Data_Sheet_1_Risk factors and coronary artery outcomes of coronary artery aneurysms differing in size and emergence time in children with Kawasaki disease.docx

Coronary artery aneurysm (CAA) is a serious cardiac complication arising from Kawasaki disease (KD) and is becoming the leading cause of acquired heart disease in children. The aim of this study was to determine the potential risk factors associated with coronary artery aneurysms (CAAs), which differ in size and emergence time, and track its regression within 3 years of onset. The laboratory data, clinical features, and coronary artery outcomes of patients, who were diagnosed with KD and received treatment from January 2003 to January 2019 were retrospectively analyzed. A total of 484 pediatric patients with KD were examined during the study period. Among them, 130 (26.9%) presented with CAA, including mid- to large-sized CAA in 38 patients (7.9%) and de novo CAA after intravenous immunoglobulin (IVIG) treatment in 22 patients (4.5%). Albumin-to-globin (A/G) ratio was significantly negatively associated with the absolute internal diameter of coronary artery at 1 month of onset and may be used as a predictor of mid- to large-sized CAA development in patients with KD. The area under the receiver operating characteristic curve was 0.637 (95% confidence interval: 0.551–0.724), and a cutoff of 1.32 yielded a sensitivity and specificity of 79 and 49%, respectively, for predicting mid- to large-sized CAA development. De novo CAA after IVIG may lead to an increased risk of developing progressive CAA [13 (59.1%) of 22 vs. 31 (28.7%) of 108; P = 0.006] and had significantly greater changes in both the magnitude of CAA dimension variation and maximum z-score of the coronary arteries at 2 and 4 weeks and then 3 months after onset (P < 0.001). Kaplan–Meier survival analysis revealed that the estimated median time of aneurysm persistence was significantly higher in the progressive CAA group than in the non-progressive CAA group (25 vs. 4 months, P < 0.001), as well as among the three groups of patients (giant CAA > medium-sized CAA > small-sized CAA, P < 0.001). Children with KD who had low A/G ratio were more likely to develop mid- to large-sized CAA. Nevertheless, de novo CAA after IVIG treatment may increase the risk of more severe arterial damage and development of progressive coronary artery damage; and both mid- to large-sized and de novo CAA could dramatically prolong coronary artery normalization time. Thus, aggressive risk modifications should be employed, and close monitoring with frequent echocardiography is needed for this vulnerable patient population.

冠状动脉瘤（Coronary artery aneurysm, CAA）是川崎病（Kawasaki disease, KD）引发的严重心脏并发症，目前已成为儿童获得性心脏病的首要致病原因。本研究旨在明确与不同尺寸、不同发病时间的冠状动脉瘤相关的潜在危险因素，并追踪其在发病后3年内的消退转归。研究回顾性分析了2003年1月至2019年1月期间确诊为KD并接受治疗的患儿的实验室数据、临床特征及冠状动脉转归。研究期间共纳入484例KD患儿，其中130例（26.9%）合并CAA，包括38例（7.9%）中大型冠状动脉瘤，以及22例（4.5%）静脉注射免疫球蛋白（intravenous immunoglobulin, IVIG）治疗后新发的CAA。白蛋白/球蛋白（Albumin-to-globin, A/G）比值与发病1个月时的冠状动脉绝对内径呈显著负相关，可作为KD患儿发生中大型CAA的预测指标。受试者工作特征曲线下面积为0.637（95%置信区间：0.551~0.724），当截断值为1.32时，预测中大型CAA发生的灵敏度为79%、特异度为49%。IVIG治疗后新发的CAA可能增加进展性CAA的发生风险[22例中13例（59.1%） vs 108例中31例（28.7%）；P=0.006]，且在发病后2周、4周及3个月时，冠状动脉瘤直径变化幅度及冠状动脉最大Z值均出现显著升高（P<0.001）。Kaplan-Meier生存分析显示，进展性CAA组的动脉瘤持续中位时间显著高于非进展性CAA组（25个月 vs 4个月，P<0.001）；按冠状动脉瘤大小分组（巨大CAA>中型CAA>小型CAA），三组间的动脉瘤持续时间同样存在显著差异（P<0.001）。KD患儿若A/G比值较低，发生中大型CAA的风险更高。此外，IVIG治疗后新发的CAA可能加重动脉损伤，增加进展性冠状动脉损伤的风险；且中大型CAA与新发CAA均会显著延长冠状动脉恢复正常的时间。因此，针对这类高危患儿群体，应采取积极的风险干预措施，并通过频繁的超声心动图检查进行密切监测。