The diagnostic and prognostic value of heparin-binding protein in cerebrospinal fluid for patients with intracranial infections

Abstract

Background

This study aims to evaluate the diagnostic and prognostic value of heparin-binding protein (HBP) in cerebrospinal fluid (CSF) for patients with intracranial infections.

Methods

This study included 211 subjects, of whom 138 were diagnosed with intracranial infections, 20 were patients with non-infectious inflammatory encephalopathies, and 53 controls who were eventually excluded from intracranial infections and inflammatory encephalopathies. The levels of HBP and procalcitonin (PCT) in CSF were detected in the subjects, and the diagnostic value of CSF HBP and PCT for intracranial infections was assessed using the receiver operating characteristic (ROC) curves. In addition, CSF HBP levels in patients with intracranial infections were dynamically monitored on days 1, 5, and 9 post-treatment.

Results

The levels of HBP in CSF were significantly higher in the infection group compared to both the non-infectious inflammatory encephalopathy group and the control group. The area under the ROC curve (AUC) for CSF HBP in diagnosing intracranial infection was 0.916 (95% CI 0.870-0.950), which was significantly higher than that of CSF PCT (AUC: 0.543, 95% CI 0.474-0.612). Furthermore, the combination of CSF HBP and white blood cell (WBC) counts exhibited a significantly higher AUC of 0.957 (95% CI 0.920-0.980) compared to HBP alone (P<0.05). The AUC for the combination of CSF HBP and PCT was 0.920 (95% CI 0.875-0.953). In addition, elevated concentrations of CSF HBP were observed in patients with bacterial infections and positive microbiological results (P<0.05). Following treatment, CSF HBP levels in patients with intracranial infections showed a significant decrease from day 1 to day 9.

Conclusions

The level of HBP in CSF serves as a reliable diagnostic marker for identifying intracranial infections, particularly aiding in the identification of bacterial infections. In addition, they can be used as a valuable tool for monitoring the severity and prognosis of intracranial infection.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40001-024-02183-x.

Introduction

Intracranial infection is an intracranial disease caused by viruses, bacteria, fungi, or parasites, which can affect the brain parenchyma, ventricles, and meninges, leading to various diseases, such as brain abscess and meningitis [1]. It is usually secondary to neurosurgical diseases or related operations. Due to the limitations of the blood-brain barrier on drug penetration and antibiotic resistance issues, the treatment effect is often poor, which may aggravate the condition, prolong hospitalization, and even endanger life [2]. Furthermore, neurological dysfunction may remain after recovery. Therefore, timely and accurate detection of pathogens and targeted treatment are key to accurate diagnosis, effective treatment, and good prognosis.

Although imaging examinations can serve as auxiliary diagnostic tools for intracranial infections, their definitive diagnosis still relies on laboratory tests. Cerebrospinal fluid (CSF) microbiological culture is regarded as the "gold standard", but it often suffers from low positive rates due to its time-consuming nature and susceptibility to specimen contamination. In addition, drug sensitivity testing is also time-consuming, which is not conducive to timely treatment [3]. Routine CSF examination can indicate inflammation, but it lacks specificity; although routine biochemical indicators have reference value, there is no universally accepted cutoff value, limiting their application [4]. Therefore, it is particularly urgent to explore biomarkers specific to intracranial infections.

In recent years, research on CSF infection markers has increasingly focused on differentiating between bacterial and viral infections. Key indicators under investigation include procalcitonin (PCT), C-reactive protein (CRP), lactic acid, and heparin-binding protein (HBP). HBP, a member of the polymorphonuclear neutrophil serine protease family, is rapidly released from activated neutrophils during early inflammatory responses [5, 6], establishing it as a novel infection marker. Elevated levels of HBP in peripheral blood have been observed in conditions, such as sepsis, urinary tract infections, ventilator-associated pneumonia, and COVID-19 pneumonia, indicating its utility in disease diagnosis [7–9]. Notably, HBP concentrations are significantly higher in cases of bacterial meningitis compared to both viral meningitis patients and healthy controls, demonstrating superior diagnostic value over traditional inflammatory markers like lactic acid and PCT [10–13]. Furthermore, in pediatric cases of purulent meningitis, iatrogenic meningitis and ventriculitis, HBP exhibited greater diagnostic efficiency than PCT [14–16]. However, research on the use of CSF HBP for diagnosing bacterial intracranial infections remains limited. In septic patients, HBP not only aids in early diagnosis but also provides prognostic information. When used alongside the quick sequential organ failure assessment (qSOFA), HBP enhances the accuracy of mortality predictions in sepsis [15]. Nevertheless, its prognostic significance in intracranial infections is still under investigation.

In the present study, we detected HBP levels in CSF samples from patients with intracranial infection, non-infectious inflammatory encephalopathy and control group. The aim was to evaluate the role of CSF HBP in the diagnosis of intracranial infection and analyze its expression characteristics in bacterial intracranial infection. In addition, by continuously monitoring changes in CSF HBP levels in patients with bacterial intracranial infections, the study further explored the potential of HBP as a prognostic indicator for intracranial infections.

Materials and methods

Study design and patient population

This single-center observational study was conducted at The First Affiliated Hospital of Nanchang University. The study population included 211 patients who were admitted to the Neurology and Neurosurgery departments between June 2022 and February 2023. 138 patients diagnosed with intracranial infections comprised the infection group, which included 124 cases of bacterial infections and 14 cases of infections caused by other pathogens (8 patients with viral infections, 4 with tuberculosis, 1 with a fungal infection, and 1 with syphilis). 20 subjects with clinically suspected neuroinflammatory diseases (excluding infections) formed the non-infectious inflammatory encephalopathy group, and 53 subjects excluded from intracranial infections and inflammatory encephalopathies made up the control group.

Typically, the complete resolution of an infection requires 7-10 days [17, 18], which is aligns with the clinical course observed in the patients included in this study. To evaluate the prognostic value of HBP in intracranial infections, we defined the first, fifth, and ninth day post-diagnosis as the early, middle, and late stages of treatment, respectively, based on the patients' treatment trajectories. A total of 37 patients with intracranial infections were monitored for HBP levels at these three timepoints. Among them, 22 patients had HBP levels measured at all three timepoints, while 15 patients were not monitored at the ninth day.

The study was approved by the Ethics Committee of The First Affiliated Hospital of Nanchang University. All CSF samples are the remaining specimens after clinical laboratory examination, the study obtained informed consents from patients.

Diagnostic criteria

Inclusion criteria for intracranial infection is according to CDC/NHSN Surveillance Definitions [19, 20].

Bacterial intracranial infection: (1) definitive diagnosis of an infection: a. positive cultures or positive findings on Gram staining of cerebrospinal fluid; b. positive cultures of blood. (2) Diagnosis of a potential infection: a. clinical sign or symptoms cannot otherwise be explained by other causes (fever > 38  or headache or vomiting or altered mental status or focal neurological impairments); b. CSF WBC count > 100 × 10⁶/L or when the CSF WBC is (10-100) × 10⁶/L, the CSF protein is higher than 500 mg/L or the CSF glucose is lower than 2.5 mmol/L; c. CT or MRI findings: meningitis often indicates diffuse brain oedema; ventriculitis indicates ventricular dilatation or fluid level in the ventricle; circular enhancement can be seen in brain abscesses.

Viral intracranial infection: The presence of clinical symptoms, WBC of > 15/mm³ with predominance of mononuclear/lymphocyte cells in the absence of any bacterial intracranial infection laboratory criteria.

Tuberculous, fungal, and syphilitic intracranial infection: positive microbiological laboratory result in CSF.

The non-infectious inflammatory encephalopathy group [21, 22] comprised 20 subjects, including 12 cases of antibody-mediated autoimmune encephalitis [23], 3 cases of Guillain–Barré syndrome [24], 3 cases of systemic lupus erythematosus [25], 1 case of Wernicke's encephalopathy [26], and 1 case of brainstem encephalitis.

The control group comprised 53 subjects who excluded from intracranial infections and inflammatory encephalopathies, and demonstrated CSF WBC of ≤100 × 10⁶/L and glucose levels of ≥2.5 mmol/L.

The exclusion criteria were: (1) patients do not meet the above diagnostic criteria; (2) age < 18 years; (3) patients with malignant tumours; and (4) neutropenic patients.

Data collection

Cerebrospinal fluid samples were collected in sterile tubes under aseptic conditions by the attending physician and were sent for testing immediately. The CSF samples were centrifuged at 1500 × g for 5 min to separate the supernatant for the analysis of CSF proteins, glucose, chloride, HBP, and PCT. Cytological analysis included WBC counting and differentiation, microbiological assessment included Gram stain and bacterial culture of the CSF. All tests and sample inoculations were completed within 2 h of collection.

HBP and PCT levels in the CSF were measured using the ELISA Fluorescent Immunalyzer Model AFS-1000 (Guangzhou Labmis Biotech Co., Ltd., Guangzhou, China). The limit of detection (LOD) for HBP was 1 ng/mL, with an analytical sensitivity of 0.01 ng/mL; for PCT, the LOD was 0.05 ng/mL, with the same analytical sensitivity of 0.05 ng/mL. All assays were performed in accordance with the manufacturer's instructions.

Statistical analysis

We used SPSS 23.0 (SPSS, Armonk, NY) and graphpad prism 8.0 (graphpad software, La Jolla, CA) for statistical analysis. Continuous variables are first tested by Shapiro Wilk normality test. Those with normal distribution are shown as mean ± standard deviation (SD), while those with non-normal distribution are shown as median and interquartile interval (IQR). Student t test or Mann–Whitney U test was used for comparison between the two groups, and one-way ANOVA or Kruskal = Wallis H test was used for three groups or more. Categorical variables were expressed as percentages and analyzed by ײ test or Fisher exact test. The results of multivariate logistic regression analysis were expressed as p value, odds ratio (or) and 95% confidence interval (CI). The diagnostic ability of cerebrospinal fluid biomarkers was evaluated by the area under the ROC curve (AUC). Spearman test was used for correlation analysis. The changes of cerebrospinal fluid markers in patients with continuous monitoring were compared by standardized method (x-μ)/α, i.e., the value of the variable minus the mean divided by the standard deviation. P < 0.05 means statistically significant, P < 0.05, P < 0.01, P < 0.001.

Results

Baseline characteristics

A comparison of demographic and baseline data are summarized in Table 1. No significant difference in age, gender, underlying diseases among the three groups were found (P > 0.05). In regard to the clinical treatment, surgery and placement of external ventricular drainage device were more frequently observed in infection group (P < 0.001). Besides, the proportion of patients with fever (P < 0.001), altered consciousness/coma (P < 0.001) and motor deficits (P < 0.001) was significantly higher in the infection group. Higher neurological sequelae frequency (P = 0.002) and longer hospital durations (P < 0.001) were also showed in the infection group, while it had lower  Glasgow Coma Scale (GCS) scores (P < 0.001) compared with non-infectious inflammatory encephalopathy group and control group.

Table 1.

Basic characteristics of all patients

Variables	Infection group (n=138)	Non-infectious inflammatory encephalopathy group (n=20)	Control group (n=53)	P value
Sex (male: female)	81: 57	8: 12	22: 31	0.052
Age, years (median, IQR)	48.5, 12	59, 25	58, 28	0.209
Underlying diseases (n, %)
Digestive system disease	25 (18.1)	5 (25)	8 (15.1)	0.647
Respiratory disease	19 (13.8)	4 (20)	2 (3.8)	0.081
Cardiovascular disease	59 (42.8)	8 (40)	22 (41.5)	0.967
Central nervous system disease	36 (26.1)	3 (15)	17 (32.1)	0.332
Clinical treatment (n, %)
Surgery	99 (71.7)	0	14 (26.9)	< 0.001*
External ventricular drainage	98 (71)	0	18 (34)	< 0.001*
Vital signs (n, %)
Headache	39 (28.5)	4 (20)	19 (35.8)	0.397
Fever	103 (75.2)	2 (10.5)	5 (9.4)	< 0.001
Altered consciousness/coma	86 (62.8)	2 (10)	15 (28.3)	< 0.001
Epilepsy	13 (9.5)	1 (5)	6 (11.3)	0.762
Motor deficits	84 (61.3)	0	7 (13.2)	< 0.001*
Prognosis parameters
Hospital durations (day) (median, IQR)	28, 13	19, 2	13.5, 8	< 0.001
GCS score (median, IQR)	13, 6	15, 0	15, 0	< 0.001
Hospital mortality (n, %)	0	0	0	-
Neurological sequelae (n, %)	86 (62.8)	5 (4.3)	24 (46.2)	0.002

P value for the comparison among Infection group, Non-infectious inflammatory encephalopathy group and Control group

IQR: interquartile range; GCS score: Glasgow Coma Scale score

^*P value for Infection group and Control group. Neurologic sequelae include cerebral palsy, epilepsy, and cognitive deficits

Diagnostic accuracy of CSF HBP for intracranial infection

The levels of biomarkers in CSF and blood samples were compared (Table 2). In CSF samples, levels of HBP were significantly higher in the infection group compared to both the non-infectious inflammatory encephalopathy group and the control group (P < 0.05), while PCT did not show a significant difference among the three groups (P = 0.089). In addition, WBC count, percentage of polymorphonuclear neutrophils (PMN %), and protein levels were significantly elevated in the infection group compared to the non-infectious inflammatory encephalopathy group and the control group (P < 0.05). In contrast, glucose and chloride levels were significantly lower in the infection group than in the non-infectious inflammatory encephalopathy group and the control group (P < 0.05). In blood samples, WBC count, neutrophil count, PMN %, monocyte count, CRP, and serum amyloid A (SAA) levels were significantly higher in the infection group compared to both the non-infectious inflammatory encephalopathy group and the control group (P < 0.05). Lymphocyte count and percentage of lymphocytes were significantly lower in the infection group than in the non-infectious inflammatory encephalopathy group and the control group (P < 0.05).

Table 2.

Comparison in CSF and peripheral blood biomarkers of all patients

Variables	Infection group (n=138)	Non-infectious inflammatory encephalopathy group (n=20)	Control group (n=53)	P value	PA	PB	PC
CSF parameters
WBC (×106/L)	250, 575	20, 29	1, 7	<0.001	<0.001	<0.001	0.288
PMN (%)	0.8, 0.95	0.0, 0.0	0.0, 0.0	<0.001	<0.001	<0.001	-
Protein (mg/L)	1186.5, 1563	639, 1043	571.5, 527	<0.001	<0.001	0.001	0.034
Glucose (mm/L)	2.86 ± 1.51	3.74 ± 0.70	3.77 ± 0.63	<0.001	<0.001	0.001	0.816
Cl (mm/L)	122.87 ± 8.88	126.66±2.51	126.61±3.83	0.001	0.001	0.021	0.995
PCT (ng/mL)	0.22, 2.34	0.96, 2.51	0.18, 0.31	0.089	ns	ns	ns
HBP (ng/mL)	57.02, 69.94	9.77, 9.78	1.65, 2.35	<0.001	<0.001	<0.001	0.051
Peripheral blood parameters
WBC (× 109/L)	9.08±3.05	6.65 ± 2.29	6.48±2.08	<0.001	<0.001	0.001	0.562
Neutrophil number (×109/L)	7.50±3.05	4.14±1.83	4.37±1.82	<0.001	<0.001	<0.001	0.864
Neutrophil %	80.64±9.13	61.33±7.64	66.08±13.54	<0.001	<0.001	<0.001	0.393
Lymphocyte number (×109/L)	0.90±0.39	1.77±0.23	1.50±0.72	<0.001	<0.001	<0.001	0.074
Lymphocyte%	9.75, 7.5	27.5, 15.1	24.65, 20.8	<0.001	<0.001	<0.001	0.444
Monocyte number (×109/L)	0.51, 0.38	0.49, 0.35	0.41, 0.32	<0.001	<0.001	0.034	0.568
Monocyte %	6.75, 2.5	7.5, 0.6	7.3, 1.33	0.774	ns	ns	ns
CRP (mg/L)	14.05, 48.8	0.8, 8.27	5.05, 10.31	<0.001	<0.001	0.001	0.738
SAA (mg/L)	60.55, 151.96	18.07, 25.94	9.0, 41.61	0.031	0.021	0.13	0.988

Continuous variables are expressed as the median (interquartile range) or mean±standard deviations (SD). P value for the comparison between Infected group, non-infectious inflammatory encephalopathy group and Control group; P_A value for the Infected group and control group; P_B value for the Infected group and non-infectious inflammatory encephalopathy group, P_C value for the non-infectious inflammatory encephalopathy group and control group

CSF: cerebrospinal fluid. PMN: polymorphonuclear neutrophils; PMN %: percentage of polymorphonuclear neutrophils; Cl: chloride; HBP: heparin-binding protein; PCT: procalcitonin; CRP: C-reactive protein. ns: not significant

Multivariate regression was performed to determine the indicators in CSF correlated with intracranial infection (Table S1). The results identified CSF HBP (OR 1.182, 95% CI 1.0831.290, P<0.001), WBC (OR 1.039, 95% CI 1.003-1.077, P = 0.031), protein (OR 1.000, 95% CI 1.0001.001, P= 0.045) and glucose (OR 0.305, 95% CI 0.131-0.706, P = 0.005) as independent risk factors for intracranial infection. To assess the ability of the above indicators to identify intracranial infections. ROC analyses were performed. The diagnostic efficacy of CSF HBP (AUC = 0.916, 95% CI 0.870-0.950) is significantly higher than PCT (AUC = 0.543, 95% CI 0.474-0.612), WBC (0.905, 95% CI 0.857-0.941), protein (AUC = 0.852, 95% CI 0.796-0.897) and glucose (AUC = 0.753, 95% CI 0.689-0.810) (P < 0.05). When combined HBP and WBC, it achieved the largest AUC of 0.957 (95% CI 0.920–0.980), which is higher than HBP alone (P = 0.0019). The AUC for the combination of CSF HBP and PCT was 0.920 (95% CI 0.875-0.953) (Fig. 1) (Table 3).

Fig. 1.

ROC Curve analysis. ROC analysis of CSF parameters for predicting intracranial infection

Table 3.

Diagnostic efficiency of CSF biomarkers in distinguishing intracranial infection

Parameters	AUC	Cutoff value	Sensitivity	Specificity	95%CI	P value
CSF HBP	0.916	16.63	78.99	94.52	0.870-0.950	< 0.001
CSF PCT	0.543	2.62	24.64	89.04	0.474-0.612	0.29
CSF WBC	0.905	20	80.43	91.78	0.857-0.941	< 0.001
CSF glucose	0.753	2.81	53.28	97.26	0.689-0.810	< 0.001
CSF protein	0.852	718	89.05	68.49	0.796-0.897	< 0.001
CSF WBC + HBP	0.957	0.618	88.41	97.26	0.920-0.980	< 0.001
CSF HBP + PCT	0.920	0.47	88.41	89.04	0.875-0.953	< 0.001

ROC: receiver operator characteristic; AUC: area under the curve; CI: confidence interval

The value of CSF HBP in identifying bacterial intracranial infection

All patients (n =211) were classified into two groups based on their diagnosis: the bacterial infection group (n = 124) and the non-bacterial infection group (n = 87). The non-bacterial infection group included 14 patients with infections caused by other pathogens. The results indicated that CSF HBP levels were significantly higher in the bacterial infection group (61.4, interquartile range [IQR]: 21.54-79.8) compared to the non-bacterial infection group (4.51, IQR: 1.25-12.3). Similarly, PCT levels were significantly elevated in the bacterial infection group (0.245, IQR: 0.12-2.71) compared to those in the non-bacterial infection group (0.2, IQR: 0.05-0.72) (P < 0.05). In addition, HBP and PCT levels were significantly higher in bacterial infection cases compared to those with infections caused by other pathogens (P < 0.05) (Fig. 2A, B). To assess the ability of HBP and PCT to diagnose intracranial bacterial infections, ROC analysis was performed that the AUC for HBP in diagnosing bacterial intracranial infections was 0.881, which was significantly higher than PCT at 0.586 (P < 0.05) (Figure S1, Table S2).

Fig. 2.

HBP and PCT levels in CSF samples. CSF HBP (A) and PCT (B) levels in bacterial intracranial infection group (n = 124), non-bacterial intracranial infection (n = 87) and other pathogenic infection (n = 14). CSF HBP (C) and PCT (D) levels in positive culture (n = 23) and negative culture (n = 188) groups. Data are shown as dot plot with mean ± SEM. Kruskal-Wallis H test in (A) and (B), Kruskal–Wallis test in (C) and (D).^*P < 0.05; ^**P < 0.01; ^***P < 0.001

Based on the results of blood or CSF cultures, patients were categorized into two groups: positive culture (n = 23) and negative culture (n = 188). The HBP levels in the positive culture group were significantly higher than those in the negative culture group (P < 0.05) (Fig. 2C), while CSF PCT levels displayed no statistically significant difference between the two groups (Fig. 2D). The microbial culture results and corresponding HBP concentrations are presented in Table S3. Among the 23 positive cases, there were 5 positive blood cases and 18 positive CSF cases. Gram-positive bacteria accounted for 9 cases, whereas gram-negative bacteria constituted 14 cases. Of the total, 14 patients exhibited positive cultures, with 7 patients having repeated positive cultures and the remaining 7 patients each having a positive culture from a single sample. The most frequently isolated organism was Klebsiella pneumoniae. Notably, patients with Staphylococcus infections (including S. hominis, S. capitis, and S. epidermidis) exhibited higher HBP concentrations than those with other bacterial infections.

Correlation analysis of CSF parameters

Spearman's correlation analysis was conducted between CSF biomarkers (Fig. 3). The results showed a strong positive correlation between CSF HBP and WBC (P < 0.001, r = 0.638) and PMN% (P < 0.001, r = 0.667), the correlation between CSF HBP and PCT (P < 0.001, r = 0.314) and protein (P < N0.001, r = 0.519) were relatively weak. GCS score demonstrated negative correlation with CSF HBP (P < 0.001, r = 0.433), WBC (P < 0.001, r = 0.438), as well as PMN% (P < 0.001, r = - 0.425) and protein (P < 0.001, r= -0.557), while it is positively correlated with glucose (P < N0.001, r = 0.271).

Fig. 3.

Correlations between CSF biomarkers. Correlation of CSF HBP with biomarkers in CSF samples as well as GCS with biomarkers in CSF. Analyzed by spearman test

Dynamic changes of HBP in intracranial infection patients

To track the prognosis of patients with intracranial infection after treatment, we followed up 37 patients with intracranial infection, and detected the levels of CSF biomarkers at the first, fifth and ninth days after treatment. The Glasgow Coma Scale (GCS) score is the most widely used neurological assessment based on eye opening, verbal and motor behavior. GCS can reflect the severity of acute brain injury [27]. We use GCS score as an index to evaluate the prognosis of patients with intracranial infection. The levels of CSF biomarkers at the 1th, 5th and 9th post-treatment were analyzed. A standardized method was employed to compare the trends in GCS scores and inflammation-related markers on these days (Fig. 4A). Over time, levels of CSF HBP, WBC, and PMN% exhibited a decreasing trend, with HBP showing the most significant reduction. In contrast, GCS scores gradually increased, while CSF PCT levels demonstrated no significant changes. The comparison of these biomarkers is presented in Fig. 4B. Specifically, CSF HBP, WBC, and PMN% decreased significantly over time, with levels on day 5 being lower than those on day 1, and levels on day 9 lower than those on day 5 (P < 0.05).

Fig. 4.

Dynamic changes of CSF parameters in infection group. 37 patients in infection group were continuously monitored, HBP, PCT, WBC, PMN% in CSF samples and GCS scores were detected. A Comparison between the trends of these biomarkers were shown after normalisation. The dotted lines show the error bars. Changes of CSF HBP, PCT, WBC and PMN% among days 1 (n = 37), 5 (n = 37) and 9 (n = 22) were shown (B). Data are shown as dot plot with mean ± SEM. Analyzed by Kruskal–Wallis H test ^*P < 0.05; ^**P < 0.01; ^***P < 0.001

Discussion

Early diagnosis of intracranial infection is crucial for reducing mortality and disability rates. This study compared the diagnostic value of HBP, PCT, and traditional CSF biomarkers for intracranial infections, and explored the value of CSF HBP in distinguishing between bacterial and non-bacterial intracranial infections. Meanwhile, the dynamic change trend of CSF HBP in patients with intracranial infections was analyzed. Our research indicates that, compared to CSF PCT and other traditional detection indicators, CSF HBP demonstrates higher accuracy in the diagnosis of intracranial infections and can effectively predict the prognosis of intracranial infections. It is worth noting that previous studies have focused on the effectiveness of HBP in the diagnosis of meningitis and ventriculitis, while this study broadens this perspective.

This study found that the CSF HBP level in patients with intracranial infection significantly increased. When the cutoff value of CSF HBP is set at 16.63 ng/mL, the sensitivity of this indicator is 78.99%, and the specificity is as high as 94.52%, its AUC is 0.916, demonstrating the important role of HBP in the diagnosis of central nervous system infection. The diagnostic value of combining WBC with HBP surpasses that of any single indicator, with an AUC value as high as 0.957. Correlation analysis showed that HBP was significantly positively correlated with PMN% and WBC in CSF. This finding is closely related to the characteristics of HBP, which is pre-stored in neutrophils and rapidly released upon encountering bacteria or inflammatory factors [6, 28]. Interestingly, in some patients with bacterial infections, although the WBC and protein levels may be within the normal range, the HBP concentration is significantly elevated, reflecting the active state of functional neutrophils rather than a simple change in WBC count. Therefore, in terms of diagnosis, HBP has obvious advantages over traditional WBC and PMN% indicators. A multivariate logistic regression analysis was conducted on CSF indicators. The results indicated that CSF HBP and white blood cells are independent risk factors for intracranial infection.

The ROC curve analysis results showed that the diagnostic performance of CSF HBP was significantly better than that of PCT, with AUCs of 0.916 and 0.543, respectively. This finding is consistent with the research results of Kong et al. [15], indicating that PCT is inferior to HBP in diagnosing meningitis and ventriculitis. Although PCT can indicate the presence of infection, it is insufficient in excluding non-infection. In addition, it is worth noting that the combined application of HBP and PCT did not improve the accuracy of CSF HBP in the diagnosis of intracranial infection (P > 0.05). In addition, we also found a positive correlation between CSF HBP and PCT, and the interaction mechanism between the two is worthy of further exploration. Although the CSF PCT level in patients with bacterial infection is higher than that in non-infected patients, its diagnostic effect is still inferior compared to CSF HBP.

All patients were classified into the bacterial infection group and the non-bacterial infection group. The non-bacterial infection group included patients with intracranial infections caused by various pathogens (including viruses, tuberculosis, and syphilis), those with non-infectious inflammatory encephalopathies, and control group. Collectively, these conditions represent the majority of cases encountered in neurosurgery, excluding intracranial infections. Our analysis revealed that levels of HBP and PCT in the bacterial infection group were significantly elevated compared to those in the non-bacterial infection group. ROC curve analysis demonstrated that the AUC for HBP in diagnosing bacterial intracranial infections was 0.881, which was significantly higher than PCT at 0.586 (P < 0.05) (Figure S1, Table S2). These results suggest that HBP exhibits greater diagnostic accuracy for bacterial intracranial infections then PCT. Moreover, the HBP levels in the bacterial infection group were significantly higher than that in the other pathogen infection group, consistent with the research findings of Emine et al. [10], the results suggested that HBP is highly effective in distinguishing bacterial infections from other pathogenic causes.

In this study, the CSF HBP in the CSF culture-positive group was significantly higher than that in the culture-negative group, indicating that HBP levels may be significantly influenced by the bacterial load in blood or CSF. Johanna et al. found in their study on plasma HBP levels in sepsis patients that the release of HBP in plasma from patients infected with Streptococcus strains was significantly higher than that from patients infected with Staphylococcus aureus or Escherichia coli [29]. Currently, it remains unclear whether there are differences in CSF HBP levels caused by different strains of bacteria leading to intracranial infections. This study found that patients infected with coagulase-negative staphylococci exhibited an elevated trend in HBP levels compared to those infected with Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas adaceae et al. (Table S3). Due to the sensitivity limitations of the cultivation method, the positive cultivation rate in this study was only 18.5%, resulting in insufficient representative data on the specific impact of various bacteria on CSF HBP levels. Although there is currently no conclusive evidence directly indicating how different bacterial species specifically affect changes in HBP levels, Ariane et al.'s research report points out that after infection with different strains, the HBP levels in the blood will rise at different rates over time [30]. Based on these observations, we propose a hypothesis that the strain of bacteria and the duration of infection may have different effects on the level of CSF HBP. However, this hypothesis still needs to be verified and refined through more in-depth research.

In the non-infectious inflammatory encephalopathy group, the CSF HBP levels in patients were significantly lower than those in the infection group, yet slightly higher than those in the control group. This group of patients was primarily diagnosed with autoimmune encephalitis (AE), a type of encephalitis mediated by autoimmune mechanisms, characterized by acute or subacute onset, with cognitive impairment and psychiatric symptoms as its main clinical features [23, 31]. Compared to control group, these patients exhibited only slight changes in CSF HBP levels. This phenomenon may be attributed to the relatively stable levels of WBC and PMN% in CSF, which to some extent explains the slight fluctuations in HBP levels. It is noteworthy that this study reports the CSF HBP levels in AE patients for the first time. Typically, the diagnosis of AE heavily relies on the detection of autoimmune antibodies in CSF and blood [32]. However, beyond AE, several studies have also revealed the potential diagnostic value of HBP in other autoimmune diseases. For instance, Tian et al. discovered that HBP effectively distinguishes between active and inactive adult-onset Still's disease [33], further broadening the application prospects of HBP in the diagnosis of autoimmune diseases.

We conducted a dynamic analysis of CSF indicators in patients with intracranial infections on the days 1, 5, and 9. The research findings revealed that CSF HBP, WBC, and PMN% gradually decreased with the extension of treatment duration. Notably, HBP showed the most significant decrease among these three indicators. Concurrently, the GCS score exhibited an upward trend. As the GCS score is a crucial indicator for assessing the degree of coma and the severity of acute traumatic brain injury [27], its increase signifies an improvement in the patient's condition. Correlation analysis indicated a negative correlation between CSF HBP and GCS score, suggesting a close association between the decrease in HBP levels and the improvement in the patient's condition (i.e., the increase in GCS score). Based on the GCS score, patients were categorized into two groups: those with good prognosis and those with poor prognosis. Specifically, GCS < 8 indicates severe injury, while 9-15 denotes mild or moderate injury [27]. The analysis results showed that the CSF HBP concentration in patients with poor prognosis was significantly higher than that in patients with good prognosis (Figure S2). However, there was no significant correlation between GCS score and PCT. During the continuous monitoring in this study, from the day 1 to the day 9, there was no significant change in the CSF PCT levels of patients. These studies suggest that HBP outperforms PCT and other traditional biomarkers in prognosis assessment.

This study exhibits novelty in several aspects: first, the patient population we included is extensive, encompassing both hospital-acquired and community-acquired intracranial infection cases. This design ensures that the research findings align more closely with real-world clinical scenarios. Second, this study innovatively investigates the prognostic value of CSF HBP levels in intracranial infections through dynamic monitoring of HBP changes. According to existing literature, this is the first report on the role of CSF HBP in the prognosis of intracranial infections. Furthermore, we have also reported CSF HBP levels in patients with autoimmune encephalitis for the first time. However, this study also has some limitations. First, the sample size is relatively small, which may affect the representativeness and reliability of the results. Therefore, future studies with larger scales and multi-center designs are needed to further validate our findings. Second, some patients may have received certain treatments before enrollment, which may have a certain impact on the research results, making it difficult for us to fully and accurately evaluate the prognostic value of HBP.

Conclusion

CSF HBP levels serve as a reliable diagnostic marker for identifying intracranial infections, particularly aiding in the identification of bacterial infections. In addition, they can be used as a valuable tool for monitoring the severity and prognosis of intracranial infection. These findings can be applied to clinical treatment, enabling clinicians to comprehensively evaluate the patient's condition, timely improve treatment plans, and thus improve the prognosis of intracranial infection patients.

Author contributions

YTY and JWC: writing—original draft preparation, PF and JQX: investigation and methodology, QL: project administration. FZ and ZKH: conceptualization, writing—review and editing. All authors have reviewed the results and approved the final version of the manuscript.

Funding

The study was supported by Jiangxi Administration of Traditional Chinese Medicine (2022A356), Jiangxi Department of Education (GJJ2200104), the High-end Talents Project of Jiangxi "Double Thousand Plan" Science and Technology Innovation (jxsq2019201094), the National Natural Science Foundation of China (32060181, 82360322), Outstanding Youth Fund of Jiangxi Natural Science Foundation (20212ACB216006), Foundation of Nanchang Key Laboratory of Diagnosis of Infectious Diseases (Hongkezi 2022 No. 233), the Province Natural Science Foundation of Jiangxi Province (20232ACB206027, 20242BAB20388).

Availability of data and materials

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

All procedures performed in the present study were in accordance with the Declaration of Helsinki and the study was reviewed and approved by Ethics Committee of The First Affiliated Hospital of Nanchang University (2023) CDYFYYLK (02-051).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.