To the best of the authors’ knowledge, this represents the first study to focus on preoperative serological tests for predicting the failure of reimplantation using clinical follow-up as a reference standard. In this regard, we found that CRP and plasma fibrinogen values were high in the failed reimplantation group and demonstrated high diagnostic efficiency in predicting persistent infection.
Comparison with previous studies
After a first-stage debridement is performed, including spacer insertion and following the use of antibiotics, it is difficult to determine whether PJI is controlled [17, 18]. Although previous studies [9, 10, 19] have attempted to utilize CRP and ESR values to evaluate infection status, results have been variable. In fact, the reference standards, including culture, could introduce the possibility of false-positive or -negative results. While the first International Consensus Meeting on PJI previously established an algorithm to diagnose PJI , it is not suitable for the diagnosis of persistent infection prior to reimplantation . Clinical results with careful follow-up should represent the gold standard means to retrospectively judge infection control prior to reimplantation. Diaz-Ledezma et al.  have previously defined the success criteria for treating PJI. Beyond serum CRP and ESR values, Shahi et al.  assessed another possible preoperative serological test to determine the status of infection prior to reimplantation; however, data was insufficient, with limited cases.
In our study, the AUC value of serum CRP is above 0.8, which indicates that this is a reliable test for predicting reimplantation success in the treatment of PJI. Using the optimal cutoff value of 9.4 mg/L, CRP had a specificity of over 90%, while its sensitivity was 72.7%. This result is similar to that obtained when using serum CRP to diagnose PJI [20, 21], suggesting it has limited utility for ruling out persistent infection before second-stage reimplantation surgery. Hoell et al.  and Kusuma et al.  both reported that the specificity of CRP was above 90%, which was similar to our results. However, compared to our CRP cutoff value, the results from Hoell et al.  and Kusuma et al.  were much higher: 25 mg/L and 177.5 mg/L, respectively. Due to their use of a high cutoff value, the specificity of serum CRP in those works was increased at the expense of decreased sensitivity, which was reduced to 44% and 13%, respectively. Other studies [19, 23, 24] used 10 mg/L as the cutoff value of serum CRP, which is the value of the MSIS criteria for PJI diagnosis; however, the results obtained were variable. Several studies [10, 19, 23] used ESR to predict persistent infection after the first-stage procedures. The sensitivities were similar to the results of the current study, while the specificities were less, thus revealing that the ability to rule in persistent infection was compromised. Although ESR is a systemic marker of infection, it can be variable due to many factors, including antibiotic use , iatrogenic trauma from the first-stage procedure, and the presence of systemic inflammation before the index surgery , among others. One study  had only 21 cases, which means that there was selection bias due to limited cases. The other studies [10, 19, 23] had a shorter time interval between the two stages than in our study. The first-stage procedure will influence serum CRP for at least 3 weeks and the ESR level for even longer , which may compromise accuracy if the time interval is short. The average time interval in our cohort was more than 160 days, which was enough time for the serum CRP and ESR values to decrease after the first-stage revision.
Implications for clinical practice
Local infection can initiate an inflammatory reaction characterized by vasodilation and increased endothelial permeability, which activates coagulation factors and prevents the spread of microorganisms into the systemic circulation . The coagulation will activate fibrinolysis, while bacteria that overcome the fibrin confinement will also convert plasminogen to plasmin with kallikrein, both of which will elevate the serum D-dimer level [29, 30]. Shahi et al.  first reported the utilization of serum D-dimer for diagnosing PJI and its use for predicting persistent infection before reimplantation. In their cohort, there were only 29 reimplantation cases with D-dimer data, of which five had elevated D-dimer levels. Among those, two patients experienced treatment failure after reimplantation and another three patients were still in follow-up. Due to the limited cases and the short time to follow-up, we could not conclude that serum D-dimer was an excellent test to assess prior reimplantation. The current study found that D-dimer had only fair diagnostic efficiency for predicting persistent infection prior to reimplantation. There are several potential reasons for this. First, aside from infection, trauma, soft-tissue injury, and hematoma could induce a high D-dimer value . Second, after the first stage of debridement and spacer insertion, prophylactic anticoagulation medicine is prescribed for DVT. These factors could influence the coagulation state, which infers that the D-dimer is not as precise for predicting persistent infection prior to reimplantation. The use of plasma fibrinogen for diagnosing PJI was first studied by Li et al. Our study was the first to investigate the efficiency of fibrinogen for predicting reimplantation success. A previous study reported that human neutrophils could induce the formation of fibrinogen. Moreover, fibrinogen may mediate neutrophil–endothelial cell adherence in sepsis. Our study showed that the AUC value of fibrinogen was good, and it was routinely analyzed before surgery, so it was able to provide more information before we decided to do reimplantation.
There are several limitations of this study. First, the study had a relatively small sample size of 119 patients, including only 11 patients with clinical failure, which may introduce statistical bias. With respect to the D-dimer and plasma fibrinogen tests, this study is the first to report their utility for predicting reimplantation success or failure. Second, this is a retrospective study, which introduces the drawbacks inherent to all retrospective studies, including the possibility of missing information and heterogeneity among cases in the cohort. However, all cases in the current study were recent cases from a single center with set inclusion criteria, thereby reducing the possibility of confounding. Third, only serologic tests were evaluated, while synovial WBC count, PMN%, and intraoperative tissue culture may have provided further information. Serologic tests provide more convenience in sampling, less pain to the patient, and are not dependent on obtaining a synovial fluid aspirate or intraoperative tissue culture. Finally, clinical results were used as the reference standard, which may have introduced bias into the results. Reinfection could be a new infection after reimplantation, with bacteria that are different from those in a previous infection. Previous reports used alternative reference standards, such as positive cultures  or combined tests . However, currently, there is no gold standard method to detect and/or evaluate persistent infection. The Delphi-based consensus is widely accepted as a treatment target , which is most important in clinical practice.
In summary, serum CRP and plasma fibrinogen are good tests for predicting the success of reimplantation after two-stage revision procedures for patients with PJI. Further prospective studies with additional cases are needed to determine the utility of these tests and their optimal cutoff values.