免疫球蛋白无应答川崎病再次免疫球蛋白、英夫利昔单抗和激素治疗队列研究

背景 IVIG无应答KD患儿的治疗方案包括再次IVIG、英夫利昔单抗(IFX)和激素(IMP),目前不同治疗方案的疗效评价不一.目的 IVIG无应答KD患儿再次IVIG、IFX和IMP治疗效果比较.研究设计队列研究.方法 以IVIG无应答KD患儿为队列人群,再次治疗和补救治疗(再次治疗无反应)在江西省儿童医院(我院)中...     

A practical approach to refractory Kawasaki disease

Kawasaki disease (KD) is a medium vessel vasculitis and is the most common cause of acquired heart disease in childhood. If left untreated, KD leads to coronary artery aneurysms in 15–25% of patients and the mortality rate in the UK is currently 0.4%. As such, KD is an important preventable cause of heart disease in the young. The aetiology of KD remains unknown, but most likely it represents an aberrant inflammatory host response to one or more as yet unidentified immunological trigger(s) in genetically predisposed individuals. The purpose of this article is not to provide an exhaustive review of KD. Rather we provide practical guidance to the clinical approach to refractory KD. Only brief background on the pathogenesis and epidemiology of KD, and emerging newer clinical trials is provided, to place our clinical approach in context.     

静脉人免疫球蛋白无反应型川崎病患儿的循证治疗

目的：针对近期收治的1例IVIG无反应型川崎病的患儿,我们进行了证据检索和评价,以期找到更有效的治疗方法。方法：通过计算机检索UpToDate(2012.10)、Cochrane图书馆（Issue 10,2012）、PubMed（1978~2012.10）、CNKI（1978~2012.10）等数据库,查找免疫球蛋白或糖皮质激素治疗IVIG无反应型川崎病及病情缓解有关的系统评价、临床随机对照试验等,并对所获证据进行GRADE评价。结果：高质量的临床证据表明,小剂量激素联合IVIG治疗IVIG无反应型川崎病,其在退热效果及减少冠状动脉扩张方面,均优于单纯IVIG治疗。根据此临床证据,结合医生经验及家属意愿对该患儿实施甲强龙（2mg/kg,ivd）联合第三剂IVIG（1g/kg）治疗,激素逐渐减量维持,并继续采用阿司匹林、双嘧达莫等治疗。经治疗后,患儿体温及各实验室指标逐渐恢复正常,心脏彩超随访半年未见有冠状动脉进一步损伤。结论：小剂量激素联合IVIG治疗IVIG无反应型川崎病可有效退热及减少冠脉扩张,长期效果需待进一步观察。     

Serum albumin level predicts initial intravenous immunoglobulin treatment failure in Kawasaki disease

Objectives: Kawasaki disease (KD) is a systemic vasculitis primarily affecting children who are <5 years old. Intravenous immunoglobulin (IVIG) is the standard therapy for KD. However, many patients with KD still show poor response to initial IVIG treatment. This study was conducted to investigate the risk factors for initial IVIG treatment failure in KD. Methods: Children who met KD diagnosis criteria and were admitted for IVIG treatment were retrospectively enrolled for analysis. Patients were divided into IVIG‐responsive and IVIG‐resistant groups. Initial laboratory data before IVIG treatment were collected for analysis. Results: A total of 131 patients were enrolled during the study period. At 48 h after completion of initial IVIG treatment, 20 patients (15.3%) had an elevated body temperature. Univariate analysis showed that patients who had initial findings of high neutrophil count, abnormal liver function, low serum albumin level (≤2.9 g/dL) and pericardial effusion were at risk for IVIG treatment failure. Multivariate analysis with a logistic regression procedure showed that serum albumin level was considered the independent predicting factor of IVIG resistance in patients with KD (p = 0.006, OR = 40, 95% CI: 52.8–562). There was no significant correlation between age, gender, fever duration before IVIG treatment, haemoglobin level, total leucocyte and platelet counts, C‐reactive protein level, or sterile pyuria and initial IVIG treatment failure. The specificity and sensitivity for prediction of IVIG treatment failure in this study were 96% and 34%, respectively. Conclusion: Pre‐IVIG treatment serum albumin levels are a useful predictor of IVIG resistance in patients with KD.     

川崎病静脉注射丙种球蛋白无反应预测模型研究现状

川崎病(Kawasaki disease,KD)是一种急性自身免疫性系统性血管炎,是发达国家儿童获得性心脏病的主要病因。KD最严重的后果是冠状动脉病变(coronary artery lesions,CALs),与KD的预后相关。临床研究证实静脉注射丙种球蛋白(IVIG)耐药是CALs的独立危险因素。近年来,一系列的预测模型已被开发来评估IVIG耐药的风险。然而,目前基于KD儿童人口学特征、临床表现、实验室检查及遗传特性的IVIG耐药性预测评分系统在不同民族和同一民族不同地区的人群中存在显著差异,尚未建立适用普遍人群的预测模型。     

大剂量静脉注射丙种球蛋白无反应性川崎病的临床分析

目的 探讨对大剂量静脉注射丙种球蛋白(IVIG)无反应性川崎病的发生率及临床特点,以及再治疗方案的选择.方法 回顾性总结2000年1月至2006年12月入院的KD患儿的临床资料,根据对首次大剂量IVIG有无反应分成IVIG敏感组和无反应组,比较两组的临床特点.结果 诊断为川崎病并接受IVIG治疗患儿222例,其中IVIG敏感者185例,无反应者37例,发生率16.67%(37/222).无反应组接受IVIG治疗时间早,发热时间长,住院时间长,白细胞总数、中性粒细胞比值、CRP明显高于敏感组,而血浆白蛋白明显低于敏感组.IVIG无反应组合并冠状动脉病变14例(37.84%),明显高于IVIG敏感组(15.68%).IVIG无反应组合并噬血细胞综合征2例,多发性冠状动脉瘤及心肌梗死者1例,多脏器功能衰竭死亡1例.对IVIG无反应者的冉治疗,给予IVIG追加疗法,甲基泼尼松龙冲击治疗,泼尼松口服治疗.结论 IVIG无反应性川崎病较IVIG敏感性川崎病更易发生冠状动脉病变和严重并发症;接受IVIG治疗时间、发热时间、中性粒细胞比值、CRP、血浆白蛋白是IVIG无反应的危险因素.对IVIG无反应性川崎病可以用IVIG追加治疗,无效者选用糖皮质激素.     

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目的分析儿童静脉注射免疫球蛋白(IVIG)不敏感川崎病的临床特点。方法对2005-01—2005-12在重庆医科大学儿童医院住院的233例川崎病的患儿进行病例回顾性分析。结果IVIG不敏感川崎病共31例(占13.3%)。IVIG不敏感川崎病中男女性别比为4.17∶1,明显高于IVIG敏感川崎病1.43∶1(P<0.05)。两组川崎病年龄构成差异无显著性(P>0.05)。IVIG不敏感川崎病中有中度以上冠状动脉扩张或冠状动脉瘤者6例(6/31,19.4%),明显高于IVIG敏感川崎病(5/202,2.4%)(P<0.05)。川崎病患儿发生IVIG耐药的可能危险因素有外周血白细胞、中性粒细胞比例、血红蛋白、C反应蛋白、血沉、血浆白蛋白、乳酸脱氢酶等,分析结果提示血浆白蛋白降低及男性可能与IVIG不敏感川崎病有关,但仅此两项指标尚不能预测IVIG不敏感川崎病的发生。IVIG不敏感川崎病冠脉病变发生危险因素无阳性发现。IVIG不敏感川崎病患儿中14例通过复用IVIG后临床症状得以缓解,仅8例在复用IVIG后症状仍不能控制而加用激素治疗。结论IVIG不敏感川崎病并不少见且较IVIG敏感川崎病更易发生较严重冠状动脉病变,川崎病患儿发生IVIG耐药及IVIG不敏感川崎病冠脉病变发生的危险因素不肯定。复用IVIG及必要时在抗凝基础上加用激素对IVIG不敏感川崎病治疗有较好疗效。     

对川崎病患儿静脉注射丙种球蛋白耐药临床预测模型建立的质疑

目的 对川崎病(KD)患儿IVIG耐药预测模型提出质疑。方法 回顾性收集经复旦大学附属儿科医院(我院)首次诊断和治疗的KD病例,全样本人群按7∶3比例随机分为建模组和验证组,通过单因素及多因素Logistic回归分析建立IVIG耐药预测模型并行验证,将KD患儿按性别、年龄、发热天数和KD类型等分层,在不同的分层中单独建模和验证;基于全样本人群验证已发表的11个IVIG耐药预测模型,考察通过临床症状、体征和实验室指标是否能满足临床预测KD患儿IVIG耐药。结果 符合本文纳入和排除标准的1 360例KD患儿进入本文分析。男875例(64.3%);年龄中位数1.8(0.9,3.2)岁;IVIG耐药组和敏感组分别为171和1 189例;建模组和验证组分别为952和408例。建模组和验证组人口学特征、主要临床表现、实验室指标、IVIG耐药率和冠脉病变率差异均无统计学意义(P >0.05);建模组中建立的IVIG耐药模型中,男性、发病年龄≥2岁、N%≥0.75、Hb≥110 g·L^-1各计1分,应用首剂IVIG发热≥5 d、ALB≥34 g·L^-1、Na⁺≥133 mmol·L^-1各计2分,AUC为0.818(95% CI:0.774~0.861),总分≥5时,敏感度和特异度分别为0.767和0.726。验证组中AUC为0.777(95% CI:0.712~0.842),敏感度和特异度分别为0.627和0.776。对11个IVIG耐药预测模型验证,以相应预测界值计算敏感度0.272~0.799,特异度0.412~0.926。结论 基于KD患儿人口学特征、临床症状、体征和实验室指标行KD患儿IVIG耐药预测特异度和敏感度均＜75%,对临床预测KD患儿IVIG耐药作用有限。     

Intravenous immune globulin in neonatal immune hemolytic disease: does it reduce hemolysis?

We studied the effect of intravenous immune globulin (IVIG) on hemolysis in term, hyperbilirubinemia, Coombs'positive infants utilizing measurement of carboxyhemoglobin fraction corrected for inhaled carbon monoxide (COHbc), a sensitive indicator of hemolysis. COHbc values were determined before and after IVIG infusion. In those babies who responded with a decrease in serum total bilirubin ( n = 19). no exchange transfusions were required and COHbc levels decreased significantly by 24 h post-IVIG from 1.37 ± 0.31 to 1.12 ± 0.26% tHb ( p < 0.0001). There were no corresponding decreases in COHbc levels (1.89 ± 0.54 to 1.82 ± 0.48% tHb; ( p > 0.05) among those whose serum bilirubin levels did not decrease in response to IVIG ( n = 7), and all of these infants required exchange transfusions. Furthermore, the extent of the decrease in COHbc was related to the degree of decrease in serum bilirubin levels, such that the percentage decrease of bilirubin at 24 h was directly correlated with the percentage decrease of COHbc at 24 h ( p = 0.007). We conclude that IVIG, when successful, inhibits hemolysis in these infants.     

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.     

对川崎病患儿静脉注射丙种球蛋白耐药临床预测模型建立的质疑

目的 对川崎病(KD)患儿IVIG耐药预测模型提出质疑。方法 回顾性收集经复旦大学附属儿科医院(我院)首次诊断和治疗的KD病例,全样本人群按7∶3比例随机分为建模组和验证组,通过单因素及多因素Logistic回归分析建立IVIG耐药预测模型并行验证,将KD患儿按性别、年龄、发热天数和KD类型等分层,在不同的分层中单独建模和验证;基于全样本人群验证已发表的11个IVIG耐药预测模型,考察通过临床症状、体征和实验室指标是否能满足临床预测KD患儿IVIG耐药。结果 符合本文纳入和排除标准的1 360例KD患儿进入本文分析。男875例(64.3%);年龄中位数1.8(0.9,3.2)岁;IVIG耐药组和敏感组分别为171和1 189例;建模组和验证组分别为952和408例。建模组和验证组人口学特征、主要临床表现、实验室指标、IVIG耐药率和冠脉病变率差异均无统计学意义(P >0.05);建模组中建立的IVIG耐药模型中,男性、发病年龄≥2岁、N%≥0.75、Hb≥110 g·L^-1各计1分,应用首剂IVIG发热≥5 d、ALB≥34 g·L^-1、Na⁺≥133 mmol·L^-1各计2分,AUC为0.818(95% CI:0.774~0.861),总分≥5时,敏感度和特异度分别为0.767和0.726。验证组中AUC为0.777(95% CI:0.712~0.842),敏感度和特异度分别为0.627和0.776。对11个IVIG耐药预测模型验证,以相应预测界值计算敏感度0.272~0.799,特异度0.412~0.926。结论 基于KD患儿人口学特征、临床症状、体征和实验室指标行KD患儿IVIG耐药预测特异度和敏感度均＜75%,对临床预测KD患儿IVIG耐药作用有限。     

不同剂量静脉丙种球蛋白或加甲泼尼龙治疗无反应川崎病患儿疗效观察

目的:探讨不同剂量静脉丙种球蛋白（IVIG）或加甲泼尼龙治疗无反应川崎病（KD）患儿疗效观察。方法:回顾性收集2002至2010年首都医科大学附属北京儿童医院IVIG无反应KD住院患儿的临床资料,根据归纳的6种IVIG或加甲泼尼龙的给药方法分为IVIG 2 g组、IVIG 1次1 g组和IVIG 2次1 g组（1次1 g组不敏感病例再次IVIG 1次1 g组方案）。以接受不同剂量IVIG或加甲泼尼龙（2 mg·kg-1×3 d）治疗后48 h患儿体温降至38℃以下定义为敏感,以接受不同剂量IVIG或加甲泼尼龙治疗2周后超声心动图判断冠状动脉是否损伤。结果:9年间在KD急性期接受规范首剂IVIG 2 g·kg-1治疗无反应KD的发生率为18.3%（230/1 257）。IVIG 2 g组40例,36例敏感（90.0%）,4例加用甲泼尼龙敏感;IVIG 1次1 g组190例,123例敏感（64.7%）,7例加用甲泼尼龙敏感;IVIG 2次1 g组60例,25例敏感,35例加用甲泼尼龙敏感。不加甲泼尼龙时,IVIG 2 g组与IVIG 1次1 g组敏感率差异有统计学意义（P<0.01）;IVIG 2 g组与IVIG 1次1 g组、IVIG 2次1 g组敏感率之和差异无统计学意义（P=0.082）。不加甲泼尼龙时,3组中IVIG敏感184例,发生冠状动脉损伤44.0%;IVIG不敏感46例,加甲泼尼龙治疗后均敏感,发生冠状动脉损伤32.6%;加或不加甲泼尼龙治疗的KD患儿发生冠状动脉损伤差异无统计学意义（P=0.183）。3组发生冠状动脉损伤差异无统计学意义（P=0.623）。加或不加甲泼尼龙治疗时,IVIG 1 g·kg-1给药冠状动脉损伤的结局不比IVIG 2 g·kg-1给药差,在药费上减少了一半,如仍不敏感还可选择甲泼尼龙或再次IVIG 1 g·kg-1给药。结论:IVIG无反应的KD患儿中,IVIG 2 g·kg-1比IVIG 1 g·kg-1治疗效果好,因经济条件等所限不能行IVIG 2 g·kg-1再治疗者,可选择先行IVIG 1 g·kg-1治疗,仍不敏感时可选择甲泼尼龙,也可选择再次IVIG 1 g·kg-1治疗。     

Time interval of measles vaccination in patients with Kawasaki disease treated with additional intravenous immune globulin

A standard treatment with a dose of 2 g/kg of intravenous immune globulin (IVIG) is sometimes ineffective in some patients with Kawasaki disease (KD), who are commonly treated with additional IVIG. An interval of 6 to 7 months in Japan and 11 months in the United States is recommended before vaccination against measles after IVIG treatment for KD, but it is not known how long after treatment with additional IVIG. We studied the persistence of measles antibody titers in six episodes of KD in five patients without history of measles infection or vaccination, 4 to 28 months of age, after additional infusion of IVIG. The total dose was 4 g/kg in five episodes and 6 g/kg in one episode. Enzyme immunoassay antibody titers against measles were still positive (400) in all patients tested 3 months after additional infusion of IVIG and positive in one patient and equivocal (200 and <400) in three patients after 6 months, but negative (<200) in all after 9 months following infusion. Neutralization test antibody titers against measles were still positive (1:4) in all patients 3 months after additional infusion of IVIG, but only one after 6 months, and negative (<1:4) in all after 9 months following infusion. Conclusion: we suggest that an appropriate interval between infusion of 4 g/kg of intravenous immune globulin and measles vaccination be 9 months. The 11-month interval recommended in the United States for 2 g/kg may be longer than necessary.Abbreviations EIA enzyme immunoassay - HI hemagglutination inhibition - IVIG intravenous immune globulin - KD Kawasaki disease - NT neutralization test