Background

Although intravenous immunoglobulin (IVIG) is effective therapy for Kawasaki disease, 10–20% of patients have recrudescent fever as a sign of persistent inflammation and require additional treatment. We aimed to compare infliximab with a second infusion of IVIG for treatment of resistant Kawasaki disease.

Methods

In this multicentre comparative effectiveness trial, patients (aged 4 weeks to 17 years) with IVIG resistant Kawasaki disease and fever at least 36 h after completion of their first IVIG infusion were recruited from 30 hospitals across the USA. Patients were randomly assigned (1:1) to second IVIG (2 g/kg over 8–12 h) or intravenous infliximab (10 mg/kg over 2 h without premedication), by using a randomly permuted block randomisation design with block size of two or four. Patients with fever 24 h to 7 days following completion of first study treatment crossed over to receive the other study treatment. The primary outcome measure was resolution of fever at 24 h after initiation of study treatment with no recurrence of fever attributed to Kawasaki disease within 7 days post-discharge. Secondary outcome measures included duration of fever from enrolment, duration of hospitalisation after randomisation, and changes in markers of inflammation and coronary artery Z score. Efficacy was analysed in participants who received treatment and had available outcome values. Safety was analysed in all randomised patients who did not withdraw consent. This clinical trial is registered with ClinicalTrials.gov, NCT03065244.

Findings

Between March 1, 2017, and Aug 31, 2020, 105 patients were randomly assigned to treatment and 103 were included in the intention-to-treat population (54 in the infliximab group, 49 in the second IVIG group). Two patients randomised to infliximab did not receive allocated treatment. The primary outcome was met by 40 (77%) of 52 patients in the infliximab group and 25 (51%) of 49 patients in the second IVIG infusion group (odds ratio 0·31, 95% CI 0·13–0·73, p=0·0076). 31 patients with fever beyond 24 h received crossover treatment: nine (17%) in the infliximab group received second IVIG and 22 (45%) in second IVIG group received infliximab (p=0·0024). Three patients randomly assigned to infliximab and two to second IVIG with fever beyond 24h did not receive crossover treatment. Mean fever days from enrolment was 1·5 (SD 1·4) for the infliximab group and 2·5 (2·5) for the second IVIG group (p=0·014). Mean hospital stay was 3·2 days (2·1) for the infliximab group and 4·5 days (2·5) for the second IVIG group (p<0·001). There was no difference between treatment groups for markers of inflammation or coronary artery outcome. 24 (44%) of 54 patients in the infliximab group and 33 (67%) of 49 in the second IVIG group had at least one adverse event. A drop in haemoglobin concentration of at least 2g/dL was seen in 19 (33%) of 58 patients who received IVIG as either their first or second study treatment (three of whom required transfusion) and in three (7%) of 43 who received only infliximab (none required transfusion; p=0·0028). Haemolytic anaemia was the only serious adverse events deemed definitely or probably related to study treatment, and was reported in nine (15%) of 58 patients who received IVIG as either their first or second study treatment and none who received infliximab only.

Interpretation

Infliximab is a safe, well tolerated, and effective treatment for patients with IVIG resistant Kawasaki disease, and results in shorter duration of fever, reduced need for additional therapy, less severe anaemia, and shorter hospitalisation compared with second IVIG infusion.

Funding

Patient Centered Outcomes Research Institute.

中文翻译：

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英夫利昔单抗与第二种静脉注射免疫球蛋白在美国治疗耐药性川崎病 (KIDCARE)：一项随机、多中心比较有效性试验

背景

尽管静脉注射免疫球蛋白 (IVIG) 是川崎病的有效治疗方法，但 10-20% 的患者有复发性发热作为持续炎症的征兆，需要额外治疗。我们旨在比较英夫利昔单抗与第二次静脉注射免疫球蛋白治疗耐药性川崎病的效果。

方法

在这项多中心有效性比较试验中，从美国 30 家医院招募了患有 IVIG 耐药川崎病且在完成首次 IVIG 输注至少 36 小时后发烧的患者（年龄 4 周至 17 岁）。通过使用块大小为两个或四个。完成第一个研究治疗后 24 小时至 7 天出现发热的患者交叉接受其他研究治疗。主要结局指标是研究治疗开始后 24 小时发热消退，且出院后 7 天内没有因川崎病引起的发热复发。次要结局指标包括入组后的发热持续时间、随机分组后的住院持续时间以及炎症标志物和冠状动脉 Z 评分的变化。在接受治疗并具有可用结果值的参与者中分析了疗效。在所有未撤回同意的随机化患者中分析安全性。该临床试验已在 ClinicalTrials.gov 注册，NCT03065244。

发现

2017 年 3 月 1 日至 2020 年 8 月 31 日期间，105 名患者被随机分配接受治疗，103 名患者被纳入意向治疗人群（英夫利昔单抗组 54 名，IVIG 第二组 49 名）。随机接受英夫利昔单抗的两名患者没有接受分配的治疗。英夫利昔单抗组 52 名患者中的 40 名 (77%) 和第二次 IVIG 输注组 49 名患者中的 25 名 (51%) 达到主要结局（优势比 0·31，95% CI 0·13–0·73 , p=0·0076)。31 名发热超过 24 小时的患者接受了交叉治疗：英夫利昔单抗组中的 9 名 (17%) 接受了第二次 IVIG，第二次 IVIG 组中的 22 名 (45%) 接受了英夫利昔单抗 (p=0·0024)。随机分配到英夫利昔单抗组和 2 到第二次 IVIG 的 3 名发烧超过 24 小时的患者没有接受交叉治疗。英夫利昔单抗组的平均发烧天数为 1·5 (SD 1·4)，第二个 IVIG 组为 2·5 (2·5) (p=0·014)。英夫利昔单抗组的平均住院时间为 3·2 天 (2·1)，第二个 IVIG 组为 4·5 天 (2·5) (p<0·001)。在炎症或冠状动脉结果的标志物方面，治疗组之间没有差异。英夫利昔单抗组 54 名患者中的 24 名 (44%) 和第二 IVIG 组中 49 名患者中的 33 名 (67%) 至少发生了一次不良事件。接受 IVIG 作为第一次或第二次研究治疗的 58 名患者中有 19 名 (33%) 的血红蛋白浓度下降至少 2g/dL（其中 3 名需要输血），43 名患者中有 3 名 (7%)仅接受英夫利昔单抗（不需要输血；p=0·0028）。

解释

英夫利昔单抗对 IVIG 耐药川崎病患者是一种安全、耐受性良好且有效的治疗方法，与第二次 IVIG 输注相比，可缩短发热持续时间、减少对额外治疗的需求、减轻严重的贫血以及更短的住院时间。

资金

以患者为中心的结果研究所。