Effects of methylprednisolone pulse on cytokine levels in Kawasaki disease patients unresponsive to intravenous immunoglobulin

This study aimed to determine the effects of intravenous methylprednisolone pulse (IVMP) therapy on cytokine levels in patients with acute Kawasaki disease (KD) unresponsive to initial intravenous immunoglobulin (IVIG) therapy. Fifteen KD patients unresponsive to initial IVIG, 2 g/kg/day, were randomized to receive IVMP (n = 7), 30 mg/kg/day for 3 days or additional IVIG (n = 8), 2 g/kg/day, and plasma cytokine levels were compared. The fraction of febrile patients was significantly lower in the IVMP group than in the additional IVIG group on day 2 (0/7 vs. 3/8, p = 0.03), but not on day 4 and later (3/7 vs. 4/8, p = 1.00) because of recurrent fever. The prevalence of coronary lesions was similar between the two groups (2/7 vs. 2/8, p = 1.00). The ratios of plasma levels of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 to those at enrollment (defined as day 1) were significantly lower in the IVMP group on day 4 (0.50 +/- 0.27 vs. 1.01 +/- 0.46, 0.53 +/- 0.39 vs. 0.93 +/- 0.44, p = 0.02 and 0.045, respectively), but not on day 7 (0.54 +/- 0.34 vs. 0.88 +/- 0.39, 0.76 +/- 0.39 vs. 0.61 +/- 0.17, p = 0.07 and 0.83, respectively). The ratios of interleukin-2 receptor, interleukin-6, and vascular endothelial cell growth factor to those at enrollment did not differ significantly between the two groups. In conclusion, for KD patients unresponsive to initial IVIG, IVMP suppresses cytokine levels faster, but subsequently similarly, compared with additional IVIG.     

再次应用静脉丙种球蛋白无反应川崎病的预测因素分析

目的 探讨再次应用丙种球蛋白（简称丙球）无反应川崎病(KD)的危险因素及预测指标。方法 收集2010年1月至2015年1月在重庆医科大学附属儿童医院收治的初次丙球无反应并接受再次丙球治疗的KD患儿,分为再次丙球有反应组和无反应组,对2组的临床特征及实验室指标进行回顾性分析。结果 81例KD患儿进入分析,再次丙球有反应组占75.3%（61/81）,无反应组占24.7%（20/81）。两组性别、年龄、初次丙球治疗前后临床表现和2次丙球使用间隔时间差异均无统计学意义。在初次丙球使用前,冠状动脉病变发生率、血常规（WBC、PLT、Hb、N）、CRP、肝功能、电解质等指标再次丙球有反应组和无反应组差异均无统计学意义。再次丙球治疗前与初次应用丙球前,血常规和CRP指标差值再次丙球有反应组和无反应组差异均无统计学意义。结论 初次丙球使用前的临床表现及实验室指标不能预测初次丙球无反应KD再次应用丙球是否有效,初次应用丙球后的临床表现及血常规、CRP指标对再次应用丙球是否有效亦无提示作用。     

激素与静脉丙种球蛋白及其联合应用治疗静脉丙种球蛋白无反应川崎病的回顾性对照研究

目的 探讨激素对静脉丙种球蛋白（IVIG）无反应川崎病（KD）患儿的治疗价值。方法 回顾性收集重庆医科大学附属儿童医院IVIG无反应KD住院患儿,根据再治疗情况分为IVIG组、激素组和IVIG+激素组;将应用激素者根据激素应用途径分为静脉滴注序贯口服激素组和口服激素组。统计各组患儿的总热程、平均热退时间、治疗前后实验室检查结果并计算治疗前后的差值与治疗前值的比值（即差值比△）、急性期及出院后6、12、24个月冠状动脉病变和随访中的血栓形成情况。结果 IVIG无反应KD患儿143例进入本文分析。IVIG组107例,激素组12例, IVIG+激素组24例,3组性别、年龄、体重差异无统计学意义。IVIG+激素组治疗后WBC高于IVIG组,△WBC、△PLT均低于IVIG组,△CRP高于IVIG组,总热程长于IVIG组;急性期冠状动脉瘤发生率及随访至6个月时冠状动脉扩张发生率高于IVIG组,差异均有统计学意义;激素组△WBC低于IVIG组,总热程长于IVIG组,差异均有统计学意义。静脉滴注序贯口服激素组和口服激素组各18例,2组性别、年龄、体重差异无统计学意义,口服激素组再次治疗前和再次治疗后CRP均低于静脉滴注序贯口服激素组, 口服激素组△PLT高于静脉滴注序贯口服激素组,2组随访时点冠状动脉扩张和冠状动脉瘤发生率差异均无统计学意义。随访病例中,静脉滴注序贯口服激素组有2例出现血栓,经积极抗凝治疗后血栓消失。结论 IVIG无反应KD患儿再治疗时应用激素或再次IVIG无反应后应用激素,与单纯IVIG相比急性期治疗效果相近,且均不增加远期冠状动脉损伤的发生率;选择普通剂量口服或者静脉滴注序贯口服疗法临床效果相近,但静脉滴注序贯口服激素较口服激素有更高的血栓形成风险。     

川崎病丙种球蛋白治疗策略与心脏损害及冠状动脉病变的相关性研究(1998-2008上海地区调查报告)(英文)

目的 川崎病(Kawasaki disease,KD)是一种病因未明的全身血管炎性综合征,伴冠状动脉病变(coronary artery lesion,CAL);大剂量静脉注射丙种球蛋白(intravenous immunoglobulin,IVIG)治疗KD的临床疗效肯定,但目前IVIG的用法和用量尚存在争议.该研究主要为评价不同IVIG方法治疗.KD的效果,探讨最佳治疗方案.方法 由上海市儿科心血管学组制定统一的KD调查表,发放到上海提供儿科服务的50家医院.回顾性分析1998-2008年上海地区住院KD患者的临床资料.共收集完全符合要求的KD患者资料表格1682例,其中男性1064例(63.3%),女性618例(36.7%);发病年龄(2.57±2.33)岁(0.1～18.8岁).治疗KD的IVIG方案包括1 g/ks×1次、2 g/kg×1次、0.4～0.5 g/kg×5次、1 g/kg×2次、2 g/kg×2次及其他.采用SAS 6.12统计软件包进行统计分析,计数资料采用X2检验计算;计量资料数据以X-±s表示,采用t检验.结果 在KD病程的5～10 d应用IVIG有助于最大化降低KD患者的CAL发生率;所有IVIG的KD患者中,应用方案1g/kg×2次治疗者心脏损害、冠脉病变的发生率均为最低,差异有统计学意义(P<0.05).结论 在KD病程5～10 d以IVIG 1g/kg×2次的剂量,有助于最大化降低KD患者的CAL发生率.     

川崎病丙种球蛋白耐药及冠状动脉损伤早期预测指标的研究进展

川崎病是急性全身性血管炎综合征,主要影响冠状动脉.该病的长期预后取决于冠状动脉病变程度.早期应用大剂量静脉丙种球蛋白可以减少冠状动脉病变,丙种球蛋白耐药者冠状动脉病变风险大,早期预测丙种球蛋白耐药及冠脉损伤、及时采取措施对改善预后意义重大.该文对川崎病丙种球蛋白耐药及冠状动脉损伤的预测指标作一介绍.     

Intravenous immunoglobulin preparation type: Association with outcomes for patients with acute Kawasaki disease

Manlhiot C, Yeung RSM, Chahal N, McCrindle BW. Intravenous immunoglobulin preparation type: Association with outcomes for patients with acute Kawasaki disease.
Pediatr Allergy Immunol 2010: 21: 515–521.
© 2010 John Wiley & Sons A/S To determine whether two different intravenous immunoglobulin (IVIG) preparations were equally efficacious in the treatment of Kawasaki disease (KD). Single centre retrospective review of all patients treated with IVIG for KD between January 1990 and April 2007. Comparison of IVIG (dose 2 g/kg) from two commercial preparations; Iveegam^® stabilized with sugar (lyophilized, 5 g/ml glucose, pH 6.4–7.2, IgA 10 μg/ml, 5% IgG/ml) and Gamimune^® stabilized through acidification (no sugar, pH 4.0–4.5, IgA 270 μg/ml, 5% 1990–1999, 10% 1999–2007 IgG/ml). Propensity‐adjusted differences in duration of fever after treatment initiation, frequency of retreatment with IVIG, hospital stay and maximum coronary artery z‐score. A total of 954 patients were included, 862 (90%) were treated with Iveegam^® and 92 (10%) were treated with Gamimune^®. Patients’ demographic, clinical and laboratory characteristics were similar between the two groups. In propensity‐adjusted models, Iveegam^® was found to be associated with higher probability of non‐response to IVIG (12% vs. 5%, p = 0.05) and longer median duration of fever after IVIG [1 (1–27) vs. 1 (1–8) days, p = 0.02] than Gamimune^®. Nevertheless, Gamimune^® was found to be associated with longer median duration of hospital stay [5 (2–49) vs. 4 (2–76) days, p < 0.0001] and higher median maximum coronary artery z‐score both at the end of the acute phase (+1.4 vs. +0.8, p < 0.0001) and 6–8 weeks after the acute phase (+0.7 vs. +0.4, p < 0.0001). IVIG preparations with lower IgA content and stabilized with glucose appear to be associated with improved coronary artery outcomes for patients with KD.     

Safety from thromboembolism using intravenous immunoglobulin therapy in Kawasaki disease: Study of whole-blood viscosity

BACKGROUND: High-dose intravenous infusions of immunoglobulin (IVIG) are well established as a standard therapy for Kawasaki disease (KD) for reducing the risk of coronary artery aneurysms. IVIG therapy might increase the blood viscosity both in vitro and in vivo, which has been reported as a risk factor for cardiovascular or cerebrovascular thromboembolism in adults. METHODS: We measured the whole-blood viscosity in vitro, serum IgG and albumin, and blood hematocrit in 10 patients with KD and 10 with non-KD (five with acute encephalitis, one with sepsis, one with idiopathic thrombocytopenic purpura, one with Guillain-Barré syndrome, one with insulin-dependent diabetes mellitus, and one with Evans syndrome) before and after IVIG therapy. RESULTS: The blood viscosity increased significantly after IVIG therapy in the patients with non-KD, but did not increase in those with KD. CONCLUSION: The results of the present study suggest that the use of IVIG therapy for KD might be relatively safe, with no risk of thromboembolism due to hyperviscosity.     

川崎病患儿并发冠状动脉病变的危险因素分析

目的：探讨川崎病(KD)并发冠状动脉病变(CAL)的危险因素。方法：收集2006年1月至2012年1月间诊断为KD的527例患儿的临床资料,对15个可能与CAL发生有关的因素进行单因素和多因素logistic回归分析。结果：单因素分析显示,患儿年龄、性别、KD类型、大剂量丙种球蛋白（IVIG）治疗起始时间、对IVIG治疗的反应、使用糖皮质激素、发热持续时间及C反应蛋白等因素在合并和未合并CAL两组患儿中差异有统计学意义（P8岁、男性、非典型KD、IVIG治疗开始于发热后10 d 以上、对IVIG治疗无反应、发热持续时间>10 d为CAL发生的独立危险因素（OR分别为2.076、1.890、1.972、1.426、3.251、2.301、1.694,均P8岁）、男性、非典型KD、IVIG治疗起始时间较晚、对IVIG治疗无反应、发热持续时间较长是CAL发生的独立危险因素。     

Analysis of Kawasaki disease showing elevated antibody titres of Yersinia pseudotuberculosis

AIM: To elucidate a clinical difference between patients with Kawasaki disease documented with Yersinia pseudotuberculosis infection and patients with Kawasaki disease without Yersinia pseudotuberculosis infection. PATIENTS AND METHODS: From January 1985 to July 2004, 452 patients were diagnosed with Kawasaki disease. Forty-two patients had elevated antibody titres of Yersinia pseudotuberculosis and/or positive stool culture (Yersinia-positive group). Three hundred and thirty patients had no elevated antibody titres (Yersinia-negative group). We compared the clinical characteristics retrospectively. RESULTS: The age of onset in the Yersinia-positive group (3.05+/-2.20 y) was significantly higher than that in the Yersinia-negative group (2.31+/-2.05 y) (p=0.03). The age-adjusted statistical analysis demonstrated that the incidence of coronary artery lesions (dilatations plus aneurysms) in the Yersinia-positive group (22/42, 52.4%) was significantly higher than in the Yersinia-negative group (105/330, 31.8%) (p=0.001), and the incidence of additional administration of immunoglobulin in the Yersinia-positive group (13/36, 36.1%) was significantly higher than in the Yersinia-negative group (41/256, 16.0%) (p=0.004). CONCLUSION: Our data suggest that Yersinia pseudotuberculosis infection might play a role in the developing mechanism of poor response to therapy and the tendency to develop coronary artery lesions in Kawasaki disease patients.     

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

目的分析中性粒细胞与淋巴细胞比值(NLR)及血小板与淋巴细胞比值(PLR)对川崎病(KD)免疫球蛋白(IVIG)敏感性的预测作用。方法采用回顾性队列研究,以404例初诊川崎病患者为研究对象,收集IVIG治疗前后的血常规、NLR和PLR值,通过ROC曲线确定NLR和PLR在预测川崎病IVIG不敏感的最佳cut-off值;用logistic回归确定IVIG不敏感的独立预测因素。结果 404例川崎病患者中31例IVIG不敏感。与IVIG敏感组相比,IVIG不敏感组的冠状动脉扩张发生率明显增高(P0.01);启用IVIG时的病程较短(P0.05);IVIG治疗前后的NLR、PLR水平以及CRP均较高(P0.05)。IVIG治疗前、后的NLR和PLR对川崎病IVIG不敏感最佳预测值分别为4.36、162和1.45、196。多元回归分析显示IVIG治疗前的病程、CRP,以及IVIG治疗前后的NLR和PLR是IVIG不敏感的独立预测因素。结论 NLR和PLR可能作为川崎病患者丙球不敏感的预测指标。     

Effect of intravenous immunoglobulin on inhibiting peripheral blood lymphocyte apoptosis in acute Kawasaki disease

This study aimed to explore the therapeutic mechanism of intravenous immunoglobulin (IVIG) for Kawasaki disease (KD). Peripheral blood lymphocytes (PBLs) obtained from 26 children with KD and 20 age-matched healthy children were stimulated with anti-CD3 monoclonal antibody (mAb), and the percentage of apoptotic cells and DNA fragmentation were assayed at 0, 12, 24, 48 and 72 h in vitro. The patients were divided into two groups: one treated with aspirin combined with IVIG (n = 16) and one treated with aspirin alone (n = 10). PBLs were stimulated by phytohaemagglutinin to evaluate the lymphocyte proliferative response. Compared with normal controls, the apoptotic cell percentage and the DNA fragmentation were markedly decreased (p < 0.001) and delayed in PBLs from KD patients. After IVIG treatment, the decreased percentage of apoptotic cell and delayed DNA fragmentation were restored to the state of the normal controls, accompanied by a fast clinical remission compared with the aspirin-alone group. The lymphocyte proliferative response was also decreased 3-5 d after IVIG therapy (p < 0.001). Conclusion: The results suggest that decreased PBL apoptosis may be involved in the pathogenesis of KD. The therapeutic mechanism of IVIG in KD may be partially due to the reversal of the inhibited lymphocyte apoptosis, and may have implications for other autoimmune diseases with inefficient lymphocyte apoptosis.     

川崎病所致严重冠状动脉病变单中心队列研究

背景：川崎病（KD）所致严重冠状动脉病变（CAL）容易导致患儿发生冠状动脉事件或死亡,对远期预后及生存质量具有重要影响。 目的：总结分析伴严重CAL的KD患儿的中远期临床转归,为KD患儿长期随访管理及预后评估提供依据。 设计：队列研究。 方法：检索复旦大学附属儿科医院（我院）HIS系统,纳入2008年1月至2019年12月出院诊断为KD,经我院冠状动脉造影（CAG）确诊为KD所致严重CAL的＜18岁患儿。排除合并其他引起严重CAL和影响严重CAL预后疾病者。所有患儿在门诊及病房由资深心血管专科医生随访,均以药物治疗为基础,伴冠状动脉严重狭窄及心肌缺血的患儿经多学科讨论后予手术治疗。以确诊及随访期间出现心肌缺血、心肌梗死或死亡的患儿为预后不良组,反之则为预后良好组,观察出现不良预后及CAL的演变情况,分析不良预后的影响因素。 主要结局指标：不良预后发生情况和CAL的恢复情况。 结果：144例KD所致严重CAL患儿纳入本文分析。其中男117例（81.2%）,女27例;KD中位发病年龄2.2（1.0,4.5）岁,中位随访时间1.6（0,3.4）年,确诊为严重CAL时病程为5.0（3.0,21.3）月。144例KD所致严重CAL患儿共累及276支冠状动脉,56例（38.9%）累及单支冠状动脉,88例（61.1%）累及≥2支冠状动脉。发生巨大冠状动脉瘤（GCAA)122例,单支冠状动脉多发中小型冠状动脉瘤（CAA)8例,GCAA合并单支冠状动脉多发中小型CAA 6例,受累冠状动脉均狭窄8例;62例发生冠状动脉狭窄,其中冠状动脉闭塞31例。预后不良组54例（37.5%）,均存在心肌缺血,其中14例患儿缺血心肌处发生过有记录的急性心肌梗死,1例患儿因心肌梗死所致严重心力衰竭死亡。多因素分析结果显示,≥2支冠状动脉受累的患儿是单支冠状动脉受累的患儿发生不良预后风险的2.6倍（OR=2.602,95%CI：1.201~5.634）,合并冠状动脉狭窄的患儿是未合并冠状动脉狭窄的患儿发生不良预后风险的3倍（OR=3.055,95%CI：1.450~6.437）。共行179次CAG,114例（208支受累冠状动脉）行1次CAG,30例（68支受累冠状动脉）行≥2次CAG。68支受累冠状动脉首次确诊时,51支为GCAA,末次随访时好转率为4.0%;3支为多发中小型CAA,末次随访时好转率为66.6%;2支为单个中小型CAA,至末次随访均发生狭窄（狭窄程度约50%）;12支为狭窄,至末次随访时均未好转。 结论：GCAA是KD所致严重CAL的主要类型,且难以恢复,单支冠状动脉多发中小型CAA好转率较高。冠状动脉狭窄及多支冠状动脉受累是KD所致严重CAL患儿发生不良预后的影响因素。     

川崎病丙种球蛋白无反应型易感基因研究

目的应用靶向测序技术探索川崎病(KD)丙种球蛋白无反应易感基因,筛选KD高危人群。方法选择2016年12月至2018年10月收治的190例KD患儿,其中静脉注射丙种球蛋白(IVIG)无反应33例、敏感151例,以及99例健康儿童。采集外周静脉血全基因组DNA,采用靶向捕获测序技术,分析比较基因差异位点。结果 KD患儿和健康儿童之间FCGR3A(rs77144485)、IL15RA(rs2228059)、IL-6(rs13306435)基因型的差异均有统计学意义(P0.05)。IVIG无反应和敏感KD患儿之间,在位于IL-2RB、IL-24、BMPR1A、GZMB、KDR、KIR2DS4、CARD11、CHUK等基因区域的10个单核苷酸多态性位点的基因型频率差异有统计学意义(P均0.05)。结论靶向捕获测序技术初步筛选出IL-2RB、IL-24、BMPR 1 A、GZMB、KDR、KIR 2 DS 4、CARD 11、CHUK等KD丙种球蛋白无反应型易感基因。     

Optimal dosage and differences in therapeutic efficacy of IGIV in Kawasaki disease

In an initial study, three groups of patients with Kawasaki disease received either aspirin alone or alkylated immunoglobulin G intravenous preparation (IGIV) 200 mg/kg daily x3 days + aspirin, or 400 mg/kg alkylated IGIV daily x3 days + aspirin. In a second study, three groups of patients were treated with either 100, 200 or 400 mg/kg of native IGIV in combination with aspirin daily for 5 days. While the regimen of 200 mg/kg native IGIV daily x 5 days was found to be effective, the incidence of coronary artery lesions (CAL) was even less on a regimen of 400 mg/kg daily x 5 days. It is therefore suggested that a better therapeutic effect can be achieved with a 400 mg/kg dose of native IGIV. Based on the results from these two studies, it is assumed that native IGIV is more effective in inhibiting CAL formation and persistence than the chemically modified preparation in which the biological activity of the Fc region in the immunoglobulin G molecule is altered.     

他汀类药物在川崎病治疗中的研究进展

川崎病是一种自身免疫性血管炎性疾病,主要累及中小动脉,尤其是冠状动脉,冠状动脉损伤程度与川崎病的预后密切相关。他汀类药物在心血管疾病中的治疗作用已被证实,近年来研究发现其在川崎病的治疗中也发挥重要作用,对川崎病急性期及恢复期阻止冠脉动脉瘤形成具有潜在价值。现就他汀类药物在川崎病治疗中的研究进展作一综述。     

川崎病165例临床分析

目的探讨川崎病(KD)的临床特征、实验室检查、冠脉损害的危险因素及治疗方法。方法对山东省立医院儿科1995年8月至2005年7月诊治的165例KD患儿资料进行了回顾性分析和总结。结果165例KD中典型136例,不典型29例,男114例,女51例,男女比例约为2.2∶1。年龄最小23d,最大11岁。<1岁41例,1～3岁68例,>3～5岁23例,>5岁33例。平均发病年龄2岁8个月。合并冠脉损害者44例,其中冠脉扩张26例,冠脉瘤13例,巨大冠脉瘤5例。对合并冠脉损害者随访6个月至3年,完全恢复正常者40例,5例巨大冠脉瘤患者,1例完全恢复,其余4例未恢复,1例合并冠脉血栓形成。结论不典型KD冠脉损害率高,KD发病10d内用丙球效果好,2g/kg单次注射明显优于0.4g/(kg.d)连用5d的疗法,WBC升高、ALB降低、男性及发热时间长是KD合并冠脉损害的危险因素。     

A sibship with recurrent Kawasaki disease and coronary artery lesion

Although epidemiologic studies of Kawasaki disease suggest an infectious etiology, the cause of this mysterious disease remains unclear. We describe the occurrence of five episodes of Kawasaki disease over a six-year period in three siblings. Two of the three children experienced recurrent Kawasaki disease and developed coronary artery lesions, which included giant coronary artery aneurysms in the youngest child. The non-contemporaneous occurrence of the disease in these three children emphasizes the importance of a genetic basis and/or environmental factors in the etiology of Kawasaki disease.     

Re-treatment for immune globulin-resistant Kawasaki disease: A comparative study of additional immune globulin and steroid pulse therapy

BACKGROUND: We compared the efficacy and safety of additional intravenous immune globulin (IVIG) therapy with steroid pulse therapy in patients with IVIG-resistant Kawasaki disease. METHODS: Two-hundred and sixty-two consecutive patients had been treated with a single dose of IVIG (2 g/kg) and aspirin (30 mg/kg per day). Thirty-five patients (13.4%) were not clinical responders to the initial IVIG treatment. They received an additional IVIG treatment (1 g/kg) within 48 h after the initial treatment. Seventeen patients (6.5%) did not respond to the additional IVIG treatment. We randomly divided these patients into two groups: group 1 consisted of eight patients who were treated with a single additional dose of IVIG (1 g/kg), while group 2 consisted of nine patients who were treated with steroid pulse therapy. RESULTS: The IVIG-resistant patients had a high incidence of coronary artery lesions (CAL; 48.6%). Five patients (62.5%) in group 1 had CAL, including two patients who each had a giant aneurysm and three patients who each had a small aneurysm. Seven patients (77.8%) in group 2 had CAL, including two patients who each had a giant aneurysm, two patients who each had a small coronary aneurysm and three patients who each showed transient dilatation during steroid pulse therapy. There was no significant difference in the incidence of CAL between the two groups. The duration of high fever in group 2 (1.4~0.7 days) was significantly shorter than in group 1 (4.8~3.4 days; P<0.05). The medical costs for the treatment of patients in group 2 (113, 012 yen +/- 22,084) were significantly lower than those for group 1 (144,194 yen +/- 12,914; P<0.05). CONCLUSIONS: Steroid pulse therapy may be useful in the treatment of patients with IVIG-resistant Kawasaki disease who experience prolonged fever. However, transient dilatation of the coronary artery is observed during steroid pulse therapy, so careful echocardiographic examination should be performed for those patients receiving steroid pulse therapy for the sake of early detection of coronary artery abnormalities.