【摘要】 目的 分析结核性脑膜炎(tuberculous meningItis,TBM)患者脑脊液miR-200a和miR-4652-3p表达及其对疾病严重程度和预后的预测价值。方法 选择2018年1月～2022年12月于青岛市胸科医院就诊的187例结核性脑膜炎患者,按照病情程度分为Ⅰ期(n=62)、Ⅱ期(n=76)和Ⅲ期(n=49),根据预后情况分为预后良好组(n=131)和预后不良组(n=56)。qRT-PCR法检测脑脊液miR-200a和miR-4652-3水平表达。Spearman法分析miR-200a和miR-4652-3p与临床资料间相关性;ROC曲线分析脑脊液miR-200a和miR-4652-3p水平对结核性脑膜炎患者疾病严重程度及预后的预测价值。多因素Logistic回归分析预后不良影响因素。结果 Ⅰ期、Ⅱ期、Ⅲ期结核性脑膜炎患者脑脊液miR-200a (1.05±0.14,0.91±0.14,0.76±0.13)和miR-4652-3p (0.92±0.11,0.78±0.11,0.65±0.10)表达水平依次降低,差异具有统计学意义(F=61.079,87.203,均P<0.001)。预后良好组患者脑脊液miR-200a(0.95±0.14)和miR-4652-3p(0.82±0.11)表达水平显著高于预后不良组患者(0.84±0.13,0.73±0.10),差异具有统计学意义(t=5.025,5.262,均P<0.05);预后良好患者脑脊液腺苷脱氨酶和TNF-α,IL-23,LTB4,CRP,mRS评分显著低于预后不良患者,差异具有统计学意义(t=5.649,7.721,11.150,9.455,11.314,14.407,均P<0.05)。结核性脑膜炎患者脑脊液miR-200a和miR-4652-3p水平呈正相关(r=0.405,P <0.001);miR-200a,miR-4652-3p与LTB4,TNF-α,CRP,mRS评分,IL-23,腺苷脱氨酶呈负相关(r=-0.472,-0.466,-0.461,-0.435,-0.422,-0.419;-0.459,-0.531,-0.471,-0.417,-0.513,-0.408,均P <0.05)。miR-200a,miR-4652-3p预测患者疾病严重程度的AUC (95%CI)分别为0.881 (0.825～0.923)和0.878 (0.822～0.921),二者联合预测的AUC (95%CI)为0.945 (0.902～0.973),高于单项检测,差异具有统计学意义(Z=3.008,2.960,all P=0.003)。脑脊液miR-200a和miR-4652-3p水平评估患者预后不良的AUC (95%CI)为0.749 (0.681～0.809)和0.756 (0.688-0.816),二者联合评估患者预后不良的AUC(95%CI))为0.839 (0.778～0.889),高于二者单独检测,差异有统计学意义(Z=2.994,2.697,P=0.003,0.007)。腺苷脱氨酶[OR (95%CI):1.106 (1.033～1.185)]、miR-200a[OR (95%CI):0.529 (0.369～0.744)]、miR-4652-3p[OR(95%CI):0.471 (0.310～0.715)]、CRP[OR(95%CI):4.423(1.459～13.412)]、TNF-α [OR(95%CI):1.196(1.061～1.348)]、IL-23[OR (95%CI):4.809 (1.086～3.013)]和LTB4[OR (95%CI):1.327 (1.064～1.655)]为结核性脑膜炎患者预后不良的影响因素(均P<0.05)。结论 结核性脑膜炎患者脑脊液miR-200a和miR-4652-3p表达下调,与疾病严重程度及预后密切相关,二者联合能较好地预测结核性脑膜炎严重程度及预后,具有一定临床价值。更多还原

【Abstract】 Objective To analyze the expression of microRNA(miR)-200a and miR-4652-3p in cerebrospinal fluid of patients with tuberculous meningitis(TBM) and their predictive value for disease severity and prognosis.Methods A total of 187patients with tuberculous meningitis who visited Qingdao Chest Hospital from January 2018 to December 2022 were regarded and separated into stage Ⅰ(n=62),stage Ⅱ(n=76) and stage Ⅲ(n=49) according to the severity of the condition.There were 131cases in the good prognosis group and 56 cases in the poor prognosis group according to the prognosis.The qRT-PCR method was applied to detect the expression levels of miR-200a and miR-4652-3p in cerebrospinal fluid.Spearman method was used to analyze correlation among miR-200a,miR-4652-3p and clinical data.ROC curve was applied to analyze the predictive value of cerebrospinal fluid miR-200a and miR-4652-3p levels in evaluating the severity and prognosis of tuberculosis meningitis patients.Multivariate logistic regression was applied to analyze the influencing factors of poor prognosis in patients.Results The expression levels of miR-200a(1.05 ± 0.14,0.91 ± 0.14,0.76 ± 0.13) and miR-4652-3p(0.92 ± 0.11,0.78 ± 0.11,0.65 ± 0.10) in the cerebrospinal fluid of patients with stage Ⅰ,Ⅱ,and Ⅲ tuberculous meningitis were decreased sequentially,and the differences were significant(F=61.079,87.203,all P<0.05).The expression levels of miR-200a(0.95 ± 0.14) and miR-4652-3p(0.82 ± 0.11)in cerebrospinal fluid of patients with good prognosis tuberculous meningitis were higher than those of patients with poor rognosis(0.84±0.13,0.73±0.10),and the differences were statistically significant(t=5.025,5.262,all P<0.05),while the levels of cerebrospinal fluid adenosine deaminase,TNF-α,IL-23,LTB4,CRP and mRS scores in patients with good prognosis were lower than those inpatients with poor prognosis(t=5.649,7.721,11.150,9.455,11.314,14.407,all P<0.05).There was a positive correlation between the levels of miR-200a and miR-4652-3p in cerebrospinal fluid of patients with tuberculous meningitis(r=0.405,P<0.001).The levels of miR-200a and miR-4652-3p in cerebrospinal fluid were negatively correlated with LTB4,TNF-α,CRP,mRS scores,IL-23 and adenosine deaminase(r=-0.472,-0.466,-0.461,-0.435,-0.422,-0.419;-0.459,-0.531,-0.471,-0.417,-0.513,-0.408,all P <0.05).The AUC(95%CI) of miR-200a and miR-4652-3p to assess disease severity were0.881(0.825～0.923) and 0.878(0.822～0.921),respectively.The AUC(95%CI) of both combination in assessing the severity of patients was 0.945(0.902～0.973),which was higher than the single detection,and the differences were significant(Z=3.008,2.960,all P=0.003).The AUC(95%CI) of poor prognosis patients evaluated by cerebrospinal fluid miR-200a and miR-4652-3p levels were 0.749(0.681～0.809) and 0.756(0.688～0.816),and the AUC of poor prognosis patients evaluated by both combination was 0.839(0.778～0.889),which was higher than that measured separately,and the differences were significant(Z=2.994,2.697,P=0.003,0.007).Adenosine deaminase [OR(95%CI):1.106(1.033～1.185)],miR-200a [OR(95%CI):0.529(0.369～0.744)],miR-4652-3p [OR(95%CI):0.471(0.310～0.715)],C-reactive protein [OR(95%CI):4.423(1.459～13.412)],TNF-α [OR(95%CI):1.196(1.061～1.348)],IL-23 [OR(95%CI):4.809(1.086～3.013)],and LTB4 [OR(95%CI):1.327(1.064～1.655)] were influencing factors for poor prognosis in patients with tuberculous meningitis(all P<0.05).Conclusion The expressions of miR-200a and miR-4652-3p in cerebrospinal fluid of patients with tuberculous meningitis were down-regulated,and they were closely related to the severity and prognosis of the disease.The combination of the miR-200a and miR-4652-3p could better predict the severity and prognosis of tuberculous meningitis,which may have a certain clinical value.更多还原