The Globulin, Albumin To Globulin Ratio(A/G) and Neutrophil To Lymphocyterate (NLR) Do Not Perform Better Than CRP and ESR in PJI Diagnosis

Objective: To test the significance of serum C-reactive protein (CRP), the erythrocyte sedimentation rate (ESR), globulin(GLB) ,albumin to globulin ratio(A/G), and neutrophil to lymphocyterate(NLR) in periprosthetic joint infection (PJI) diagnosis. Methods: We retrospectively analyzed the clinical data of 115 patients diagnosed from January 2017 to December 2020 with PJI (PJI group, median age 71.00 years [range, 41-94 years], 24 males, 29 females), and aseptic loosening (aseptic group, median age 68.50 years [range, 34 – 85 years], 32 male, 30 female) in our department. Demographic data and thesensitivity and specificity of preoperative CRP, ESR, GLB,A/G, and NLR in PJI diagnosis were compared. Results: There were no significant differences when the demographic data of the two groups were compared. The expression level of CRP (24.89 mg/L([IQR], 0.1 to 200)), ESR (3 (70.97) had no significant advantages over CRP and ESR. Conclusion: globulin, A/G and NLR are not better than CRP and ESR in PJI diagnosis.


Introduction
With the improvement of average life expectancy and the emphasis on quality of life, TKA/THA has been used as a treatment for the end-stage joint diseases such as knee osteoarthritis and femoral head necrosis ， TKA/THA is a effective operation to Relieve pain and enhance the quality of life. Gradually become widely accepted and more and more developed.
However, accompanied by an increase in the number of operation ， postoperative complications, especially the periprosthetic joint infection (PJI), have been increasingly recorded over decades [1][2][3] . The rate of debilitating PJI following TJA is approximately 1-2.5%, produce a huge burden on the patient and health care system [3,4] .
The early clinical manifestations of PJI are not typical, and traditional serological indicators are difficult to diagnose. Therefore, finding an easily accessible blood indicator is critical for the diagnosis of PJI. Consequently, additional efforts are required to optimize PJI diagnosis by determining the appropriate and effective biomarkers.
In recent studies, some new blood indicators have been proposed by scholars and have shown excellent diagnostic efficacy, including FIB [15] , globulin [6] , A/G (albumin to globulin ratio) [6] , NLR(neutrophil to lymphocyterate) [5] . Bao-Zhan YU (5) found that the NLR values are more accurate than CRP and may be considered as useful parameters for the diagnosis of PJI. Yongyu Ye (6) found that Both globulin and A/G ratio were associated with PJI and may serve as potential adjuvant biomarkers in the diagnosis of PJI. Li, Rui [15] found that FIB has good sensitivity and specificity for diagnosing PJI, with values as good as those of classical markers(CRP and ESR).
Similarly, our study [11] also affirm the diagnostic value of FIB, but there aren't any further papers related to the diagnostic value of GLB,A/G and NLR in PJI. The exact role of GLB, A/G and NLR in PJI is still unknown. Therefore, we aimed to evaluate the diagnostic value of NLR ,Globulin and A/G ratio in PJI.

Inclusion and Exclusion Criteria
After Institutional Review Board approval for this study was obtained, we retrospectively reviewed the clinical data of patients who had been diagnosed with PJI, and aseptic loosening between January 2017 and December 2020.

Inclusion Criteria
The inclusion criteria were: (I) patients had been diagnosed with PJI, and aseptic loosening and received corresponding treatment (spacer insertion surgery, and revision arthroplasty) in our department from January 2017 to December 2020; (II) patients whose data were available for preoperative blood CRP,

Exclusion Criteria
The exclusion criteria include the following: patients with

4.General Information of Participants
According to the above inclusion and exclusion criteria, the clinical data of 115 patients who had been diagnosed with PJI, and aseptic loosening from January 2017 to December 2020 were analyzed. These patients were divided into two groups according to the diagnosis: a PJI group (PJI) and an aseptic group (aseptic loosening). For each patient, demographic information (gender and age) and preoperative blood CRP, ESR, Globulin, A/G and NLR were recorded.

Definition of Periprosthetic Joint Infection and Aseptic
Loosening Periprosthetic joint infection was defined using the MSIS Criteria [8] . Aseptic loosening was defined using the criteria in our previous published paper [7] .

6.Measuring Methods
Preoperative blood CRP, ESR, Globulin，A/G and NLR were measured preoperatively .The sensitivity and specificity of preoperative CRP, ESR Globulin，A/G and NLR in PJI diagnosis were compared among the two different groups.

Statistical Analysis
Quantitative data were recorded as mean±standard deviation. t test was used for comparison between two means.
Nonparameter test are used when the data do not fit the normal distribution. A P-value less than 0.05 was considered significant difference. On the other hand, receiver operating characteristic (ROC) analysis was carried out to establish the diagnostic performance of blood proteins by MedCalc 19.0.4 (MedCalc Software, Ostend, Belgium). Several parameters, including sensitivity, specificity , area under the curve (AUC), and diagnostic odds ratio (DOR),were employed. Typically, AUC > 0.7 was considered acceptable. The optimal threshold for the diagnosis of PJI was determined by the Youden index. P < 0.05 was regarded as statistically significant.

Results
There were 53 cases in infected group and 62 cases in aseptic loosening group based on the MSIS criteria. There was no significantly different in age, gender between two groups. The characteristics of each cohort are shown in (Table 1)。 in the aseptic loosening group (p < 0.001). In this study，we use the calculated cutoff value of the references as a standard at first，the ROC curve analysis didn't show an encouraging results which has been published in the references [5,6] . (Table 3   and protein, forming a slimy layer defined as biofilm ( 10 ) . These biofilms provide a barrier that reduces penetration of antimicrobial agents ( 9 ) .Once the BBF has been formed，the antibiotics can just eliminate the planktonic bacteria，after our treatment of antibiotics，the symptoms transiently disappear ,but the BBF still remain and release bacteria, resulting in another infection ( 10 ) .  ( 11 ) . We still need to find a convenient and efficient blood tests for PJI diagnosis.
WBC, CRP and ESR are classic markers and commonly used to diagnose infectious diseases, but they can't show a sufficient sensitivity and specificity in the diagnosis of PJI. Bedair et al. [4] reported that the sensitivity of CRP in serum for diagnosing early PJI was only 53%.
Therefore, it has become a new direction for researchers to find the relationships between the PJI and common blood tests. And someone has been recognized. Alisina's [12] study shows that serum D-dimer is a promising marker for the diagnosis of PJI.
This test may also have a great utility for determining the optimal timing of reimplantation. D-dimer have also been included in the diagnostic guidelines of PJI [13] . Eventhough， there still have a study shows that The serum D-dimer does not take any advantage over the CRP and ESR for diagnosis of PJI [14] .
In earlier studies, Angkananard T's study shows that the NLR could been used as an available indicator to predict outcomes of infected patients. [16] Meyer E [17] found that the A/G ratio can represent the infection in our body .Moreover，Schmilovitz-Weiss H [18] found that the A/G ratio is a efficient marker to predict outcomes in cancer patients.
Based on these results ,many researchers were attracted to find the association between the NLR, Globulin ,A/G and PJI.
Bao-zhan YU's study found that NLR values are more accurate than CRP and may be considered as useful parameters for the diagnosis of early PJI. But this study showed that NLR could be used for the diagnosis of PJI, but the diagnostic efficacy was lower than CRP and ESR. The probable reasons are analyzed as follows：1、Bao-zhan YU's study mainly included patients with early PJI, while this study mainly included patients with chronic PJI, cause the majority of clinically confirmed patients with chronic PJI were found .Therefore，The conclusion of this study may have more clinical guiding significance.
Yongyu Ye's research shows both globulin and A/G ratio were associated with PJI and may serve as potential adjuvant biomarkers in the diagnosis of PJI. But He did not compare the diagnostic value of the globulin and A/G ratio with CRP and ESR. In this study, the results also shows that Globulin and A/G could be used in the diagnosis of PJI, but their diagnostic efficacy didn't better than the CRP and ESR.

Limitations:
(1)the number of included patients in our study is only 149； (2)we excluded patients with acute PJI, which account for a small percentage of patients in our department;