In this prospective study, we analyzed and compared serum and synovial inflammatory factors in patients with chronic infection and aseptic after knee and hip arthroplasties. Our data indicate that serum and synovial CRP was significantly higher in the chronic infected group than in the aseptic group (35 mg/l vs 21.5 mg/l, and 9.93 mg/l vs 3.58 mg/l, p < 0.001, Table 2). We found a strong correlation between serum and synovial fluid CRP level (r = 0.523, P = .0012). This suggests that the circulatory system CRP is detected by spreading to the synovial fluid through increased vascular and synovial permeability due to infection[13, 19]. We determined that the serum CRP threshold for diagnosing chronic PJI was 10mg/l, which was significantly lower than the results (39.8 mg/l) of a recent multicentric study conducted by Parvizi. We found that when the threshold of synovial CRP was 7.26 mg/l, the AUC area of chronic PJI was as high as 93.70% (95％CI 0.869 to 0.976). However, the thresholds for synovial CRP that we determined were different from previous studies[13, 21] (2.8mg/l to 9.5mg/ml), which may be due to reduced inflammatory response in chronic PJI patients with low-toxic infections, as well as differences in measurement.
Meanwhile, we also show that when serum CRP > 10.2mg/l or synovial CRP > 7.26mg/l, the diagnosed NPV value reached 96.67%. This combination can significantly improve diagnostic sensitivity, but specificity will be sacrificed. In our cohort, there will be 29 aseptic patients who will be misdiagnosed with an infection. Accordingly, when serum and synovial CRP were both high than 10.2 mg/l and 7.26 mg/l, respectively, the diagnostic PPV value reached 1, and the specificity of diagnosis was improved to 1. This combination can be prepared to exclude non-infected patients and improve the efficiency of clinical diagnosis. To our knowledge, this is the first study to use different predictive models of serum and synovial CRP in the identification of chronic PJI.
The sensitivity of serum CRP reached 84.62% was in line with that of a previously published study, included 4934 participants, by Parvizi J et al. However, the serum CRP showed false-positive cases and, hence, a reduced specificity in our study, resulting in a potential overtreatment with unnecessary surgical revisions and prolonged antimicrobial treatment if used alone. The reasonable explanation is that CRP, a factor secreted by a variety of cells, increases to different degrees when the body is stimulated by inflammation[3, 5]. Therefore, we investigated inflammatory markers of local synovial fluid in joints with higher specificity. Based on previous studies, detection time and economic benefits, we focused on the value of synovial CRP in differentiating chronic PJI[13, 14, 23, 24]. Our study indicated the synovial CRP possess a 93.10% diagnostic specificity and 89.69% diagnostic accuracy in identifying chronic PJI (Table 3). However, the analysis found that synovial-CRP sensitivity in differentiating chronic PJI was only 84.62%, ranging from 69.5% to 94.1%. A possible reason for the low sensitivity is the formation of mature biofilms in patients with chronic infection, which protect the pathogen against the host immune system resulting in a weakened immune response and, hence, reduced release of CRP[25, 26]. Therefore, we also do not recommend the use of synovial CRP alone for the diagnosis of chronic PJI.
Therefore, we recommend the combined application of serum CRP and synovial CRP to timely detect chronic PJI. The current data suggested that the combination model I of serum and synovial CRP (Serum CRP > 10.2 OR Synovial CRP > 7.26) be first used to achieve higher diagnostic sensitivity and to reduce the false negative rate of diagnosis. And then using the combined model II of serum and synovial CRP (Serum CRP > 10.2 AND Synovial CRP > 7.26) to improve diagnostic specificity and thus reduce the false positive rate. The effectiveness of this joint diagnostic approach was recently recognized in a systematic review by Abdelbary et al. After this screening, histopathology and other tests can be used in the remaining patients to minimize missed and misdiagnosis. There was no consensus on the optimal thresholds of serum CRP alone and its combination with synovial CRP for the detection of chronic PJI. The current study established thresholds for serum and synovial CRP (10.2mg/l and 7.26mg/l, respectively), and developed two predictive models for the diagnosis of chronic PJI that were highly valuable. In addition, based on the premise of effectiveness, serum and synovial CRP have low cost-effectiveness, (USD $12 per test) and the detection ability of CRP is available in many hospitals. Therefore, this combination method has the potential to be widely used.
There were some limitations in the present study. First of all, there is no clear consensus on the exact time of postoperative chronic PJI. Although the time of biofilm maturation and previous published studies were used as references in this study, cases of acute infection in included chronic PJI patients could not be completely excluded[4, 28, 29]. Second, this study involved a single center, and the sample size was relatively small, with only 39 cases in the chronic PJI group and 58 cases in the aseptic group. However, this preliminary trial shows valuable results and warrants a larger multicentric study to verify the efficacy of serum and synovial CRP in the diagnosis of chronic PJI. Finally, patients with recent antibiotic use were excluded from this study for the elimination of confounding factors. However, this may reduce the number of patients enrolled, limiting the generalizability of the results of this study.