Systemic immune-inflammation index and postoperative anxiety after transforaminal endoscopic lumbar discectomy

Abstract

BACKGROUND

Transforaminal endoscopic lumbar discectomy (TELD) has increased significantly in recent years because of perceived advantages over traditional open lumbar discectomy as an effective and less invasive surgical technique. Although pain is effectively managed in most patients with TELD, postoperative anxiety has emerged as a substantial concern. Developing reliable predictors of postoperative anxiety in patients undergoing TELD is urgently needed. The predictive ability of the systemic immune-inflammation index (SII), a subclinical inflammatory marker, has attracted interest in its ability to predict various postoperative events, including anxiety. To date, the influence of SII on postoperative anxiety in patients undergoing TELD is undetermined.

AIM

To investigate the association between SII, selected inflammatory and immune-related markers, and postoperative anxiety in patients undergoing TELD.

METHODS

This retrospective study included 180 patients who underwent TELD from 2022 to 2023. Participants were divided into anxiety and non-anxiety groups based on the Hospital Anxiety and Depression Scale-Anxiety assessment score, performed two weeks after surgery. SII value and levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, C reactive protein (CRP), procalcitonin (PCT), rheumatoid factor (RF), antinuclear antibodies, and immunoglobulin G, A, and M, were measured pre- and postoperatively. Multivariate logistic regression was performed to identify independent predictors of postoperative anxiety.

RESULTS

Of the 180 patients included in this study, 47 (26.1%) exhibited postoperative anxiety. Patients in the anxiety group had higher levels of SII, TNF-α, IL-6, CRP, and PCT than those in the non-anxiety group. Pre-operative RF levels were significantly higher in patients with postoperative anxiety (P = 0.032). Multivariate logistic regression analysis revealed that elevated levels of postoperative SII [odds ratio (OR) = 1.003, 95% confidence interval (CI): 1.001-1.005, P = 0.008], IL-6 (OR = 1.087, 95%CI: 1.021-1.158, P = 0.009), and CRP (OR = 1.045, 95%CI: 1.012-1.079, P = 0.007) were associated with higher odds of experiencing postoperative anxiety.

CONCLUSION

This study showed that higher levels of SII, IL-6, and CRP in patients who had undergone TELD can identify those at increased risk of developing postoperative anxiety.

Key Words: Systemic immune-inflammation index; Postoperative anxiety; Transforaminal endoscopic lumbar discectomy; Inflammatory markers; C-reactive protein; Interleukin-6

Core Tip: This study found that increased levels of the systemic immune-inflammation index, interleukin-6, and C reactive protein following surgery are potential independent markers associated with the development of anxiety following a surgical procedure in patients undergoing transforaminal endoscopic lumbar discectomy. Assessing these combined inflammatory markers can serve as a risk stratification methodology to identify target patients who may develop anxiety following surgery. The results of this study support the growing focus on inflammation as a potential influence on the psychological aspect of recovery from spinal surgery.

INTRODUCTION

Lumbar disc herniation (LDH) is a common spinal condition that affects the quality of life of patients due to pain and disability[1]. Transforaminal endoscopic lumbar discectomy (TELD) is a minimally invasive method in the management of LDH[2]. Compared with traditional open discectomy, TELD is associated with less postoperative recovery time and less damage to the surrounding tissues[3]. However, patients undergoing TELD often experience multiple psychological sequelae, among which anxiety is prevalent and concerns clinicians[4,5].

The incidence of anxiety after spinal surgery ranges from 20% to 40%, and it negatively influences postoperative pain intensity, satisfaction, and functional recovery of the patient[6,7]. Poorer clinical outcomes and preoperative anxiety was identified after a follow-up of patients who underwent percutaneous transforaminal endoscopic discectomy[8]. Moreover, among older patients, anxiety is the sole determinant of postoperative delirium following elective lumbar surgery[9]. These findings indicate the urgent necessity to recognize and treat postoperative anxiety in these patients. Although previous studies have associated preoperative anxiety, pain burden, disability, and functional status with postoperative psychological outcomes after spinal surgery, most investigations have relied on clinical or questionnaire-based variables and have not sufficiently evaluated whether perioperative inflammatory markers could improve risk prediction[6-9].

The systemic immune-inflammation index (SII) is a new metric that reflects the status of the immune system and inflammation in the body. It is defined as the product of platelet and neutrophil counts divided by the lymphocyte count. The SII can reliably predict postoperative complications and has been evaluated for postoperative delirium and severe complications after abdominal surgery[10,11]. The SII uses data from three types of peripheral blood components, and compared with traditional inflammatory markers used alone, the SII more accurately reflects the balance of inflammation and immune response of the body[12].

Biochemical inflammatory markers such as C-reactive protein (CRP), procalcitonin (PCT), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) are important when considering the impact of the inflammatory response after surgery[13,14]. Within the cascade thrombin-induced pro-inflammatory cytokines, TNF-α and IL-6 act within the regulation of the liver to produce acute-phase reactants, such as CRP[15,16]. PCT is an important marker for distinguishing between postoperative infection and inflammation[17]. Finally, the regulation of antibodies [i.e., immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM), and rheumatoid factor (RF)] indicates an alteration in the immune response and is also observed within postoperative recovery[18,19].

The connection between inflammation and mental health is a growing area of research. Many researchers believe that inflammation causes anxiety, depression, and a host of other mental disorders. Many reasons have been identified, including inflammation causing changes to the brain, that disrupts the hypothalamic-pituitary-adrenal axis and alters the balance of neurotransmitters[13,20,21]. However, no studies have attempted to associate the SII, biochemical and immune inflammatory markers, and anxiety after a TELD procedure. Therefore, we sought to identify the association between SII and a wide range of biochemical and immune inflammatory markers [TNF-α, IL-6, CRP, PCT, RF, antinuclear antibodies (ANA), IgG, IgA, IgM] and anxiety resulting from the TELD procedure. The aim was to uncover predictive markers that can be used for early clinical interventions in the future.

MATERIALS AND METHODS

Study design and patient selection

This is a retrospective study, this study included patients from the Orthopedic Department of the First Hospital of Putian City, Hebei Province Hospital of Traditional Chinese Medicine, West China School of Public Health and West China Fourth Hospital, Sichuan University Jointly conducted. The study was approved by the Medical Ethics Committee of Putian First Hospital. The study also followed the principles of the Declaration of Helsinki. Given the retrospective nature of the study, the need to obtain individual informed consent was deemed unnecessary and was waived.

We examined medical records of consecutive patients who underwent TELD for single-level LDH from January 2022 to December 2023. Initially, 213 patients were identified. Following inclusion and exclusion criteria, 180 patients were selected for the final study population.

The inclusion criteria were as follows: (1) Patients aged 18-75 years; (2) Patients with single-level LDH verified by magnetic resonance imaging; (3) Patients who underwent conservative treatment prior to surgery for at least 6 weeks and considered treatment unsuccessful; (4) Patients who underwent TELD under local anesthesia in the presence of monitored sedation; (5) Patients who provided complete preoperative and postoperative laboratory data with complete inflammatory and immune markers; and (6) Patients who underwent Hospital Anxiety and Depression Scale-Anxiety subscale (HADS-A) assessment 2 weeks postoperatively.

Patients who met any of the following criteria were excluded from the study: (1) Patients diagnosed with anxiety disorder, any depressive disorder, or any other mental illness, those who underwent treatment for any of the aforementioned disorders, and those who were treated with psychotropic medications including anxiolytics or antidepressants; (2) Patients who had previously undergone lumbar surgery, and those who underwent revision surgery; (3) Patients diagnosed with systemic lupus erythematosus or inflammatory bowel disease; (4) Patients with an active infection; (5) Patients with cardiac, hepatic, or renal failure of any degree; (6) Patients diagnosed with autoimmune diseases and who met the criteria for treatment with immunosuppressive medications; and (7) Patients with incomplete medical records and those with loss to follow-up within the first 2 weeks after surgery.

Surgical procedure

All surgical procedures are performed by two experienced orthopedic surgeons, while an experienced laboratory physician is responsible for processing and analyzing blood samples and laboratory biomarkers. The surgical procedures were performed using the standardized TELD technique. The patients were positioned in the lateral decubitus position on a radiolucent table with the affected side facing upward. The spine surgeon, using fluoroscopy, identified the optimal skin entry point to be 12-14 cm lateral to the midline, and infiltrated the skin with 1% lidocaine. Using an 18-gauge spinal needle, the entry point in the skin was accessed, and the needle was directed to the level of the disc, using anteroposterior and lateral fluoroscopic views. The surgeon inserted a guidewire using the spinal needle, and, following dilation, a working cannula was inserted. The endoscope was introduced, and the herniated disc material was removed using endoscopic forceps and radiofrequency ablation. Adequate decompression of the structures was ensured by the traversing root of the nerve and the dural sac. Normal saline was used to maintain the operative field, and the working cannula was removed after achieving hemostasis. The incision was closed with a stitch, and a dressing was done. The patients were mobilized on the same day with the help of a physiotherapist, and most patients were discharged within 1-2 days post operatively.

Data collection and laboratory measurements

Demographic and clinical data were collected from the electronic medical records and included age, sex, body mass index (BMI), smoking status, symptom duration, herniation level, American Society of Anesthesiologists (ASA) physical status level, surgery duration, intraoperative blood loss, and hospital length of stay. Preoperative pain was measured using the Visual Analog Scale (VAS) for back and leg pain. The Oswestry Disability Index (ODI) was used to measure functional disability.

Peripheral venous blood samples were collected from all patients at two time points: (1) Within 24 hours before surgery (preoperative); and (2) On postoperative day 3. An automated hematology analyzer (Sysmex XN-9000, Sysmex Corporation, Kobe, Japan) was used to perform complete blood counts and determine total neutrophil, lymphocyte, and platelet counts. The SII was calculated using the following formula: SII = platelet count × neutrophil count/lymphocyte count.

The biochemical inflammatory markers were measured as follows: Serum TNF-α and IL-6 levels were analyzed using ELISA (R&D systems, Minneapolis, MN, United States). CRP level was assessed on an automated chemistry analyzer, via a latex-enhanced immunoturbidimetric assay (Roche Cobas C702, Roche Diagnostics, Mannheim, Germany). PCT level were measured using the Roche Cobas e801 via an Electrochemiluminescence Immunoassay. RF level was assessed using an immunoturbidimetric assay with, the upper reference limit was 20 IU/mL. ANA were assessed via indirect immunofluorescence using HEp-2 cells, with a positive result set at a titer of 1: 100. Serum levels of IgG, IgA, and IgM were measured using Siemens BN II (Siemens Healthcare Diagnostics, Marburg, Germany).

Assessment of postoperative anxiety

To quantify anxiety two weeks postoperatively, the HADS-A was administered. The HADS is a 14-item self-administered, validated, two-part survey. The anxiety portion comprises seven items, whereas the depression portion comprises the remaining seven items. Respondents are scored from 0 to 3 on each of the 14 items for a possible total anxiety subscale score of 0 to 21. To identify clinically meaningful anxiety, an HADS-A score of ≥ 8 was utilized, according to established protocols and previous studies[22]. Participants were categorized into the anxiety group if their HADS-A score ≥ 8, and into the non-anxiety group if their score was < 8. A research nurse administered the HADS-A and other anxiety-related questionnaires and remained blinded to the patient’s lab results. For participants who were unable to independently complete the HADS-A, research nurses provided reading assistance. The research nurses did not interpret the survey items for the participants.

Statistical analysis

SPSS (Windows v.26.0) and R (v.4.2.1) were used to perform the statistical analyses. The Shapiro-Wilk test was used to examine the normality of continuous variables. For continuous variables, the independent samples t-test was used to compare normally distributed data expressed as the mean ± SD, whereas the Mann-Whitney U test was used to compare non-normally distributed data, and the data are presented as the median and interquartile range. Categorical variables were compared using the χ² test or Fisher’s exact test, as appropriate, and are expressed as n (%).

Potential risk factors for postoperative anxiety were identified using univariate logistic regression analysis. Risk factors were included in the multivariate analysis by logistic regression using a forward stepwise selection approach if they achieved a P value < 0.10 in the univariate analysis. For each risk factor, odds ratios (OR) and their 95% confidence interval (CI) were determined. Receiver operating characteristic (ROC) Curves were generated, and the area under the curve (AUC) was determined, to assess independent risk factors for anxiety and their predictive capacity. The Youden index (sensitivity + specificity - 1) was used to determine optimal cutoff values. The correlation between inflammatory markers and HADS-A scores was assessed using Spearman’s rank correlation. A two-tailed P value of < 0.05 was considered statistically significant.

RESULTS

Baseline characteristics

Among the 180 patients enrolled in this study, 47 (26.1%) were assigned to the anxiety group (HADS-A ≥ 8) and 133 (73.9%) to the non-anxiety group (HADS-A < 8). The clinical and demographic baseline characteristics of the two study groups are shown in Table 1. No statistically significant differences were observed between the two study groups regarding age, sex, BMI, smoking status, herniation level, ASA classification, procedural duration, and intraoperative blood loss (P > 0.05). Compared with the non-anxiety group, the anxiety group had a longer duration of preoperative symptoms (P = 0.021), a higher preoperative VAS score for leg pain (P = 0.014), and a higher preoperative ODI score (P = 0.008).

Table 1 Baseline demographic and clinical characteristics of patients in the anxiety and non-anxiety groups, n (%).

Variable	Anxiety group (n = 47)	Non-anxiety group (n = 133)	P value
Age (years)	48.6 ± 11.3	46.9 ± 12.1	0.408
Sex (male/female)	25/22	74/59	0.763
BMI (kg/m2)	24.8 ± 3.2	24.3 ± 3.5	0.392
Smoking status	14 (29.8)	32 (24.1)	0.438
Duration of symptoms (months)	8.4 ± 5.6	6.5 ± 4.8	0.021
Herniation level			0.651
L3/4	3 (6.4)	10 (7.5)
L4/5	26 (55.3)	68 (51.1)
L5/S1	18 (38.3)	55 (41.4)
ASA class (I/II/III)	18/24/5	56/64/13	0.812
Operative time (min)	62.4 ± 15.8	58.7 ± 14.2	0.138
Intraoperative blood loss (mL)	18.3 ± 8.6	16.5 ± 7.9	0.192
Preoperative VAS-back pain	5.8 ± 1.9	5.3 ± 1.7	0.092
Preoperative VAS-leg pain	7.1 ± 1.6	6.4 ± 1.8	0.014
Preoperative ODI (%)	58.6 ± 14.2	52.1 ± 13.8	0.008
Hospital stay (days)	2.8 ± 1.1	2.5 ± 0.9	0.072

BMI: Body mass index; ASA: American Society of Anesthesiologists; ODI: Oswestry Disability Index; VAS: Visual Analog Scale.

Comparison of inflammatory and immune markers

Table 2 summarizes the pre- and postoperative inflammatory and immune markers in the two groups. No significant differences in the preoperative values of SII, TNF-α, IL-6, CRP, and PCT were observed between the anxiety and non-anxiety groups (all P > 0.05). However, SII (587.4 ± 198.6 vs 423.8 ± 156.3, P < 0.001), TNF-α (28.6 ± 9.4 pg/mL vs 21.3 ± 7.8 pg/mL, P < 0.001), IL-6 (45.8 ± 18.7 pg/mL vs 29.4 ± 12.6 pg/mL, P < 0.001), CRP (32.4 ± 14.5 mg/L vs 19.8 ± 10.3 mg/L, P < 0.001), and PCT (0.18 ± 0.09 ng/mL vs 0.11 ± 0.06 ng/mL, P < 0.001) were all higher in the anxiety group.

Table 2 Comparison of inflammatory and immune markers between anxiety and non-anxiety groups.

Variable	Anxiety group (n = 47)	Non-anxiety group (n = 133)	P value
Preoperative SII	412.5 ± 168.3	389.6 ± 152.7	0.396
Postoperative SII	587.4 ± 198.6	423.8 ± 156.3	< 0.001
Preoperative TNF-α (pg/mL)	15.4 ± 6.2	14.1 ± 5.8	0.208
Postoperative TNF-α (pg/mL)	28.6 ± 9.4	21.3 ± 7.8	< 0.001
Preoperative IL-6 (pg/mL)	8.6 ± 4.3	7.9 ± 3.8	0.307
Postoperative IL-6 (pg/mL)	45.8 ± 18.7	29.4 ± 12.6	< 0.001
Preoperative CRP (mg/L)	4.8 ± 3.2	4.2 ± 2.9	0.248
Postoperative CRP (mg/L)	32.4 ± 14.5	19.8 ± 10.3	< 0.001
Preoperative PCT (ng/mL)	0.05 ± 0.03	0.04 ± 0.02	0.312
Postoperative PCT (ng/mL)	0.18 ± 0.09	0.11 ± 0.06	< 0.001
Preoperative RF (IU/mL)	16.8 ± 8.4	13.5 ± 6.9	0.032
Postoperative RF (IU/mL)	17.2 ± 8.1	14.8 ± 7.3	0.058
ANA positive, n (%)	8 (17.0)	16 (12.0)	0.287
Preoperative IgG (g/L)	12.4 ± 2.8	12.8 ± 3.1	0.438
Postoperative IgG (g/L)	11.6 ± 2.5	12.3 ± 2.9	0.068
Preoperative IgA (g/L)	2.3 ± 0.8	2.2 ± 0.7	0.446
Postoperative IgA (g/L)	2.1 ± 0.7	2.2 ± 0.8	0.618
Preoperative IgM (g/L)	1.2 ± 0.4	1.1 ± 0.5	0.226
Postoperative IgM (g/L)	1.1 ± 0.4	1.1 ± 0.4	0.854

SII: Systemic immune-inflammation index; TNF-α: Tumor necrosis factor alpha; IL-6: Interleukin-6; PCT: Procalcitonin; CRP: C-reactive protein; RF: Rheumatoid factor; IgG: Immunoglobulin G; IgA: Immunoglobulin A; IgM: Immunoglobulin M.

With regard to immune markers, preoperative RF levels were significantly higher in the anxiety group compared with the non-anxiety group (16.8 ± 8.4 IU/mL vs 13.5 ± 6.9 IU/mL, P = 0.032). The positive rate of ANA was comparable in the two groups (P = 0.287). No significant differences were found in the preoperative or postoperative values of IgG, IgA, and IgM between the two groups. However, postoperative IgG levels in the anxiety group were lower (P = 0.068) than those in the non-anxiety group (Table 2).

Univariate and multivariate logistic regression analysis

Table 3 shows the findings of the univariate and multivariate analyses for the identification of risk factors potentially associated with postoperative anxiety. Postoperative anxiety was significantly influenced by the duration of preoperative symptoms, preoperative VAS-leg pain, preoperative ODI, postoperative SII, postoperative levels of TNF-α, IL-6, CRP, and PCT, and preoperative level of RF. All of the above factors were also included in the multivariate logistic regression model.

Table 3 Univariate and multivariate logistic regression analysis of risk factors for postoperative anxiety.

Variable	Univariate OR (95%CI)	P value	Multivariate OR (95%CI)	P value
Duration of symptoms	1.058 (1.004-1.114)	0.034	-	-
Preop VAS-leg pain	1.248 (1.042-1.495)	0.016	-	-
Preop ODI	1.034 (1.009-1.060)	0.009	1.028 (0.998-1.059)	0.068
Postop SII	1.004 (1.002-1.006)	< 0.001	1.003 (1.001-1.005)	0.008
Postop TNF-α	1.098 (1.052-1.146)	< 0.001	-	-
Postop IL-6	1.106 (1.056-1.159)	< 0.001	1.087 (1.021-1.158)	0.009
Postop CRP	1.069 (1.041-1.098)	< 0.001	1.045 (1.012-1.079)	0.007
Postop PCT	1.084 (1.012-1.162)	0.022	-	-
Preop RF	1.048 (1.004-1.094)	0.033	-	-

ODI: Oswestry Disability Index; VAS: Visual Analog Scale; SII: Systemic immune-inflammation index; TNF-α: Tumor necrosis factor alpha; IL-6: Interleukin-6; PCT: Procalcitonin; CRP: C-reactive protein; RF: Rheumatoid factor; OR: Odds ratio; CI: Confidence interval.

The multivariate model determined that the three independent risk factors for postoperative anxiety were SII (OR = 1.003, 95%CI: 1.001-1.005, P = 0.008), IL-6 (OR = 1.087, 95%CI: 1.021-1.158, P = 0.009), and CRP (OR = 1.045, 95%CI: 1.012-1.079, P = 0.007). In the multivariate model, the ODI score also indicated a near significance (P = 0.068) (Table 3).

ROC curve analysis

Table 4 presents the results of the ROC curve analysis to investigate the predictive values of individual risk factors for postoperative anxiety. The AUC for postoperative SII was 0.728 (95%CI: 0.647-0.809), with the best threshold being 498.5 (sensitivity = 72.3%, specificity = 66.9%). For postoperative IL-6, the AUC was 0.751 (95%CI: 0.672-0.830), with the best cutoff being 35.2 pg/mL (sensitivity = 68.1%, specificity = 73.7%). The AUC of postoperative CRP was 0.738 (95%CI: 0.658-0.818), with the best threshold being 24.8 mg/L (sensitivity = 70.2%, specificity = 69.2%). For the combination of these three markers, the AUC was equal to 0.836 (95%CI: 0.770-0.902), indicating that the combination of these three markers provided better predictive value than each of the three markers did individually.

Table 4 Receiver operating characteristic curve analysis of independent risk factors for postoperative anxiety.

Variable	AUC (95%CI)	Cut off	Sensitivity (%)	Specificity (%)
Postop SII	0.728 (0.647-0.809)	498.5	72.3	66.9
Postop IL-6	0.751 (0.672-0.830)	35.2 pg/mL	68.1	73.7
Postop CRP	0.738 (0.658-0.818)	24.8 mg/L	70.2	69.2
Combined model	0.836 (0.770-0.902)	-	78.7	76.7

SII: Systemic immune-inflammation index; IL-6: Interleukin-6; CRP: C-reactive protein; AUC: Area under the curve; CI: Confidence interval.

Correlation analysis

Using Spearman’s correlation analysis, positive associations were found between HADS-A scores and the following factors: Postoperative SII (r = 0.412, P < 0.001), postoperative TNF-α (r = 0.368, P < 0.001), postoperative IL-6 (r = 0.445, P < 0.001), postoperative CRP (r = 0.398, P < 0.001), and postoperative PCT (r = 0.286, P < 0.001). No significant correlations with HADS-A scores were found for postoperative levels of IgG (r = -0.124, P = 0.097), IgA (r = -0.038, P = 0.614), or IgM (r = -0.021, P = 0.782). A weak positive correlation was observed between preoperative RF levels and HADS-A scores (r = 0.168, P = 0.024) (Table 5).

Table 5 Spearman’s rank correlation analysis between inflammatory/immune markers and Hospital Anxiety and Depression Scale-Anxiety subscale scores.

Variable	Correlation coefficient (r)	P value
Postoperative SII	0.412	< 0.001
Postoperative TNF-α	0.368	< 0.001
Postoperative IL-6	0.445	< 0.001
Postoperative CRP	0.398	< 0.001
Postoperative PCT	0.286	< 0.001
Preoperative RF	0.168	0.024
Postoperative IgG	-0.124	0.097
Postoperative IgA	-0.038	0.614
Postoperative IgM	-0.021	0.782

SII: Systemic immune-inflammation index; TNF-α: Tumor necrosis factor alpha; IL-6: Interleukin-6; PCT: Procalcitonin; CRP: C-reactive protein; RF: Rheumatoid factor; IgG: Immunoglobulin G; IgA: Immunoglobulin A; IgM: Immunoglobulin M.

DISCUSSION

This retrospective study aimed to explore how the SII, along with various biochemical and immune inflammatory markers, correlates with the occurrence of postoperative anxiety in patients who underwent TELD. Our analysis showed that 26.1% of patients who underwent the procedure developed postoperative anxiety. Furthermore, a heightened risk of developing postoperative anxiety was observed with elevated levels of the SII, IL-6, and CRP following the procedure. To the best of our knowledge, our study is the first to investigate the combined impact of the SII, along with biochemical inflammatory markers (TNF-α, IL-6, CRP, PCT), and immune markers (RF, ANA, IgG, IgA, IgM) on predicting postoperative anxiety after TELD procedures.

The rate of postoperative anxiety (26.1%) in our cohort aligns with other studies that have been published related to this particular area. Substantial anxiety symptoms after lumbar disc surgery have been reported by Apaydin et al[4], who noted that the microendoscopic approach resulted in lower levels of anxiety compared with microscopic microdiscectomy. In a related study, Mou et al[9] reported that preoperative anxiety was associated with an increased risk of developing postoperative delirium in older patients following lumbar disc surgery, underscoring the importance of a perioperative anxiety evaluation. Additionally, Shi et al[8], showed that the presence of anxiety in patients who underwent percutaneous transforaminal endoscopic discectomy, contributed significantly to poorer pain and functional status outcomes at the follow-up appointment. Subsequent studies regarding lumbar spine procedures have been able to substantiate the claim that postoperative anxiety is highly prevalent, and also a substantial complication. In our cohort, patients experiencing anxiety also had longer symptom duration, higher preoperative leg-pain VAS scores, and higher ODI scores, but these variables were not retained as independent predictors after adjustment; this difference from some reports emphasizing pain or psychosocial predictors may be related to the short two-week assessment window, TELD-specific perioperative stress, and collinearity among pain, disability, and inflammatory responses.

SII is receiving increasing attention in the literature as a potential biomarker applicable to surgical research. In a large retrospective cohort of 29608 patients, Song et al[10] showed that the SII was a superior predictor of postoperative delirium for older patients in non-neurosurgical and non-cardiac surgery. Additionally, Jiao et al[11] found that the SII within the first hour of the postoperative period was a significant predictor of severe postoperative complications in patients undergoing upper abdominal surgery. In the present study, the postoperative SII was independently associated with the presence of postoperative anxiety, with an AUC of 0.728. The SII combines components of platelets, neutrophils and lymphocytes which reflects the body’s pro-inflammatory and immunological responses. This may also provide an explanation for the ability of SII to predict anxiety, as the condition is recognized for its increased immune response[23].

The influence of pro-inflammatory cytokines, particularly IL-6, on anxiety and mood disorders has also drawn attention in the research on the acute phase response to surgical and traumatic injuries and the associated complications. IL-6 was correlated with the severity of surgical trauma and associated complications. In lumbar disc surgery, IL-6 levels increase following discectomy and are associated with postoperative pain[24]. The observation that postoperative IL-6 was an independent predictor of anxiety (OR = 1.087) is consistent with studies of centripetal change in the nervous system correlating with increased peripheral inflammation. IL-6 crosses the blood-brain barrier and activates glial cells, resulting in neuro-inflammation, and affects the balance of the brain’s serotonin and dopamine systems, which can lead to anxiety[20,21].

CRP is synthesized in the liver in response to IL-6 and plays a major role as a marker of systemic inflammation[25,26]. Elevated levels of CRP postoperatively are associated with anxiety. Previous research has shown that CRP level elevations are associated with psychological complications. A large longitudinal research study found that elevated levels of CRP at the time of trauma were associated with the development of chronic pain after trauma in a specific sex and that levels of CRP are elevated in patients with an increased level of anxiety in different patient populations. CRP levels are validated objective clinical markers in the area of spinal surgery and can help predict the recovery process after surgery in case of lumbar discectomy, with an increased level of CRP in the postoperative period being associated with an increased level of postoperative inflammation and worse surgical outcomes[27].

Our study found significantly elevated concentrations of TNF-α in patients experiencing anxiety. TNF-α is involved in pain mechanisms occurring after lumbar discectomy, with TNF-α levels at the site of surgery correlating with pain at both short- and long-term postoperative follow-ups[28]. The statistical significance of TNF-α was not retained in our multivariate model and is likely to be collinear with IL-6 and CRP. However, its higher levels in patients in the anxiety group still suggest the presence of inflammatory changes linked to psychological alterations. PCT levels were also significantly elevated in the anxiety group. PCT is used to differentiate bacterial infection from other inflammatory processes. In our multivariate model, the PCT did not reach statistical significance. However, its elevation may reflect the impact of surgical stress and the degree of inflammatory response and damage, which contribute to anxiety through the persistence of inflammatory response signaling[17].

The finding of a higher preoperative RF in the anxiety group should be interpreted with caution. RF is typically associated with rheumatoid arthritis and other autoimmune disorders, and a slight elevation of RF in non-autoimmune settings may indicate nonspecific low-grade immune activation[18]. In this study, RF showed only a weak correlation with HADS-A scores and was not retained in the multivariate model; therefore, RF should be considered an exploratory signal rather than an independent predictor of postoperative anxiety. ANA positivity and immunoglobulin levels (IgG, IgA, IgM) did not differ significantly between groups, suggesting that acute inflammatory markers may be more relevant to postoperative anxiety than to broader humoral immune indicators.

In our study, we performed a combined ROC analysis and found that combined SII, IL-6, and CRP provided a greater AUC (0.836) than any single biomarker alone, indicating that combined SII, IL-6, and CRP markers provided the best postoperative anxiety prediction. Clinically, this is an important finding as measuring combined SII, IL-6, and CRP is readily accessible and less time-consuming. Therefore, combined SII, IL-6, and CRP could help healthcare providers identify high-risk postoperative anxiety patients and allow provision of psychological assistance, behavioral therapy, and/or anxiety medication. Identifying and managing postoperative anxiety, especially when combined with SII, IL-6, and CRP, would improve psychological and functional recovery and would have a positive impact on surgery outcomes.

This study had certain limitations. First, due to the retrospective nature of the study, the causality of inflammatory markers and postoperative anxiety cannot be fully established. Second, the study was conducted in a single center with a small patient population, which limits the generalization of the findings to larger populations. Third, the anxiety assessment was performed at only one time point (2 weeks after surgery), which does not allow to achieve a complete postoperative psychological assessment. Fourth, patients with psychiatric disorders were excluded from the study; however, some participants may have experienced anxiety or depressive symptoms and were not diagnosed with a psychiatric disorder. Fifth, due to the nature of the retrospective study, some confounding factors such as postoperative pain management, social support, and the characteristics of the participants were not included in this study. Next, in order to provide a perspective on the psychological assessment and role of systemic inflammation and postoperative anxiety, it is important to expand the scope of research by focusing on the time element to attribute greater value to this relationship and offer additional elements of social support. Furthermore, preoperative HADS-A scores were not available for all patients; thus, anxiety at 2 weeks may represent new-onset postoperative anxiety or continuation of unrecognized preoperative anxiety, which may have overestimated the postoperative anxiety rate and limits causal inference. Future studies should include anxiety assessments at 1 month, 3, months and 6 months, together with repeated measurements of inflammatory markers, to better characterize the dynamic relationship between inflammation and anxiety. More detailed postoperative pain trajectories and analgesic use should also be collected to separate inflammatory effects from pain-related anxiety.

CONCLUSION

This retrospective analysis revealed that approximately 25% of patients developed anxiety after TELD. The presence of higher SII, IL-6, and CRP values in the postoperative period was independently associated with increased anxiety. The combination of the three inflammatory markers was the best predictor of anxiety. The higher preoperative RF levels observed in anxious patients in this study should be considered hypothesis-generating and requires validation in prospective studies. These findings indicate the role of systemic inflammation in the development of postoperative anxiety and provides a potential inflammatory biomarker and a potential therapeutic target for early preventive treatment.