The study was approved by the Institutional Review Board of the First Affiliated Hospital of Guangzhou University of Chinese Medicine (approval No. 2019205). This single-center, retrospective, cohort study enrolled patients who underwent revision arthroplasty because of delayed or chronic infection of joint arthroplasties and aseptic loosening of an implant from March 2013 to December 2018 in the First Affiliated Hospital of Guangzhou University of Chinese Medicine. PJI was diagnosed based on the MSIS criteria noted in Table 1^[20]. Patients were excluded if they had hematological disease or underwent a blood transfusion within the last year, used ongoing antiplatelet drugs, had a history of recent trauma or dislocation (within 2 weeks), used lipid emulsion, associated with hepatic disease or other site infections.

A total of 214 patients were recruited for the final analysis. Based on the MSIS criteria, 77 patients were classified into the PJI group (129 hips and 8 knees), while 137 patients were classified into the aseptic loosening group. The mean age in the PJI group was 60.6±13.1 years (range, 21-80 years); of them, 30 were men and 47 were women. The mean age in the aseptic loosening group was 64.0±11.7 years (range, 30-86 years); of them, 64 were men and 73 were women. No significant intergroup differences were detected in gender or age (P > 0.05). The characteristics of the enrolled patients are shown in Table 2. 

Serum PLT was significantly higher in the PJI group (330.36 ± 91.25 × 10⁹/L) than in the aseptic loosening group (238.67 ± 60.82 × 10⁹/L) (P < 0.001). WBC, ESR, and CRP values were also significantly higher among patients with PJI (P < 0.05). The mean MPV was also significantly higher in the PJI group than in the aseptic loosening group (P < 0.001). No significant intergroup differences were detected in the PDW values (P > 0.05; Table 3).

The ROC curves showed that ESR had the highest AUC (0.829), followed by CRP (0.820), and PLT (0.804). The AUCs of these three markers were all between 0.8 and 0.9, indicating good diagnostic value for PJI. In contrast, MPV had an AUC of 0.695, which was the second lowest value but slightly higher than the AUC of WBC (0.619). The AUCs of these two markers were both lower than 0.7, indicating poor diagnostic value (Figure 1). 

The serum PLT demonstrated a sensitivity of 64.94% and a specificity of 85.40% for diagnosing PJI. Using Youden’s index, the optimal cutoff value for PLT was 300 × 10⁹/L, which resulted in a good PPV and NPV of 69.56% and 81.56%, respectively. Based on the ROC analysis, when WBC was above 7.62 × 10⁹/L, the sensitivity, specificity, PPV, and NPV were 55.84%, 67.88%, 48.86%, and 73.02%, respectively. Using a cutoff value for ESR of   31 mm/h, the sensitivity, specificity, PPV, and NPV were 77.92%, 75.91%, 63.83%, and 85.83%; using a cutoff value for CRP at 10.9 mg/L, the sensitivity, specificity, PPV, and NPV were 79.22%, 75.91%, 64.21%, and 86.55%, respectively. For MPV, the optimal cutoff value was 8.4%, resulting in sensitivity, speci?city, PPV, and NPV of 48.05%, 83.94%, 62.71%, and 74.19%, respectively (Table 4).

Further analyses of the combined diagnostic value of PLT, WBC, ESR, and CRP were performed to improve their diagnostic accuracies. The combination of serum PLT and WBC/ESR improved the specificity and specificity (Table 5). PLT combined with the CRP improved the specificity but decreased the sensitivity. Promising AUC values indicating good diagnostic accuracy were obtained for the combinations of PLT and WBC (AUC = 0.805), PLT and CRP (AUC = 0.865), PLT and ESR (AUC = 0.880), ESR and CRP (AUC = 0.845), and ESR and WBC (AUC = 0.837) (Figure 2). Among them, the combined analysis of PLT and ESR had the highest AUC. The sensitivity, specificity, and AUC were 84.42%, 79.96%, and 0.880 (95%CI, 0.829-0.920).

Further analyses of the combined diagnostic value of PLT, WBC, ESR, and CRP were performed to improve their diagnostic accuracies. The combination of serum PLT and WBC/ESR improved the specificity and specificity (Table 5). PLT combined with the CRP improved the specificity but decreased the sensitivity. Promising AUC values indicating good diagnostic accuracy were obtained for the combinations of PLT and WBC (AUC = 0.805), PLT and CRP (AUC = 0.865), PLT and ESR (AUC = 0.880), ESR and CRP (AUC = 0.845), and ESR and WBC (AUC = 0.837) (Figure 2). Among them, the combined analysis of PLT and ESR had the highest AUC. The sensitivity, specificity, and AUC were 84.42%, 79.96%, and 0.880 (95%CI, 0.829-0.920).

Periprosthetic joint infection (PJI), the main cause of modern total joint arthroplasty failure, affects 25%-38% of revision procedures^[1-4]. In revision arthroplasty, it is important to distinguish periprosthetic infection from aseptic failure as their respective treatment protocols and impact on patient health differ greatly^[5-6].

Although the diagnostic criteria of PJI are well defined by the Musculoskeletal Infection Society (MSIS)^[7], the sensitivity and specificity of present serological markers for PJI require improvement. Inflammatory markers such as white blood cell (WBC) count, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) have been generally used to screen for infection because of their simplicity and cost-effectiveness^[8-9]. The recently identified synovial fluid biomarkers such as alpha-defensin demonstrate high sensitivity and specificity, but they also exhibit high false-negative and sensitivity rates that appear to be related to organism type^[10-11]. Moreover, obtaining synovial fluid is invasive and painful for patients. Hence, a reliable serological test that can help to diagnose PJI is required.

Previous studies have paid great attention to inflammatory markers and rarely focused on other serum parameters. Recent studies maintain that platelet (PLT) count and platelet indices such as mean platelet volume (MPV) and platelet distribution width (PDW) play an important role in infectious and inflammatory diseases^[12-18]. Zhang et al.^[19] first demonstrated that serum PLT is a promising marker for the diagnosis of deep surgical site infection after open induction internal fixation for traumatic limb fractures. However, few studies have focused on the relationship between PLT and PJI. This retroprospective study aimed to identify the sensitivity, specificity, and positive and negative predictive values of PLT for diagnosing PJI after total joint arthroplasty.

中国组织工程研究杂志出版内容重点：人工关节；骨植入物；脊柱；骨折；内固定；数字化骨科；组织工程

Subjects

A total of 214 patients were enrolled in this retroprospective study. A diagnosis of PJI was confirmed in 77 patients according to the MSIS criteria^[20], while the remaining 137 patients were aseptic cases. Furthermore, data on WBC counts, ESR, CRP levels, and PLT of all patients were investigated. All blood samples were obtained from vein on the day of admission and stored in tubes containing ethylenediaminetetraacetic acid, and then were analyzed automatically using internationally certified devices.

The study was approved by the Institutional Review Board of the First Affiliated Hospital of Guangzhou University of Chinese Medicine (approval No. 2019205). This single-center, retrospective, cohort study enrolled patients who underwent revision arthroplasty because of delayed or chronic infection of joint arthroplasties and aseptic loosening of an implant from March 2013 to December 2018 in the First Affiliated Hospital of Guangzhou University of Chinese Medicine. PJI was diagnosed based on the MSIS criteria noted in Table 1^[20]. Patients were excluded if they had hematological disease or underwent a blood transfusion within the last year, used ongoing antiplatelet drugs, had a history of recent trauma or dislocation (within 2 weeks), used lipid emulsion, associated with hepatic disease or other site infections.

 Methods

Patient sex, age, and involved joint were recorded. Venous blood samples were obtained from peripheral vein on the day of admission and then analyzed for serum PLT, PDW, WBC, CRP, and ESR. Threshold values for the laboratory markers were based on the levels outlined by the International Consensus Meeting on PJI^[21]. Results of intraoperative testing and findings were reviewed and included in the analysis. The following intraoperative findings were recorded: presence of purulent fluid in the joint as documented in the operative report, presence of acute inflammation on the frozen section or the pathology report, intraoperative synovial fluid, and/or tissue cultures. At our institution, at least three intraoperative tissue culture specimens were taken and cultured for 3 and 7 days.

Statistical analysis

Patients’ baseline characteristics and the results of the diagnostic tests were compared between the groups using independent-samples t-test. P values of < 0.05 were considered statistically significant. Receiver operating characteristic (ROC) curves were generated to determine the diagnostic value of each test for the assessment of PJI. The area under the curve (AUC) and 95% confidence interval (CI) were calculated. The discriminatory value of each curve was interpreted as excellent (0.9-1), good (0.8-0.89), fair (0.7-0.79), poor (0.6-0.69), or as failing or having no discriminatory capacity (0.5-0.59). Using the method described by Youden^[22], the optimal cutoff point for each marker as a diagnostic marker of PJI was calculated. Additionally, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios (LR) were calculated. We also determined the diagnostic accuracy of the combined tests of PLT with other biomarkers. Data were analyzed using IBM SPSS Statistics 21 and MedCalc for Windows version 15.0 (MedCalc Software).

Synovial fluid biomarkers such as alpha-defensin and leucocyte esterase are reliable markers of PJI. Deirmengian et al.^[32] examined 43 biomarkers and reported 100% sensitivity and specificity for the alpha-defensin enzyme-linked immunosorbent assay for detecting PJI. The high accuracy of the alpha-defensin enzyme-linked immunosorbent assay was supported by a recent meta-analysis from Wyatt et al., who calculated a sensitivity of 100% and specificity of 96%^[33]. Another advantage of this method is the fact that it delivers consistent results regardless of the organism type or virulence or prior antibiotic therapy^[34]. However, the main drawbacks of this test are its high cost and the lack of widespread availability.

Leucocyte esterase reportedly has predictive value for diagnosing PJI, with a sensitivity and specificity of 79.2% and 80.8% to 100% and 93.8%, retrospectively^[35-36]. However, it could not be determined when either an inadequate amount of fluid was available or no fluid was retrieved from the joint.

In the present study, ROC curves demonstrated that ESR was the best blood parameter for diagnosing PJI, similar to that reported by Li et al.^[37]. ESR and CRP alone present a sensitivity of 77.92% and 79.22% and specificity of 75.91% and 75.91%, respectively, close to those of the present study^[38].

Blood biomarkers are simple and practical methods for diagnosing PJI. Previous studies have focused on inflammatory markers, but they have rarely focused on platelet count and platelet indices. Platelet and platelet indices are proposed biomarkers for predicting or monitoring some infections and inflammatory diseases^{[12-16, 18, 39-43]}. Zhang et al.^[12] suggested that PDW combined with PLT can be an important additional test for the diagnosis of deep surgical site infection after open induction internal fixation for traumatic limb fractures. Rubio et al.^[43] found that initial platelet and leukocyte counts might be useful for making the clinical differential diagnosis of fever in the returning traveler. Gupta et al.^[41] implied that PLT and plateletcrit could be used as markers of disease severity in malaria. Demirdal et al.^[13] concluded that elevated platelet-to-lymphocyte ratio can predict osteomyelitis in diabetic foot infection. Celik et al.^[15] revealed that MPV decreased in ventriculoperitoneal shunt infection and suggested that MPV and PDW can be used for the diagnosis of ventriculoperitoneal shunt infection in children with an accuracy of at least 75%. Lee et al.^[16] found that MPV was positively correlated with CRP and could be an inflammatory marker to determine the disease activity in tuberculosis patients. MPV could also predict urinary tract infection^[18]. Kim et al.^[17] reported that the incidence of abnormal PLT count increased with age in respiratory virus infection patients and those with a prolonged hospital stay. Platelet and platelet indices increased in cirrhotic patients with ascitic fluid infection^[44]. In addition, MPV level and average PLT decreased after bloodstream infection^[45].

In the current study, PLT and MPV differed significantly between the PJI and aseptic loosening groups. PLT had an AUC of 0.804, which indicated that it had good performance in the diagnosis of PJI. Based on the ROC analysis, using a cutoff value of 300 × 10⁹/L, PLT had better specificity and PPV than ESR and CRP alone. Moreover, the combined analysis of PLT and ESR had the highest AUC with a sensitivity and specificity of 84.42% and 79.56%, respectively, which proved that PLT could be a potential predictor for diagnosing PJI. To our knowledge, few studies have evaluated the role of platelet and platelet indices as a diagnostic test for PJI. In this retrospective study, PLT and PDW have potential value for diagnosing PJI and had good performance when combined with ESR.

Platelets, anucleate cell fragments circulating in the blood, play a basic role in hemostasis and thrombosis. The reason for the elevated platelet level in PJI patients remains unknown. Previous studies have demonstrated that megakaryocytes, the progenitor cells of platelets, are induced by the release of inflammatory cytokines and rupture and rapidly release platelets^[46]. Megakaryocytes exposed to varying bone marrow environments produce different platelets that enter the circulation primed to respond to and combat inflammation, infection, or injury. We believe that platelets play an antibacterial role in PJI development as an immune response triggered by megakaryocytes. Some inflammatory states in PJI induce populations of committed MK progenitors, giving rise to platelets in response. In addition, pathogens could change and spread platelet shape as a result of great responsiveness of platelets to bacteria^[47]. Thus, PDW would decrease in PJI patients. In contrast, infection could enhance bone marrow activity and cause thrombocytosis, which may explain the increased level of PLT in PJI. However, this hypothesis requires further confirmation by studies with larger sample sizes. 

It is concluded that PLT is a valuable biomarker for the diagnosis of PJI. However, the use of PLT alone has some disadvantages. PLT combined with ESR could make all the statistical indices adequate and within range. It is acknowledged that the platelet indices cannot be the sole diagnostic tool for PJI.

Several limitations should be considered. First, this was a retrospective study, so selection bias may influence its results. Second, limited numbers of PJI cases were enrolled in this study due to the low infection rate in our department. Further analyses with larger sample sizes are needed.

中国组织工程研究杂志出版内容重点：人工关节；骨植入物；脊柱；骨折；内固定；数字化骨科；组织工程

关节假体周围感染：是关节置换后灾难性并发症之一，由于缺乏特异性指标，细菌培养阳性率低，其诊断是临床研究的难点。#br# 血小板计数：是指计数单位容积血液中血小板的数量。目前研究发现在一些感染性疾病中，血清中血小板计数会升高，提示血小板计数可作为预测感染性疾病的诊断指标。#br# 中国组织工程研究杂志出版内容重点：人工关节；骨植入物；脊柱；骨折；内固定；数字化骨科；组织工程

血小板计数：是指计数单位容积血液中血小板的数量。目前研究发现在一些感染性疾病中，血清中血小板计数会升高，提示血小板计数可作为预测感染性疾病的诊断指标。

中国组织工程研究杂志出版内容重点：人工关节；骨植入物；脊柱；骨折；内固定；数字化骨科；组织工程#br#