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Predictive value of lymphocyte ratio and CRP level for early detection of surgical site infection following lumbar spinal surgery


 Objective To investigate the predictive value of laboratory predictors, such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cell (WBC) count, and WBC differential count, for the early diagnosis of surgical site infection (SSI) after lumbar spinal surgery. We also sought to determine the diagnostic thresholds for these markers. Methods A total of 112 patients participated in the study: 11 patients who developed SSI after lumbar spinal surgery (SSI group) and 91 non-SSI patients as controls (non-SSI group). White blood cell (WBC) count, WBC differential count, CRP level, and ESR were determined 1 day before surgery and on postoperative day (POD) 1, POD3, and POD7. The diagnostic thresholds for these markers were determined with the receiver operating characteristic curve. Results CRP, ESR, and WBC were significantly higher in the SSI group than in the non-SSI group on POD3 and POD7 ( P < 0.05). The lymphocyte ratio was significantly lower in the SSI group, compared with the non-SSI group, on POD3 ( P < 0.05). Analysis of the receiver operating characteristic curve revealed that lymphocyte ratio < 11.5% on POD3 (sensitivity 90.9%, specificity 75.4%, area under the curve [AUC] 0.919), and C-reactive protein level > 26 mg/dL on POD7 (sensitivity 90.9%, specificity 87.7%, area under the curve [AUC] 0.954) were significant laboratory predictors for the early detection of SSI. Conclusion Lymphocyte ratio < 11.5% on POD3 and CRP levels > 26.5 mg/dL on POD7 are reliable predictors for SSI after lumbar spinal surgery.

data, imaging techniques 4−7 , and local findings such as tenderness, swelling, redness, and purulent discharge 8 . Due to their objectivity, low cost, convenience and non-invasiveness, several laboratory markers, such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cell (WBC) count, and WBC differential count 8−10 are garnering increased attention as tools with which to screen for SSI. However, clinicians often struggle to interpret these indicators correctly.
Our study was designed to investigate the predictive value of total WBC count, WBC differential count, CRP level, and ESR in the diagnosis of SSI after lumbar spinal surgery. We sought to identify the most significant laboratory predictors for the early detection of SSI and to determine the appropriate cut-off values for these predictors using the receiver operating characteristic (ROC) curve.

Methods
During the period from January 2015 to June 2018, there are 851 patients who underwent lumbar spinal surgery at the Department of Orthopedic Surgery, Shaanxi Provincial People's Hospital. We retrospectively reviewed the medical records of 112 patients. SSI was determined according to criteria provided by the U.S Centers for Disease Control and Prevention 11  Age, gender, operating time, and intraoperative blood loss were evaluated and recorded. CRP, ESR, WBC count, and neutrophil and lymphocyte ratio before surgery and on postoperative day (POD) 1, POD3, and POD7 were collected and analyzed. CRP and ESR were measured by latex agglutination, and WBC count was measured with an automatic cell counter. Neutrophil and lymphocyte ratios were determined by analyzing the WBC count.
Statistical analysis was performed with SPSS 24.0 for Windows (SPSS, Inc., IBM) and Graphpad Prism 7 (GraphPad Software, La Jolla, CA, USA). Data are expressed as mean ± standard deviation (SD).
Continuous variables are presented as means and standard deviations. Categorical variables are summarized as the number and percentage of the total study population. Normally distributed continuous variables were compared using the two-sided independent t-test. Categorical variables were analyzed with the Chi-square test. We determined appropriate diagnostic cutoffs for the markers selected with the ROC curve. Statistical significance was defined as P < 0.05.

Demographics and patient information
The final sample consisted of 112 patients: 11 patients who developed deep SSI (SSI group) and 91who did not (non-SSI group). The SSI group included 7 male and 4 female patients; the non-SSI group included 37 female and 54 male patients. The mean age of patients in the SSI group was 55.82 ± 20.89 years; the mean age of patients in the non-SSI group was 55.55 ± 14.43 years. Operating time was 223.64 ± 90.36 minutes in the SSI group (range, 120-420), and 189.74 ± 80.70 minutes (range, 60-450) in the non-SSI group. Intraoperative blood loss was 600.00 ± 303.32 mL (range, 200-1000) in the SSI group and 442.11 ± 251.21 mL (range, 100-1000) in the non-SSI group. There were no significant difference between the groups in age, sex, operating time, or intraoperative blood loss (P > 0.05) ( Table 1). The patients who had degenerative disease had undergone PLIF or discectomy surgery. There was no difference between groups in terms of surgical technique, anesthetic procedure, etc. with antibiotics, the bacterial species identified by blood culture was S. aureus. The timeline for the onset of infection after surgery is shown in Table 2. All patients recovered after undergoing surgery or receiving treatment with antibiotics ( Table 2). Biochemical markers There were no significant differences between groups in the level of any chemical marker measured before surgery. On POD 1, the WBC count in the SSI group (15.65 ± 6.05) was significantly higher than that in the non-SSI group (12.07 ± 3.95; t = -2.51; p = 0.01), but there was no significant difference between groups in CRP, ESR, neutrophil ratio, or lymphocyte ratio (Fig. 1).
On POD 3, there was no significant difference in WBC count between the SSI group (12.55 ± 3.78) and the non-SSI group (10.29 ± 3.65; t = -1.69; p = 0.096) (Fig. 2). The neutrophil ratio in the SSI group (0.84 ± 0.07) was significantly higher than that in the non-SSI group (0.75 ± 0.10; t = -2.77, p =  The biochemical markers used most widely for the early diagnosis of SSI are CRP, ESR, total WBC count, and differential WBC count. Several studies have reported the usefulness of these biomarkers and found that the combined use of normal CRP, ESR, and WBC levels reliably predicts the absence of infection after lumbar spinal surgery 14.15 Changes in ESR and CRP after surgery may be used to distinguish between infected and non-infected patients. Larsson et al. 17 were the first to report changes in CRP level after lumbar posterior surgery; the authors observed that CRP level returned to baseline (< 10 mg/L) within 21 days after surgery. However, Takahashi et al 18 . reported that postoperative CRP level peaked on day 2, and Aono et al. 19 reported that CRP level peaked on day 4.
Postoperative CRP levels peaked between POD2 and POD4. Iwata et al. 16 reported that a CRP level > 10 mg/dL at 4 days postoperatively was useful for the definitive diagnosis of SSI. Kyu et al. 20 reported that the observation of abnormal CRP levels three days postoperatively should cause the clinician to be highly suspicious of infection.
It is believed that CRP levels remain elevated or increase further at POD4, suggesting that SSI is more likely to occur. 16.18.22 The results showed that the level of CRP had increased significantly on POD 3 in the SSI group and remained high on POD7. In the non-SSI group, CRP levels had increased significantly on POD3, then decreased slightly by POD7 (Fig. 1D). In both the SSI and the non-SSI group, ESR levels had increased significantly at POD3, but were then observed to have decreased slightly on POD7 (Fig. 1E). ESR increased to peak levels at POD5, followed by a slow and irregular decreasing trend 17 . Therefore, CRP appears to be more suitable than ESR for evaluating infection.
Our results showed that CRP levels had increased in all patients on POD1. In non-SSI patients, decreases in CRP levels were observed on POD3 and POD7. However, in the SSI group, CRP levels were higher on POD3 and decreased on POD7. We determined the diagnostic cutoff for CRP by using the ROC curve. If CRP levels are > 26 mg/dL on POD7, infection should be highly suspected, and the antibiotic regimen should be changed or increased in dose.
Several factors have been reported to affect postoperative CRP levels. These factors include blood loss, preoperative CRP levels, and the segment on which spinal surgery was performed. For example, surgery in the lumbar region is associated with higher postoperative CRP levels than surgery in other areas. 21 . Given the uncertainty of the use of CRP as a diagnostic tool for SSI, additional laboratory predictors are needed to distinguish between infected and non-infected patients at the postoperative stage.
WBC counts and lymphocyte counts were first reported to be helpful for the early diagnosis of surgical wound infections after lumbar surgery by Takahashi et al. 22  Our results showed that, in all patients, neutrophil count increased and lymphocyte count decreased on POD1. In non-SSI patients, neutrophil count began to decrease on POD3, which is also when lymphocyte count began to increase. However, in infected patients, a further increase in neutrophil count and decrease in lymphocyte count were detected on POD3 (Fig. 1B,C). We therefore chose to determine the diagnostic cutoff for lymphocyte ratio using the ROC curve. If lymphocyte ratio was less than 11.5% at POD3, infection was highly suspected, as in studies performed previously. We believe that POD4 lymphocyte count is more useful than POD7 lymphocyte count because the data can be obtained earlier during the course of postoperative recovery. POD4 lymphocyte count appears to be an important indicator of SSI after posterior lumbar surgery.
In this study, we analyzed the sensitivity and specificity of five laboratory markers for the early detection of SSI. Two laboratory markers were found to have acceptable levels of sensitivity and specificity.

Availability of data and materials
All data generated or analyzed during this study are included in this article. We confirm that the availability of data and materials refers to the raw data generated and used for this study. The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Authors' contributions
WBW supervised the project and contributed to all stages of the present study. DPD and LQG participated in the design of the study, revised the manuscript, and approved the final version. WBW and SJD contributed to interpreting the data and writing the final manuscript. LW and JW contributed to writing and editing the manuscript. All authors read and approved the final manuscript.

Funding
No funding was obtained for this study.

Ethics approval and consent to participate
The study protocol was approved by the Institutional Review Board of Shaanxi Provincial People's Hospital (No. 027, 2014), and written informed consent was obtained from all study participants.