Objectives: Varicella-zoster virus (VZV) is one of the most common etiologies of viral meningitis/encephalitis. The early clinical manifestations and cerebrospinal fluid (CSF) changes of VZV meningitis/encephalitis lack specificity, and it is easy to be misdiagnosed as other viral encephalitides or tuberculous meningitis. This study aims to investigate whether the clinical characteristics, CSF analysis findings, and CSF cytokine levels could distinguish VZV meningitis/encephalitis from central nervous system (CNS) herpes simplex virus (HSV) and Mycobacterium tuberculosis (MTB) infections.
Methods: The medical records from 157 CNS infections, including 49 HSV (45 HSV-1, 4 HSV-2), 55 VZV, and 53 MTB infections between January 2018 and June 2021 in the Cytology Laboratory, Department of Neurology, Third Xiangya Hospital of Central South University were retrospectively reviewed. The data of 3 groups included demographic characteristics, laboratory results, radiographic findings, and outcomes. The levels of 12 cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, IFN-γ, IFN-α, and TNF-α) in the CSF of 68 patients (13 HSV, 22 VZV, and 33 MTB infection cases) were quantified. Clinical and laboratory data were compared among the 3 groups.
Results: The most common clinical manifestations in the 3 groups were fever, headache, vomiting, and neck stiffness. The clinical manifestations of HSV and VZV CNS disease were similar, although fever and altered consciousness were less common in the VZV group than those in the HSV and MTB groups (63.6% vs 87.8% vs 96.2%, P<0.001, and 14.5% vs 26.5% vs 47.2%, P=0.004, respectively). Seven patients (7/55, 12.7%) presented cutaneous zoster in the VZV group. CSF leukocyte count was significantly higher in the VZV group (230×106 cells/mL) and MTB groups (276×106 cells/mL) than that in the HSV group (87×106 cells/mL, P=0.002). CSF protein level was significantly higher in the VZV than that in the HSV group (1 034 mg/L vs 694 mg/L, P=0.011) but lower than that in the MTB group (1 744 mg/L, P<0.001). IL-6 (VZV vs HSV vs MTB: 2 855.93 pg/mL vs 2 128.26 pg/mL vs 354.77 pg/mL, P=0.029) and IL-8 (VZV vs HSV vs MTB: 4 001.46 pg/mL vs 1 578.11 pg/mL vs 1 023.25 pg/mL, P=0.046) levels were significantly different among the 3 groups and were elevated in the VZV group.Post hoc analysis revealed that IL-6 and IL-8 were significantly higher in the VZV group than those in the MTB group (P=0.002 and P=0.035, respectively), but not in the HSV group (P>0.05).
Conclusions: VZV meningitis/encephalitis presents with CSF hypercellularity and proteinemia, challenging the classical view of CSF profiles in viral encephalitis. CSF IL-6 and IL-8 levels are elevated in patients with VZV meningitis/encephalitis, indicating a more intense inflammatory response in these patients.
目的: 水痘-带状疱疹病毒(varicella-zoster virus，VZV)是最常见引起病毒性脑膜炎/脑炎的致病菌之一.VZV脑膜炎/脑炎早期临床表现和脑脊液(cerebrospinal fluid，CSF)变化缺乏特异性，容易被误诊为其他病毒性脑炎或结核性脑膜炎。因此本研究探讨VZV脑膜炎/脑炎与中枢神经系统(central nervous system，CNS)单纯疱疹病毒(herpes simplex virus，HSV)、结核分枝杆菌(Mycobacteriumtuberculosis，MTB)感染的临床特征、CSF结果及CSF细胞因子水平的区别。方法: 回顾性研究2018年1月至2021年6月中南大学湘雅三医院神经内科细胞学实验室确诊的157例CNS感染患者的医疗记录，其中感染HSV 49例(HSV-1 45例，HSV-2 4例)，VZV 55例，MTB 53例。收集的3组数据，包括人口学特征、实验室结果、影像学结果和疾病结局。对68例(13例HSV，22例VZV和33例MTB)患者CSF中的12个细胞因子(IL-1β，IL-2，IL-4，IL-5，IL-6，IL-8，IL-10，IL-12p70，IL-17，IFN-γ，IFN-α，TNF-α)水平进行检测。比较3组患者的临床和实验室资料。结果: 3组患者最常见的临床表现是发热、头痛、呕吐和颈部僵硬。HSV和VZV CNS疾病的临床表现相似。与HSV和MTB组相比，VZV组发热(63.6% vs 87.8% vs 96.2%，P<0.001)和意识改变(14.5% vs 26.5% vs 47.2%，P=0.004)更少见。VZV组有7例(12.7%)患者出现皮肤带状疱疹。VZV组(230×106/mL)和MTB组(276×106/mL)CSF白细胞计数显著高于HSV组(87×106/mL，P=0.002)，此外，VZV组CSF蛋白水平显著高于HSV组(1 034 mg/L vs 694 mg/L，P=0.011)，但低于MTB组(1 744 mg/L，P<0.001)。所测细胞因子中，3组IL-6(VZV vs HSV vs MTB：2 855.93 pg/mL vs 2 128.26 pg/mL vs 354.77 pg/mL，P=0.029)、IL-8(VZV vs HSV vs MTB：4 001.46 pg/mL vs 1 578.11 pg/mL vs 1 023.25 pg/mL，P=0.046)水平比较差异有统计学意义，其中VZV组IL-6和IL-8水平显著升高。事后分析显示：VZV组的IL-6和IL-8明显高于MTB组(分别为P=0.002和P=0.035)，但与HSV组相比差异无统计学意义(P>0.05)。结论: VZV脑膜炎/脑炎表现为CSF高细胞数和高蛋白质，这改变了我们对病毒性脑炎CSF谱的传统认识。VZV脑膜炎/脑炎患者CSF IL-6和IL-8水平升高，提示这些患者的炎症反应更为强烈。.
目的: 水痘-带状疱疹病毒(varicella-zoster virus，VZV)是最常见引起病毒性脑膜炎/脑炎的致病菌之一.VZV脑膜炎/脑炎早期临床表现和脑脊液(cerebrospinal fluid，CSF)变化缺乏特异性，容易被误诊为其他病毒性脑炎或结核性脑膜炎。因此本研究探讨VZV脑膜炎/脑炎与中枢神经系统(central nervous system，CNS)单纯疱疹病毒(herpes simplex virus，HSV)、结核分枝杆菌(Mycobacterium tuberculosis，MTB)感染的临床特征、CSF结果及CSF细胞因子水平的区别。
方法: 回顾性研究2018年1月至2021年6月中南大学湘雅三医院神经内科细胞学实验室确诊的157例CNS感染患者的医疗记录，其中感染HSV 49例(HSV-1 45例，HSV-2 4例)，VZV 55例，MTB 53例。收集的3组数据，包括人口学特征、实验室结果、影像学结果和疾病结局。对68例(13例HSV，22例VZV和33例MTB)患者CSF中的12个细胞因子(IL-1β，IL-2，IL-4，IL-5，IL-6，IL-8，IL-10，IL-12p70，IL-17，IFN-γ，IFN-α，TNF-α)水平进行检测。比较3组患者的临床和实验室资料。
结果: 3组患者最常见的临床表现是发热、头痛、呕吐和颈部僵硬。HSV和VZV CNS疾病的临床表现相似。与HSV和MTB组相比，VZV组发热(63.6% vs 87.8% vs 96.2%，P<0.001)和意识改变(14.5% vs 26.5% vs 47.2%，P=0.004)更少见。VZV组有7例(12.7%)患者出现皮肤带状疱疹。VZV组(230×106/mL)和MTB组(276×106/mL)CSF白细胞计数显著高于HSV组(87×106/mL，P=0.002)，此外，VZV组CSF蛋白水平显著高于HSV组(1 034 mg/L vs 694 mg/L，P=0.011)，但低于MTB组(1 744 mg/L，P<0.001)。所测细胞因子中，3组IL-6(VZV vs HSV vs MTB：2 855.93 pg/mL vs 2 128.26 pg/mL vs 354.77 pg/mL，P=0.029)、IL-8(VZV vs HSV vs MTB：4 001.46 pg/mL vs 1 578.11 pg/mL vs 1 023.25 pg/mL，P=0.046)水平比较差异有统计学意义，其中VZV组IL-6和IL-8水平显著升高。事后分析显示：VZV组的IL-6和IL-8明显高于MTB组(分别为P=0.002和P=0.035)，但与HSV组相比差异无统计学意义(P>0.05)。
结论: VZV脑膜炎/脑炎表现为CSF高细胞数和高蛋白质，这改变了我们对病毒性脑炎CSF谱的传统认识。VZV脑膜炎/脑炎患者CSF IL-6和IL-8水平升高，提示这些患者的炎症反应更为强烈。
Keywords: central nervous system; clinical feature; cytokine; herpes simplex virus; infection; tuberculous meningitis; varicella-zoster virus.