Abstract
Tuberculous meningitis (TBM) is the most serious type of tuberculosis infection, and there is a lack of accurate diagnostic targets for TBM. Therefore, it is of great clinical and public health significance to find a specific target for early diagnosis and prediction of the prognosis of TBM. From January 2021 to February 2024, 110 TBM patients and 122 patients with non-tumor, non-infectious headaches were admitted to Hunan Chest Hospital. To compare the two groups, cerebrospinal fluid (CSF) levels of sCD163 and MMP-9, as well as serum NCAM1 protein levels, were detected by ELISA. Multivariate logistic regression analysis or Spearman analysis was then performed to investigate the correlation between these protein levels and the MRC (Medical Research Council) stage or the short-term prognosis in TBM patients. sCD163 and MMP-9 were elevated in the CSF of TBM patients compared to controls. Oppositely, the protein levels of serum NCAM1 was decreased. The levels of CSF sCD163, MMP-9 and serum NCAM1 are associated with MRC stage and short-term prognosis of TBM patients, and the combined CSF sCD163, MMP-9 and serum NCAM1 have the best value in predicting the short-term prognosis of TBM patients.
Keywords: Tuberculous meningitis, sCD163, MMP-9, NCAM1, Prognosis
Subject terms: Biomarkers, Diseases
Introduction
Tuberculous meningitis (TBM) is an inflammatory disease of the meninges and meninges caused by Mycobacterium tuberculosis, which is the most serious type of tuberculosis infection and the most common tuberculosis of the central nervous system1,2. According to statistics, TBM accounts for about 70% of neurotuberculosis3. The mortality rate of tuberculous meningitis can be as high as 30–40%, and it poses a significant risk of central nervous system sequelae, including neurological dysfunction, language disorders, visual and auditory impairments, psychiatric symptoms, and epilepsy, among others 4. Epileptic seizures are one of the frequent and severe complications associated with tuberculous meningitis. The onset of TBM is insidious, and there is a lack of typical symptoms, early diagnosis, prognostic targets, and easy to miss the best treatment period. At the same time, there is a lack of accurate diagnostic targets for TBM in clinical, which also directly affects the disease process and clinical treatment of patients. Therefore, it is urgent to find a specific target to accurately judge the severity of tuberculous meningitis and predict the prognosis of patients.
The destruction of the blood-brain barrier is considered to be an important part of the pathological basis of TBM5,6, and the increased permeability of the blood-brain barrier in TBM patients suggests that the composition of cerebrospinal fluid(CSF) may be changed. Therefore, it is suggested that various indicators in cerebrospinal fluid are helpful in assessing the severity of tuberculous meningitis and guiding prognosis prediction. Studies have shown that cerebrospinal fluid MMP-9 can improve the permeability of the blood-brain barrier by degrading extracellular matrix and basal membrane components7,8, which can aggravate the condition and poor prognosis of TBM, indicating that MMP-9 plays an important role in the pathogenesis and prognosis of TBM, and is a good indicator for monitoring TBM.
M2 macrophages, as one of the phenotypically polarized subtypes of macrophages, exhibit an anti-inflammatory phenotype and play a pivotal role in tissue repair, inflammation resolution, induction of immune tolerance, and protection against excessive inflammation. Previous studies have found that M2 macrophages significantly enhanced their activity in active tuberculosis and played a leading role in the occurrence and development of tuberculous granulomas, and sCD163 can be used as a marker of M2 macrophage activation9,10, suggesting that the level of sCD163 can be used as an important indicator to assess the severity of active tuberculosis. Studies have reported that TBM can also cause nerve cell damage, leading to reduced synthesis of NCAM111, and the lack of NCAM1 in cerebrospinal fluid is related to the onset and progression of TBM, NCAM1 is expected to be a potential marker for the prognosis of TBM. In summary, the levels of cerebrospinal fluid sCD163, MMP-9 and serum NCAM1 are closely related to the pathogenesis and prognosis of TBM.
In this study, 110 TBM patients and 122 non tumor and non infectious headache patients were admitted to Hunan Chest Hospital. The clinical information of the patients was collected, and the protein level of cerebrospinal fluid sCD163, MMP-9 and serum NCAM1 were detected by ELISA, and correlated with prognosis and clinical stage in TBM patients. This study aimed to find a specific and accurate target for assessing the severity of TBM and predicting patient outcomes.
Materials and methods
Patients
The patient population consisted of 110 patients with tuberculous meningitis(TBM) were admitted to Hunan Chest Hospital from January 1, 2021 to February 28,2024. 122 non-tumor and non-infectious headache patients of the same period were selected as the control group. Diagnosis of TBM was based on clinical criteria, CSF findings, neuroimaging, and other evidence related to tuberculosis12. The non-tumor, non-infective headache group fulfills the diagnostic criteria related to non-tumor, non-infective headaches in Neurology13. Patients with tumor-related headache or infectious headache can be excluded through CSF testing and brain MRIs. There were 68 males and 42 females in the TBM group. The ages ranged from 18 to 70, with an average age of (43.62 ± 4.21) years. According to the MRC stage, the TBM group was divided into stage I (25 cases), stage II (48 cases), and stage III (37 cases). As controls, there were 74 males and 48 females. The age was 19–68 years old, with an average age of (43.62 ± 4.08) years. Exclusion criteria for this study were included HIV co-infection, cerebrovascular emergencies, epilepsy, Parkinson, malignant tumors, autoimmune diseases, pregnancy or lactation. One or more serious abnormalities in the normal physiological functions. This study was approved by the Ethics Committee of Hunan Chest Hospital (LS2023011601), and fully informed consent was obtained from the patients. All methods were performed in accordance with the relevant guidelines and regulations.
Methods
On the day of admission, the patients underwent lumbar puncture, 2 ml of cerebrospinal fluid was extracted, 3000 rpm, 10 min, and stored at -80 ℃. It was used to measure the levels of sCD163 (Shanghai Enzyme-linked Biotechnology Co., Ltd. China) and MMP-9 (Tianjin Yueteng Biotechnology Co., Ltd. China) in cerebrospinal fluid. In the early morning of the next day, 5 ml of fasting venous blood was obtained and 3000 rpm, 10 min, and stored at -80 ℃ to measure the serum NCAM1 (Shanghai Zhuoyu Biotechnology Co. Ltd. China) level. The ELISA procedure is performed according to the instructions.
The patients in the TBM group received symptomatic treatment on the day of admission, and after the results of various examinations were available, after comprehensive evaluation by physicians, they were treated with anti-inflammatory hormones + HRZE regimen on the second day after admission, and the prognosis of TBM patients was evaluated by the modified Rankin scale on the 8th week of treatment, and they were divided into (good prognosis group, n = 69) and (poor prognosis group, n = 41).
Statistical analysis
SPSS28.0 was used to analyze the data, the normality of the continuous data was expressed as (mean ± standard deviation), the independent samples t-test was used for comparison between the two groups, and the one-way ANOVA was used for comparison between multiple groups. Ridit analysis was used for comparison of grade data between the two groups. The correlation between cerebrospinal fluid sCD163, MMP-9 and serum NCAM1 levels and MRC stage was analyzed by Spearman correlation analysis, and the effects of cerebrospinal fluid sCD163, MMP-9 and serum NCAM1 levels on the short-term prognosis were analyzed by multivariate logistic regression analysis after adjusting for covariates. ROC curves were plotted using MedCalc 20.0.22 software. The difference was significantly expressed as P < 0.05.
Results
The expression levels of sCD163 and MMP-9 in the TBM group increased, and the expression level of NCAM1 decreased
110 TBM patients and 122 non tumor with non infectious headache patients were admitted to Hunan Chest Hospital. The protein level of cerebrospinal fluids CD163, MMP-9 and serum NCAM1 were detected by ELISA. Compared with the control group, the expression levels of sCD163 and MMP-9 in the TBM group increased, and the expression level of NCAM1 decreased (Fig. 1; Table 1, p < 0.05).
Fig. 1.
The expression levels of sCD163 and MMP-9 in 110 TBM patients and 122 non tumor with non infectious headache patients.
Table 1.
The expression levels of sCD163 and MMP-9 in 110 TBM patients and 122 non tumor with non infectious headache patients (
± s).
| n | sCD163 (ng/L) | NCAM1 (mg/L) | MMP-9 (µg/L) | |
|---|---|---|---|---|
| TBM | 110 | 104.59 ± 11.28 | 211.87 ± 16.32 | 88.34 ± 21.85 |
| Control | 122 | 72.46 ± 8.59 | 246.71 ± 20.14 | 52.88 ± 12.17 |
| t | 24.545 | 14.535 | 15.464 | |
| P | < 0.001 | < 0.001 | < 0.001 |
The expression levels of CSF sCD163, MMP-9 were positively, and serum NCAM1 was negatively correlated with the MRC stage of TBM patients
The expression levels of CSF sCD163, MMP-9 and serum NCAM1 in TBM patients with MRC stage were compared, and the expression levels of CSF sCD163 and MMP-9 increased with the increase of MRC stage, while the expression level of serum NCAM1 decreased with the increase of MRC stage (Fig. 2; Table 2, p < 0.05).
Fig. 2.
The expression levels of sCD163 (A), MMP-9 (B) and serum NCAM1 (C) in TBM patients with MRC stage.
Table 2.
The expression levels of sCD163 MMP-9 and serum NCAM1 in TBM patients with MRC stage (
± s).
| MRC stage | n | sCD163 (ng/L) | NCAM1 (mg/L) | MMP-9 (µg/L) |
|---|---|---|---|---|
| I stage | 50 | 90.21 ± 7.44 | 228.47 ± 16.55 | 68.69 ± 10.02 |
| II stage | 42 | 102.23 ± 10.15 | 211.95 ± 14.38 | 90.63 ± 12.38 |
| III stage | 18 | 117.22 ± 15.58 | 194.00 ± 8.36 | 97.65 ± 15.44 |
| F | 49.67 | 39.73 | 57.51 | |
| P | < 0.001 | < 0.001 | < 0.001 |
The expression levels of CSF sCD163 and MMP-9 were positively correlated with the MRC stage of TBM patients (r = 0.667, 0.736, p < 0.05), and NCAM1 level was negatively correlated with the MRC stage of TBM patients (r = – 0.666, p < 0.05) (Fig. 3; Table 3).
Fig. 3.
Correlation analysis between sCD163, NCAM1 and MMP-9 levels and MRC stage in TBM patients.
Table 3.
Correlation analysis between sCD163, NCAM1 and MMP-9 levels and MRC stage in TBM patients.
| MRC stage | sCD163 (ng/L) |
NCAM1 (mg/L) |
MMP-9 (µg/L) |
|---|---|---|---|
| r | 0.667 | – 0.666 | 0.736 |
| P | < 0.001 | < 0.001 | < 0.001 |
High levels of CSF sCD163, MMP-9 and low levels of serum NCAM1 are associated with a worse prognosis in the short term with TBM patients
The clinical data of the patients were collected. There were no significant differences in gender, cognitive abnormalities, comorbidities, length of hospital stay, white blood cell count, albumin, serum potassium, and serum sodium levels in the good prognosis group compared with those in the poor prognosis group. And then, there were significant differences in hydrocephalus, altered consciousness, cranial nerve palsy, MRC stage, cerebrospinal fluid(CSF) sCD163 and MMP-9 levels, and serum NCAM1 levels in the good prognosis group compared with the poor prognosis group (Table 4).
Table 4.
Comparison of general clinical data between poor prognosis group and favorable prognosis group.
| Hallmark | Total population (N = 110)1 |
Poor prognosis group (N = 49)1 |
Favorable prognosis group (N = 61)1 |
P-value2 |
|---|---|---|---|---|
| Gender | 0.610 | |||
| Male | 68/(62%) | 29/(59%) | 39/(64%) | |
| Female | 42/(38%) | 20/(41%) | 22/(36%) | |
| Age | 42.05 ± 4.24 | 42.29 ± 4.10 | 41.87 ± 4.37 | 0.642 |
| BMI index | 0.175 | |||
| Normal | 77/(70%) | 32/(65%) | 45/(74%) | |
| Slender | 18/(16%) | 7/(14%) | 11/(18%) | |
| Overweight | 15/(14%) | 10/(20%) | 5/(8.2%) | |
| Hydrocephalus | 0.025 | |||
| No hydrocephalus | 94/(85%) | 46/(94%) | 48/(79%) | |
| With hydrocephalus | 16/(15%) | 3/(6.1%) | 13/(21%) | |
| Change in consciousness | 0.023 | |||
| No change in consciousness | 69/(63%) | 25/(51%) | 44/(72%) | |
| With change in consciousness | 41/(37%) | 24/(49%) | 17/(28%) | |
| Cognitive abnormality | 0.075 | |||
| Non-cognitive abnormality | 89/(81%) | 36/(73%) | 53/(87%) | |
| Cognitive abnormality | 21/(19%) | 13/(27%) | 8/(13%) | |
| Cranial nerve paralysis | 0.012 | |||
| No cranial nerve paralysis | 97/(88%) | 39/(80%) | 58/(95%) | |
| With cranial nerve paralysis | 13/(12%) | 10/(20%) | 3/(4.9%) | |
| Hypertension | 0.917 | |||
| Non-hypertension | 69/(63%) | 31/(63%) | 38/(62%) | |
| Hypertension | 41/(37%) | 18/(37%) | 23/(38%) | |
| Diabetes | 0.952 | |||
| Non-diabetes | 76/(69%) | 34/(69%) | 42/(69%) | |
| Diabetes | 34/(31%) | 15/(31%) | 19/(31%) | |
| Hyperlipidemia | 0.509 | |||
| Non-hyperlipidemia | 89/(81%) | 41/(84%) | 48/(79%) | |
| Hyperlipidemia | 21/(19%) | 8/(16%) | 13/(21%) | |
| Hospital stay | 28.75 ± 4.96 | 28.29 ± 4.82 | 29.13 ± 5.07 | 0.392 |
| MRC stage | < 0.001 | |||
| Stage I | 50/(45%) | 9/(18%) | 41/(67%) | |
| Stage II | 42/(38%) | 27/(55%) | 15/(25%) | |
| Stage III | 18/(16%) | 13/(27%) | 5/(8.2%) | |
| White blood cell count | 7.98 ± 1.74 | 8.17 ± 1.49 | 7.83 ± 1.92 | 0.200 |
| Albumin | 38.00 ± 3.75 | 37.76 ± 3.47 | 38.20 ± 3.99 | 0.510 |
| Blood potassium | 3.60 ± 1.28 | 3.52 ± 1.35 | 3.67 ± 1.23 | 0.952 |
| Blood sodium | 131.97 ± 15.69 | 130.29 ± 16.90 | 133.31 ± 14.64 | 0.222 |
|
Cerebrospinal fluid sCD163 (ng/L) |
99.22 ± 13.99 | 106.29 ± 16.50 | 93.54 ± 8.02 | < 0.001 |
|
Serum NCAM1 (mg/L) |
216.52 ± 19.21 | 206.91 ± 14.45 | 224.24 ± 19.17 | < 0.001 |
|
Cerebrospinal fluid MMP-9 (µg/L) |
81.80 ± 17.04 | 90.78 ± 13.97 | 74.59 ± 15.89 | < 0.001 |
1n/(%); Mean ± SD.
2Pearson’s Chi-squared test; Wilcoxon rank sum test.
CSF sCD163, MMP-9 and serum NCAM1 levels were taken as independent variables, and hydrocephalus, altered consciousness, cranial nerve palsy, and MRC stage were taken as covariates and assigned, the result showed that elevated levels of CSF sCD163 and MMP-9 were risk factors, and elevated serum NCAM1 levels were protective factors for the short-term prognosis of TBM patients (Table 5, p < 0.05).
Table 5.
Correlation of cerebrospinal fluid sCD163, MMP-9 and serum NCAM1 levels on the prognosis of TBM patients.
| Hallmark | Before adjustment | After adjustment* | ||||
|---|---|---|---|---|---|---|
| OR value | OR 95%CI1 | P value | OR value |
OR 95%CI1 | P value | |
| Low Cerebrospinal fluid sCD163 | 0.92 | 0.88, 0.95 | < 0.001 | 0.96 | 0.91, 1.00 | 0.047 |
| High serum NCAM1 | 1.06 | 1.03, 1.09 | < 0.001 | 1.03 | 1.00, 1.06 | 0.040 |
| High Cerebrospinal fluid MMP-9 | 0.93 | 0.90, 0.96 | < 0.001 | 0.96 | 0.93,1.00 | 0.030 |
*Hydrocephalus, altered consciousness, cranial nerve palsy, and MRC stage were adjusted; 1OR = Odds Ratio, CI = Confidence Interval.
Cerebrospinal fluid sCD163, MMP-9, and serum NCAM1 levels alone and in combination predicted the short-term prognosis of TBM patients
The combined CSF sCD163, MMP-9, and serum NCAM1 had the best effect in predicting the short-term prognosis of TBM patients compared with those biomarker separate (AUC 0.841, sensitivity 0.770, specificity 0.796, accuracy 0.782) (Fig. 4; Table 6).
Fig. 4.
A The ROC curves of sCD163, MMP-9 and NCAM1dan on the short-term prognosis of TBM patients were detected alone or in combination, B: The calibration curves of sCD163, MMP-9 and NCAM1dan for short-term prognosis of TBM patients were detected alone or in combination.
Table 6.
Cerebrospinal fluid sCD163, MMP-9, and serum NCAM1 levels alone and in combination predicted the short-term prognosis of TBM patients.
| Hallmark | AUC value | 95% CI | Yoden Index | Best cut-off value | Sensitivity | Specificity | Accuracy |
|---|---|---|---|---|---|---|---|
|
Cerebrospinal fluid sCD163 (ng/L) |
0.764 | (0.664,0.864) | 1.587 | 98.66 | 0.852 | 0.735 | 0.800 |
|
Cerebrospinal fluid MMP-9 (µg/L) |
0.772 | (0.683,0.861) | 1.460 | 215.31 | 0.705 | 0.755 | 0.727 |
| Serum NCAM1 (mg/L) | 0.798 | (0.713,0.883) | 1.550 | 78.235 | 0.672 | 0.878 | 0.764 |
| Combined | 0.841 | (0.766,0.916) | 1.566 | 0.629※ | 0.770 | 0.796 | 0.782 |
Discussion
TBM is a disease caused by Mycobacterium tuberculosis (MTB) infection, which crosses the blood-brain barrier and enters the central nervous system14–16. With the progression of the disease, patients with TBM may develop vascular blockage, increasing the risk of cerebral infarction17,18. However, the commonly used TBM rapid screening technology has some problems such as long time consuming and low positive rate. Therefore, it is crucial in clinical and public health contexts to identify a specific and precise target for early diagnosis of tuberculous meningitis and for predicting the prognosis of TBM patients. This will enhance our understanding of the disease conditions and improve patient outcomes.
The study indicates that when MTB infects the meninges, macrophages and monocytes are activated, participating in the immune response mediated by T cells, stimulating the secretion of sCD16319–21, which leads to an upregulation of sCD163 expression, resulting in an increase in the level of sCD163 in the cerebrospinal fluid of patients. Meanwhile, other studies have shown that MMP-9 levels in cerebrospinal fluid are elevated, which degrades extracellular matrix and damages the blood-brain barrier, causing central nervous system injury22, and also inhibits the formation of NCAM1, and when the blood serum level of NCAM1 is low23, it can backfire on damaged nerve cells and newly formed nerve cells, causing the patient’s condition to worsen and exacerbate the TBM patient’s condition. The levels of cerebrospinal fluid sCD163, MMP-9, and serum NCAM1 are closely related to the onset and prognosis of TBM. Our study showed that the levels of cerebrospinal fluid sCD163 and MMP-9 in the TBM group are higher than those in the control group, and the level of serum NCAM1 in the TBM group is lower than that in the control group. The above differences are all p < 0.05, indicating that the levels of cerebrospinal fluid sCD163, MMP-9, and serum NCAM1 are at different levels in TBM and non-tumor non-infectious headache, and that the levels of cerebrospinal fluid sCD163 and MMP-9 in TBM patients are positively correlated with the MRC staging of TBM patients, while the level of serum NCAM1 is negatively correlated with the MRC staging of TBM patients. This suggests that the elevated levels of cerebrospinal fluid sCD163, MMP-9, and serum NCAM1 can affect the MRC staging of TBM patients, indicating that cerebrospinal fluid sCD163, MMP-9, and serum NCAM1 are good indicators for monitoring the progression of TBM.
This study retrospectively analyzed the factors affecting the short-term prognosis of TBM patients, and focused on the impact of cerebrospinal fluid sCD163, MMP-9 and serum NCAM1 levels on the short-term prognosis of patients, which is of great significance for guiding the next clinical treatment. The results of this study also show that: After adjusting for hydrocephalus, changes in consciousness, cranial nerve palsy, and MRC stage in multivariate analysis, increased cerebrospinal fluid sCD163 and MMP-9 levels were risk factors for the short-term prognosis of TBM patients, and increased NCAM1 levels were protective factors for the short-term prognosis of TBM patients (P < 0.05). The combined detection of sCD163, NCAM1 and MMP-9 levels has high efficacy in predicting the prognosis of TBM patients. It can be seen that the combined detection of sCD163, NCAM1 and MMP-9 levels can effectively predict the short-term prognosis of TBM patients. The combined detection of the three indicators can effectively make up for the deficiency of the detection of a single indicator, so the prediction efficiency is high. Based on the principle of “early detection and early treatment”, by detecting the changes in the levels of the above three indicators, it can help provide references for clinicians to dynamically adjust drug dosage or treatment plan, and actively promote the rehabilitation of patients.
In summary, the changes of cerebrospinal fluid sCD163, MMP-9 and serum NCAM1 levels can affect MRC stage and short-term prognosis of TBM patients, and the combined detection of the three levels has high efficacy in predicting the short-term prognosis of patients, and the above indicators can be dynamically monitored clinically to actively promote the disease status of patients. However, this study also has the following shortcomings: As a single-center retrospective study, there may be information deviation in the process of general data statistics; TBM may relapse after recovery, but limited by research funds and human factors, this study only studied the short-term follow-up, and did not study the short- and medium-term prognosis of patients by COX risk ratio analysis. In the future, the above deficiencies should be eliminated in order to obtain more representative research conclusions.
Acknowledgements
We are thankful to the individuals patients for contributing to our research.
Author contributions
Q.W., H.C., T.Y., Z.F. and M.D. designed the study, Q.C., Q.L., T.Y., Z.F. and G.Z. collected the samples. H.C., T.Y., Z.F.Q.C. and Q.L performed the literature search and collected the data. T.Y performed the statistical analysis. T.Y., Y.W, B.D., Q.W. and H.C analyzed the data, T.Y. wrote the main manuscript text, Q.W. and H.C. coordinated the paper. All authors read and approved of the final manuscript.
Funding
This work was supported by Clinical Medical Technology Innovation Guide Project of Hunan Province (2021SK50703).
Data availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
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Contributor Information
Hongmei Chen, Email: 453730409@qq.com.
Qi Wang, Email: wqi0628@163.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.