Abstract
Objective
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).
Conclusion
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.
Keywords: herpes simplex virus, varicella-zoster virus, tuberculous meningitis, central nervous system, infection, clinical feature, cytokine
Abstract
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: 单纯疱疹病毒, 水痘-带状疱疹病毒, 结核性脑膜炎, 中枢神经系统, 感染, 临床特征, 细胞因子
Varicella-zoster virus (VZV), a neurotropic α- herpesvirus, is the second most commonly identified pathogen responsible for encephalitis after herpes simplex virus (HSV)[1-3]. Primary VZV infection often causes chickenpox, after which VZV remains latent in cranial, dorsal root, and autonomic ganglia throughout life[4-5]. VZV encephalitis can arise during primary infection or on reactivation[6].
However, the lack of typical cutaneous changes in primary infection of up to 60% of patients with reactivated VZV may hinder the diagnosis[7]. In addition, some patients with VZV meningitis/encephalitis can easily be misdiagnosed as other viral encephalitides or tuberculous meningitis due to non-specific clinical signs and symptoms and cerebrospinal fluid (CSF) changes in the early phase[8-10]. Therefore, this study aims to identify the main clinical manifestations and CSF findings of VZV meningitis/encephalitis compared with CNS Mycobacterium tuberculosis (MTB) and HSV infections to increase our understanding of the clinical and laboratory features to minimize misdiagnosis, and to explain differences in the clinical presentation and immune mechanisms underlying these 3 different infections via examination of CSF cytokine levels.
1. Subjects and methods
1.1. Study design and patients
This retrospective study was performed from January 2018 to June 2021 in the Cytology Laboratory, Department of Neurology, the Third Xiangya Hospital of Central South University, China. Only patients with a confirmed microbiological diagnosis of CNS HSV, VZV, or MTB infection were included. The exclusion criteria were: 1) incomplete medical records for review, 2) lack of CSF for analysis, 3) combined with HIV infection, 4) bacterial, fungal, or non-infectious cause of meningitis, and 5) patients younger than 14 years of age. The study was approved by the Institutional Review Board of the Third Xiangya Hospital of Central South University (NO. 22019).
1.2. Definitions and data collection
CNS VZV/HSV infection was defined as: 1) clinical signs of encephalitis and/or meningitis, 2) VZV/HSV DNA in the CSF detected by polymerase chain reaction (PCR) or next-generation gene sequencing (NGS), and 3) a favorable outcome with supportive or antiviral treatment.
CNS MTB infection was defined as: 1) clinical signs of encephalitis and/or meningitis, 2) acid-fast bacilli in the CSF smear, a positive CSF culture, and/or positive PCR or NGS for MTB.
Meningitis was defined as the presence of the signs and symptoms of meningitis (fever, headache, and meningeal signs) and a leucocyte count >5×106/L. Encephalitis was defined as patients with similar CSF findings but with additional loss of consciousness, behavioral changes, seizures, focal neurological signs, electroencephalogram (EEG) abnormalities, or CNS imaging compatible with encephalitis.
The medical records of the included patients were reviewed. Data of the 3 groups were collected on basic demographics, underlying diseases or conditions, clinical manifestations (e.g., fever, headache, vomiting, cutaneous zoster, seizures, cognitive disorders, involuntary movements, mental disorder, altered consciousness, cranial nerve palsies, neck stiffness, pathological signs, duration of symptoms before admission), laboratory data, radiographic findings, and outcomes (modified Rankin scale for neurologic disability 0-2 points, modified Rankin scale 3-5 points, and in-hospital crude mortality).
1.3. Measurement of CSF cytokines
To further explain differences in clinical presentation and immune mechanisms, we examined cytokine levels in the CSF, and 68 patients (13 HSV, 22 VZV, and 33 MTB) had sufficient CSF for cytokine testing. A total of 2 mL CSF was collected in sterile tubes after lumbar puncture at enrollment and centrifuged at 300 g for 10 min. The supernatants were stored at -80 ℃ until analysis. Cytokines were detected by multiple microsphere flow immunofluorescence according to the manufacturer’s instructions (Qingdao Raisecare Biotechnology Co., Ltd, Shandong, China; lot number: 20190801). Levels of 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 were measured.
1.4. Statistical analysis
Statistical analysis was performed using SPSS 26.0 software (SPSS Inc., Chicago, IL, USA). Continuous variables were presented as means±standard deviation ( ±s) for normally distributed data or medians and interquartile ranges (IQR) for non-normally distributed data. If the cytokine concentrations were below the assay’s limit of detection, a value equal to the lower limit of quantitation (LLOQ) was reported. Categorical variables were reported as absolute and relative frequencies. One-way ANOVA (for continuous variables) or the Chi-square test (for categorical variables) were performed for multi-group comparisons. Duncan’s post hoc test was used when the variances were equal and the Games-Howell test when the variances were unequal. A P<0.05 was regarded as statistically significant.
2. Results
2.1. Clinical characteristics of the different infection groups
A total of 157 patients with CNS infections [49 HSV (45 HSV-1, 4 HSV-2), 55 VZV, and 53 MTB] were included in this retrospective study. The diagnostic results of NGS or PCR are shown in supplementary Table 1 (https://doi.org/10.11817/j.issn.1672-7347.2022.210725T1). The clinical characteristics of these patients are shown in Table 1. There were no significant differences in age and gender among the 3 groups. The most frequent acute symptoms (>60% of cases) in any group were fever, headache, vomiting, and neck stiffness, i.e., the main symptoms of intracranial infections, as expected. Fever and altered consciousness were less common in the VZV group than those in the HSV and MTB groups [35(63.6%) vs 43(87.8%) vs 51(96.2%), P<0.001; 8(14.5%) vs 13(26.5%) vs 25(47.2%), P=0.004, respectively]. Notably, cutaneous zoster was significantly more common in the VZV group (7/55, 12.7%) than that in the MTB group (0/53, 0%, P=0.022) but not in the HSV group (1/49, 2.0%, P=0.094). There were 7 patients with rash in the VZV group, of which 3 were elderly (>60 years) (1 had an immune disorder and was on long-term steroid medication, and 2 had a history of underlying hypertension and coronary heart disease), 1 was a 53-year-old male with a history of chronic gastritis, 2 were young adults without other disease aged 33 and 36 years, respectively, and another 15-year-old adolescent had an 8-month history of recurrent herpes.
Table 1.
Clinical characteristics of the enrolled patients
| Variables | HSV group(n=49) | VZV group(n=55) | MTB group (n=53) | P | P1(HSV vs VZV) | P2(HSV vs MTB) | P3(VZV vs MTB) |
|---|---|---|---|---|---|---|---|
| Age ( ±s)/year | 40.53±18.62 | 42.93±17.76 | 47.96±35.73 | 0.698 | — | — | — |
| Gender (male)/[No.(%)] | 27(55.1) | 35(63.6) | 30(56.6) | 0.635 | — | — | — |
| Underlying disease/[No.(%)] | |||||||
| None | 29(59.2) | 33(60.0) | 23(43.4) | 0.155 | — | — | — |
| Diabetes mellitus | 3(6.1) | 1(1.8) | 4(7.5) | <0.001 | <0.001 | <0.99 | 0.034 |
| Hepatitis B | 1(2.0) | 4(7.3) | 5(9.4) | 0.238 | — | — | — |
| Syphilis | 1(2.0) | 1(1.8) | 1(1.9) | 0.996 | — | — | — |
| Immunosuppression | 2(4.1) | 2(3.6) | 3(5.7) | 0.259 | — | — | — |
| Cancer | 3(6.1) | 0(0.0) | 3(5.7) | 0.070 | — | — | — |
| Pneumonia | 21(42.9) | 22(40.0) | 36(67.9) | 0.007 | 0.768 | 0.011 | 0.004 |
| Pulmonary MTB | 0(0.0) | 2(3.6) | 12(22.6) | <0.001 | 0.527 | <0.001 | 0.003 |
| Other | 14(28.6) | 17(30.9) | 24(45.3) | 0.153 | — | — | — |
Table 1.
(continued)
| Variables | HSV group(n=49) | VZV group(n=55) | MTB group (n=53) | P | P1(HSV vs VZV) | P2(HSV vs MTB) | P3(VZV vs MTB) |
|---|---|---|---|---|---|---|---|
| Clinical manifestations/[No.(%)] | |||||||
| Fever | 43(87.8) | 35(63.6) | 51(96.2) | <0.001 | 0.005 | 0.222 | <0.001 |
| Headache | 43(87.8) | 47(85.5) | 52(98.1) | 0.030 | 0.732 | 0.094 | 0.042 |
| Vomiting | 21(42.9) | 24(43.6) | 27(50.9) | 0.657 | — | — | — |
| Cutaneous zoster | 1(2.0) | 7(12.7) | 0(0.0) | 0.003 | 0.094 | 0.969 | 0.022 |
| Seizure | 11(22.4) | 5(9.1) | 5(9.4) | 0.080 | — | — | — |
| Cognitive disorder | 7(14.3) | 2(3.6) | 8(15.1) | 0.103 | — | — | — |
| Involuntary movement | 2(4.1) | 3(5.5) | 1(1.9) | 0.600 | — | — | — |
| Speech disorder | 9(18.4) | 5(9.1) | 5(9.4) | 0.268 | — | — | — |
| Dyskinesia | 8(16.3) | 7(12.7) | 11(20.8) | 0.532 | — | — | — |
| Mental disorder | 13(26.5) | 6(10.9) | 11(20.8) | 0.121 | — | — | — |
| Altered consciousness | 13(26.5) | 8(14.5) | 25(47.2) | 0.004 | 0.129 | 0.077 | 0.001 |
| Cranial nerve palsies | 5(10.2) | 7(12.7) | 3(5.7) | 0.451 | — | — | — |
| Neck stiffness | 26(53.1) | 31(56.4) | 48(90.6) | <0.001 | 0.736 | <0.001 | <0.001 |
| Pathological signs | 5(10.2) | 1(1.8) | 10(18.9) | 0.008 | 0.159 | 0.217 | 0.003 |
| Course of illness ( ±s)/d | |||||||
| Symptom duration | 8.67±6.77 | 6.64±4.88 | 18.43±17.42 | <0.001 | 0.195 | 0.001 | <0.001 |
| Length of the hospital stay | 17.08±7.70 | 17.56±11.41 | 26.66±17.86 | <0.001 | 0.965 | 0.002 | 0.006 |
| GCS on admission | 13.9±1.52 | 14.64±0.91 | 13.92±1.74 | 0.011 | 0.004 | 0.995 | 0.014 |
| Outcome/[No.(%)]* | |||||||
| Good outcome (mRS 0-2) | 44(89.8) | 51(92.7) | 34(64.2) | <0.001 | 0.856 | 0.002 | <0.001 |
| Severe disability (mRS 3-5) | 4(8.2) | 2(3.6) | 11(20.8) | <0.001 | <0.001 | <0.001 | 0.006 |
| Death | 0(0.0) | 0(0.0) | 5(9.4) | 0.004 | 1.000 | 0.081 | 0.061 |
HSV: Herpes simplex virus; VZV: Varicella-zoster virus; MTB: Mycobacterium tuberculosis; GCS: Glasgow Coma Scale; mRS: Modified Rankin scale. *Patiants with missing outcome data were excluded.
With respect to underlying diseases, there were no significant differences in immunocompetence among the 3 groups (HSV vs VZV vs MTB: 59.2% vs 60.0% vs 43.4%, P=0.155). Pulmonary computed tomography scans were performed after hospital admission in all patients, and patients in the MTB group had significantly higher rates of pneumonia (36/53, 67.9%, P=0.007) and pulmonary MTB (12/53, 22.6%, P<0.001) than those with viral infection. Symptom duration and length of hospital stay were shorter in the VZV group than those in the HSV and MTB groups [(6.64±4.88) d vs (8.67±6.77) d vs (18.43±17.42) d, P<0.001; (17.56±11.41) d vs (17.08±7.70) vs (26.66±17.86) d, P<0.001, respectively], probably because of the heightened immune response to VZV causing symptoms during the early clinical course. Glasgow Coma Scale (GCS) score on admission was the highest in the VZV group (14.64±0.91, P=0.011), indicating that VZV infection tends to be less severe.
With respect to outcomes, VZV infection had a better prognosis than HSV and MTB infection (modified Rankin scale 0-2 points 92.7% vs 89.8% vs 64.2%, P<0.001); moreover, 5 MTB infection patients died, none in the HSV and VZV groups.
2.2. Laboratory and radiographic characteristics of the different infection groups
The laboratory data are shown in Table 2. Pleocytosis was observed in the CSF in all groups. CSF leukocyte counts were significantly higher in the VZV group (230×106 cells/L) and the MTB group (276× 106 cells/L) than those in the HSV group (87×106 cells/L, P=0.002). Leukocyte counts of over 100×106, 200×106, and 500×106 cells/L were more common in the VZV group (83.64% vs 54.55% vs 14.55%) and the MTB group (92.45% vs 66.04% vs 18.88%) than those in the HSV group (44.90% vs 24.49% vs 6.12%), but these differences were not statistically significant (all P>0.05). The proportion of leukomonocytes in the HSV and VZV groups was higher than that in the MTB group [(81.55±12.34)% vs (80.24±13.73)% vs (48.02±24.43)%, P<0.001], while the mixed cell population and neutrophils in the MTB group were more than those in the HSV and VZV groups [(38.43±26.51)% vs (3.26±6.84)% vs (3.48±10.18)%, P<0.001]. CSF protein level in the VZV group was significantly higher 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).The CSF protein level exceeded 2 g/L in 1 HSV, 8 VZV, and 17 MTB patients (2.04%, 14.55%, and 32.08%, respectively; P=0.111). Compared with the other 2 groups, the MTB group tended to have a higher opening pressure and CRP and lower CSF/serum glucose ratio, CSF chlorine, and serum sodium than the other 2 groups (all P<0.05). There was no statistically significant difference in CSF monocyte proportion, plasma cell proportion, or eosinophil proportion among the 3 groups.
Table 2.
Laboratory data of the enrolled patients
| Variables | HSV group (n=49) | VZV group (n=55) | MTB group (n=53) |
|---|---|---|---|
| CSF opening pressure/mmH2O | 181.84±82.4 | 199.1±85.9 | 272.55±130.9 |
| CSF leukocyte count/(×106 cells·L-1) | 87(58-181) | 230(117-396) | 276(167-456) |
| CSF leukocyte count ≥100×106 cells/L/[No.(%)] | 22(44.90) | 46(83.64) | 49(92.45) |
| CSF leukocyte count ≥200×106 cells/L/[No.(%)] | 12(24.49) | 30(54.55) | 35(66.04) |
| CSF leukocyte count ≥500×106 cells/L/[No.(%)] | 3(6.12) | 8(14.55) | 10(18.88) |
| CSF neutrophils proportion/% | 3.26±6.84 | 3.48±10.18 | 38.43±26.51 |
| CSF leukomonocyte proportion/% | 81.55±12.34 | 80.24±13.73 | 48.02±24.43 |
| CSF monocyte proportion/% | 14.28±9.79 | 14.34±7.91 | 11.93±4.78 |
| CSF plasmocyte proportion/% | 0.71±1.90 | 1.36±2.27 | 0.89±1.41 |
| CSF eosinophil proportion/% | 0.39±1.88 | 0.44±0.81 | 0.53±2.15 |
| CSF protein/(mg·L-1) | 694(520-1 099) | 1 034(748-1 551.7) | 1 744(1 109.01-2 238) |
| CSF protein >2 g/L/[No.(%)] | 1(2.04) | 8(14.55) | 17(32.08) |
| CSF sugar/(mmol·L-1) | 3.42±0.85 | 3.25±0.95 | 2.40±1.53 |
| CSF-serum glucose ratio | 0.61±0.15 | 0.60±0.17 | 0.47±0.79 |
| CSF chlorine/(mmol·L-1) | 122.39±5.06 | 119.93±6.25 | 111.4±9.60 |
| Blood leukocyte count/(×109·L-1) | 7.85±2.78 | 7.91±2.55 | 7.81±3.20 |
| Serum sodium/(mmol·L-1) | 136.66±4.99 | 137.20±4.85 | 132.24±6.74 |
| CRP/(mg·L-1) | 3.20(1.25-9.94) | 2.56(1.23-9.32) | 4.77(2.13-21.89) |
The radiographic findings are shown in Table 3. A total of 120 patients had head magnetic resonance imaging (MRI) results documented (36/55 VZV, 34/49 HSV, and 50/53 MTB patients). In the VZV group, only 3 patients had infarction or hemorrhage and no patient developed hydrocephalus; there were no statistically significant differences among the 3 groups (P=0.383 and P=0.282, respectively).
Table 3.
Radiographic findings
| Variables | HSV group (n=34) | VZV group (n=36) | MTB group (n=50) | P | P1(HSV vs VZV) |
P2(HSV vs MTB) |
P3(VZV vs MTB) |
|---|---|---|---|---|---|---|---|
| Infarction-hemorrhage/[No.(%)] | 2(5.9) | 3(8.3) | 5(10.0) | 0.383 | — | — | — |
| Hydrocephalus/[No.(%)] | 2(5.9) | 0(0.0) | 5(10.0) | 0.282 | — | — | — |
| Meningeal enhancement/[No.(%)] | 13(38.2) | 26(72.2) | 29(58.0) | <0.001 | <0.001 | 0.016 | 0.047 |
| Lesion enhancement/[No.(%)] | 13(38.2) | 3(8.3) | 0(0.0) | <0.001 | 0.001 | <0.001 | 0.074 |
| Meningeal and lesion enhancement/[No.(%)] | 8(23.5) | 7(19.4) | 21(42.0) | 0.008 | 0.049 | 0.253 | 0.020 |
HSV: Herpes simplex virus; VZV: Varicella-zoster virus; MTB: Mycobacterium tuberculosis.
2.3. Cytokine profiles of the different infection groups
CSF levels of 12 cytokines of the 3 groups are shown in Table 4. There were statistically significant differences in the levels of IL-6 and IL-8 among the 3 groups. Compared with the other 2 groups, IL-6 and IL-8 levels in the VZV group were increased (VZV vs HSV vs MTB, IL-6: 2 855.93 pg/mL vs 2 128.26 pg/mL vs 354.77 pg/mL, P=0.029; IL-8: 4 001.46 pg/mL vs 1 578.11 pg/mL vs 1 023.25 pg/mL, P=0.046). Post hoc analysis revealed that the levels of 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. The levels of IL-1β, IL-2, IFN-γ, IFN-α, and TNF-α were increased in the HSV and VZV groups compared with the MTB group, but these differences were not statistically significant (all P>0.05).
Table 4.
CSF cytokine profiles of the enrolled patients
| Cytokines | HSV group(n=13) | VZV group(n=22) | MTB group(n=33) | P |
|---|---|---|---|---|
| IL-2/(pg·mL-1) | 28.07(13.21-55.31) | 30.98(15.22-57.45) | 19.47(9.86-38.15) | 0.294 |
| IL-4/(pg·mL-1) | 2.41(2.29-2.86) | 2.40(2.29-3.06) | 2.47(2.27-2.79) | 0.191 |
| IL-5/(pg·mL-1) | 12.6(7.12-147.19) | 7.28(4.18-19.4) | 13.75(4.74-77.13) | 0.102 |
| IL-1β/(pg·mL-1) | 45.59(4.90-77.59) | 67.27(23.68-106.05) | 34.35(6.62-70.06) | 0.156 |
| IL-6/(pg·mL-1) | 2 128.26(146.66-4 148.26) | 2 855.93 (1 011.51-4 971.34) | 354.77(44.96-1 051.40) | 0.029 |
| IL-8/(pg·mL-1) | 1 578.11(418.03-4 300.73) | 4 001.46 (736.23-6 305.15) | 1 023.25 (451.02-2 949.62) | 0.046 |
| IL-10/(pg·mL-1) | 10.23(5.86-36.97) | 34.42(10.02-120.70) | 34.53(12.74-72.86) | 0.336 |
| IL-17/(pg·mL-1) | 6.83(2.57-13.84) | 10.12(3.06-52.56) | 10.56(3.05-31.24) | 0.779 |
| IFN-γ/(pg·mL-1) | 442.62(4.53-1 775.77) | 416.94(5.11-2 089.79) | 84.11(5.84-543.96) | 0.782 |
| IFN-α/(pg·mL-1) | 2.83(1.79-3.37) | 3.34(2.07-5.62) | 2.00(1.44-5.06) | 0.632 |
| IL-12P70/(pg·mL-1) | 2.14(1.99-2.62) | 2.19(2.08-2.85) | 2.41(2.15-2.83) | 0.959 |
| TNF-α/(pg·mL-1) | 2.28(2.28-13.65) | 3.90(2.28-19.40) | 2.28(2.28-3.27) | 0.156 |
HSV: Herpes simplex virus; VZV: Varicella-zoster virus; MTB: Mycobacterium tuberculosis. Non-normally distributed data are presented as median (interquartile range).
Table 2.
(continued)
| Variables | P | P1(HSV vs VZV) | P2(HSV vs MTB) | P3(VZV vs MTB) |
|---|---|---|---|---|
| CSF opening pressure/mmH2O | <0.001 | 0.550 | <0.001 | 0.003 |
| CSF leukocyte count/(×106 cells·L-1) | 0.002 | 0.010 | <0.001 | 0.908 |
| CSF leukocyte count ≥100×106 cells/L/[No.(%)] | 0.303 | — | — | — |
| CSF leukocyte count ≥200×106 cells/L/[No.(%)] | 0.260 | — | — | — |
| CSF leukocyte count ≥500×106 cells/L/[No.(%)] | 0.069 | — | — | — |
| CSF neutrophils proportion/% | <0.001 | 0.997 | <0.001 | <0.001 |
| CSF leukomonocyte proportion/% | <0.001 | 0.865 | <0.001 | <0.001 |
| CSF monocyte proportion/% | 0.191 | — | — | — |
| CSF plasmocyte proportion/% | 0.197 | — | — | — |
| CSF eosinophil proportion/% | 0.913 | — | — | — |
| CSF protein/(mg·L-1) | <0.001 | 0.011 | <0.001 | <0.001 |
| CSF protein >2 g/L/[No.(%)] | 0.111 | — | — | — |
| CSF sugar/(mmol·L-1) | <0.001 | 0.600 | <0.001 | <0.001 |
| CSF-serum glucose ratio | <0.001 | 0.971 | <0.001 | <0.001 |
| CSF chlorine/(mmol·L-1) | <0.001 | 0.073 | <0.001 | <0.001 |
| Blood leukocyte count/(×109·L-1) | 0.982 | — | — | — |
| Serum sodium/(mmol·L-1) | <0.001 | 0.841 | <0.001 | <0.001 |
| CRP/(mg·L-1) | 0.025 | 0.978 | 0.042 | 0.058 |
HSV: Herpes simplex virus; VZV: Varicella-zoster virus; MTB: Mycobacterium tuberculosis. Normally distributed data are presented as ±s, and non-normally distributed data are presented as median (interquartile range). 1 mmH2O=0.098 kPa.
3. Discussion
VZV is a relatively common but poorly recognized cause of CNS infection[10-11], and the development of PCR and NGS diagnostic methods has revealed a greater prevalence than previously appreciated[12-13]. Over 50% of causative pathogens of CNS infections remain unidentified[14-15], and the diagnosis of VZV meningitis/encephalitis is similarly challenging. VZV is mainly diagnosed by PCR or NGS to detect VZV DNA in the CSF during the acute phase of the disease[6, 16-18]. However, PCR has limitations such as long reaction time, few sequence targets, and limited length of each reaction, limiting the clinical application of the method. NGS is a newer and unbiased technique to improve the detection of a wide range of pathogens in CNS infections[19-21], and it is a promising alternative diagnostic tool for microorganism detection[22]. Indeed, the sensitivity and specificity of NGS for detecting CNS infections were at the ranges of 50.7%-84.4% and 85.7%-99.0%, respectively[23-25]. Most of the cases reported here were NGS-confirmed cases.
The clinical features of VZV meningitis/encephalitis are non-specific, with common infectious symptoms including headache, fever, altered mental status, focal neurological signs, and sometimes seizures[6, 26-28]. Indeed, we found that altered consciousness, mental disorder, cranial nerve palsies, and seizures are relatively frequent symptoms.
Only 7(12.7%) VZV meningitis/encephalitis patients had cutaneous zoster in our cohort, far less than the 33% reported by Hong et al[9] and 31.5% by Alvarez et al[12], but similar to a recent nationwide study of VZV encephalitis from Denmark of only 11%[28]. Patients with skin manifestations are highly suggestive of VZV infection and should prompt a rapid etiological diagnosis. In addition, we found that VZV meningitis/encephalitis tended to have a shorter symptom duration and higher GCS on admission, suggesting a shorter disease course and milder symptoms in VZV compared with CNS HSV and MTB infections.
The CSF leukocyte counts in the HSV group were 87×106 (IQR: 58×106-181×106) cells/L and were <200×106 cells/L in most patients (75.51%), with a few patients (6.12%) with counts ≥500×106 cells/L. The CSF protein was 694 (IQR: 520-1 099) mg/L. These values are consistent with the conventional understanding of viral encephalitis, which is classically taught as a normal or mildly increased leukocyte count (usually <200× 106 cells/L) and a mild CSF proteinemia (usually < 1 000 mg/L)[29-30].
Compared with HSV, however, our patients with VZV meningitis/encephalitis exhibited hypercellularity and increased protein levels. The CSF leukocyte count were 230×106 (IQR: 117×106-396×106) cells/L in the VZV group, with over half of patients (54.6%) ≥200×106 cells/L and 16.4% patients ≥500×106 cells/L. Also, CSF protein levels were significantly higher in the VZV group, with a median of 1 034 (IQR: 748-1 551.7) mg/L and 58.2% of patients >1 000 mg/L. Similar findings have been reported in previous studies[31]. CSF leukocyte counts were significantly higher in patients infected with VZV (301×106 cells/L) than those in patients infected with HSV-1 (117×106 cells/L). Therefore, our data showed that VZV meningitis/encephalitis is different from other viral encephalitides, here represented by HSV, which usually exhibits hypercellularity and proteinemia in contrast to the classical understanding of viral encephalitis.
These features (hypercellularity and raised protein levels) can contribute to misdiagnosis as tuberculous meningitis. Nevertheless, the cytology of VZV meningitis/encephalitis was different to MTB, with a lymphocyte predominance in VZV and HSV CNS infections and mixed cytology in MTB with a significant proportion of neutrophils, lymphocytes, and monocytes critically discriminating between VZV and MTB CNS infection. These differences should discriminate these 2 conditions.
We also examined CSF cytokine levels, and the tested cytokines were elevated in all 3 encephalitides, as demonstrated previously[32-36]. We found that the levels of IL-6 and IL-8 were the highest in the VZV group, which may reflect the characteristics of the different pathogens and triggered host immune mechanisms. IL-6 is a key player in the acute early pro-inflammatory response following infection and is significantly elevated in both HSV and VZV encephalitis[37-38]. High IL-6 level enhances the permeability of the blood-brain barrier[38], perhaps facilitating leukocyte entry and protein influx from the blood. The IL-8 level was significantly increased in the CSF of patients with VZV CNS infection and associated with polymorphonuclear leukocyte (PMN) influx[36]. However, we observed few PMNs in the CSF of patients with VZV infections, and the reason may be neutrophils can enter the CNS and disappear rapidly during the early phase of the disease.
This study has several limitations. First, the limited availability of CSF specimens limited cytokine analysis, cytokine changes were not tracked dynamically, and cytokine levels were only analyzed during viral encephalitis without correlation with complications or long-term outcomes. Second, this was a retrospective study, some data were not available, and patients were not followed-up for long-term neurological sequelae. Finally, our cohort did not include other CNS outcomes such as myelitis and neuritis.
In conclusion, compared with HSV and MTB CNS infection, VZV meningitis/encephalitis has a short course and a good prognosis, with a characteristic and diagnostic rash only occurring in a small proportion of patients and lacking specificity. Contrary to conventional wisdom on viral encephalitis, patients with VZV meningitis/encephalitis tend to have higher CSF leukocyte counts, predominantly with lymphocytes, and protein levels. CSF IL-6 and IL-8 levels were most clearly elevated in patients with VZV meningitis/encephalitis, indicating a more intense immune response. The mechanisms of inflammation in VZV meningitis/encephalitis are still unclear and need to further exploration.
Contributions: MA Caiyu Collected and analyzed data, and writed the manuscript; LU Yuying Collected and analyzed data; CHEN Han, ZHANG Qinghua, ZHANG Qingxia, and HU Hao Collected and checked data; SONG Zhi Interpreted the patient data and conducted the statistical analysis; CHEN Ru, LIU Ding Designed the study, conducted the statistical analysis, and reviewed the manuscript. All authors have read and agreed to the final text.
Appendix.
Supplementary Table 1 Confirmed cerebrospinal fluid test results for all enrolled cases
| Number | Gender | Age/year | CSF NGS | Ct value by PCR | ||
|---|---|---|---|---|---|---|
| species | uniq_reads | RPM | ||||
| HSV group | ||||||
| 1 | Female | 29 | HSV-1 | 30 | ||
| 2 | Male | 38 | HSV-1 | 4 | 0.471 204 293 | |
| 3 | Female | 67 | HSV-1 | 291 | ||
| 4 | Male | 26 | HSV-1 | 144 736 | 2 074.326 645 | |
| 5 | Female | 62 | HSV-1 | 90 131 | 5 932.574 111 | |
| 6 | Male | 58 | HSV-1 | 75 808 | 2 157.937 218 | |
| 7 | Female | 68 | HSV-1 | 44 514 | ||
| 8 | Male | 55 | HSV-1 | 29 147 | 2 351.256 241 | |
| 9 | Male | 53 | HSV-1 | 4 859 | 463.196 073 9 | |
| 10 | Female | 35 | HSV-1 | 3 312 | 312.903 795 4 | |
| 11 | Female | 74 | HSV-1 | 1 599 | ||
| 12 | Female | 52 | HSV-1 | 847 | 67.654 707 63 | |
| 13 | Male | 53 | HSV-1 | 130 | ||
| 14 | Male | 17 | HSV-1 | 123 | 27.289 869 67 | |
| 15 | Female | 37 | HSV-1 | 116 | 10.865 226 05 | |
| 16 | Male | 17 | HSV-1 | 80 | 6.870 350 222 | |
| 17 | Male | 38 | HSV-1 | 30 | 1.373 917 576 | |
| 18 | Female | 68 | HSV-1 | 24 | 1.623 169 445 | |
| 19 | Male | 18 | HSV-1 | 20 | 1.952 312 998 | |
| 20 | Female | 21 | HSV-1 | 19 | 2.317 996 977 | |
| 21 | Male | 54 | HSV-1 | 16 | 1.458 336 599 | |
| 22 | Female | 19 | HSV-1 | 16 | 2.330 354 218 | |
| 23 | Male | 15 | HSV-1 | 14 | 1.263 057 192 | |
| 24 | Male | 29 | HSV-1 | 14 | 1.246 178 238 | |
| 25 | Female | 59 | HSV-1 | 11 | 1.990 942 299 | |
| 26 | Male | 60 | HSV-1 | 11 | 0.700 617 218 | |
| 27 | Male | 28 | HSV-1 | 11 | 1.192 106 306 | |
| 28 | Male | 43 | HSV-1 | 10 | 1.845 018 45 | |
| 29 | Male | 51 | HSV-1 | 9 | 1.363 007 522 | |
| 30 | Male | 48 | HSV-1 | 8 | 0.772 719 076 | |
| 31 | Male | 28 | HSV-1 | 7 | 0.743 981 034 | |
| 32 | Male | 43 | HSV-1 | 7 | 0.637 412 005 | |
| 33 | Male | 52 | HSV-1 | 6 | 0.634 400 158 | |
| 34 | Female | 33 | HSV-1 | 6 | 0.461 944 44 | |
| 35 | Male | 76 | HSV-1 | 5 | 0.456 621 547 | |
| 36 | Female | 78 | HSV-1 | 4 | 0.551 699 559 | |
| 37 | Female | 20 | HSV-1 | 4 | 0.271 205 416 | |
| 38 | Female | 31 | HSV-1 | 3 | 0.592 885 375 | |
| 39 | Male | 46 | HSV-1 | 3 | 0.261 751 189 | |
| 40 | Male | 29 | HSV-1 | 2 | 0.121 839 944 | |
| 41 | Male | 58 | HSV-1 | 2 | 0.190 801 17 | |
Supplementary Table 1 (continued)
| Number | Gender | Age/year | CSF NGS | Ct value by PCR | ||
|---|---|---|---|---|---|---|
| species | uniq_reads | RPM | ||||
| 42 | Female | 25 | HSV-1 | 2 | 0.163 778 622 | |
| 43 | Female | 25 | HSV-1 | 2 | 0.087 631 586 | |
| 44 | Male | 52 | HSV-1 | 29 | ||
| 45 | Male | 14 | HSV-1 | 36 | ||
| 46 | Female | 11 | HSV-2 | 2 162 | ||
| 47 | Female | 23 | HSV-2 | 727 | 60.859 493 43 | |
| 48 | Female | 20 | HSV-2 | 162 | 39.320 388 35 | |
| 49 | Female | 30 | HSV-2 | 4 | ||
| VZV group | ||||||
| 3 | Male | 56 | VZV | 105 146 | ||
| 4 | Female | 24 | VZV | 104 817 | 5 204.154 466 | |
| 5 | Male | 40 | VZV | 103 840 | 12 045.527 55 | |
| 6 | Female | 20 | VZV | 30 720 | 2 809.710 697 | |
| 7 | Male | 14 | VZV | 30 398 | 6 651.641 138 | 24 |
| 8 | Female | 49 | VZV | 29 452 | 2 141.638 419 | |
| 9 | Male | 70 | VZV | 21 394 | ||
| 10 | Female | 89 | VZV | 21 347 | ||
| 11 | Male | 36 | VZV | 7 151 | 618.063 958 5 | 27 |
| 12 | Male | 56 | VZV | 6 865 | 783.098 398 1 | |
| 13 | Female | 16 | VZV | 5 571 | 593.150 311 7 | |
| 14 | Female | 43 | VZV | 4 070 | 29.521 319 | |
| 15 | Female | 64 | VZV | 4 010 | ||
| 16 | Female | 15 | VZV | 3 306 | 587.752 768 4 | |
| 17 | Male | 69 | VZV | 3 240 | 278.914 550 7 | |
| 18 | Female | 42 | VZV | 3 030 | 458.407 881 3 | |
| 19 | Male | 18 | VZV | 2 908 | 167.632 581 2 | |
| 20 | Male | 30 | VZV | 2 110 | 444.210 526 3 | |
| 21 | Female | 23 | VZV | 1 996 | 775.402 492 6 | |
| 22 | Female | 32 | VZV | 1 695 | 178.409 240 1 | |
| 23 | Male | 29 | VZV | 1 407 | 253.057 554 | |
| 24 | Male | 46 | VZV | 1 317 | 100.719 790 9 | |
| 25 | Male | 57 | VZV | 759 | 78.486 247 43 | |
| 26 | Male | 33 | VZV | 550 | 36.160 092 7 | |
| 27 | Male | 59 | VZV | 529 | 75.444 261 88 | |
| 28 | Male | 54 | VZV | 127 | 19.833 585 29 | |
| 29 | Male | 56 | VZV | 83 | 14.143 350 87 | |
| 30 | Female | 49 | VZV | 71 | 5.950 379 534 | |
| 31 | Female | 51 | VZV | 49 | 2.287 981 188 | |
| 32 | Male | 57 | VZV | 49 | 3.892 072 048 | |
| 33 | Male | 63 | VZV | 48 | 3.555 074 172 | |
| 34 | Male | 24 | VZV | 36 | ||
| 35 | Male | 15 | VZV | 35 | 2.345 756 617 | |
| 36 | Male | 56 | VZV | 31 | ||
| 37 | Male | 20 | VZV | 29 | ||
| 38 | Female | 45 | VZV | 23 | 2.107 236 727 | |
Supplementary Table 1 (continued)
| Number | Gender | Age/year | CSF NGS | Ct value by PCR | ||
|---|---|---|---|---|---|---|
| species | uniq_reads | RPM | ||||
| 39 | Male | 71 | VZV | 21 | 2.223 960 913 | |
| 40 | Male | 71 | VZV | 17 | 2.407 998 862 | |
| 41 | Female | 35 | VZV | 16 | 0.912 388 884 | |
| 42 | Male | 38 | VZV | 14 | 4.722 116 912 | |
| 43 | Female | 32 | VZV | 12 | ||
| 44 | Male | 41 | VZV | 7 | 0.980 676 058 | |
| 45 | Female | 41 | VZV | 6 | 0.704 225 352 | |
| 46 | Female | 60 | VZV | 5 | 0.601 727 005 | |
| 47 | Male | 26 | VZV | 5 | 1.179 245 283 | |
| 48 | Male | 67 | VZV | 5 | 0.864 854 543 | |
| 49 | Male | 24 | VZV | 4 | 0.322 463 232 | |
| 50 | Male | 61 | VZV | 4 | 0.374 545 477 | |
| 51 | Female | 51 | VZV | 3 | 0.344 399 62 | |
| 52 | Male | 47 | VZV | 3 | 0.427 960 057 | |
| 53 | Male | 30 | VZV | 2 | 0.243 673 386 | |
| 54 | Male | 53 | VZV | 2 | 0.364 344 384 | |
| 55 | Male | 26 | VZV | 35 | ||
| 56 | Male | 38 | VZV | 1 | 0.223 196 101 | |
| 57 | Female | 29 | VZV | 31 | ||
| MTB group | ||||||
| 1 | Female | 58 | MTB | 3 | ||
| 2 | Female | 31 | MTB | 10 | ||
| 3 | Male | 65 | MTB | 57 | ||
| 4 | Male | 29 | MTB | 5 | ||
| 5 | Male | 32 | MTB | 5 | ||
| 6 | Female | 266 | MTB | 10 | ||
| 7 | Female | 62 | MTB | 8 | ||
| 8 | Female | 31 | MTB | 12 | ||
| 9 | Male | 24 | Positive* | |||
| 10 | Male | 65 | Positive* | |||
| 11 | Male | 53 | Positive* | |||
| 12 | Male | 53 | Positive* | |||
| 13 | Male | 57 | Positive* | |||
| 14 | Male | 49 | Positive* | |||
| 15 | Female | 41 | Positive* | |||
| 16 | Female | 48 | Positive* | |||
| 17 | Female | 85 | Positive* | |||
| 18 | Female | 65 | Positive* | |||
| 19 | Female | 32 | Positive* | |||
| 20 | Male | 28 | Positive* | |||
| 21 | Male | 28 | Positive* | |||
| 22 | Male | 48 | Positive* | |||
| 23 | Female | 15 | Positive* | |||
| 24 | Female | 19 | Positive* | |||
Supplementary Table 1 (continued)
| Number | Gender | Age/year | CSF NGS | Ct value by PCR | ||
|---|---|---|---|---|---|---|
| species | uniq_reads | RPM | ||||
| 25 | Female | 39 | Positive* | |||
| 26 | Female | 64 | Positive* | |||
| 27 | Male | 22 | Positive* | |||
| 28 | Male | 54 | Positive* | |||
| 29 | Female | 27 | Positive* | |||
| 30 | Male | 40 | Positive* | |||
| 31 | Male | 40 | Positive* | |||
| 32 | Male | 20 | Positive* | |||
| 33 | Male | 50 | Positive* | |||
| 34 | Male | 50 | Positive* | |||
| 35 | Female | 29 | Positive* | |||
| 36 | Male | 69 | Positive* | |||
| 37 | Male | 69 | Positive* | |||
| 38 | Male | 64 | Positive* | |||
| 39 | Male | 62 | Positive* | |||
| 40 | Female | 24 | Positive* | |||
| 41 | Male | 17 | Positive* | |||
| 42 | Female | 14 | Positive* | |||
| 43 | Male | 14 | Positive* | |||
| 44 | Male | 22 | Positive* | |||
| 45 | Male | 54 | Positive* | |||
| 46 | Female | 62 | Positive* | |||
| 47 | Female | 53 | Positive* | |||
| 48 | Female | 77 | Positive* | |||
| 49 | Male | 34 | Positive* | |||
| 50 | Female | 17 | Positive* | |||
| 51 | Male | 51 | Positive* | |||
| 52 | Male | 71 | Positive* | |||
| 53 | Female | 49 | Positive* | |||
HSV-1: Herpes simplex virus-1; HSV-2: Herpes simplex virus-2; VZV: Varicella-zoster virus; MTB: Mycobacterium tuberculosis; CSF: Cerebrospinal fluid; NGS: Next-generation gene sequencing; PCR: Polymerase chain reaction; PRM: Reads of exon model per million mapped reads. *Acid-fast bacilli test.
Funding Statement
This work was supported by the National Natural Science Foundation of China (81801295).
Conflict of Interest
The authors declare that they have no conflicts of interest to disclose.
Note
http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2022101345.pdf
References
- 1. Boucher A, Herrmann JL, Morand P, et al. Epidemiology of infectious encephalitis causes in 2016[J]. Med Mal Infect, 2017, 47(3): 221-235. 10.1016/j.medmal.2017.02.003. [DOI] [PubMed] [Google Scholar]
- 2. Mailles A, Stahl JP, Steering Committee and Investigators Group . Infectious encephalitis in France in 2007: a national prospective study[J]. Clin Infect Dis, 2009, 49(12): 1838-1847. 10.1086/648419. [DOI] [PubMed] [Google Scholar]
- 3. Granerod J, Ambrose HE, Davies NW, et al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study[J]. Lancet Infect Dis, 2010, 10(12): 835-844. 10.1016/S1473-3099(10)70222-X. [DOI] [PubMed] [Google Scholar]
- 4. Richter ER, Dias JK, Gilbert JE, et al. Distribution of herpes simplex virus type 1 and varicella zoster virus in Ganglia of the human head and neck[J]. J Infect Dis, 2009, 200(12): 1901-1906. 10.1086/648474. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Laing KJ, Ouwendijk WJD, Koelle DM, et al. Immunobiology of varicella-zoster virus infection[J]. J Infect Dis, 2018, 218(suppl_2): S68-S74. 10.1093/infdis/jiy403. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Grahn A, Studahl M. Varicella-zoster virus infections of the central nervous system—Prognosis, diagnostics and treatment[J]. J Infect, 2015, 71(3): 281-293. 10.1016/j.jinf.2015.06.004. [DOI] [PubMed] [Google Scholar]
- 7. Tabaja H, Sharara SL, Abi Aad Y, et al. Varicella zoster virus infection of the central nervous system in a tertiary care center in Lebanon[J]. Med Mal Infect, 2020, 50(3): 280-287. 10.1016/j.medmal.2019.08.005. [DOI] [PubMed] [Google Scholar]
- 8. Jeong YS, Jeon M, Park JH, et al. Machine-learning-based approach to differential diagnosis in tuberculous and viral meningitis[J]. Infect Chemother, 2021, 53(1): 53-62. 10.3947/ic.2020.0104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Hong SI, Kim T, Jung J, et al. Tuberculous meningitis-mimicking varicella-zoster meningitis[J]. Infect Chemother, 2017, 49(2): 123-129. 10.3947/ic.2017.49.2.123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Shikova E, Kumanova A, Tournev I, et al. Varicella zoster virus infection in neurological patients in Bulgaria[J]. J Neurovirol, 2021, 27(2): 272-278. 10.1007/s13365-021-00952-6. [DOI] [PubMed] [Google Scholar]
- 11. Parkes-Smith J, Chaudhuri A. Varicella zoster virus: an under-recognised cause of central nervous system infections? [J]. Intern Med J, 2022, 52(1): 100-104. 10.1111/imj.15048. [DOI] [PubMed] [Google Scholar]
- 12. Alvarez JC, Alvarez J, Tinoco J, et al. Varicella-zoster virus meningitis and encephalitis: an understated cause of central nervous system infections[J/OL]. Cureus, 2020, 12(11): e11583 [2021-02-17]. 10.7759/cureus.11583. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Kleinschmidt-DeMasters BK, Gilden DH. Varicella-zoster virus infections of the nervous system: clinical and pathologic correlates[J]. Arch Pathol Lab Med, 2001, 125(6): 770-780. 10.5858/2001-125-0770-VZVIOT. [DOI] [PubMed] [Google Scholar]
- 14. le Maréchal M, Mailles A, Seigneurin A, et al. A prospective cohort study to identify clinical, biological, and imaging features that predict the etiology of acute encephalitis[J]. Clin Infect Dis, 2021, 73(2): 264-270. 10.1093/cid/ciaa598. [DOI] [PubMed] [Google Scholar]
- 15. Aldriweesh MA, Shafaay EA, Alwatban SM, et al. Viruses causing aseptic meningitis: a tertiary medical center experience with a multiplex PCR assay[J]. Front Neurol, 2020, 11: 602267. 10.3389/fneur.2020.602267. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Stránská R, Schuurman R, de Vos M, et al. Routine use of a highly automated and internally controlled real-time PCR assay for the diagnosis of herpes simplex and varicella-zoster virus infections[J]. J Clin Virol, 2004, 30(1): 39-44. 10.1016/j.jcv.2003.08.006. [DOI] [PubMed] [Google Scholar]
- 17. Persson A, Bergström T, Lindh M, et al. Varicella-zoster virus CNS disease: viral load, clinical manifestations and sequels[J]. J Clin Virol, 2009, 46(3): 249-253. 10.1016/j.jcv.2009.07.014. [DOI] [PubMed] [Google Scholar]
- 18. Stahl JP. Update on HSV and VZV infections of the brain[J]. Rev Neurol (Paris), 2019, 175(7/8): 442-444. 10.1016/j.neurol.2019.07.010. [DOI] [PubMed] [Google Scholar]
- 19. Wilson MR, Sample HA, Zorn KC, et al. Clinical metagenomic sequencing for diagnosis of meningitis and encephalitis[J]. N Engl J Med, 2019, 380(24): 2327-2340. 10.1056/NEJMoa1803396. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Schlaberg R, Chiu CY, Miller S, et al. Validation of metagenomic next-generation sequencing tests for universal pathogen detection[J]. Arch Pathol Lab Med, 2017, 141(6): 776-786. 10.5858/arpa.2016-0539-RA. [DOI] [PubMed] [Google Scholar]
- 21. Li ZY, Dang D, Wu H. Next-generation sequencing of cerebrospinal fluid for the diagnosis of unexplained central nervous system infections[J]. Pediatr Neurol, 2021, 115: 10-20. 10.1016/j.pediatrneurol.2020.10.011. [DOI] [PubMed] [Google Scholar]
- 22. Tsamis KI, Sakkas H, Giannakis A, et al. Evaluating infectious, neoplastic, immunological, and degenerative diseases of the central nervous system with cerebrospinal fluid-based next-generation sequencing[J]. Mol Diagn Ther, 2021, 25(2): 207-229. 10.1007/s40291-021-00513-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Miao Q, Ma YY, Wang QQ, et al. Microbiological diagnostic performance of metagenomic next-generation sequencing when applied to clinical practice[J]. Clin Infect Dis, 2018, 67(suppl_2): S231-S240. 10.1093/cid/ciy693. [DOI] [PubMed] [Google Scholar]
- 24. Miller S, Naccache SN, Samayoa E, et al. Laboratory validation of a clinical metagenomic sequencing assay for pathogen detection in cerebrospinal fluid[J]. Genome Res, 2019, 29(5): 831-842. 10.1101/gr.238170.118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Yan LP, Sun WW, Lu ZH, et al. Metagenomic Next-Generation Sequencing (mNGS) in cerebrospinal fluid for rapid diagnosis of Tuberculosis meningitis in HIV-negative population[J]. Int J Infect Dis, 2020, 96: 270-275. 10.1016/j.ijid.2020.04.048. [DOI] [PubMed] [Google Scholar]
- 26. Pahud BA, Glaser CA, Dekker CL, et al. Varicella zoster disease of the central nervous system: epidemiological, clinical, and laboratory features 10 years after the introduction of the varicella vaccine[J]. J Infect Dis, 2011, 203(3): 316-323. 10.1093/infdis/jiq066. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. le Bot A, Ballerie A, Pronier C, et al. Characteristics and outcome of varicella-zoster virus central nervous system infections in adults[J]. Eur J Clin Microbiol Infect Dis, 2021, 40(11): 2437-2442. 10.1007/s10096-021-04245-y. [DOI] [PubMed] [Google Scholar]
- 28. Herlin LK, Hansen KS, Bodilsen J, et al. Varicella zoster virus encephalitis in Denmark from 2015 to 2019-A nationwide prospective cohort study[J]. Clin Infect Dis, 2021, 72(7): 1192-1199. 10.1093/cid/ciaa185. [DOI] [PubMed] [Google Scholar]
- 29. Solomon T, Michael BD, Smith PE, et al. Management of suspected viral encephalitis in adults: association of British Neurologists and British Infection Association National Guidelines[J]. J Infect, 2012, 64(4): 347-373. 10.1016/j.jinf.2011.11.014. [DOI] [PubMed] [Google Scholar]
- 30. Tunkel AR, Glaser CA, Bloch KC, et al. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America[J]. Clin Infect Dis, 2008, 47(3): 303-327. 10.1086/589747. [DOI] [PubMed] [Google Scholar]
- 31. Lee GH, Kim J, Kim HW, et al. Herpes simplex viruses (1 and 2) and varicella-zoster virus infections in an adult population with aseptic meningitis or encephalitis: a nine-year retrospective clinical study[J/OL]. Medicine (Baltimore), 2021, 100(46): e27856 [2022-04-15]. 10.1097/MD.0000000000027856. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Liu QQ, Gao Y, Zhang BY, et al. Cytokine profiles in cerebrospinal fluid of patients with meningitis at a tertiary general hospital in China[J]. J Microbiol Immunol Infect, 2020, 53(2): 216-224. 10.1016/j.jmii.2018.08.019. [DOI] [PubMed] [Google Scholar]
- 33. van Laarhoven A, Dian S, van Dorp S, et al. Immune cell characteristics and cytokine responses in adult HIV-negative tuberculous meningitis: an observational cohort study[J]. Sci Rep, 2019, 9(1): 884. 10.1038/s41598-018-36696-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Manyelo CM, Solomons RS, Walzl G, et al. Tuberculous meningitis: pathogenesis, immune responses, diagnostic challenges, and the potential of biomarker-based approaches[J/OL]. J Clin Microbiol, 2021, 59(3): e01771-e01720 [2022-03-31]. 10.1128/JCM.01771-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Wang JJ, Cheng Y, Ma YT, et al. Cytokines and chemokines expression pattern in herpes simplex virus type-1 encephalitis[J]. Neurosci Lett, 2021, 763: 136170. 10.1016/j.neulet.2021.136170. [DOI] [PubMed] [Google Scholar]
- 36. Lind L, Eriksson K, Grahn A. Chemokines and matrix metalloproteinases in cerebrospinal fluid of patients with central nervous system complications caused by varicella-zoster virus[J]. J Neuroinflammation, 2019, 16(1): 42. 10.1186/s12974-019-1428-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Bociąga-Jasik M, Cieśla A, Kalinowska-Nowak A, et al. Role of IL-6 and neopterin in the pathogenesis of herpetic encephalitis[J]. Pharmacol Rep, 2011, 63(5): 1203-1209. 10.1016/s1734-1140(11)70640-5. [DOI] [PubMed] [Google Scholar]
- 38. Dvorak F, Martinez-Torres F, Sellner J, et al. Experimental herpes simplex virus encephalitis: a long-term study of interleukin-6 expression in mouse brain tissue[J]. Neurosci Lett, 2004, 367(3): 289-292. 10.1016/j.neulet.2004.06.010. [DOI] [PubMed] [Google Scholar]