IVIG无反应的ROC曲线下面积、敏感度和特异度分别为0.73、52%和87%[17]。 Chen等发现外周血NLR≥2.51 可预测1 岁以下KD患儿IVIG无反应,ROC曲线下面积为0.692,预测敏感度和特异度分别为54.5%和80%[18]。而Hua、 Kawamura及Chantasiriwan分别发现IVIG治疗前外周血NLR≥2.8、NLR≥3.83 及NLR>3.2 为IVIG无反应的独立危险因素,上述指标可和其他指标结合进一步建立预测IVIG无反应的预测模型[19-21]

  • 1.10 外周血血小板计数与淋巴细胞计数比值(Platelet-to-lymphocyte Ratio,PLR)

  • Kawamura和Yuan分别报道IVIG治疗前PLR≥ 150、PLR≥162 预示IVIG无反应高风险[20, 22]。这两个研究均显示IVIG无反应患儿较IVIG敏感的患儿存在血小板计数下降及淋巴细胞计数减少,但血小板计数下降的程度轻于淋巴细胞计数,因此PLR水平升高。

  • 2 IVIG无反应KD的预测模型

  • 由于单项预测因子预测IVIG治疗无反应的价值有限,KD研究者开发了数个IVIG无反应预测评分系统。Kobayashi预测评分系统通过分析528 名KD患儿(其中IVIG无反应患儿148名) 的临床资料建立如下评分系统:年龄≤12月(1分)、治疗前发热天数≤4天(2分)、外周血中性粒细胞百分比≥ 80%(2 分)、C-反应蛋白(C-reactive Protein,CRP) ≥100 mg/L(1 分)、血小板≤300×109/L(1 分)、谷草转氨酶(Aspartate Sminotransferase,AST)≥100 IU/L(2 分) 和血清钠≤133 mmol/L(2 分),此预测评分系统的ROC曲线下面积为0.85,总分≥4 分时预测IVIG无反应的敏感度和特异度分别为86%和68%[23]。而Egami评分系统通过分析320 名KD患儿(其中IVIG无反应患儿41 名) 的临床资料, 建立了如下评分系统:年龄≤6 月(1 分)、治疗前发热天数≤4 天(1 分)、CRP≥80 mg/L(1 分)、血小板≤300×109/L(1 分) 和ALT≥80 IU/L(2 分), 总分≥3分时预测IVIG无反应的ROC曲线下面积为0.79,预测敏感度和特异度分别为78%和76%[24]。 Sano通过分析112名KD患儿(其中IVIG无反应患儿22名),建立了预测评分系统如下:CRP≥70 mg/L(1 分)、总胆红素(Total Bilirubin,TBIL)≥0.9 mg/dL(1分) 和AST≥200 IU/L(1分),总分≥2分时预测IVIG无反应的敏感度和特异度分别为77%和86%[25]。发表于2007 年的美国San Diego评分系统纳入了362 名KD患儿(其中IVIG无反应者60 名) 进行研究,预测指标包括治疗前发热天数≤4 天(1 分)、杆状核细胞≥20%(2分)、谷氨酰肽酶(Gamma-Glutamyltransferase, GGT)≥60 IU/L(1 分)和根据年龄校正的血红蛋白Z值≤-2(1分),总分≥2分时预测IVIG无反应的敏感度和特异度分别为73.3%和61.9%[26]。Sato等以KD患儿血液中细胞因子为研究重点,得到的预测IVIG无反应的评分系统如下:中性粒细胞百分比≥75%(2分)、IL-6≥ 140 pg/mL(2 分) 和70 pg/mL≤IL-6<140 pg/mL(1 分),总分≥3 分时预测敏感度和特异度分别为85%和77%[27]。中国台湾地区的研究者通过回顾性分析181名KD患儿(IVIG无反应者22名) 的临床资料,于2015 年发表如下评分系统:中性粒细胞百分比≥60%(2 分)、白蛋白≤35 g/L(1 分) 和淋巴结肿大(1 分),当界值为3 分时,预测IVIG无反应的敏感度和特异度分别为90.9%和81.3%[28]。 泰国的研究者通过回顾性分析当地217 名KD患儿(其中IVIG无反应者26 例) 的临床资料,研究成果发表于2018 年,评分系统包括红细胞比容≤30%(1分)、血小板计数≤300×109/L(1分)、AST≥ 40 IU/L(1分)和NLR ≥ 3.2(1分),该评分系统ROC曲线下面积为0.796,当总分≥2 分时判定为IVIG无反应,预测IVIG无反应的敏感度和特异度分别为80.8%和66.8%[21]

  • 但多个研究发现上述评分系统应用于中国大陆地区患儿时价值有限。北京首都儿科研究所在1 569 名KD儿童中进行了上述评分系统的验证,Egami评分系统和Kobayashi评分系统预测IVIG无反应的敏感度分别仅为14%和16%,而预测IVIG无反应的特异度分别为86%和85%,San Diego评分系统预测IVIG无反应的敏感度为95%,但预测特异度仅为3%,Formosa评分系统预测IVIG无反应的敏感度和特异度分别为43%和47%[29]。苏州儿童医院对于505 名KD患儿进行研究,将Kobayashi、 Egami、Kawamura、Sano、Formosa系统应用于上述人群中预测IVIG无反应的敏感度分别为72%、44%、 48%、20%和68%,而特异度分别为62%、82%、 66%、91%和48%[30]。因此将日本、美国等地评分系统应用于中国大陆地区的KD患儿时预测IVIG无反应的价值较低。

  • 近年来,中国大陆学者建立了多个模型用于预测IVIG无反应,最早发表于2013年。研究者通过回顾性研究北京儿童医院1 177 名KD患儿,其中IVIG无反应者211名,得到如下预测评分系统:治疗前发热天数≤4 天(2 分)、中性粒细胞百分比≥ 80%(2 分)、CRP≥80 mg/L(2 分)、多形性红斑(1 分)和肛周改变(1分),此评分系统ROC曲线下面积为0.672,患儿总分≥4 分被预测为IVIG无反应, 其敏感度为54.1%,特异度为71.2%[31]。2016 年, 苏州儿童医院学者通过分析910 名KD患儿(其中IVIG无反应患儿46 名) 的临床资料,得到评分系统如下:年龄≤6月(2分)、白蛋白≤35 g/L(2分)、 皮疹(1 分)、四肢硬肿(1 分) 及中性粒细胞百分比≥80%(1 分),此评分系统曲线下面积为0.77, 总分≥3 分时预测IVIG无反应的敏感度为71.4%, 特异度为76%[32]。研究者通过回顾性分析浙江儿童医院2 126名诊断为KD的儿童,其中IVIG无反应的患儿380名,建立如下评分系统:发热持续时间≥7 天(2 分)、诊断延迟(1 分)、GGT≥25 IU/L(1 分)、钠≤135 mmol/L(1 分)、 NLR≥2.8(1 分) 和血小板 ≤350×109/L(1 分),该预测评分体系ROC曲线下面积为0.685,总分≥4 分时预测IVIG无反应的敏感度为60.7%,特异度66.5%[33]。首都儿科研究所学者纳入1 360 名KD患儿进行研究, 其中IVIG无反应的患儿78例,IVIG无反应的独立预测因素及评分如下:CRP≥90 mg/L(3分)、中性粒细胞百分比≥70%(2.5分)、血清钠<135 mmol/L(3 分)、白蛋白<35 g/L(2.5 分) 和总胆红素>20 μmol/L(5 分),此评分系统ROC曲线下面积为0.77,总分≥6 分时预测IVIG无反应患儿的敏感度和特异度分别为56%和79%,该评分系统于2019 年发表[34]。同样于2019 年发表的重庆儿童医院的一项研究纳入5 277 名KD患儿,其中IVIG无反应者348 名,结论显示低龄、冠状动脉病变程度重、 红细胞分布宽度及总胆汁酸升高、淋巴细胞比例、 血小板计数、白蛋白及钠水平降低,均为IVIG无反应独立危险因素,上述变量构成Logistic回归预测模型,ROC曲线下面积为0.74,预测敏感度为76%,特异度为59%[35]。我们最近的研究表明,以年龄≤ 24月(3.0分)、IVIG治疗前中性粒细胞计数 ≥ 10×109/L(3.0 分)、淋巴细胞计数 ≤ 3×109/L(3.5 分)、平均血小板体积 ≥ 10.5 pL(3.5 分)及白蛋白 ≤ 37 g/L(2.5 分) 构成预测模型,当总分 ≥ 6.5 时, 可较好地预测IVIG无反应。

  • IVIG无反应严重影响KD患儿治疗及预后,其预测一直是研究者探讨的焦点问题,期望通过探讨有效的预测方法,不断提高预测IVIG无反应的准确性。早期准确预测IVIG无反应并对IVIG无反应的高危KD患儿加强干预,对于改善患儿预后具有重要意义。

  • 参考文献

    • [1] KAWASAKI T.Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children[J].Arerugi,1967,16(3):178-222.

    • [2] MC CRINDLE B W,ROWLEY A H,NEWBURGER J W,et al.Diagnosis,treatment,and long-term management of Kawasaki disease:a scientific statement for health professionals from the American Heart Association[J].Circulation,2017,135(17):e927-e999.

    • [3] ELEFTHERIOU D,LEVIN M,SHINGADIA D,et al.Management of Kawasaki disease[J].Arch Dis Child,2014,99(1):74-83.

    • [4] 江载芳,申昆玲,沈颖.诸福棠实用儿科学(第八版)[M].北京:人民卫生出版社,2014:787.

    • [5] PARK H M,LEE D W,HYUN M C,et al.Predictors of nonresponse to intravenous immunoglobulin therapy in Kawasaki disease[J].Korean J Pediatr,2013,56(2):75-79.

    • [6] KUO H C,LIANG C D,WANG C L,et al.Serum albumin level predicts initial intravenous immunoglobulin treatment failure in Kawasaki disease[J].Acta Paediatr,2010,99(10):1578-1583.

    • [7] XIE T,WANG Y,FU S,et al.Predictors for intravenous immunoglobulin resistance and coronary artery lesions in Kawasaki disease[J].Pediatr Rheumatol Online J,2017,15(1):17.

    • [8] YAMAMOTO N,SATO K,HOSHINA T,et al.Utility of ferritin as a predictor of the patients with Kawasaki disease refractory to intravenous immunoglobulin therapy[J].Mod Rheumatol,2015,25(6):898-902.

    • [9] KONG W X,MA F Y,FU S L,et al.Biomarkers of intravenous immunoglobulin resistance and coronary artery lesions in Kawasaki disease[J].World J Pediatr,2019,15(2):168-175.

    • [10] YOSHIMURA K,KIMATA T,MINE K,et al.N-terminal pro-brain natriuretic peptide and risk of coronary artery lesions and resistance to intravenous immunoglobulin in Kawasaki disease[J].J Pediatr,2013,162(6):1205-1209.

    • [11] KIM S Y,HAN M Y,CHA S H,et al.N-terminal probrain natriuretic peptide(NT proBNP)as a predictive indicator of initial intravenous immunoglobulin treatment failure in children with Kawasaki disease:a retrospective study[J].Pediatr Cardiol,2013,34(8):1837-1843.

    • [12] SHAO S,LUO C,ZHOU K,et al.The role of agespecific N-terminal pro-brain natriuretic peptide cutoff values in predicting intravenous immunoglobulin resistance in Kawasaki disease:a prospective cohort study[J].Pediatr Rheumatol Online J,2019,17(1):65.

    • [13] WU Y,LIU F F,XU Y,et al.Interleukin-6 is prone to be a candidate biomarker for predicting incomplete and IVIG nonresponsive Kawasaki disease rather than coronary artery aneurysm[J].Clin Exp Med,2019,19(2):173-181

    • [14] DU S,HUANG Y,JIN H,et al.Protective mechanism of hydrogen sulfide against chemotherapy-induced cardiotoxicity[J].Front Pharmacol,2018,9:32.

    • [15] LIN J,ZHAO H,JIAO F,et al.Lymphocyte hydrogen sulfide production predicts intravenous immunoglobulin resistance in children with Kawasaki disease:a preliminary,single-center,case-control study[J].Medicine(Baltimore),2018,97(47):e13069.

    • [16] ANGKANANARD T,ANOTHAISINTAWEE T,MCEVOY M,et al.Neutrophil lymphocyte ratio and cardio-vascular disease risk:a systematic review and metaanalysis[J].Biomed Res Int,2018,2018:2703518.

    • [17] HA K S,LEE J,JANG G Y,et al.Value of neutrophillymphocyte ratio in predicting outcomes in Kawasaki disease[J].Am J Cardiol,2015,116(2):301-306.

    • [18] CHEN Y B,HUA Y,ZHANG C Y,et al.Neutrophilto-lymphocyte ratio predicts intravenous immunoglobulin-resistance in infants under 12-months old with Kawasaki disease[J].Front Pediatr,2019,7:81.

    • [19] HUA W,MA F Y,WANG Y,et al.A new scoring system to predict Kawasaki disease with coronary artery lesions[J].Clin Rheumatol,2019,38(4):1099-1107.

    • [20] KAWAMURA Y,TAKESHITA S,KANAI T,et al.The combined usefulness of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in predicting intravenous immunoglobulin resistance with Kawasaki disease[J].J Pediatr,2016,178:281-284.e1.

    • [21] CHANTASIRIWAN N,SILVILAIRAT S,MAKONKAE YOON K,et al.Predictors of intravenous immunoglobulin resistance and coronary artery aneurysm in patients with Kawasaki disease[J].Paediatr Int Child Health,2018,38(3):209-212.

    • [22] 袁迎第,孙军,李鹏飞,等.中性粒细胞与淋巴细胞比值及血小板与淋巴细胞比值对于川崎病IVIG敏感性的预测价值[J].中国当代儿科杂志,2017,19(4):410-413.

    • [23] KOBAYASHI T,INOUE Y,TAKEUCHI K,et al.Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease[J].Circulation,2006,113(22):2606-2612.

    • [24] EGAMI K,MUTA H,ISHII M,et al.Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease[J].J Pediatr,2006,149(2):237-240.

    • [25] SANO T,KUROTOBI S,MATSUZAKI K,et al.Prediction of non-responsiveness to standard high-dose gammaglobulin therapy in patients with acute Kawasaki disease before starting initial treatment[J].Eur J Pediatr,2007,166(2):131-137.

    • [26] BAR-MEIR M,KALISKY I,SCHWARTZ A,et al.Prediction of Resistance to intravenous immunoglobulin in children with kawasaki disease[J].J Pediatric Infect Dis Soc,2018,7(1):25-29.

    • [27] SATO S,KAWASHIMA H,KASHIWAGI Y,et al.Inflammatory cytokines as predictors of resistance to intravenous immunoglobulin therapy in Kawasaki disease patients[J].Int J Rheum Dis,2013,16(2):168-172.

    • [28] LIN M T,CHANG C H,SUN L C,et al.Risk factors and derived formosa score for intravenous immunoglobulin unresponsiveness in Taiwanese children with Kawasaki disease[J].J Formo Med Assoc,2016,115(5):350-355.

    • [29] SONG R,YAO W,LI X.Efficacy of four scoring systems in predicting intravenous immunoglobulin resistance in children with Kawasaki disease in a children's hospital in Beijing,North China[J].J Pediatr,2017,184:120-124.

    • [30] QIAN W,TANG Y,YAN W,et al.A comparison of efficacy of six prediction models for intravenous immunoglobulin resistance in Kawasaki disease[J].Ital J Pediatr,2018,44(1):33.

    • [31] FU P P,DU Z D,PAN Y S.Novel predictors of intravenous immunoglobulin resistance in Chinese children with Kawasaki disease[J].Pediatr Infect Dis J,2013,32(8):e319-e323.

    • [32] TANG Y,YAN W,SUN L,et al.Prediction of intravenous immunoglobulin resistance in Kawasaki disease in an east China population[J].Clin Rheumatol,2016,35(11):2771-2776.

    • [33] HUA W,SUN Y,WANG Y,et al.A new model to predict intravenous immunoglobin-resistant Kawasaki disease[J].Oncotarget,2017,8(46):80722-80729.

    • [34] YANG S,SONG R,ZHANG J,et al.Predictive tool for intravenous immunoglobulin resistance of Kawasaki disease in Beijing[J].Arch Dis Child,2019,104(3):262-267.

    • [35] TAN X H,ZHANG X W,WANG X Y,et al.A new model for predicting intravenous immunoglobin-resistant Kawasaki disease in Chongqing:a retrospective study on 5 277 patients[J].Sci Rep,2019,9(1):1722.

    • [36] WU S,LIAO Y,SUN Y,et al.Prediction of intravenous immunoglobulin resistance in Kawasaki disease in children[J].World J Pediatr,2020,16(6):607-613.

  • 参考文献

    • [1] KAWASAKI T.Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children[J].Arerugi,1967,16(3):178-222.

    • [2] MC CRINDLE B W,ROWLEY A H,NEWBURGER J W,et al.Diagnosis,treatment,and long-term management of Kawasaki disease:a scientific statement for health professionals from the American Heart Association[J].Circulation,2017,135(17):e927-e999.

    • [3] ELEFTHERIOU D,LEVIN M,SHINGADIA D,et al.Management of Kawasaki disease[J].Arch Dis Child,2014,99(1):74-83.

    • [4] 江载芳,申昆玲,沈颖.诸福棠实用儿科学(第八版)[M].北京:人民卫生出版社,2014:787.

    • [5] PARK H M,LEE D W,HYUN M C,et al.Predictors of nonresponse to intravenous immunoglobulin therapy in Kawasaki disease[J].Korean J Pediatr,2013,56(2):75-79.

    • [6] KUO H C,LIANG C D,WANG C L,et al.Serum albumin level predicts initial intravenous immunoglobulin treatment failure in Kawasaki disease[J].Acta Paediatr,2010,99(10):1578-1583.

    • [7] XIE T,WANG Y,FU S,et al.Predictors for intravenous immunoglobulin resistance and coronary artery lesions in Kawasaki disease[J].Pediatr Rheumatol Online J,2017,15(1):17.

    • [8] YAMAMOTO N,SATO K,HOSHINA T,et al.Utility of ferritin as a predictor of the patients with Kawasaki disease refractory to intravenous immunoglobulin therapy[J].Mod Rheumatol,2015,25(6):898-902.

    • [9] KONG W X,MA F Y,FU S L,et al.Biomarkers of intravenous immunoglobulin resistance and coronary artery lesions in Kawasaki disease[J].World J Pediatr,2019,15(2):168-175.

    • [10] YOSHIMURA K,KIMATA T,MINE K,et al.N-terminal pro-brain natriuretic peptide and risk of coronary artery lesions and resistance to intravenous immunoglobulin in Kawasaki disease[J].J Pediatr,2013,162(6):1205-1209.

    • [11] KIM S Y,HAN M Y,CHA S H,et al.N-terminal probrain natriuretic peptide(NT proBNP)as a predictive indicator of initial intravenous immunoglobulin treatment failure in children with Kawasaki disease:a retrospective study[J].Pediatr Cardiol,2013,34(8):1837-1843.

    • [12] SHAO S,LUO C,ZHOU K,et al.The role of agespecific N-terminal pro-brain natriuretic peptide cutoff values in predicting intravenous immunoglobulin resistance in Kawasaki disease:a prospective cohort study[J].Pediatr Rheumatol Online J,2019,17(1):65.

    • [13] WU Y,LIU F F,XU Y,et al.Interleukin-6 is prone to be a candidate biomarker for predicting incomplete and IVIG nonresponsive Kawasaki disease rather than coronary artery aneurysm[J].Clin Exp Med,2019,19(2):173-181

    • [14] DU S,HUANG Y,JIN H,et al.Protective mechanism of hydrogen sulfide against chemotherapy-induced cardiotoxicity[J].Front Pharmacol,2018,9:32.

    • [15] LIN J,ZHAO H,JIAO F,et al.Lymphocyte hydrogen sulfide production predicts intravenous immunoglobulin resistance in children with Kawasaki disease:a preliminary,single-center,case-control study[J].Medicine(Baltimore),2018,97(47):e13069.

    • [16] ANGKANANARD T,ANOTHAISINTAWEE T,MCEVOY M,et al.Neutrophil lymphocyte ratio and cardio-vascular disease risk:a systematic review and metaanalysis[J].Biomed Res Int,2018,2018:2703518.

    • [17] HA K S,LEE J,JANG G Y,et al.Value of neutrophillymphocyte ratio in predicting outcomes in Kawasaki disease[J].Am J Cardiol,2015,116(2):301-306.

    • [18] CHEN Y B,HUA Y,ZHANG C Y,et al.Neutrophilto-lymphocyte ratio predicts intravenous immunoglobulin-resistance in infants under 12-months old with Kawasaki disease[J].Front Pediatr,2019,7:81.

    • [19] HUA W,MA F Y,WANG Y,et al.A new scoring system to predict Kawasaki disease with coronary artery lesions[J].Clin Rheumatol,2019,38(4):1099-1107.

    • [20] KAWAMURA Y,TAKESHITA S,KANAI T,et al.The combined usefulness of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in predicting intravenous immunoglobulin resistance with Kawasaki disease[J].J Pediatr,2016,178:281-284.e1.

    • [21] CHANTASIRIWAN N,SILVILAIRAT S,MAKONKAE YOON K,et al.Predictors of intravenous immunoglobulin resistance and coronary artery aneurysm in patients with Kawasaki disease[J].Paediatr Int Child Health,2018,38(3):209-212.

    • [22] 袁迎第,孙军,李鹏飞,等.中性粒细胞与淋巴细胞比值及血小板与淋巴细胞比值对于川崎病IVIG敏感性的预测价值[J].中国当代儿科杂志,2017,19(4):410-413.

    • [23] KOBAYASHI T,INOUE Y,TAKEUCHI K,et al.Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease[J].Circulation,2006,113(22):2606-2612.

    • [24] EGAMI K,MUTA H,ISHII M,et al.Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease[J].J Pediatr,2006,149(2):237-240.

    • [25] SANO T,KUROTOBI S,MATSUZAKI K,et al.Prediction of non-responsiveness to standard high-dose gammaglobulin therapy in patients with acute Kawasaki disease before starting initial treatment[J].Eur J Pediatr,2007,166(2):131-137.

    • [26] BAR-MEIR M,KALISKY I,SCHWARTZ A,et al.Prediction of Resistance to intravenous immunoglobulin in children with kawasaki disease[J].J Pediatric Infect Dis Soc,2018,7(1):25-29.

    • [27] SATO S,KAWASHIMA H,KASHIWAGI Y,et al.Inflammatory cytokines as predictors of resistance to intravenous immunoglobulin therapy in Kawasaki disease patients[J].Int J Rheum Dis,2013,16(2):168-172.

    • [28] LIN M T,CHANG C H,SUN L C,et al.Risk factors and derived formosa score for intravenous immunoglobulin unresponsiveness in Taiwanese children with Kawasaki disease[J].J Formo Med Assoc,2016,115(5):350-355.

    • [29] SONG R,YAO W,LI X.Efficacy of four scoring systems in predicting intravenous immunoglobulin resistance in children with Kawasaki disease in a children's hospital in Beijing,North China[J].J Pediatr,2017,184:120-124.

    • [30] QIAN W,TANG Y,YAN W,et al.A comparison of efficacy of six prediction models for intravenous immunoglobulin resistance in Kawasaki disease[J].Ital J Pediatr,2018,44(1):33.

    • [31] FU P P,DU Z D,PAN Y S.Novel predictors of intravenous immunoglobulin resistance in Chinese children with Kawasaki disease[J].Pediatr Infect Dis J,2013,32(8):e319-e323.

    • [32] TANG Y,YAN W,SUN L,et al.Prediction of intravenous immunoglobulin resistance in Kawasaki disease in an east China population[J].Clin Rheumatol,2016,35(11):2771-2776.

    • [33] HUA W,SUN Y,WANG Y,et al.A new model to predict intravenous immunoglobin-resistant Kawasaki disease[J].Oncotarget,2017,8(46):80722-80729.

    • [34] YANG S,SONG R,ZHANG J,et al.Predictive tool for intravenous immunoglobulin resistance of Kawasaki disease in Beijing[J].Arch Dis Child,2019,104(3):262-267.

    • [35] TAN X H,ZHANG X W,WANG X Y,et al.A new model for predicting intravenous immunoglobin-resistant Kawasaki disease in Chongqing:a retrospective study on 5 277 patients[J].Sci Rep,2019,9(1):1722.

    • [36] WU S,LIAO Y,SUN Y,et al.Prediction of intravenous immunoglobulin resistance in Kawasaki disease in children[J].World J Pediatr,2020,16(6):607-613.

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