Front Immunol:HIV阴性免疫活性隐球菌脑膜炎患者感染后炎症反应综合征的免疫学预测指标

2022-06-23 从医路漫漫 MedSci原创

HIV

在开始HAART后,约10%至42%的HIV-CM患者出现新的症状或现有症状恶化,并且有效的抗真菌治疗无效,这被称为隐球菌相关免疫重建炎症综合征(IRIS)。

背景:隐球菌脑膜炎(CM)是一种重要的世界性机会性感染。每年,大约有180,000人死于艾滋病,占艾滋病相关死亡的15%。由于高效抗逆转录病毒疗法(HAART),与艾滋病毒相关的新型隐球菌感染相对减少。然而,在开始HAART后,约10%至42%的HIV-CM患者出现新的症状或现有症状恶化,并且有效的抗真菌治疗无效,这被称为隐球菌相关免疫重建炎症综合征(IRIS)。类似的免疫反应也可能发生在先前健康的个体中,这被称为感染后炎症反应综合征(PIIRS) 。PIIRS的临床表现类似于CM的复发和持续感染。因此,CM患者PIIRS的早期识别和治疗是至关重要的。

在我们之前的研究中,我们发现与无PIIRS的患者相比,HIV未感染和非移植的男性CM患者的听力损失、脑室-腹腔分流(VPS)、两性霉素B治疗、高脑脊液(CSF)压和隐球菌计数的发生率增加。此外,我们发现基线听力损伤和高脑脊液压(≥230 mmH2O)是PIIRS的临床有用预测因子,但该研究没有调查血清免疫因子和炎症相关的细胞学和生化特征作为预测因子的可能性。

目的:研究免疫活性隐球菌性脑膜炎(CM)患者血清免疫因子与感染后炎症反应综合征(PIIRS)的相关性,探讨血清免疫因子是否可用于预测PIIRS的发展。

方法:从347例CM患者中选择30例PIIRS患者和87例非PIIRS患者。我们分析了一般临床信息和免疫学指标(细胞因子、补体、免疫球蛋白、炎症、相关细胞学和生化指标)。Spearman相关分析和主成分分析用于探讨变量对PIIRS的影响。此外,通过随机森林分类器识别变量,以预测PIIRS的发展。生存分析证实了预测因子的临床价值。

结果:与无PIIRS的患者相比,PIIRS患者的基线血清白细胞介素-6 (IL-6,P = 0.006)、免疫球蛋白M (IgM,P = 0.004)较低,而基线中性粒细胞比率较高(P <0.001)。基线中性粒细胞比率(r = 0.359,P = 0.001)、IgM(r = 0.272,P = 0.025)和IL-6(r = 0.259,P = 0.027)与PIIRS显著相关。结合主成分分析和随机森林结果,中性粒细胞比率、中性粒细胞计数、IgM、IL-6和D-二聚体是有用的预测因子。随机森林预测的准确率为75.00%,AUC和灵敏度分别为0.76和70%。从治疗到PIIRS时间的进一步生存分析显示,PIIRS的发展与IgM(超过98天的治疗)和中性粒细胞比率/计数相关。

表1 HIV阴性隐球菌性脑膜炎患者首次就诊(基线)与PIIRS发作的比较。

图1 基线数据中具有显著统计差异的每个变量的趋势。(A)散点图显示了PIIRS和非PIIRS患者之间NETR、IL-6和IgM的显著差异。(B)散点图显示了基线和PIIRS发作时患者的NETR、IL-6、NETC、IgM和D-二聚体的显著差异。数据(A)采用双样本Wilcoxon秩和检验;数据(B)采用Wilcoxon符号秩检验;P <0.05表示有统计学差异,P <0.01表示有显著统计学差异。

表2 PIIRS发病具体情况的Spearman相关分析

图2 Spearman相关分析显示与PIIRS有较强相关性的变量。水平直方图显示研究变量与PIIRS之间的相关性,柱子越长,相关性越高。横坐标的负值表示负相关,而正值表示正相关。*有显著统计学差异的变量(p<0.05)。

图3主成分分析筛选出与PIIRS发展相关的重要特征变量。(A)通过主成分分析将样本简化为二维后,观察样本在主成分分析的前两个主成分中的投影分布;红点1代表PIIRS患者,绿点2代表没有PIIRS患者;(B)我们分析前两个维度的特征重要性,特征重要性显示在面板(B)中,列越长,重要性越高。

图5 从治疗到PIIRS的Kaplan-Meier时间曲线,按IgM、NETR、IL-6和d-d分组。在曲线的跳跃点观察PIIRS病例,最多随访600天。每个变量按参考范围的最大值分组。(A)从治疗到PIIRS的IgM (≤2.2克/升)与IgM (>2.2克/升);(B)当随访时间少于98天时,从治疗到PIIRS的IgM (≤2.2 g/L)与IgM(> 2.2g/L);(C)当随访时间超过98天时,从治疗到PIIRS的IgM (≤2.2 g/L)与IgM(> 2.2g/L);(D)从治疗到PIIRS,NETR (≤70%)对NETR(> 70%);(E)从治疗到PIIRS的IL-6 (≤7 pg/ml)与IL-6(> 7pg/ml);(F)从治疗到PIIRS的d-d (>0.5毫克/毫升)与d-d (≤0.5毫克/毫升)。

结论:基线中性粒细胞比率、中性粒细胞计数、IgM、IL-6和D-二聚体可能是HIV阴性免疫活性CM患者PIIRS的临床有用预测因子。

原文出处:Wang Y,  Wei H,  Shen L,et al.Immunological Predictors of Post Infectious Inflammatory Response Syndrome in HIV-Negative Immunocompetent Cryptococcal Meningitis.Front Immunol 2022;13

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    2022-06-23 xugc

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