PJI is a very serious complication that can occur after total joint arthroplasty and has a devastating consequence if not diagnosed properly. Thus, the MSIS initially proposed criteria for the diagnosis of PJI and then modified these criteria during the International Consensus Meeting (ICM) in 2013 [6]. However, it is still difficult to diagnose PJI preoperatively in some cases, such as those with dry aspiration, negative culture findings, and systemic inflammatory diseases. In an effort to accurately diagnose PJI in a more timely manner, several previous studies examined the potential use of novel biomarkers such as CD4+ blood monocytes [19], α-defensin [20], leukocyte esterase [8], and calprotectin [21], and found that they had greater diagnostic value than traditional biomarkers, including CRP and ESR. However, the measurement of these novel parameters can be expensive and is unavailable in some institutions. Our purpose was to identify simple and practical biomarkers for the early diagnosis of PJI. Thus, we assessed the diagnostic performance of NLR, PLR, PVR, GLB, AGR, and CRP/AGR, the biomarkers that are easily obtained from routine blood tests, and then compared their diagnostic performance with those of the traditional biomarkers. To compare the diagnostic value of novel biomarkers, the ROC curves—which are used as a measure of the performance of a screening or diagnostic test—and the AUC values of these indicators were calculated. A higher AUC of a biomarker is usually associated with a higher diagnostic value for PJI.

Based on a literature review, we found that this study is the first to show that CRP/AGR gives a better diagnostic performance for PJI compared with traditional biomarkers (CRP and ESR). In this study, we compared the diagnostic performance of the tested biomarkers in terms of distinguishing patients in the PJI and the aseptic failure groups. Each of these novel biomarkers showed a significant difference in PJI patients compared with aseptic failure patients, similar to the traditional biomarkers. Our ROC analysis indicated that the optimal cutoff values of the novel biomarkers were 2.71 for NLR, 132.67 for PLR, 34.31 for PVR, 33.8 for GLB, 1.19 for AGR, and 5.08 for CRP/AGR. CRP/AGR was the only serum biomarker that showed excellent diagnostic performance, with a sensitivity of 82.98% and a specificity of 82.91%, followed by CRP and ESR, which showed good diagnostic performance. NLR, PLR, GLB, and AGR showed fair diagnostic performance, and PVR provided only poor diagnostic value for PJI. Notably, PLR had the highest sensitivity (85.11%) among all five tested biomarkers, and its sensitivity was even greater than those of CRP (82.98%) and ESR (63.83%).

Serum albumin is typically used as the biomarker to evaluate nutritional condition, which has been proven to be negatively related to septic failure after joint replacement [22]. Serum globulin mainly contains immunoglobulins, interleukin-6, and complements; it responds to infection and elevates with inflammatory reactions [23]. Thus, serum albumin, globulin, and the albumin-to globulin ratio (AGR) are utilized to determine a patient’s infective status, including PJI after joint replacement. In a prospective study by Huang et al., it was found that hypoproteinemia (albumin < 35 g/L) is closely related to aseptic failure after joint replacement [24]. A retrospective study by Shang et al. reported that the level of GLB was significantly elevated and the level of AGR was significantly decreased in a PJI group, with an AUC of 0.784 for GLB and 0.826 for AGR [18]. Another study by Shi et al. demonstrated that CRP/albumin gave excellent performance in the diagnosis of PJI, with an AUC of 0.941, which was better than those of CRP (0.937) and ESR (0.914) [25]. Inspired by the research of Shi et al., we used CRP/AGR as a novel biomarker to predict PJI, and found that this reduced the error associated with the use of either CRP or AGR to diagnose infection [25]. For the first time, we found that CRP/AGR gave better performance than CRP and ESR, with an AUC of 0.902.

PVR, NLR, and PLR are easily accessible and routinely available parameters in clinical practice. Besides the convenience and minimal expense necessary, previous studies have reported that these three biomarkers are generally useful for the diagnosis of infection [26]. A retrospective study by Paziuk et al. [13] demonstrated that the PVR provided acceptable performance for diagnosing PJI, with an AUC of 0.69 (48.10% sensitivity, 80.85% specificity) at a cutoff value of 31.70, similar to our cutoff value (34.31). They also reported that the combined application of PVR, CRP, and ESR significantly improved diagnostic performance. Sigmund et al. [16] evaluated the diagnostic value of PVR in a cohort of 177 patients who required revision surgery after THA (n = 91) and TKA (n = 86). They found that the individual use of PVR gave a sensitivity of 43% and a specificity of 81%, significantly inferior to those of CRP. They also found that the combined use of CRP + PVR did not improve the diagnostic performance relative to CRP alone. Our results are consistent with those of Sigmund et al. [16]. We therefore conclude that PVR should not be considered a reliable test for the diagnosis of PJI. Other studies also considered the use of NLR and PLR as biomarkers for inflammatory responses and infections. Qu et al. [27] measured the NLR in 2160 patients with bloodstream infections (BSIs) and 2523 healthy controls and found that NLR was significantly higher in the BSI group. They concluded that NLR had a strong association with BSIs caused by Gram-negative bacteria, Gram-positive bacteria, and fungi. Shen et al. [28] demonstrated that an elevated PLR was related to an increased risk of mortality, based on an analysis of the clinical data on 5537 patients with sepsis. Some other recent studies found that NLR and PLR were potentially useful for predicting PJI. In particular, a retrospective study by Zhao et al. [29] demonstrated that NLR and PLR were significantly higher in an early PJI group than in a non-PJI group, and that NLR might be more valuable than PLR based on ROC analysis. They used an NLR cutoff of 2.77, similar to our cutoff (2.71). Similarly, Yu et al. [14] found that NLR was effective in diagnosing PJI (AUC: 0.802, 85% sensitivity, 68.3% specificity, 34.7% PPV, 95.8% NPV) with a cutoff value of 2.13. However, Zhao et al. [29] and Yu et al. [14] demonstrated that NLR and PLR had greater predictive value for the diagnosis of PJI than ESR and CRP, in stark contrast to our results. Our further analysis indicated that this was most likely due to differences in the characteristics of the enrolled patients; in our study, all examined patients had chronic PJI, but the other two studies [14, 29] examined patients who had acute PJI. Thus, we conclude that NLR and PLR have only limited diagnostic value for PJI.

The pathogen culture result is the most valuable indicator of a diagnosis of PJI, and it can be used to guide the subsequent antibiotic selection. However, in some cases, due to a combination of microbial, host, and antibiotic factors, the microbiological culture results remain negative. According to the previous studies, the prevalence of culture-negative PJI ranges from 5 to 42% [30,31,32]. Thus, we conducted a subgroup analysis based on the culture results. In this study, the incidence of culture-negative PJI was 31.91%. We found that there were significant differences in terms of CRP, NLR, PLR, and CRP/AGR between the culture-positive PJI subgroup and the culture-negative PJI group, indicating that these biomarkers have the potential to predict negative culture results. However, all the tested biomarkers showed lower diagnostic accuracies in culture-negative PJI than in culture-positive PJI. Thus, more attention should be paid to the diagnosis of culture-negative PJI. Some novel strategies, such as a delayed incubation period of up to 14 days, utilizing augmented media for atypical organisms, sonication-based and chemical-based biofilm dislodgment methods, and next-generation sequencing technologies, have been recommended to improve the yield of the culture [33].

There are several limitations of our study. First, this is a retrospective study and therefore has the limitations inherent to studies with this design. Our exclusion of patients with missing critical data or complicated by autoimmune diseases might have led to some bias. Second, there is no gold standard for the diagnosis of PJI. However, the MSIS criteria are considered the best method for its diagnosis, although this standard has low sensitivity in patients with low-virulence bacterial infections [19, 34]. To reduce the possibility of misdiagnosis, we excluded patients who underwent second-stage reimplantation due to the difficulty of determining their infection status. Finally, we examined 164 cases from a single institution, and this small sample size limited the generalizability of our conclusions. Therefore, well-designed multicenter studies with larger samples are needed to evaluate the value of novel biomarkers for the diagnosis of PJI.