Barstad Bjørn, Henningsson Anna J, Tveitnes Dag, Ushakova Anastasia, Noraas Sølvi, Ask Ingvild S, Bosse Franziskus J, Øymar Knut
Department of Pediatric and Adolescent Medicine, Stavanger University Hospital, Stavanger, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway.
Division of Clinical Microbiology, Laboratory Medicine, Jönköping Region Jönköping County, Sweden; Department of Clinical and Experimental Medicine, Linköping University, Sweden; Division of Clinical Microbiology, Department of Clinical and Experimental Medicine, Linköping University Hospital, Linköping, Sweden.
Cytokine. 2020 Mar 18;130:155023. doi: 10.1016/j.cyto.2020.155023.
Lyme neuroborreliosis (LNB) is characterized by cerebrospinal fluid (CSF) inflammation with several cytokines/chemokines and B-lymphocytes. Clinically, LNB in children may be difficult to discriminate from non-Lyme aseptic meningitis (NLAM). We aimed to identify CSF cytokine/chemokine patterns in children with LNB, NLAM and controls and elucidate the diagnostic value of these cytokines/chemokines alone or in combination to discriminate between LNB and NLAM.
Children with symptoms suggestive of LNB were included prospectively and categorized as LNB, NLAM or controls (no pleocytosis). Cytokines/chemokines in CSF were measured by multiplex bead assays and levels were compared between the three groups by nonparametric statistical tests. Previous results from the same children on the established biomarker, CXCL13, were included in the statistical analyses. The diagnostic properties of cytokines/chemokines to discriminate between LNB and NLAM were determined by receiver operating characteristic curve analyses with estimates of area under curve (AUC). To explore diagnostic properties of combinations of cytokines/chemokines, prediction models based on logistic regression were used.
We included 195 children with LNB (n = 77), NLAM (n = 12) and controls (n = 106). Children with LNB had higher CSF levels of CCL19, CCL22 and CXCL13 compared to NLAM and controls, whereas INFγ was higher in NLAM than in LNB and controls. CXCL13 was the superior single cytokine/chemokine to discriminate LNB from NLAM (AUC 0.978). The combination CXCL13/CCL19 (AUC 0.992) may possibly improve the specificity for LNB, especially for children with moderate CXCL13 levels.
The intrathecal immune reaction in LNB is characterized by B cell associated chemokines. Whether the combination CXCL13/CCL19 further improves discrimination between LNB and NLAM beyond the diagnostic improvements by CXCL13 alone needs to be tested in new studies.
莱姆病神经疏螺旋体病（LNB）的特征是脑脊液（CSF）出现炎症，伴有多种细胞因子/趋化因子和B淋巴细胞。临床上，儿童LNB可能难以与非莱姆无菌性脑膜炎（NLAM）相区分。我们旨在确定LNB、NLAM患儿及对照组脑脊液中的细胞因子/趋化因子模式，并阐明这些细胞因子/趋化因子单独或联合使用对区分LNB和NLAM的诊断价值。
前瞻性纳入有LNB症状提示的儿童，并分为LNB组、NLAM组或对照组（无细胞增多）。通过多重微珠分析测定脑脊液中的细胞因子/趋化因子，并通过非参数统计检验比较三组之间的水平。将同一批儿童先前关于既定生物标志物CXCL13的结果纳入统计分析。通过曲线下面积（AUC）估计的受试者工作特征曲线分析来确定细胞因子/趋化因子区分LNB和NLAM的诊断特性。为了探索细胞因子/趋化因子组合的诊断特性，使用基于逻辑回归的预测模型。
我们纳入了195名儿童，其中LNB组77名、NLAM组12名和对照组106名。与NLAM组和对照组相比，LNB组儿童脑脊液中CCL19、CCL22和CXCL13水平更高，而NLAM组的INFγ高于LNB组和对照组。CXCL13是区分LNB与NLAM的最佳单一细胞因子/趋化因子（AUC 0.978）。CXCL13/CCL19组合（AUC 0.992）可能会提高LNB的特异性，尤其是对于CXCL13水平中等的儿童。
LNB的鞘内免疫反应以B细胞相关趋化因子为特征。CXCL13/CCL19组合能否在CXCL13单独诊断改善的基础上进一步提高LNB和NLAM之间的鉴别能力，有待新的研究进行验证。
