The present meta-analysis showed that the pooled sensitivity and specificity of synovial fluid PCR are 70% and 92%, respectively. The AUC value of the SROC was 0.9252. These results suggest that synovial fluid PCR could be used for the diagnosis of infection after hip and knee arthroplasty. The first meta-analysis of the use of PCR in the diagnosis of PJI presented the sensitivity and specificity of synovial fluid (84% and 89%, respectively), tissue samples (95% and 81%, respectively), and sonicate fluid (81% and 96%, respectively) , with moderate sensitivity and specificity levels observed for the three sample types. Interestingly, similar results were also reported by the retrospective study performed by Huang and colleagues . In 2018, Jun et al.  performed a diagnostic meta-analysis of PCR in PJI, reporting a sensitivity of 0.76 (95% CI 0.65–0.85) and specificity of 0.94 (95% CI 0.92–0.95). Unfortunately, the pooled result combines samples from synovial fluid, sonicate fluid, and intraoperative tissue. Hence, the diagnostic value of synovial fluid PCR in periprosthetic hip and knee by meta-analysis remained unexplored. The present study is the first meta-analysis evaluating the diagnostic value of synovial fluid PCR for diagnosing infection after hip and knee replacement.
In recent years, the use of joint fluid for diagnosing PJI was a topic of considerable interest. Multiple synovial fluid tests were applied in clinical practice, with several valuable tests incorporated into the new definition of MSIS . Through a literature review of the published meta-analysis of these synovial fluid methods from the MSIS guideline [26,27,28,29,30], the pooled sensitivity of these tests is superior to that of synovial fluid PCR. The specificity of synovial fluid PCR exceeded that of synovial fluid interleukin-6 (IL-6), CRP, WBC, and PMN, but was lower than synovial fluid culture, alpha-defensins, and LE. Based on the AUC value of meta-analysis of synovial fluid , only LE demonstrated excellent accuracy in the diagnosis of PJI, followed by alpha-defensins, IL-6, CRP, and PMN. Furthermore, synovial fluid WBC as well as PCR showed good accuracy (Table 4). Although the results of most synovial fluid biomarkers were superior to that of the synovial fluid PCR [26,27,28,29,30], synovial fluid culture and some PCR tests can detect bacteria and could provide a more valuable reference for further comparisons with intraoperative diagnostic results. However, the diagnostic value between synovial fluid culture and PCR for PJI detection is controversial.
Synovial fluid PCR was compared with preoperative and intraoperative tests from the included studies The PCR test was found to have better sensitivity and specificity than that of serum CRP and ESR. In contrast, lower sensitivity and specificity were observed in comparison to all intraoperative methods. Compared with synovial fluid culture, synovial fluid PCR had an almost identical level of sensitivity with synovial fluid culture (69% vs. 70%, respectively) and a lower specificity level (91% vs. 98%, respectively). Synovial fluid PCR and culture were also observed to have similar results in comparison to the previous meta-analysis of synovial fluid culture, with a sensitivity of 70% and 72%, respectively, and a specificity of 92% and 95%, respectively . Although the current meta-analysis and our subgroup results showed that the sensitivity and specificity of synovial fluid PCR were lower than that of synovial fluid, PCR has several advantages in regard to the detection of bacteria. Synovial fluid PCR has been reported to rapidly provide results within 3–72 h [14, 23, 25], and could also detect culture-negative bacteria [11, 12, 21, 22, 25]. Sujeesh and co-workers reported that the sensitivity of 16S rRNA PCR and synovial fluid culture was 68.1% and 70.2%, respectively . PJI was detected by PCR in five cases that were negative by synovial fluid culture. Synovial fluid multiplex PCR identified 12 cases negative by synovial fluid culture, with 10 cases caused by low-virulence bacteria (coagulase-negative staphylococci and Cutibacterium acnes) . The author also found that more cases of polymicrobial infections were detected by synovial PCR than synovial fluid culture (four vs. two cases), with similar results also reported by Melendez and colleagues [18, 21]. Due to rare cases of mixed infection in these studies, further research is required. However, in cases treated with antibiotics before specimen collection, the testability of synovial fluid PCR was lower than synovial fluid culture. A comparison of the PCR panel and synovial fluid culture in patients that received antibiotics within 30 days before joint aspiration revealed the sensitivity of the PCR panel and synovial culture to be 64.5% and 85.4%, respectively . In another study, PCR-ESI/MS detected eight of nine PJI cases who had received antibiotics within 30 days, whereas synovial fluid culture detected all nine cases . The use of antibiotics before PCR analysis most likely impacts culture results. Meta-regression analysis results from the current study show that the sensitivity level of cases receiving antibiotic therapy were less than cases without antibiotic therapy (73% vs. 80%). Moreover, meta-regression was also analyzed in the preoperative and intraoperative aspiration groups, with slightly higher sensitivity and lower specificity observed for the intraoperative test compared to the preoperative test (sensitivity: 77% vs. 75%, respectively; specificity: 93% vs. 96%). In contrast, the meta-analysis of synovial fluid white cell count performed by Qu and co-workers  found that preoperative collection had a higher sensitivity than intraoperative samples (91% vs. 77%, respectively), and lower specificity than that of intraoperative samples (89% vs. 97%). However, due to the limited data of the studies included from our intraoperative study (two studies) and different tests performed in these two meta-analyses, whether intraoperative and preoperative sample collection infers with the diagnostic accuracy remains an avenue for further exploration.
Although various types of synovial fluid PCR have been tested in the clinical diagnosis of PJI, the diagnostic ability has most likely been disregarded. The most frequently described disadvantage of PCR is FP results, with the potential impacting factors, including the use of different target genes, PCR type, laboratory technician skills, and laboratory conditions [13, 19, 22, 24]. The use of 16S/28S rRNA RT-PCR with high-quality control standards demonstrated excellent results, with a sensitivity of 100% and specificity of 99.5% .Sebastian and colleagues  found that DNase treatment could reduce exogenous bacterial contamination, with no FP results observed in synovial fluid PCR: however, the sensitivity was affected. Further studies are required to determine the most suitable type of PCR for PJI diagnosis and the standard procedure required.
The present study has several limitations. First, the identified studies used different types of PCR; therefore, the overall result may impact the estimates of diagnostic accuracy. Second, meta-regression analysis was not performed in regard to the prosthesis type or sample condition to further explore sources of heterogeneity. The type of prosthesis described in the included studies were the knee or both the hip and knee; however, studies focusing only on the periprosthetic hip were not found. Therefore, further analysis of differences between the hip and knee could not be performed in meta-regression analysis. Regarding the sample condition, frozen specimens were used in the studies; however, there was ambiguity in terms of the use of fresh samples. Third, the diagnostic accuracy of synovial fluid PCR may be affected by the standard definition of PJI . Fourth, the current meta-analysis only included the English article, which was published in the database of Web of Science, PubMed, and Scopus. However, the relevant published literature from other languages or other databases is probably lacking.
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