Early diagnosis is the first and most crucial step in the management of PJI. The preoperative test is the front-line to assess an infection, and it provides valuable information for primary differential diagnosis and further clinical decisions. The measurement of CRP or ESR is a preoperative examination that is a fast, convenient, simple and widely used diagnostic method for PJI. However, their diagnostic value is limited due to low diagnostic accuracy, and their levels are especially susceptible to fluctuations in patients with dual taper modular stems, slow-growing organisms, antibiotic treatment, etc. [25–27]. Unfortunately, at present, only CRP and ESR seem to be more suitable for the diagnosis of PJI than other serological tests [28]. Shahi and colleagues [13] first used serum D-dimer (850 ng/mL) for the diagnosis of PJI and showed that it had a higher sensitivity and specificity than ESR and CRP (sensitivity: 89% vs. 73% and 79%; specificity: 93% vs. 78% and 80%, respectively), even when evaluating the sensitivity and specificity of ESR and CRP combined. An earlier animal study by T. Ribera et al. [29] found that the synovial D-dimer concentration was significantly increased in foals with septic joints (p < 0.001). A prospective study measured the patient's ESR, CRP, and D-dimer levels before and after primary total hip or knee arthroplasty. D-dimer showed the largest changes during the early postoperative period; the level was sharply increased and peaked on the first day after joint replacement surgery and decreased to the baseline level on the following day. The author speculates that when D-dimer is combined with ESR and CRP, it might be effective in the early detection of PJI [30]. In the last two years, serum D-dimer was recommended as a promising biomarker for diagnosing PJI, and it was also included in the 2018 ICM criteria for PJI [31].
In the present meta-analysis, the pooled sensitivity and specificity of serum and plasma D-dimer were 0.75 (95% CI: 0.70 to 0.79) and 0.69 (95% CI: 0.66 to 0.72), respectively. The overall diagnostic value of D-dimer had an acceptable sensitivity, whereas the specificity was low. In the subgroup analysis, we found that serum D-dimer had a better sensitivity and specificity than plasma D-dimer (0.86 and 0.84 vs. 0.67 and 0.60, respectively).
In Qin L et al.’s [15] prospective study of revision hip and knee arthroplasty, the serum D-dimer had 92.73% sensitivity and 74.63% specificity with a threshold value of 1170 ng/mL. The diagnostic sensitivity and specificity of serum D-dimer were greater than those of CRP (81% and 66%, respectively) and ESR (64% and 70%, respectively) and their combination (89% and 57%, respectively). These results were similar to Shahi et al.’s previously published results [13], but both studies used different threshold values and differed in whether systemic inflammatory diseases were included. In addition, Qin L and colleagues [15] also demonstrated that the combination of serum D-dimer and CRP could achieve the highest sensitivity compared with each of them alone. However, Huang J et al. [14] found that the sensitivity and specificity of serum D-dimer, CRP, and ESR were not significantly different when using a serum CRP level of 10 mg/L (68% and 93%, respectively), ESR level of 30 mm/h (74% and 87%, respectively) and D-dimer level of 850 ng/mL (71% and 80%, respectively) as the threshold. Xiong L et al. [17] found that the diagnostic value was equivalent among serum D-dimer, CRP and ESR, and their results showed that the AUCs were 0.890, 0.831, and 0.838, respectively. From the studies described above, serum D-dimer had a better or equal diagnostic accuracy to CRP and ESR.
The diagnostic accuracy of plasma D-dimer for the diagnosis of PJI was also tested in recent years. A retrospective cohort study measured the CRP, ESR, interleukin-6 (IL-6), plasma fibrin degradation product (FDP) and D-dimer for diagnosing PJI [23]. The potentially influencing elements included inflammatory disease and antibiotic use. Compared with traditional inflammatory markers, plasma FDP and D-dimer had a lower sensitivity and specificity than CRP, ESR and IL-6. The sensitivity of the combination of D-dimer and any inflammatory marker was decreased compared with any of the indicators used alone, as well as plasma FDP. However, the sensitivity of the combination of D-dimer or any inflammatory marker was elevated compared with any of the indicators used alone, and plasma FDP also had similar results. The authors concluded that compared with traditional inflammatory markers, the diagnostic value of plasma FDP and D-dimer was limited [23]. A prospective study by Fu J and colleagues found that [16] the sensitivity of plasma D-dimer was in the middle of that of CRP and ESR (66.67% vs. 80.00% and 33.33%, respectively), while its specificity was lowest among these three blood tests (60.00%). Li R et al.[24] showed that the diagnostic value of plasma D-dimer was possibly limited, and the AUC of plasma D-dimer was inferior to plasma fibrinogen, ESR and CRP (0.657 vs. 0.852, 0.810 and 0.808, respectively). D-dimer only exhibited better performance than white blood cells (0.590). Compared with D-dimer, the diagnostic level of plasma fibrinogen was closer to that of the traditional inflammatory markers ESR and CRP. Moreover, the author also analysed the diagnostic accuracy of D-dimer and fibrinogen with coagulation-related comorbidities (malignancy, autoimmune disease, cardiovascular disease and cerebrovascular disease). The diagnostic accuracy of D-dimer ranged from 50–57.7%. For plasma fibrinogen, the diagnostic accuracy ranged from 52.4 to 92.3%. Plasma fibrinogen had a better diagnostic accuracy than D-dimer, especially in patients with malignancy. The diagnostic value of plasma D-dimer and fibrinogen before reimplantation in two-stage exchange arthroplasty for periprosthetic hip infection was assessed by Chi Xu et al [32], and the plasma D-dimer had lower sensitivity and specificity than fibrinogen (83.3% and 41.9% vs. 87.5% and 62.8%, respectively). However, the plasma D-dimer was inferior to fibrinogen. Nevertheless, compared with the previous studies of serum CRP and ESR reported before reimplantation, plasma D-dimer seems to be a better diagnostic indicator [33, 34]. The first serum D-dimer study by Shahi et al also found that the two failure cases of second stage replacement caused by reinfection had increased D-dimer levels before reimplantation surgery, while the serum CRP and ESR levels were normal [13].
Compared with previous meta-analyses of PJI diagnoses [35, 36], all included papers in this study used similar gold standards. Nonetheless, there were still several limitations in the current meta-analysis. First, of the 7 total included studies, 6 studies came from China. Whether there are any differences in D-dimer values for the diagnosis of PJI in different countries or races is unclear. However, one study on American community-dwelling elderly persons indicated that black individuals had significantly higher D-dimer levels than white individuals [37]. Further research on the D-dimer level, whether influenced by racial differences in normal or PJI patients, is needed. Second, among these 7 research papers, we only found two studies describing the situation of antibiotic use [13, 23]. In addition, all of these publications used different exclusion criteria, which might impact the diagnostic results. Third, from the meta-analysis results, we found that serum D-dimer had a better sensitivity and specificity than plasma D-dimer (86% and 84% vs. 67% and 60%, respectively). However, due to the limited data, only three studies utilized plasma D-dimer in PJI. Therefore, more PJI studies are needed to compare the diagnostic value of serum D-dimer and plasma D-dimer in the future.