Introduction
Periprosthetic joint infection (PJI) is a rare but devastating complication for patients undergoing joint arthroplasty [
1]. It has a huge impact on the joint function and quality of life of patients, causes significant morbidity, and accounts for a substantial proportion of health care expenditure [
2]. The Musculoskeletal Infection Society (MSIS) diagnostic criteria [
3] for PJI of hips and knees, slightly revised in 2013 by the International Consensus Meeting (ICM) [
4], has obtained widespread recognition.
Saxena et al. [
5] first discovered an association between coagulopathy and PJI, and some studies extended the research targeting D-dimer and fibrinogen as potential tools for PJI diagnosis. Circulating D-dimer is the characteristic product of degradation of cross-linked fibrin, and fibrinogen is a protein for blood coagulation produced primarily by hepatocytes, both of which could be assessed easily and conveniently in coagulation measurements. Based on the previous research, the new evidence-based 2018 criteria [
6] for PJI were published with a better diagnostic accuracy, in which a minor criterion of serum D-dimer was added.
However, some studies [
7‐
17] have demonstrated controversial diagnostic accuracy of D-dimer and fibrinogen as a single biomarker for PJI recently. Some showed that D-dimer was not accurate enough to distinguish PJI and aseptic loosening [
8], and others believed fibrinogen could perform better than plasma D-dimer for PJI diagnosis [
15], though D-dimer was minor criteria and fibrinogen was not in the new evidence-based 2018 criteria [
6] for PJI.
Thus, this meta-analysis aimed to explore the accuracies of D-dimer and fibrinogen for the diagnosis of PJI via synthesizing current available evidence. We sought to determine whether fibrinogen performed better than D-dimer for PJI diagnosis.
Discussion
Timely and accurate diagnosis of PJI of the hips and knees remains a major challenge for orthopedic surgeons as there are no absolutely accurate tests currently [
21,
22]. Numerous biomarkers have been discovered and become available in the recent years, including circulating D-dimer and fibrinogen in coagulation system. D-dimer and fibrinogen could be detected in coagulation test which was essential preoperative procedures. Thus, no additional costs would be incurred if D-dimer and fibrinogen were taken as regular diagnostic tools. This may be an incentive for clinicians to use them more routinely. This meta-analysis aimed to compare the diagnostic accuracy of D-dimer and fibrinogen from the available published studies. Our pooled results showed that D-dimer and fibrinogen performed well in sensitivity and specificity in diagnosing PJI, and fibrinogen achieved a significantly higher specificity. Fibrinogen had a higher positive likelihood ratio to be qualified as a rule-in diagnostic tool. Both biomarkers had a low negative likelihood ratio, making them suitable to be qualified as rule-out tools. Overall, as a single test, both of them could be used for PJI diagnosis, while fibrinogen had a higher diagnostic value.
This study had a number of limitations. First, not all of the sample sizes were big enough, and most of the studies came from the same region, and were not prospective. These may affect the quality of the trials and might have caused additional bias. Second, although low possibility of publication bias (p > 0.05) was observed by Deeks’ funnel plots, there was still some extent of publication bias because positive results tend to be more likely to be published. Third, though D-dimer and fibrinogen could be used for PJI diagnosis, the optimal cutoff values were not identified, which was of great importance for clinical applications and could not be resolved by meta-analysis. Fourth, though D-dimer and fibrinogen were considered as good individual biomarkers for PJI, combined tests of D-dimer or fibrinogen with other biomarkers like ESR or CRP might perform even better, which was to be confirmed through further prospective trials.
Both D-dimer and fibrinogen showed high sensitivity and specificity, which indicated that both could be used for clinic practice for PJI diagnosis. A guideline defines that LR+ > 2, LR− < 0.5 is considered a viable predictor, and LR + > 5, LR − < 0.2 is considered a good predictor [
23]. Great heterogeneity was found in studies for D-dimer, and univariate meta-regression analysis revealed that number of involved joints, disease spectrum, comorbidities influencing D-dimer, and sample sources were the source of heterogeneity. As for studies for fibrinogen, minor heterogeneity was found.
D-dimer is a characteristic degradation product of cross-linked fibrin [
24]. It is an established screening test for thrombotic diseases and extended its unconventional use to inflammation and infection, especially to PJI. It was proved that D-dimer had a significant differentiating ability in sepsis-related mortality [
25]. D-dimer had been considered as one of the minor criteria for its diagnostic accuracy in the newly established evidence-based PJI definition [
6]. Although Xu et al. [
14] and Huang et al. [
8] demonstrated that D-dimer had limited value and was not suitable for PJI diagnosis, our pooled results embodied these two studies showed that D-dimer had a high sensitivity and specificity to be a diagnostic tool for PJI, which were consistent with the established criteria.
Fibrinogen, a protein for blood coagulation, is synthesized by hepatocytes [
26]. While its key role in the coagulation cascade is general knowledge, fibrinogen also plays a pivotal role in regulating inflammation process and preventing infection [
27]. Our results showed that fibrinogen had a high sensitivity and specificity for PJI, which was consistent with the results exploring fibrinogen and D-dimer for PJI in the same trial [
15,
17]. Thus, it could also be used as a biomarker for PJI. Many studies exploring the connection between fibrinogen and infection found reduced fibrinogen lead to compromised pathogen clearance, exacerbated pathogen infection, and increased mortality following subcutaneous infection [
28,
29]. The underlying mechanism for connection between fibrinogen and PJI is still to be explored.
Substantial heterogeneity was found in studies for D-dimer, and its potential sources were explored by performing meta-regression and subgroup analysis. The results showed that number of involved joints, disease spectrum, comorbidities influencing D-dimer, and sample source were sources of heterogeneity. Comorbidities like inflammatory arthritis, deep vein thrombosis, a prosthetic heart valve, a history of hypercoagulation disorder, or other infectious diseases would influence the level of D-dimer [
11]. The results found higher sensitivity and specificity would be achieved when all these comorbidities were excluded. In order to get a more accurate diagnosis, these comorbidities should be carefully assessed. The meta-regression results revealed that serum D-dimer performed better than plasma levels in the diagnosis of PJI. Serum D-dimer was measured after blood clotting with consumption of fibrinogen and some other coagulation factors, which would be different from plasma D-dimer levels. Previous studies did not have a uniform conclusion about the relationship between plasma and serum D-dimer [
30‐
32]. More studies could be conducted to further exploring the difference.
Z test statistics found the pooled specificity and LR+ of fibrinogen were significantly higher than D-dimer, although no significant difference of sensitivity and LR− was found between fibrinogen and D-dimer. These indicated that fibrinogen performed better than D-dimer for PJI diagnosis. These results were consistent with other studies exploring the difference of D-dimer and fibrinogen in PJI diagnosis [
15,
17]. As we know, D-dimer is included as one minor criterion in the newly established diagnosis criteria of PJI in 2018 [
6]. Fibrinogen could be another better criterion for PJI diagnosis, and more prospective and larger-sized trials should be conducted to confirm it.
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