Inflammatory biomarkers in COVID-19-associated multisystem inflammatory syndrome in children, Kawasaki disease, and macrophage activation syndrome: a cohort study.
Inflammatory biomarkers in COVID-19-associated multisystem inflammatory syndrome in children, Kawasaki disease, and macrophage activation syndrome: a cohort study.
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DOI：
10.1016/s2665-9913(21)00139-9
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发表时间：
2021-08
期刊：
影响因子：
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通讯作者：
Schulert GS
中科院分区：
文献类型：
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作者：
Rodriguez-Smith JJ;Verweyen EL;Clay GM;Esteban YM;de Loizaga SR;Baker EJ;Do T;Dhakal S;Lang SM;Grom AA;Grier D;Schulert GS
儿童多系统炎症综合征（MIS-C）是一种可能危及生命的高度炎症综合征，发生在原发性SARS-CoV-2感染后。MIS-C的发病机制尚不明确，具体的炎症生物标志物模式是否可以区分MIS-C与其他炎症过度综合征，包括川崎和巨噬细胞活化综合征（MAS），是未知的。因此，我们旨在研究炎症生物标志物是否可用于区分这些疾病。我们研究了MIS-C和川崎病患者的前瞻性队列，以及根据既定指南诊断的新发全身性幼年特发性关节炎（JIA）和与全身性JIA相关的MAS（JIA-MAS）患者的既定队列。本研究在辛辛那提儿童医院医学中心（辛辛那提，OH，USA）进行。通过ELISA评估临床和实验室特征以及S100 A8/A9、S100 A12、白细胞介素（IL）-18、趋化因子（C-X-C基序）配体9（CXCL 9）和IL-6浓度，并使用参数和非参数检验和受试者工作特征曲线分析进行比较。在2019年4月30日至2020年12月14日期间，我们入组了19例MIS-C患者（中位年龄9·0岁[IQR 4·5-15·0]; 8例[42%]女孩和11例[58%]男孩）和9例川崎患者（中位年龄2·0岁[2·0-4·0]; 7例[78%]女孩和2例[22%]男孩）。MIS-C和川崎病患者的S100蛋白和IL-18浓度相似，但MIS-C患者的IFNγ诱导的CXCL 9中位浓度显著较高（1730 pg/mL [IQR 604-6300] vs 278 pg/mL [54-477]; p=0·038）。通过CXCL 9浓度（高vs低）对MIS-C患者进行分层，发现临床和实验室表现的严重程度不同。与MIS-C和低CXCL 9浓度的患者相比，更多CXCL 9浓度高的患者发生急性肾损伤（10人中有6人[60%] vs 5人中无[0%]），精神状态改变（10个中有4个[40%] vs 5个中没有[0%]），休克（10例中9例[90%] vs 5例中2例[40%]）和心肌功能障碍（10例中5例[50%] vs 5例中1例[20%]）;这些患者的全身炎症标志物浓度也较高，血细胞减少和凝血功能障碍的严重程度增加。相比之下，MIS-C和低CXCL 9浓度的患者与川崎患者相似，包括冠状动脉受累的频率。S100 A8/A9、S100 A12和IL-18浓度升高也有助于区分系统性JIA和川崎，具有较高的敏感性和特异性。我们的研究结果显示MIS-C与川崎的区别主要在于CXCL 9浓度升高。按CXCL 9浓度高或低对MIS-C患者进行分层，为重度MIS-C患者的MAS样病理生理学提供了支持，提出了诊断和治疗的新方法。辛辛那提儿童研究基金会、国家关节炎、肌肉骨骼和皮肤病研究所/国家卫生研究院、德国研究共同体和Jellin家庭基金会。
Multisystem inflammatory syndrome in children (MIS-C) is a potentially life-threatening hyperinflammatory syndrome that occurs after primary SARS-CoV-2 infection. The pathogenesis of MIS-C remains undefined, and whether specific inflammatory biomarker patterns can distinguish MIS-C from other hyperinflammatory syndromes, including Kawasaki disease and macrophage activation syndrome (MAS), is unknown. Therefore, we aimed to investigate whether inflammatory biomarkers could be used to distinguish between these conditions. We studied a prospective cohort of patients with MIS-C and Kawasaki disease and an established cohort of patients with new-onset systemic juvenile idiopathic arthritis (JIA) and MAS associated with systemic JIA (JIA-MAS), diagnosed according to established guidelines. The study was done at Cincinnati Children's Hospital Medical Center (Cincinnati, OH, USA). Clinical and laboratory features as well as S100A8/A9, S100A12, interleukin (IL)-18, chemokine (C-X-C motif) ligand 9 (CXCL9), and IL-6 concentrations were assessed by ELISA and compared using parametric and non-parametric tests and receiver operating characteristic curve analysis. Between April 30, 2019, and Dec 14, 2020, we enrolled 19 patients with MIS-C (median age 9·0 years [IQR 4·5–15·0]; eight [42%] girls and 11 [58%] boys) and nine patients with Kawasaki disease (median age 2·0 years [2·0–4·0]); seven [78%] girls and two [22%] boys). Patients with MIS-C and Kawasaki disease had similar S100 proteins and IL-18 concentrations but patients with MIS-C were distinguished by significantly higher median concentrations of the IFNγ-induced CXCL9 (1730 pg/mL [IQR 604–6300] vs 278 pg/mL [54–477]; p=0·038). Stratifying patients with MIS-C by CXCL9 concentrations (high vs low) revealed differential severity of clinical and laboratory presentation. Compared with patients with MIS-C and low CXCL9 concentrations, more patients with high CXCL9 concentrations had acute kidney injury (six [60%] of ten vs none [0%] of five), altered mental status (four [40%] of ten vs none [0%] of five), shock (nine [90%] of ten vs two [40%] of five), and myocardial dysfunction (five [50%] of ten vs one [20%] of five); these patients also had higher concentrations of systemic inflammatory markers and increased severity of cytopenia and coagulopathy. By contrast, patients with MIS-C and low CXCL9 concentrations resembled patients with Kawasaki disease, including the frequency of coronary involvement. Elevated concentrations of S100A8/A9, S100A12, and IL-18 were also useful in distinguishing systemic JIA from Kawasaki disease with high sensitivity and specificity. Our findings show MIS-C is distinguishable from Kawasaki disease primarily by elevated CXCL9 concentrations. The stratification of patients with MIS-C by high or low CXCL9 concentrations provides support for MAS-like pathophysiology in patients with severe MIS-C, suggesting new approaches for diagnosis and management. Cincinnati Children's Research Foundation, National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health, the Deutsche Forschungsgemeinschaft, and The Jellin Family Foundation.