The present study demonstrates that the combined method of serum IL-6 and CRP can be used for the diagnosis of periprosthetic hip and knee infection. The AUC of the combined method was higher than that of either IL-6 or CRP alone (0.9453 vs. 0.9237 and 0.9074, respectively).
Since there is no gold standard for the diagnosis of PJI, the question of how to accurately judge PJI or aseptic loosening has always been of concern to surgeons, microbiologists, and infectious disease specialists . Traditionally, the combined or single use of the erythrocyte sedimentation rate (ESR) and CRP was most commonly performed in the diagnosis of PJI, which is also one of the criteria of the MSIS definition . One meta-analysis of 12 studies of serum ESR and CRP for the diagnosis of periprosthetic hip infection showed that the sensitivity and specificity were 0.860 (95% CI, 0.825−0.890) and 0.723 (95% CI, 0.704−0.742) as well as 0.869 (95% CI, 0.83−0.899), and 0.786 (95% CI, 0.769−0.803), respectively . However, the diagnostic value of ESR and CRP was not ideal, with a blood test marker for the diagnosis of PJI still required. Serum IL-6 appears to be a superior postoperative inflammatory indicator compared with ESR and CRP. In a patient without complications from hip or knee arthroplasty surgery, the IL-6 level reached its peak value more rapidly than CRP or ESR levels, also rapidly returning to normal [29,30]. For the diagnosis of PJI, Di Cesare and colleagues found that serum IL-6 had a higher diagnostic accuracy compared with CRP and ESR in diagnosing infection following hip and knee replacement (97% and 83%, 69%, respectively) . A prospective study by Abou et al  also found similar results, namely that serum IL-6 had better diagnostic accuracy than CRP and ESR (92.5% vs. 87.5% and 82.5%, respectively). Serum IL-6 shows great potential for the diagnosis of periprosthetic hip and knee infection, and IL-6 levels strongly correlated with ESR and CRP using the combined method . The combined test of both parameters has been used recently in the diagnosis of PJI, and some reports have supported that the combination of IL-6 and CRP can improve its diagnostic accuracy [9,23–25]. The parallel combined screening test could reduce false negative results, increasing the sensitivity and lowering the specificity. Conversely, using series testing could reduce false positives and achieve higher specificity and lower sensitivity . In the present study, eight publications described the use of the combination of IL-6 and CRP in parallel or series tests. Of these, two presented both parallel and series tests and demonstrated a comparison between the combined method of CRP and ESR. Majors et al.  showed the sensitivity of IL-6 (>9.14 pg/ml) and CRP (>17 mg/l) in a parallel test and specificity in a serial test to be 93.8% and 85%, respectively. Whereas the combined CRP and ESR (>27 mm/h) showed lower sensitivity and specificity (80% and 81%, respectively). Li and colleague  reported that the sensitivity of IL-6 (>6.90 pg/ml) and CRP (>8.54 mg/l) in the parallel test was higher than that of CRP (>8.54 mg/l) combined with ESR (>22.5 mm/h; 100% vs. 86.4%), with a lower specificity to that of CRP and ESR in the serial test (93.1% vs. 96%). In the subgroup of the present study, results were divided into parallel and serial testing. The pooled sensitivity of the parallel test (94%) and the pooled specificity of the serial test (96%) in the combined method was higher than CRP or IL-6 alone.
All studies included of our meta-analysis were associated with infection after hip or knee arthroplasty. However, the surgical site is likely the potential factor that could affect the diagnostic accuracy. Several reports found that the use of IL-6 or CRP were not suitable for diagnosing infection after shoulder arthroplasty, with the sensitivity of both tests less than 50%. The reason for the low diagnostic value is potentially due to the low virulence of the detected bacterium, such as Cutibacterium acnes (C. acnes), which commonly occurs in periprosthetic shoulder infections [31,32]. Majors and colleagues  found that the sensitivity and specificity of IL-6 for C. acnes in PJI cases was 50% and 59.3%, respectively. Both the sensitivity and specificity were 66.7% for CRP. In coagulase-negative staphylococci infections, the sensitivity and specificity of IL-6 were 100% and 59.3%, respectively, whereas the sensitivity and specificity for CRP was 50% and 66.7%, respectively. The combined method of IL-6 and CRP may improve the diagnostic accuracy of low virulence bacteria. Buttaro et al. demonstrated that the specificity of IL-6 and CRP in serial tests were higher than that of IL-6 or CRP alone (100% vs. 94% and 91%, respectively), with approximately 73% of low virulence organisms presented in the study . Ettinger and co-workers  reported a specificity of 98.2% and a sensitivity of 75% for low-grade joint infection. When IL-6 was greater than 5.12 pg/mL and CRP greater than 0.3 mg/dL in serial testing, the specificity of IL-6 or CRP was lower than that of the combined method (87.7% and 64% vs. 98.2%). The author concluded the CRP and IL-6 appears to be the most helpful combination for distinguishing between aseptic loosening and low-grade infection.
In the present study, the different cut-off levels for IL-6 and CRP demonstrated a range from 3−18 mg/L for CRP and 4.7−12 pg/ml for IL-6. There is no consensus on the use of a single cut-off value, which differ amongst the various studies. For the MSIS definition, the most commonly performed cut-off for CRP was 10 mg/L and 30 mm/h for ESR . However, current thresholds for the diagnosis of PJI should be reconsidered. Bingham et al.  reported a sensitivity of CRP with a cut-off of 10 mg/L, which was lower than the 5 mg/L cut-off (85.1% vs. 95.1%). Compared with the threshold of 5 mg/L for CRP and 10 mm/h for ESR, the use of CRP and ESR screening cut-offs of 10 mg/L and 30 mm/h, respectively, would not detect nine PJI cases. The cut-off levels of serum IL-6 for the diagnosis of PJI are still debatable. Previous meta-analysis performed by Xie et al. reported that a serum IL-6 cut-off ≥10 pg/ml with greater sensitivity and specificity compared to the cut-off <10 pg/ml (77% and 98% vs. 70% and 80%, respectively). If use a sensitivity and specificity that is greater or equal to 90% as the optimal cut-off from all our included studies. Only two studies meet the criteria in both the serum IL-6 and CRP group [4,8,24], with an IL-6 cut-off of 6.6 pg/ml or 10.4 pg/ml, and CRP cut-off of 3.2 or 8.83 mg/l potentially achieving a sensitivity and specificity of 90%. When considering studies with a sensitivity and specificity greater or equal to 90% for both IL-6 and CRP, the optimal cut-off is only presented by the study of Yildirim and colleagues . The sensitivity and specificity of IL-6 with a cut-off of 6.6 pg/ml was 95% and 96%, respectively. For CRP, the sensitivity and specificity with a cut-off of 8.83 mg/L was 95% and 90%, respectively. The combined IL-6 and CRP showed a sensitivity of 99% and specificity of 98%. The high sensitivity and specificity presented in both the individual or combined methods may also be relate to the study excluding patients with inflammatory comorbidities, with none of the patients affected by antibiotic treatment. Whether the cut-offs of 6.6 pg/ml for IL-6 and 8.83 mg/l for CRP represent the most optimal cut-offs remains to be explored.
The present meta-analysis has some limitations. First, two of the included studies only had 11 cases of infection [4,23], and the small sample size potentially affected overall results. Second, although the diagnostic standard was always used to identify cases of infection, the use of different diagnostic standards to estimate the value of diagnostic tools resulted in different sensitivity and specificity values . Third, based on the current publication, two studies showed that the combined method may improve diagnostic results compared to single use in low virulence infections [9,23]. Due to the relative lack of literature, further research is required to confirm this finding.